6-13-05 Microbiology Second Half of Lecture Host-Parasite Interactions interaction between the patient (host) and the organism (parasite) Key Definitions Dynamic Balance We want to think of these things as dynamic balance an ever changing balance between the patient and the organism. Even though we always seem to think that a certain organism is always a pathogen and another organism is never a pathogen this is not a proper way to think about things. An organism with a relatively low weapon system no virulence factors can cause disease in a relatively unprotected patient and someone who is very healthy may be exposed to the plague and be extremely healthy. It is not an "always" thing that an organism always causes disease, nor is it a "never" thing. It depends on the patient. So, in general, we have different statuses of patients. Infection Types: Community In a community acquired setting we have a wide variety of people with different immune systems. In general, in a community, most people are well protected with their immune systems. Obviously "healthier" people tend to get this kind of infection, and in general less antimicrobial resistance. Nosocomial (hospital) In a hospital setting, however, the opposite is true. Most people are in a somewhat compromised manner. For example a patient is getting an IV put in their arm. That bypasses the skin which is a defense system. Also a catheter that is in someone for weeks is an opening that can get infected. On the other hand, we could have an AIDS patient or a leukemia patient whose defense systems are really low. So, we have this dynamic balance. We DO NOT want to every say ALWAYS or NEVER in terms of whether an organism can cause a problem or not. Nosocomial means to acquire the agent in a health care facility this does NOT mean that you became ill in the hospital. You ACQUIRE it in the hospital. There are many patients that come down with or die from a Nosocomial infection. It depends on their immune system status also as to how severe the infection may be. The organisms that usually cause Nosocomial infections are those that usually have multiple antibiotic resistance because we select for the antimicrobial resistance (around the hospital). They are hard to treat; they occur in patients who are somewhat compromised (immune system is not very good potentially), and the organism has multiple antibiotic resistance. They are very hard to treat. Case Study A man who acquired TB in 1957 (but is surrounded by a granuloma so it is inactive) suddenly has a reactivation of the TB. He has had TB since 1957 so is that organism going to be easier or harder to treat than someone who has just acquired TB last week. It is going to be easier to treat. Essentially, it has been out of the circulation, so it could not be selected for antimicrobial resistance. Virulence Factors Capsule found on both bacterial and fungal organisms Pili common pili is associated with gonorrhea - Also associated with UTIs (common pili) Flagella associated with UTIs Toxins Endotoxin Lipid A, etc.
Exotoxin: - Secreted by living cells - Can be found in both gram positive and gram negative cells (having an exotoxin has nothing to do with having a cell wall - It is a protein (all exotoxins are proteins) - Which means it can be denatured by chemicals or heat and we can therefore create something called a Toxoid - Toxoid alternate form of the toxin that is not virulent - We can change its immunogenicity we can stimulate an immune response to itself, the toxoid, and more importantly, the actual poisonous compound. So we can give someone a toxoid and we respond by making antibodies called antitoxin which is protective to the toxoid the fully active toxin. When it binds to the fully active toxin, it neutralizes it. The antitoxin neutralizes the toxin. - Target Cell Specific each antitoxin has a specific target cell. Each one will have a specific set of symptoms. They are all going to be different. - Botulism toxin causes a toxic paralysis limp no movement flat movement - Tetanus toxin cause a spasm muscle contraction - Each exotoxin has a very specific cell target has a specific set of symptoms - Little/No fever in general, there is little or no fever associated with an exotoxin - Quite commonly they are plasmid related - They are spread by conjugation (SRP) or by transduction (NSRP) - Examples of exotoxins - Clostridium botulinum, clostridium tetani (tetanus spasm (tetanus toxin)), diphtheria toxin (interferes with elongation factors for protein synthesis in eukaryotic cells) Endotoxin: - Part of the cell wall - Released at the time of death lots is released at the time of death - Gram negative only - LPS (Lipid A) - Cannot denature can live through heat - No toxoid possible - No antitoxin - No specific target - The endotoxin from one organism is the same as the endotoxin as another organism - IT does trigger an Il-1 enhanced immune response - Interleukin 1 - There are other interleukins involved as well, like 3 or 4, but Il-1 is the one that causes a fever (major interleukin)
- See fevers in these patients -Causes an Il-1 induced fever - We cant use antibiotics to treat this, so an approach to this would be to develop antagonists to neutralize the interleukins we are developing antagonists to interleukins. We might see this happen in clinical trials, etc. This is very new. This is a good concept because we are going to neutralize the impact that the endotoxin has on the patient; stabilize the patient; deal with their gram negative infection; then we can save the patient. Otherwise we would lose the patient. - Genome related - Endotoxin in genomic related. It is part of what is made. It is part of the genetic information that is used to make the cell wall. Every gram-negative organism has endotoxin - If we have a gram negative septicemia; it means we have a gram negative organism in the bloodstream, and the patient has the possibility of endotoxin shock. - We would have the loss of the integrity of the blood vessel; fluid would leak out of the blood vessel; the patients BP would drop; the cells would remain "behind" so the thickness of the blood increases; we often see fluid develop around the heart and the lungs pulmonary congestion will develop in the patient. Ultimately, we will see kidney involvement and kidney failure and death. - Examples - Salmonella organisms, E. coli, Pseudomonas, etc. all can do this they are all gram negative organisms Upper Respiratory Tract Etiological Agents See page 5 of notes Inner Ear Earaches Initially, the problem is not bacterial; it is a drainage problem. The fluid builds up in the middle ear that fluid media is a good media for organisms to grow after a few days. Long term treatment is to put tubes in the ear provides ventilation neutralize the pressure. By putting a tube in the ear, basically, we are maintaining the balance of the pressure, so the fluid drains better. It is a fluid (drainage) problem not a microorganism problem for the first couple of days. It is an anatomical problem. - 90% of acute URT infections are viral. - Clinical Implications of that are significant. - Flumist - way of preventing influenza vaccine for influenza - It also significantly reduced antibiotic resistance in children because they were not treated with antibiotics that they did not need to be treated with because they were not sick. - So, when they did get infections that required an antibiotic, the infection was much more easily treatable because antibiotics were not being misused. - It stopped a lot of problems. - This was an effective treatment because it stopped unnecessary prescriptions (lowered antimicrobial resistance). - Most infections are VIRAL. We do not need to treat those with antibiotics. Page 6 of notes On average, we have about 3.5 colds per year. Influenza is much less. All other infectious diseases are also much less (this includes bacterial infections). Most URT are clearly VIRAL.
Microbiology 6-14-05 Viral Agents - URT We look at these viral agents. We want to think of them in two categories. Some of these agents will cause infections in all varieties of people healthy and immunocompromised. Other agents will only cause complications in immunocompromised people dynamic balance. We want to sort this out. Normal healthy people get these infections (everyone is at equal risk): Rhinovirus Cornavirus Adenovirus Normal individuals (with a normal immune system) will not normally get parainfluenza virus or respiratory syncytial virus. These viruses are normally seen in immunocompromised patients. If a patient comes down with one of these two latter infections, then we begin to be suspicious as to whether they have a normal immune system they might be immunocompromised and not even know it or, conversely, if a patient IS immunocompromised we are going to be on alert to look for these agents that might cause problems. The big thing with URT infections is that the majority of them are viral, and they are not treated by antibacterial agents. As obvious as that is, this is still a MAJOR misuse of antimicrobial agents. The problem is really a patient-doctor relationship problem. The patient wants an antibiotic to feel better, and the doctor will do it so the patient comes back. Rhinovirus (common cold) -This affects the nose runny nose, itchy irritated eyes, increased secretions, etc. There are many serotypes of this virus. >100 of rhinovirus alone. Because there are so many serotypes, it is unlikely that we will develop a vaccine. There is no cure for the common cold. Even if we could make a vaccine and identify the particular antigens or epitotes that are the on the surface of the organism that we would have a response to if we were to expose our bodies to a hundred different serotypes in one vaccine, the body would tend to pick immunodominant epitotes or antigens, and therefore, our body would only be immune to a few dominant strains. This would NOT correct the problem. So, because of the many serotypes and because of the concept of immunodominance, we will not likely see a vaccine for rhinovirus. - Rhinovirus is spread very easily through inanimate objects fomites (doors, chairs, toys, etc. In a hospital setting, fomites spread serious hospital infections (not just rhinovirus). It could be from the pen that the doctor writes with and then it gets spread from patient to patient. The spread of the virus is mostly by NOT washing hands. This is the mechanism of spreading MANY agents to many people. - One way to affect rhinovirus (and other agents as well but remember we get 3.5 colds per year), is to just simply wash our hands more often. - We can get the virus in by rubbing our eye or get it from our hair (or picking our nose). - Of these colds that we get three times per year, most are not "caught" from someone coughing in our face we did this ourselves by rubbing the organism in our eye, throat, etc. It cant get there that easy, but we facilitate its entry into our body. - Yes, it can be spread by droplet (sneezing). But most of the time, it is spread out there by that sneezing on those inanimate objects, and that is how it gets on our hands. You CAN get it from someone sneezing on you, but it is not that likely as you "giving" it to yourself. It would have to a REAL DIRECT sneeze.
- Most of the time it is just touching things. Playing cards (easy to spread) vs. a cold place you will spread the virus and get sick by not washing your hands. - Washing our hands is MUCH better than immunization. It will reduce the spread of the virus, AND keep your hands off your face!!! - You CAN use a disinfectant soap, but it is probably not necessary. This will actually select for bacterial organisms (not viral organisms obviously), but it will select for bacterial organisms that are resistant to disinfecting agents and they will therefore be resistant against antimicrobial agents - and when an organism develops that resistance we are going to select for resistance by using the OTC kinds of antibacterial soaps. Regular soap or mild detergent does the job. Puts a charge on the organism and a charge on your hands like charges repel and the organisms get washed off. A detergent makes for better penetration. We dont have to kill the organism. We just DO NOT want them on our hands. Cornavirus (not a life-threatening virus) - > 100 serotypes - We WILL develop a serotype-specific immune response and so, out of the hundreds of serotypes, we will not that particular one again, but there are 99 other serotypes. Even though we have a good immune response to the organism, it is not going to be effective in preventing the disease because the serotype specificity and the 100 + serotypes. - Causes a minor sore throat, URT congestion (runny nose) - It is a little more evasive in the areas because receptor site matching for rhinovirus is more restrictive (rhinovirus is found mostly in JUST the nasal passages), and cornavirus has receptor site matching that lets it go further than that. So, for any virus an important virulence factor are these receptor sites. An important focus of our immune response is going to be an immune response directly toward those receptor sites. So, we will produce antibodies that will be found in the secretions that will neutralize the virus. - Cornavirus is therefore a self-limiting kind of problem. It is mostly a sore throat. It is not a big deal. We will also see cornavirus associated with some kind of middle ear infection otitis media (children). - The big thing is SARS Severe Acute Respiratory Syndrome - Cornavirus here has then stepped up its virulence. It has done so by the process called co-infection. - Viruses, such as cornavirus, can infect animals, such as birds (chickens, ducks, and water fowl) - and in eastern/southern China (Southeast Asia) towards Australia - that is the migratory bird route. As a result of this, we have increasing co-infection with migratory birds and people in the area. They usually buy their birds "fresh." The housing of these birds is such that they are ALL housed together even birds that are not usually found together (they are being sold "fresh"). The virus goes from birds to birds, and then it goes to humans. In that setting then, once it adapt to having receptor sites in the human respiratory tract, this cornavirus characteristics now allow now the passage from human to human. - This virus could get worse. We are just not sure when. This is the future we just do not know how quickly this is all going to happen or spread Now, when we have a respiratory tract infection like SARS, there is a panic among the public in terms of what to do about it. People can die very quickly from a respiratory tract spreading agent, and this really scares people. So, we do need to take appropriate precautions.
And this usually means isolation. We just need to keep those patients who are infected in the population isolated without creating a scare. There is a lot of cooperation that needs to be done. We have learned from the early epidemic of the last SARS outbreak that we need to report them early enough. If we catch it early, we can do something about it. Early reporting allows us to be more aggressive with isolation and so on and treating those patients appropriately. So, right now, with cornavirus this virus should be on our watch list. Right now, it is very mild and it is not a big deal, but we know that it is spread easily among the population; and if it in fact picks up these virulence factors on a single basis rather than just a few strains of this, and then the strains disappear. But if it becomes more common, then we need to be much more concerned with it. Hopefully, we may develop some sort of immunologic approach but with cornavirus is a whole family of viruses, so there are many serotypes. The hope is that we will come across ONLY a few very virulent varieties so that there are only a few serotypes and we will be able to develop a vaccine for it. So, there is that possibility of sort of that "sub-set" approach not against ALL cornavirus but only against those that are of the more virulent variety. There is such a massive difference between the outcomes one is a nuisance and the other is fatal. Adenovirus (more severe that rhinovirus and cornavirus rhinovirus<cornavirus<adenovirus) - Causes sore throat, runny nose, sinus infections, otitis media (earache draining problem), eye infections and can possibly cause an encephalitis (more so found in immunocompromised patients). - Eye infections (really associated with adenovirus) we see the red-eye conjunctivitis eye-infection in otherwise healthy people (milder than in immunocompromised people) we need to be careful with eye infections (esp. in immunocompromised people) because the eye once we get infected in the eye and it gets into the retina that is a straight-line to the brain. The eye is a bad place to get an infection because there are no other barriers. These three agents are those agents that we do call the "common cold." They are common as 34 times per year. The simple treatment is to stop the spread of the common cold, it is not through the use of antiviral drugs, immunization (cornavirus possibly), or prophylactically, but it is through washing your hands. This will stop the spread. We see in the Asian population the facemask as another way to stop the spread (SARS). These people are just doing this prophylactically. We for some reason do not do this. Dentists are now wearing masks. They are using this "high-speed" drill near their face, AND they are within inches of YOUR mouth. They are blasting apart a tooth or something. The aerosols from that tooth are amazing. We could get all these things coming out of peoples mouth (even 20 feet away!) We want to prevent them from breathing in things. There are A LOT of things these dentists could breathe in. The only problem now is that it makes the patient uncomfortable. Why are they wearing a mask? It is a culture thing. They all wear gloves also (dentist/assistant). We are all adapting. But remember, the mask is the most efficient way of preventing the spread of these viral agents; the most efficient way is washing your hands and keeping your hands away from your face. Parainfluenza - This is an agent that causes disease specifically in immunocompromised people. The most common patient will be the immunocompromised status of the newborn. In generally, a large protective function occurs as antibodies in the mothers bloodstream passes to the baby, so that at the time of a full-term delivery, at least one class of IGG (immunoglobulin G) is at 100% of the maternal level at the time of birth. It diminishes by about 50% every month in three months; the baby is down below protective levels. The babies own immune system does not reach full immune "adult" status until it reaches five years of age. Much of the protection is built in by the first 18 months. So from about 3 months to 18 months the baby is at some degree of risk. At 3-4 months the baby is probably at its highest degree of risk. The risk gradually decreases up
to 18 months and we get a fully adult level really of all immunoglobulins and all classes of immune responses when the child reaches five years of age. So, we have this transient immunocompromised status of the newborn. It is normal (for the baby), but it is still compromised. We can expect then that babies have more bacterial infections at 3-4 months than they do at one week of age. So, when someone has a baby they get a "manual" so, we kind of think that the baby is really fragile when we first bring them home they are actually immunologically really well protected because it has its moms antibodies. Then after 3 months, "when cabin fever starts to set in," we will take the baby out into public (also baptisms and relatives will be visiting) and all of these happen when the baby is at most risk with its immune status. It will take until they are 18 months to get that same level of protection that they once had. So, 3 months to 18 months is a bad "risk window" for infection. -A disease that is then caused is a disease called croup. This virus, parainfluenza virus, is most commonly the virus that causes this disease. This disease is associated with nasal discharge, difficultly for the child to breathe through their nose, sore throat (but they cant tell you this), earache (babies will pull on their ear because it hurts), difficulty sleeping just right (the mother may say that the baby is "fussy" this should be recognized by someone that this is not normal behavior the baby is fussy because it is not sleeping right because it usually sleeps on its right side, but there is fluid build up in the right side (earache the organism is now growing here it hurts so the baby has to sleep on its left side or belly (not sleeping in its normal position)). If the baby is breast-feeding or bottle-feeding it has to "suck" to drink "sucking" puts pressure on the ear. The baby will then probably stop eating because it hurts, and the baby is already not sleeping so it is fussy. It is fussy because it has an earache, and it is trying to tell us that. So, the babys behavior is the best way for the baby to communicate with us. Eventually, the baby will get a LRT cough this is called a "croupy" cough. Usually, the problem with this is airway maintenance maintaining an open airway (involving mucus). When we are sick and plugged up with mucus, we are able to walk around and our "mucociliary" clearance system is taking care of the problem because our cilia is moving IT up and up and we swallow it this system works better when you are walking around babies are not able to walk around so they are lying down more and as a result their lungs are getting filled with fluid, and they are not getting cleared out as much. So, organisms are NOT being removed so we have this cough. The cough is a mechanical override to the mucociliary clearance the movement of mucus up and out that has trapped the organism move it up and out is a normal defense system. What the organism can do (with this infection and with others) is it stimulates excess secretions and the secretions are thinner so the efficiency of the mucociliary clearance system is reduced. It changes the viscosity of the secretions. -Now, when the baby has difficulty breathing, this upsets the parents, they get worried and they take the baby (all bundled up and into the cold night) to the hospital. In the process of the parents taking the baby out to ER, the child breathes in cold night air and cold air opens up the respiratory tract so by the time the parents get the ER, there really is not a problem left. What we want to do is maintain an open airway, so what we can do is increase the humidity in the room. This can be very helpful. We want to treat the infection with the appropriate amount of vigilance and the appropriate level of immune response we dont want to overwhelm the child with an antiviral agent or anything like that. The side-effects of something like that are much more than the severity of the problem. Parainfluenza can develop more down the respiratory tract it can spread further than what we have talked about. Again, IMMUNOCOMPROMISED. If someone else were to develop this kind of situation, we would be suspicious about their immune status. This may mean they could be an undiagnosed leukemia patient or an AIDS patient or something like that. Or, if someone has one of these diseases, then we can be suspicious that they will come down with a parainfluenza virus infection. Respiratory Syncytial Virus Again, this virus is most commonly seen in children from about 3 months to maybe about 18 months of age. Children who are a little older might also get this, but this is not very common.
The other group that is possible with RSV are immunocompromised patients (leukemia, AIDS, organ transplant patients, etc). More viral agents: These agents are commonly associated with childhood illnesses, and they are prevented through immunization: Measles Mumps Rubella They are all spread by a droplet and to a lesser degree they are spread by fomites. But they are mostly caused by droplets so we are going to see defined outbreaks children in the same families and children in the same daycare center. The organism enters through the respiratory tract, and it will cause a viremia. The living organism is now in the bloodstream causing a viremia, and we can see localized allergic reaction to the organism we call these rashes. Measles and rubella are associated with a (typical) kind of rash. In the case of mumps, we may see some generalized redness of the skin, but mostly we see the enlargement of the salivary glands (chipmunk-like). You could get it in one or both of the salivary glands. When we have the viremia stage, we can have an infection in the brain, and that is usually very mild, but it is characterized by maybe light sensitivity. The patient will like to be in a dark room. Now, probably a high percentage of the people exposed (>30%) come down with a sub-clinical infection of these three viruses and for the most part this results in protection. They are serotype specific. There are not many serotypes of these viruses. With that understanding vaccines were developed with these three agents and are routinely given to individuals. Page 8 of notes Measles slide We see that once people we immunized we saw a lower incidence of cases of measles, but do see that right around the 1990s we did have one "blip" in the scale. That blip taught us something. We were JUST immunizing children, and the whole immunization schedule ended right around the age of twelve months. We realized at that point and time that we needed to go a little further up the age rank and get a little stronger immune response in the patient. Not everyone was responding to just the one immunization early on in life. We changed immunization schedule, and made the children be a little older when they were getting the immunization. This got rid of the problem. Actually, a few people in the 1990s had been immunized about 18 years before, these were college students now, and we had the epidemic happen around basketball season. This problem was because they were immunized when they were so young. We had to re-immunize many kids this age because they were not protected against the measles anymore. We had to re-look at all of the immunization records, etc. Basically, we just needed to raise the age of the immunization so we would be protected longer. We must immunize later on in life to "boost" the immune system. Children should be immunized again later when they are around two years old, so they can have that boosted immune system. This epidemic happened because these kids were not immunized after 1 year of age. It is important to follow the immunization schedule. (Younger children were also affected by this epidemic.) When we are immunizing against measles we are giving a live, attenuated virus so we do need to be cautious of a growing fetus. If someone is pregnant, they need to be aware of this because of the risk. Page 8 of notesMumps slide We saw the same pattern with the mumps. We developed an immunizing agent that worked, but we see this "blip" at the same time as with the measles. We changed the timing of immunization, and we solved this problem of outbreaks of this virus. Basically, the measles and mumps schedule of immunizations needed to be changed (time).
Rubella - Sometimes called "German measles."
Low-grade fever (102 F or lower) Headache General discomfort or uneasiness (malaise) Runny nose Inflammation of the eyes (bloodshot eyes) Rash with skin redness or inflammation Muscle or joint pain Encephalitis (rare) Bruising (from low platelet count, rare)
This virus responds well to immunization.
Immunizations -Sometimes we outthink ourselves. In the case of measles we did that. Initial agents that we gave the patient were all live, attenuated agents have virus create genetic deletions and these deletions take a viable organism to one that cannot replicate and these end up being sitting ducks for our immune response. Our immune response would be able to take over. If a child is immunocompromised, we can have problems with the organism even though it is really weak the patient is even weaker, so we can have some problems (remember the dynamic balance). -We wanted to develop a vaccine for measles that was a "kill-preparation" so we developed one. We eventually wanted to make the vaccine for all three of these viruses. This would be a very good idea for pregnant women and for the immunocompromised. We developed the vaccine for measles the patients produced antibodies against the virus wonderful titer everything else worked fine it went through clinical trials everything was fine and after about five years of use of it in the late 50s, we realized that we have a problem. Children that were immunized with the kill-preparation did not develop measles in the normal sense they developed it with a very high frequency higher than un-immunized people and they developed pneumonia and encephalitis. We made it worse. Their immune response produced the antibodies but no specialized T-cells. When the body saw the virus, it responded by the program that it made antibodies the body also "okay, Im done." Meanwhile, the virus that had gotten inside of cells was no longer being killed by T-cell attack and as a result, we saw a different kind of immune response. The viremia occurred and it caused pneumonia and encephalitis. We had to re-immunize all of the children because of this. We learned that we can make things worse. When we give a vaccine we are immune-modulating the patient. We are changing the way the body (immune response) responds to the agent. We hope that we change the way this occurs for the better, but this is not always the case. We still use the live, attenuated strains to vaccinate people. The other thing that we need to be aware of with many, many viruses, the younger you are, the greater the likelihood of a good outcome when infected the older you are, the greater the chance of an adverse reaction to the infection. Upwards of 70% or more of the patients (children) infected had asymptomatic infections they never saw a rash, enlarged lymphnode, or even an enlarged salivary gland nothing. But they were still
resulted in a serotype specific only one serotype (the vaccine protects against several), but they did not have an adverse outcome. - Say that we have mumps in a post-pubescent male college male. He has never had the vaccine, but he comes down with mumps. He has an increased likelihood of coming down with orchitis a relatively rare outcome among children much more common among adults orchitis is an inflammation of the testes. The patient develops an immune response to their own testicular materials sperm, epidydimis structure, and so on. As a result, they could become sterile. Usually, it is just one testicle, but it can be bilateral in which case they lost the ability to produce sperm. This is why we need to be immunized. This is also a reason as to the older the child is the greater the likelihood that the infectious agent will cause an adverse outcome. We dont understand this as a general rule of thumb (we just need to know this) we do not know why it works this way but it does. Even with more serious agents POLIO. Polio Polio probably causes a sub-clinical infection (sub clinical inapparent infections are simply asymptomatic infection by different names. well over 90% (close to 99%) of the time. Only 1% of the people actually get any kind of paralytic form. Usually, only 1% of people actually get any kind of paralytic form. Usually those cases are quite mild. They usually only involve an arm or a leg or something like that. The people that develop the severe forms of polio are, (people who have difficulty breathing (have to be on a respirator), people who develop meningitis, and people with long term paralysis that kind of thing) not the typical person. Only adults really would develop these signs and symptoms. MOST children did not get that severe, and those who did get that severe were not typical. It is very unusual to see a four-year-old on crutches. That person is not the clinical, typical case. Remember, the typical four-year-old (99 out of 100) develop nothing with polio. AND only a small percentage of the one percent develops any kind of long-lasting paralysis. That little child is not likely to have the paralysis. We are more likely to see the paralysis. Adults are much more likely to develop paralysis and death. The paradigm here is children exposed to viral agents can tolerate the infection much better many times with inapparent infections or sub-clinical infections the older they are with the first encounter, the most likely they are to have an adverse reaction. Remember this is seen with measles, mumps, and rubella. THIS IS TRUE IN GENERAL. Epstein-Barr Virus Virus is spread through the respiratory tract we can get it through the throat droplet spread. It is NOT a VERY infectious agent, even though it causes a disease called infectious mononucleosis "kissing disease." Infectious mononucleosis its agents cause a very usual series and symptoms of problems: We will see an invasion of the respiratory tract we will have a viremia it will spread throughout the body and goes to the spleen. While it is at the spleen, it triggers B-cell lymphocytes to divide the same is true in lymphnodes B-cell lymphocytes are dividing. (B-cells involve the production of antibodies an activated B-cell will become a plasma cell and a plasma cell will secrete antibodies.) This is an antigen-independent stimulation of our B-cell system. So, we will produce antibodies to antigens in which we have not seen. So, this is an antigen-independent stimulation of our B-cell lymphocytes. We call this agent (to do this) a B-cell mitogen the diagnosis is not based upon an antibody to EBV (Epstein-Barr Virus) but rather looking at oddball antibodies that you have. We call these odd-ball antibodies heterophile antibodies. We do make antibodies to many different things obviously. This is what we base the test on it is called the Monospot Serological Test or Epstein-Barr Virus infection of (mononucleosis). It
is an antibody for unusual substances such as Horse RBCs or Sheep RBCs. It obviously has not been infected by a horse. It is just responding to it synthesizing the B-cell mitogen stimulating a variety of B-cells producing an antibody even though the antigen is not there. That lymph-proliferation stimulation of the lymphocytes to divide can been seen by enlarged lymphnodes and by an enlarged spleen an enlarged spleen can be a problem for the patient if it is large enough that it extends beyond the rib-cage. Normally, we are not able to feel or see the spleen. It can extend a few inches. This also means that it is exposed. Someone can trip and fall and rupture their spleen. We want to watch out for this. The spleen is a mushy kind of structure so it is very hard to surgically repair if we get a tear in it so when something goes wrong with it, we usually just remove the spleen. We have a significant amount of T-cell and Bcell lymphocytes in the spleen the removal of it will forever make someone somewhat immunocompromised. This will change a persons life history of infection because of this injury. What we can do is use fairly potent, but short term-use compounds like prednisone decreasing the dose over a few days to just sort of take the edge off of that lympho-proliferation. It would get that spleen size down so it would not extend beyond the ribcage, and this in turn would decrease the likelihood of rupturing the spleen. There is also some discomfort in terms of abdominal fullness as the spleen fills up inside and when you lean forward you feel full. You just feel a very strange feeling. There is also a good chance that you will get a severe sore throat associated with what is going on now. This is NOT the kind of sore throat that anesthetics can just take care of. This is a sore throat that is awful. You may or may not have a fever or you may or may not feel fatigued. Feeling fatigued is related to the lympho-proliferation. We can minimize the fatigue by limiting the lympho-proliferation with the prednisone. For most patients this is an uncomplicated problem with a full recovery. It will generally take between three weeks and three months to run its course. Some patients will have problems that will extend beyond that. We can see an infection of the liver which can cause a hepatitis where your complications can be from six months to years. Recovery from this can last a long time. This is not the same hepatitis as that of hepatitis B this is from Epstein-Barr Virus. We can also have jaundice, or we could see liver enzyme irregularities and so on. Now, all of this is interesting, but it gets even more interesting. A technician at the University of Pennsylvania was working on a virus that caused Burkitts-Lymphoma in Africa when she accidentally injected herself with the agent by accidentally dropping the glass container that it was in. With this technician injecting herself with this agent, it caused her to develop mono. Then we found that what was happening with Burkitts Lymphoma is that areas of the world, particularly in central Africa, individuals that were exposed to EBV ended up with Burkitts Lymphoma. And individuals in Southern China, Northern Laos, etc, came down with a nasal pharyngeal cancer from the lymphoma. So, we think that what is happening in those other settings, there are other viral agents inserted silently (hidden lysogenic in a sense) INSIDE the B-cell And as long as that particular antigen for that B-cell does not come along - nothing happens. Then along comes EBV, and it opens up all of the antigens. This triggers ALL of the B-cells to divide including the ones that have these hidden viruses in them. So, Burkitts Lymphoma and nasal pharyngeal cancer we believe to be associated with hidden viruses. We DO NOT think that it is EBV alone we think that it is a co-infection with EBV stimulating the dividing of a cell that already has hidden in it another agent. This was a B-cell mitogen; we also have T-cell mitogens.
Microbiology 6-15-05
It is most logical to say that when you have some type of infection it is a viral infection over a bacterial infection, but when all other causes have been excluded, we will have a bacterial problem. Bacterial Agents Streptococcus pyogenes "Group A" - People think that this is the most common problem when it comes to being sick. They are wrong of course, but this bacterium is known to cause the infection of strep throat. Group A Typically, we talk about serological analysis serotyping. We use an antibody to determine a specific structure on a cell whether we serotype RBCs, ABO system etc. we can serotype organisms and that is what we see when we some characterization of an organism. This is the normal way, but in this case it is the chemical analysis of a cell wall structure known as the "C" carbohydrate. So, the "C" carbohydrate is characterized chemically into various subgroups, such as group A. Group A streptococcus pyogenes is the most common cause of human infection. There are B and D varieties that are more common in other animals birds and dogs and so on. Now, it is not specifically related to receptor site matching, so the human disease could be caused by some of these other problems, but the usual source of the disease is another human. So, most of these other streptococcus pyogenes infections are not a problem to us. Now, the source throat that we are talking about here is really age dependent as to how it presents. If we are talking about someone who is about the age of 5-7, it tends to be a chronic infection. They symptoms do not generally include a fever, and the entire oral pharynx area, the whole throat is involved. One of these receptor sites of the organism that is involved with picking its target is called the M-protein. There are many M-protein varieties in the organisms point of view, and for someone under the age of 5-7, there are multiple receptor sites throughout the entire throat. So, therefore there is a lot of tissue that can be matched (a lot of tissue can be invaded infection). So, the prime situation tends to be a young child who will see this infection. The child tends to get an earache (pulling on the ears and getting fussy). This is seen as a chronic problem. It can also involve the sinuses. When we have chronic infections of the URT, we have to look at this organism as the source of this chronic infection. The reason why the sinuses tend to be sight of chronic infection has to do with their vascularization our immune system can not get that area as well as other areas the immune system usually would be able to get rid of that organism by immune clearance (phagocytosis). So, if your body does not know that it is there (the organism) and there is no way of getting to it (sinuses), it tends to hang around. This chronic characteristic of this also makes it difficult to treat. The organism is sort of sequestered away, and the area is not well vascularized, so it hard to get drug to that area through the blood vascular system. We just will not be able to get a lot of drug to that area. This results in longer treatment. Now, we are going to go up to the age of about 10 to 12 years on the high side of things. In this age group, we will see an acute sore throat. The child will get a fever. It will only be a moderately high fever only 101 to 103 degrees. This has an abrupt onset this is an acute illness in this age group. The area involved is just the tonsil area and the back of the throat. It is not as much of an area that is involved as in the younger child. The never age range would be that of 12-14 all the way up to adult. Here, it tends to be a much milder tonsillitis, mild fever, and the infection is in a very focused part of the throat. What happens is that when you get older, you lose receptor sites to the organism. We had the receptor sites when we were younger, but the receptor sites on our cells have changed. The host cells change.
The same thing is true with fever. It takes a certain development of the immune response for us to have a good, strong fever response that is predictable. Younger children can have high fevers with a low degree of illness, so they may have a chronic infection with no fever at all. With a younger child, the fever index is NOT a good index, but when you get older, having a fever is a good indicator that we actually have an infection. When we get a fever this is actually part of our immune response. Our macrophages produce an interleukin, the interleukin is interleukin 1, and interleukin 1 then binds to the hypothalamus triggering a fever. So having a fever is part of having an immune response. So when we are reading a patients signs and symptoms - a symptom is what they are complaining of, and a sign is what you see in a patient you are reading in part the immune response of a person. It is not necessarily a direct reaction of the organism rather indirect to the immune specificity. So when a person is immunocompromised, then the symptoms that he or she may be exhibiting are not reliable. So, if a person is an AIDS patient, and they do not have any T-cells, and they are destroying the macrophage population, then their immune response to an infection will not be true (it will be muted). So, we cannot go by those signs and symptoms as an index of severity often this is the case, however. Many times we think that when we are looking at the chest X-ray, we think that what we are seeing is the organism on the chest X-ray, but the organism is ACTUALLY causing what we see on the chest X-ray to happen. It is the immune response of the organism that is responsible for most of what we see on that X-ray. So, we can have the streptococcus pyogenes infection the acute illness and you can recover and you will produce serotype specific immunity to the M-protein serotype that you saw and therefore you will generally not have a repeat infection of that particular M-protein serotype. Unfortunately there are 100+ serotypes of M-protein. So you can get this infection repeatedly, but you will not get the same infection over and over again. This organism will also cause wound infections. It can also cause a childhood problem called impetigo. This is a skin-lesion a lot irritation. It is very itchy and the children tend to scratch it A LOT. When the lesion is scratched it spreads the organism, and it adds staphylococcal aureus a second organism. This second organism in turn, can create much more of a scarring situation than one would have had originally with the organism. You can get the same combination with S. aureus entering the wound because of scratching with something like chicken pox. The name "chicken pox" is so because of the scar that is left of the skin the pox mark. Its a small one, but it is there. This pox is really there only because of the S. aureus infection that follows the scratching of the "chicken pox" infection. With these skin lesions, if you were to use something to relieve the itching, not only would you be relieving the discomfort that you would be having, but you would also be decreasing the likelihood of getting that secondary infection. So, often impetigo is a mixed infection S. pyogenes being the lead organism and S. aureus being the secondary organism that will lead to infection. Sometimes you can sort of get several things all at once. You could be invaded by a S. pyogenes organism that is producing a toxin that is most likely bacteriophage related information found on a plasmid. We call this the red-causing toxin or more specifically the erythogenic toxin of scarlet fever. There are only a few varieties of that toxin, so if you ever get scarlet fever, you really are NOT likely to get it again. You will have a protective response. It will be an antibody to the toxin. We actually have a test to see if someone has ever been exposed to the toxin we can inject a weakened for of erythogenic toxin into the skin, and if you get a spot in the skin where we injected the toxin, then we are susceptible to the toxin. If we inject it in, and we ALREADY have a neutralizing antibody, then we know that you have been exposed before. You will see no red spot. It was developed by a guy named "Dick" so it is called the "Dick Test." So, the "Dick Test" (you inject a weaken form of the toxin and look for a red spot) is a test that we can learn if a population is susceptible to the toxin with a skin test. Now, we could potentially get strep throat and we could also get at the same time scarlet fever and we could also have impetigo same organism so it could strike many different places and cause many different problems, but it would be the same organism that would be causing all of these problems. It would depend where that person had the infection. Someone could potentially have strep throat and then get scarlet fever or someone could get impetigo and
scarlet fever one person may have a sore throat and they spread it to someone else and that someone else could potentially get a totally different infection (like a lesion impetigo). You never know. Now, when you recover from the infection, you do produce an antibody to that M-protein and that can result in a whole other cluster of problems called "post-streptococcal diseases." These diseases are all related to developing an immune response to the M-protein serotype and this begins about two weeks after the initial acute infection or intoxication (if you had scarlet fever). So, just when you are getting better from having one of these problems, you develop a new problem. There are two problems that are of our primary concern: 1. Inflammation of the Kidney Post-Streptococcal Glomerulonephritis inflammation of the kidney the M-protein serotypes are molecularly larger and they have a valence of 2 the structure is BIG and we develop an antibody to it. And now we have an immune complex and the immune complex creates a latticework of antigen and antibody so we get this very big growing kind of structure - so when we have an antigen-antibody complex in which the antigen can bind to more than one antibody, and the antibody can bind to more than one antigen then we create this big latticework structure of antigen and antibody. This gets trapped in the kidney and activates acute inflammation (redness, swelling, heat, and pain) so we have inflammation inside of the kidney kidney function becomes impaired and the urine output is very low, but they are producing fluids, so there is a considerable weight gain. It might be forty pounds in one weekend (edema in the legs, arms, face, etc.). The patient then goes to the doctor and once we identify that this is the problem it is a matter of putting the patient on a diuretic, (they will go to the bathroom a lot) and the problem is resolved really. What happens is that over the next few weeks (remember that it took two weeks to develop this in the first place), the patient will develop additional antibodies, and the more antibodies the patient makes, the more they fight over that antigen that is there and the complex gets smaller. That is that immune complex is at its largest size, when antigen and antibody numbers are relatively equal. As we produce more and more antibody, the size gets smaller. Initially, when you have the antigen in your body at the initial infection, there is very little antibody so the complex is small. Then the immune response produces more antibodies, so the complex gets bigger, and lastly, the antibody production number far exceeds the antigen numbers, so the complex will start to become smaller again and eventually disappear. This will basically resolve itself. Our biggest problem is that we need to get rid of all of that water gain because it is not good for HTN, kidneys problems, or concomminent problems that is they already have one kidney or they already have problems with high blood pressure (or maybe even pulmonary congestion). But for the normal healthy person, this is more so just a nuisance. But in either event, whether it is potentially serious or not, a diuretic can get rid of this problem. Now, how do we know that this is the actual cause of the edema? The organism SHOULD be gone now. This is just a lasting effect of the immune system. So, finding the organism and culturing it now is a post-streptococcal problem. It is not an infectious disease problem really it is a result of the immune response to the organism. So, we can look at some of the immune responses, and there is one response to a compound that is NOT in any way a virulence factor of the organism it is just a good antigen and it is called Streptolysin O. So, the antibody to that is called the antibody to Streptolysin O we call that then the "ASO." - The concentration of an antibody is determined by a serological test in which you dilute out the patients serum and test to see if the antibody is still there. So, we have a series of different concentrations. Picture:
The highest dilution that gives a positive test (it is a 1/8 dilution) - that will be called the titer the titer would be 8 = this is the reciprocal of the highest dilution that we can see the antibody (gives us a positive result with the dilution). This is how we read all serological tests. We call the titer
the index of the concentration of the antibody the more that we can dilute out the antibody and still get a positive test, the more antibodies that were there in the first place. Now, the actual number is not an absolute number that is important because the titer depends upon the sensitivity of the test that we are doing it with. So, we can look for that antibody using multiple serological procedures and come out with different titers depending upon the sensitivity of the test. The numbers of the tests can VARY greatly. It does not mean that there were more or less antibody (the tests are different) we cannot compare different tests. We have to compare the same tests (with a different concentration to the get the different titer) because of sensitivity. - So, we see that a patient has a high and rising meaning that we take this "ASO" titer when a patient comes into the hospital on Friday night and we do it again on Sunday before the patient leaves. Say the patient has a (1/8) on Friday and a (1/64) on Sunday. This is a rising titer. We want to look at paired serum samples so that we can see that we are in fact on the right tract because if we are rising we are producing more antibodies and we are right on tract with that particular problem. So, a paired serum sample with rising titers rising "ASO" titers show us whether a patient is getting better. This is a good reading to see whether or not someone had an infection or not, and it is a good indicator to see if the patient is getting better or not. This streptococcal disease is one that will cure itself it will get better. We can get rid of the fluid and the patients blood pressure will go back down. The patient will not die from this. A little later we will talk about some autoimmune diseases that will present the same way except the "ASO" titer is not there something else is causing this inflammation, and we have this autoimmune disease and we have a little more life-altering kind of problem. 2. Post-Streptococcal Rheumatic Fever we also see an immune-based problem here also we have both antibodies and sensitized lymphocytes attacking all three tissues of the heart: On a particular note the attack is on the heart valves this attack will result in inflammation and damage to this part of the heart endocardium, myocardium, ectocardium and the heart valves there is damage done because of this inflammation as a result. We will recover from this damage. The body tries to recover a heart valve and when it tries the scar tissue that results will make a slightly malformed heart valve it is not how it used to be. So, we had rheumatic fever once. Now, it turns out, unfortunately, that P.S. Glomerulonephritis only has about three or four serotypes each time you have it, the likelihood of having it again becomes less and less with each infection you get it once and it is very rare to get it again IT IS VERY RARE to even get it in the first place. Rheumatic fever on the other hand, has multiple serotypes. Unlike, the immune complex that we just looked at, this rheumatic fever can actually cause an attack on your tissue. It is a cross reaction. The immune response that is designated to that particular organism is also binding to your tissue making lots of damage that is an unusual thing. Normally, our bodies would not respond to something that is like you to avoid this outcome, but in this case, we have a cross reaction of an immune base reaction. This means that the person who has rheumatic fever has something about the structure of their heart tissue that is similar to the Mprotein serotype and unfortunately, many M-protein serotypes a patient can get this again and again each time having a rheumatic fever episode to a serotype of that protein that we have never seen before but we wont get that type again the patient will just get another type because there are hundreds. Because there are so many serotypes, if a person has one episode of rheumatic fever it is very likely that person will have many more. Now, not everyone has this cross-reaction so not everyone will have to worry about this, but if you have one, the likelihood of getting it again is very great. That means that repeated episodes of sore throats or impetigo different M-protein serotypes two weeks later the patient will have some damage to their heart valves. These repeated attacks on the heart valve results in the malformation and scarring of the heart valve and then the heart valve does not work at well. So when the heart is going through a beating cycle, some of the blood is going in the opposite direction. The valve does not close properly so the blood is going in the opposite direction. You can hear this and this is called a heart murmur the louder the heart murmur, the greater the amount of blood going in the opposite direction due to a greater degree of damage to the heart valve. So, with each infection we get a rheumatic fever episode and additional damage. This is not a good pattern. Now, just
like it is very unusual to have a cross reaction of the immune response, we also respond in a very unusual clinical manner we give the patient a maintenance dose of an antibiotic such as penicillin or erythromycin this is a maintenance dose that a patient will be on potentially for years. Example: Typically what we see is that if children have this problem so we diagnose after the second or third event (maybe even the first event) this is very serious so we warn patients parents that as soon as the child gets a sore throat, they need to go the pharmacy and get a prescription that is already on hold for them. We need to communicate how important this is and after subsequent episodes and not treating every even as it should be treated (not getting the antibiotic), we will put the patient on a daily maintenance dose of the antibiotic. So, we have the patient on this maintenance dose, and then around the age of 19-20, the patient believes that they can stop the antibiotic because they do not ever remember being sick. Then someplace around 24-26 yrs, and a couple rheumatic fever attacks later, they realize that they are not invincible, and they do need to be on the medication. The damage that was already done to the heart valve, however, might lead to a valve replacement. Before treatment people would only last until their mid-20s and die of congestive heart failure. Once again, there are multiple serotypes, and we do not want to immunize the patient because that would produce an immune response and attack the heart. The target is shared between the organism's structure and the patient's own tissue this is what is happening. The antibody of the immune response that attacks the organism also attacks the cell. There are lots of things going on with Streptococcus pyogenes. There are two infectious diseases (strep throat and impetigo) that we talking about and one bacterial intoxication. Thought to ponder: Why is it that with P. S. Glomerulonephritis that we do not put someone on a maintenance antibiotic? We do not do this because of the M-protein serotypes there are only a few the likelihood of getting it in the first place is not that great, and we can handle the problem with not much long-term damage. We are always looking for ways to NOT put patients are long term antibiotics so we are very careful about just who gets them. Streptococcus pneumonia - Causes pneumonia - Can get into your lungs - It can get to your throat (without going to the lungs) will cause a sore throat, otitis media (earache), pinkeye (inflammation of the conjunctiva of the eye), easily treatable situation just because we have this in the URT does not mean that you are eventually going to get it in the lungs you can carry this organism in the throat with no disease at all - In fact during the epidemic time hospital staff that were working with patients who had pneumonia 80% of the time the hospital staff were actually carrying it in their throats with no ill effect just because you have the organism in the URT (even with the disease or carrying it without the disease) there is not an increased risk that you will get it in the lungs - Has a capsule immune response is an antibody to the capsule - There are multiple serotypes of this because there are different sugars - There is a vaccine that has multiple sugars upwards of 20 (17-23) multiple sugars There is a bit of a problem as we develop an immune response against these sugars so we use it with a protein that allows our immune system to become more active. We talked about this protein carrier and the immune system and how it works the immune response is NOT to the protein, even though it is conjugated to the protein the protein is just a platform by which our immune system will conceptually recognize all of these different sugars. And again, someone can be immunized against this and have protective antibodies and still come down with a
different serotype of the organism because the response is not to organism, it is to the sugars. The organism has different sugars and different serotypes the vaccine does not protect against those other sugars. Neisseria meningitidis This organism has a capsule made out of sugars that causes meningitis. This is droplet spread. This organism lives in the nasal passages of the throat it enters into the bloodstream we then have a bacteremia it spreads to the capillary bed and in the capillary bed we are going to see a little spot a little lesion this is called a petickia (this is a red spot). This petickii is really a hemorrhaging of the capillary bed. Now, we talked about the rash of measles and how that is an allergic reaction to the organism, but in this case, it is the actual organism causing the destruction of the capillary bed. The organism is right there in that hemorrhaged capillary bed. As the disease progresses, the persons petickii will get bigger (it will start with the size of a pinhead sized blemish and will get to the size of a pencil eraser, etc) so we will see this growing area of capillary bed damage. Ultimately, as the disease progresses several weeks later as the person is recovering, this capillary damage that was already done in the first few days which has now gotten much worse results in the necrosis of the skin and this may result in the need of skin graphs being used or may result in amputation (limbs). This can be very serious because of this petickii. Now, the organism is spreading throughout the body it will begin to affect the other organs and finally, it will go to the lining of the brain and cause meningitis (inflammation of the lining of the brain). The patient will have light sensitivity which is generally an indication that something is going on with the lining of the brain; they may have trouble staying awake, and eventually, they will be unconscious their pain threshold will aroused it will harder and harder to arouse them. There are varying degrees on consciousness. They may or may not have back pain they may or may not have a stiff neck but if this does happen this is a remarkable stiff neck. This is a good indicator because the stiffness is so severe. These symptoms obviously would be occurring before the patient loses consciousness. This is easily treatable with antibiotics. It is very easy to treat. The BBB is not a problem because of the inflammation, and so drugs cross over very easily so they can go where they need to go. The patient usually recovers from this. The key word is usually. There are some notable exceptions: 1. The first person in a cluster to come down with the problem this person is called the index patient and we often see these in clusters because they are respiratory tract spread cluster spread so we will see this is a college dorm, training camp, etc. And if we house them together and stress them a little bit that even makes it worse but a good breading ground for this organism. This is why we see this in college freshmen (stressed out their first semester) or in military recruits during their first weeks of basic training. Put people together and stress them (in a cluster) and this could happen. So, that first person in the cluster that comes down with these symptoms could be missed. People might think that it is the flu or something like that. The stiff neck could be from working out same with the back pain. If we get a rash it might be poison ivy we dont know what it is. So it is easy to write off these symptoms. These early symptoms get lost. We can mask the symptoms in a sense. It is not until the patient starts to lost consciousness they have a severe problem with maintaining consciousness that we know they will have a viremia in the body we have these petickia all over the body and we have this brain problem already, but we probably will not catch these things in the first person until they start to lose consciousness. This person is much further down the road with the disease, so when we intervene with antimicrobial agents it is a totally different problem to deal with. There are more POST problems to deal with. There are more sequelaes. A sequelae is an after effect of the infection that is the amputation and the need for skin graphs and things of that nature. So, the longer the person goes without treatment the more severe the outcome and it could even result in death. Once you get them and treat them, you have a good chance at them. If we can get them to the hospital that is a good sign. The first person the index patient is most likely to have a problem. When one person is diagnosed then everyone is scared and EVERYONE gets tested and all that stuff. Every symptom is then being checked by the patient
they go to the doctor and we may even see the whole base or the whole dorm go on antibiotics just to be on the safe side prophylactically. 2. Another category this is an unusual setting and we need to figure out what is happening is the viremia; some of the people (about 10%) will develop an attack on the adrenal glands. So, in the early stages of the viremia they havent even gone into serious brain problems yet (we do have the petickia), but their adrenal glands are destroyed. This is very serious condition we need these. So, in this event, we will see a blood pressure reading that is through the roof. We need a catheter just to get a blood pressure. The patient cannot maintain a blood pressure. So, we pump in plasma expanders or fluids and it just drains right out of them. These people generally die right away. They generally never make it out of the ER. This is called WaterhouseFriderichsen Syndrome this is an acute adrenal insufficiency. About 90% of these people die. They represent about 10% of all cases, but about 90% of all fatalities from this disease. This is not a co-infection with a virus. The bacteria have receptor sites for the adrenal glands so we dont all have the receptor sites for the bacteria on our adrenal glands 10% of us do and those of us that do are in big trouble this Waterhouse Friderichsen Syndrome is relatively rare, but if it is a problem, it is highly fatal. Before we have even gotten to the ER, we have already probably lost our adrenal glands. They have already been destroyed. Now we can do (and often do do) a spinal tap on the patient. With a spinal tap, we can find a couple of things we might find that the protein level is higher than normal. And we find that the glucose sugar levels are lower than normal and we may find lots of PMN cells and we may find lots of antibodies to the capsules (sugars) Why is the protein elevated? The antibodies is a protein so obviously the level is higher because we are producing antibodies, but the organism is also growing and the organism is a protein. The protein is growing. We can isolate the organism because it is a protein. Why is the glucose dropping? The organism is consuming the glucose. Now, we have two patients come in same episode. One has high levels of antibodies to the organism in their spinal fluid and the other person hardly has any antibody. Which one is most likely to have severe sequelae (the skin graphs, the amputations, etc)? The one with the higher amount of antibody actually means that the person has been infected longer and has a greater history of the organism and therefore they have a greater likelihood of sequelae. The person that has the low levels of the antibody we have caught them in the earlier stages of the disease and beginning treatment early means that there is less invasion. High antibody levels correlate with a greater incidence of sequelae. We do have a vaccine for this and it is basically sugar water. **We do have a campaign to alert college bound kids about this.** The vaccination is voluntary. In the military you get everything. It is a very expensive vaccine though. Corynebacterium diphtheria This organism obviously causes diphtheria. The organism is associated with diphtheria it can cause an URT infection and it can also cause a middle ear infection and a sinus infection and even a wound infection. While this organism is growing in these places it is producing a toxin diphtheria toxin. This toxin is actually a viral gene product from a virus known as betaphage (this is a particular bacteriophage). Know that this is beta-phage. So, beta-phage must invade the bacteria to cause the disease diphtheria it is not a bacterial gene product. Once we isolate the organism from the patient this is part of the analysis we want to know if the isolate is actually invaded by beta-phage is the organism actually producing the toxin? Just because the person has the organism does not mean the person has diphtheria the bacteria must have the toxin. Diphtheria toxin interferes with protein synthesis in eukaryotic cells it interferes with the elongation process of our cells resulting in starvation of our cells and the death of our cells. When we have the organism in the wound site we have a fairly noticeable fluid coming out of the
wound the exudate tends to gel like cooled gravy it is also gray in color these are the dead cells that have died due to protein starvation. The person can be tested to whether or not they are susceptible to this. This is called the "Schick" test what we do is we inject the toxin in a weakened form into our skin and look for a red reaction if we do not have a red reaction then we do not have the antibody if we do not have the red reaction that means that we neutralized the antibody and we are therefore not susceptible. But in general, we just assume to immunize everyone against this. We get this is our DPT (D-diphtheria toxoid P-pertussis (whooping cough) T-tetanus toxoid) This DPT will take care of this problem. This intoxication is highly communicable. It can spread to a very susceptible population in a very short period of time. In WWI and WWII, many people were immunized and those that were not there were wide epidemics. Those that were immunized actually had the toxoid in them, and they spread it to the people. This was an unintentional attack. So, diphtheria is indeed in fact an intoxication followed by a viral infection. Haemophilus influenzae This organism causes pneumonia and meningitis. It enters through the respiratory tract. However, in the URT this would be associated with sore throats chronic infection of sinuses otitis media (middle ear infections) and conjunctivitis of the eye. So the area that we often see is chronic infection of the sinuses and a source of the organism is the throat (this can cause ear infections and eye infections). So if we have a child that has repeated infections of haemophilus the same serotype and so on the immune response is going to be against some of the sugars they will start getting immunity as they get older. We are going to need to start thinking about some long-term treatment to get rid of the organism in the sinuses for the patient who gets repeat infections they are an endogenous source that is we have this organism in the sinuses and therefore that is the cause of these repeated infection and we cannot get rid of it. The young child is two years old and has had to sick in the hospital twice, and he has had four or five other infections of haemophilus in just his first two years of life so chances are we are looking at a chronic infection so we have to up the dose of the antibacterial treatment or we have to keep the child on it longer. We have to do something. We generally do not try to use the long-term treatment or prophylaxis approach for this one we just want to get rid of the source of this chronic infection which is then contributing to these acute infections. Again, the virulence factor is a capsule the sugars on the capsule are what we make antibodies for we can have a vaccine for this organism this is again sugar water. We immunize children with this. The sugars are what cause our immune response. Some of the sugars that are common are what cause pneumonia and meningitis is children are also sugars of the vaccine that individual children do not response to strongly by the time they respond to it strongly with the vaccine they are also at danger of getting, so we have a flaw in the system. They are trying to change the vaccine so that we can get a broader age range (younger children) to respond to it, and there are compounds that we can add to a vaccine that enhance the likelihood of getting an immune response. We call these compounds adjuvants there are both natural and synthetic adjuvents so we are playing around with a vaccine to get a greater immune response. Now, we have to identify the appropriate sugars because the children do not respond to these sugars and so they are under the age in which they have the ability to respond. We want to make a vaccine to help these younger children. LRT: General Considerations We want to remember that the lung is seen as a body surface so that inside of that sac is in a sense an area that communicates directly with the outside world. The inside of the alveolar sac communicates with the outside world. So it is inside of the body, but it is a body surface. So we have a large degree of hard particular matter we have defense systems mucociliary clearance trapping organisms, particles, dust, etc. We trap these things in the mucus, and we move it upward and then we swallow it. Some people call this the tracheal toilet - because this is constant moving. We can do things to make that not work well. If we do things to make our defenses not work as well then we increase our likelihood of getting these infections.
Other things that we have are coughing and sneezing. Anything that we do to decrease the protection system of that area of the body increases the likelihood of getting an infection we call these patient factors that increase the likelihood of getting a lung infection a predisposing factor these are patient factors. Microbiology 6-16-05 LRT: General Considerations: - Lung as a Body Surface - Predisposing Factors Predisposing Factors: The key is that just because we have the organism in the URT does not mean you are at any increased risk of getting the organism in the lungs. Having the organism does not mean you will get the disease. If you have streptococcal pneumonia in your throat from your throat culture that does not mean that you will get pneumonia unless you have the predisposing factors. And on the other side of that once we identify a patients predisposing factor we now know that they are at risk for getting lung infections, and we can be on guard for it, or we can immunize ahead of time for it. Extremes of age very young children under the age of five (the greatest risk is that of children around three to four months and the risk decreases as they get older to the age of five due to the maternal antibody protection that lasts up to about the age of three months a breast-fed baby is one that will be protected a little longer this will help their immune response) Another aspect would be a premature delivery: - This would mean that the childs development was not complete. One of the areas of the greatest concern is that of the lungs. So, children that are born in the late second trimester, 5 or 6 months of gestation, will be at great risk. We try to get away from the timing of the baby "3 months early" but try to focus more on the size of the baby. We are really more concerned with the body weight. So, if we have children that are 4 pounds or under we would be concerned about their weight even with twins but if those twins were held to a full-term pregnancy for "twins" then they are not as much of a concern. This is a developmental situation. And in particular with the lungs when we breathe in, we have to inflate, and in order to inflate properly, we have to have a certain amount of a natural surfactant which changes the surface tension, so that you can inflate the lungs more easily. One of the areas of final development is the production of this surfactant. We have even gone as far as trying to develop a surfactant that we can give to a child that has not developed far enough to make their own. The childs lungs are one of the later organs to develop, so if a child is born early then that is an area of potential attack of an organism. At the same time, we talked about maternal antibodies Immunoglobulin G this IGG class of antibodies is nearly 100% of the maternal level at the time of a full-term pregnancy. It sort of declines at a rate of about 50% every month after that.
So, we lose roughly 50% of these antibodies every month. The same things occurs on this "preside" at one month premature, the baby would only start out with 50% of the maternal level of antibodies. Two months premature would be 25%. So, the younger the baby is not only are
their developmental concerns of the lungs, but there are also less maternal antibodies. So, sometimes we wonder why doctors are concerned about delivery dates and they will do anything they can to keep the baby inside of the mother as long as possible this is why. The developmental concerns and also the protection of the baby is important. Premature babies are at a younger age involved with more of a risk of infection. The other extremes of the age are the elderly. This is not necessarily the chronological age of the person, but the physiological age of the person. The better the person is in shape and takes care of their bodies is a big factor. We do begin with how old the person is when we are dealing with this predisposing factor, but then we look more at a persons physiological age. We want to know what kind of shape they are in. We look at people who are about the age of 50, because this is the time when peoples lifestyles begin catching up with them. They may have a body that has a physiological age of 70. So, we need information to look at this predisposing factor Aspiration inhalation of fluid. This can come about by something like a "near-drowning" event, but it can also come about for other reasons. For example, a person can be careless with the way they are eating and they can aspirate food. They will then start choking this is when people say "it went down the wrong tube." So, we can get food particles in the lungs (inhaled sandwich). Another way that we can get an aspiration would be through... Intubation intubation is when you are having surgery, and for a number of reasons (one being so you do not swallow your tongue but also we are going to pass gas into your lungs and we want to maintain the airway so to maintain the airway we do this. The anesthesiologist is in charge of maintaining the airways they are in charge of the patient until they are ready for surgery then they are in charge of bringing them back alive. It is easy to put someone out; the tricky part is bringing them back around. The anesthesiologist is basically going to stick a tube down your throat when they do this, they can also add drugs that will decrease secretions so that you do not aspirate a lot of fluid we can stop the secretions of saliva for example. The shorter the duration of the surgery, for example, the less likely something will happen. If you have a long surgery there is a high degree of likelihood that you will aspirate something into your lungs and there is a higher risk of pneumonia. If a patient has just has a longer surgery that patient is at an increased risk of getting pneumonia. Physical Status of the LRT many different factors go into play here. We can look at pulmonary circulation heart/lung which can lead to (if left uncared for) fluid accumulation fluid around the heart pericardial sac fluid around the lung pleural cavity called pulmonary congestion. When we have that in the patient, then we have the lung at risk. We have a patient who is a smoker or we have a patient who is exposed to industrial hazards like acetone or something like that (basically inhaling things on a routine basis) or it could be a person who has asthma someone who has chronic asthma can result in scarring of the lungs you could be a coal miner and you are breathing in all kinds of dust the dust gets lodged into the lungs the smaller the size of the particle the deeper in the lungs it will go and it will be lodged in there (remember, the lungs are a body surface we can get our lungs dirty we cant wash our lungs very easily though, so we have to have our alveolar macrophage working to gulp the particles up and when we overwhelm the immune response with lots of particles that results in scar tissue these mediators can cause permanent changes in the lining of the lung because we are just trying to keep our lungs clean). Asbestosis this is just like breathing in the coal dust - Asbestos is a group of silicate fibers with a crystalline structure it can cause cancer - asbestosis is a fibrosis or scarring of the lung tissue this is work place related we use this in a lot of buildings, and it is usually not a problem if it is not in the powdered form when we breathe this in. We also do not want to eat this either, but it is very bad in the powdered form because it will deposit very deeply in the lungs. One should be careful in their workplace because it can be anywhere. We can also see this constant irritation problem in those people who are working with grain corn, wheat and we store these in storage areas that that air is full of these kinds of fibers and
dust and we can breathe these in deeply remember the size of the particles are a VERY important factor here. Small-sized particles are breathed in deeply, the phagocytic cells feel overwhelmed when they are trying to clean up the area, and the phagocytic cells start to develop some enzymes and other cytokines that result in damage to the lungs we are looking at patients that have a history of damage to their lungs smokers, asthmatics, certain occupational settings or people who have pulmonary congestion these are all people that we are concerned about. We can also add to that list of physical status things are those people that have had pneumonia before. So, whatever risk factors allowed them to get the pneumonia in the first place, they now have a new risk factor because they have had pneumonia and they have scar tissue already building up in the lungs. The scar tissue is not as protected as much as normal lung tissue allowing room for disease to occur. This allows an area for the organism to cause infection once again. Diabetics/Alcoholism they already have impaired phagocytic responses, and the primary area of protection in the lungs is the phagocytic response the alveolar macrophages so because they have an impaired phagocytic response and this being the primary response in the lungs at least initially that means that this initial response is flawed, and so a diabetic and an alcoholic are at an increased risked of developing pneumonia. Depression a person that is clinically depressed is immunologically suppressed. The suppression should be directly related to their T-cell lymphocyte response and as we will learn later T-cells can help B-cells make antibodies so both B-cell lymphocytes and T-cell lymphocytes are not functioning properly under the situation. This is just the tip of the iceberg with this concept and we do not have conceptual probes completed for this particular scenario we have a lack of information the tip of the iceberg here is the relationship between the brain and the immune system as indicated that when someone is depressed their immune system is suppressed. There are a lot of those kinds of anecdotal parts of the population that independently can be demonstrated that if you take a suppressed person and look at their Tcells for analysis, and you will find that they are not working well take a couple who has lived a long time together when one dies the other one is at a very increased risk of then also dying. The other spouse is at increased risk of dying in the next 3-6 months. They are depressed, their immune system is down, they are at an increased risk of developing pneumonia they get pneumonia their immune system is already down so their potential of getting rid of that disease is not very good and they die of pneumonia. We can add some other factors as well. Malnutrition - Someone who is malnourished is at an increased risk of developing any disease because the immune system is not at its optimal status in terms of its response because of nutrition. So, nutrition has an impact One of these factors alone will only cause a minor increase in risk. But they do not come alone they do come in packs. And the "package" that you have is very likely to have a very direct impact upon your immune system. Case Study Fred 67 years old. Fred has been retired from the plant where he used to work for five years. He has not yet adapted to being retired. Retirement is one of those life events that increase your risk of getting disease. It leads to depression. Life changing events like marriage, death, retirement, divorce, can all increase ones risk of getting disease. Many peoples identity is with their job, so when they retire they do not know who they are anymore. This can lead to more depression. This can lead to lower self-assurance. "They are a Plumber" they have lost their value to society. They were someone; now they are no one. His wife has just died a few months ago. His dog died a few weeks ago. His wife dying didnt bother him very much his dog dies, it bothers him a lot. He does not deal with grief well he did feel bad about his wife dying, but he did not know how to deal with it, so when his dog died he basically lost it. People around him are also dying friends, family, etc. He does not deal with grief well, so he bottles it all up. He then turns somewhere else to relieve his stress.
He starts to smoke again. He also starts to drink again. He is smoking 4-5 packs a day. He drinks continuously throughout the day. He belongs to different clubs around town and you can find him at these places at different times of the day for a different meal. He has a couple of beers and a shot everyday. He is drinking 14-20oz of alcohol a day. He does not consider himself an alcoholic because he is not drunk he has just induced his liver enzymes (alcohol dehydrogenase and so on) so he has a large tolerance he has induced these enzymes to capacity this is going to stimulate the liver and this is going to develop eventually into cirrhosis. But he is not there yet. He also has a "touch of sugar." He is a diabetic, and he is an untreated diabetic. He is also malnourished most of his caloric intake is alcohol and the rest is bar food. He is in the hospital again he has pneumonia. He had pneumonia last year also. He has a history of pneumonia, and that is another risk factor. Now, people like Fred will die early often because of bacterial pneumonia not because we cannot treat bacterial pneumonia there is not a lot of antimicrobial resistance. We just cannot get to it early enough and eventually the patient will die because their immune system is in a compromised state. The number of people that die of bacterial pneumonia is really, really high and is proportional to what you might expect. It is a lifestyle problem. He will make it through this pneumonia case. He is starting to dry out. His chemistry is starting to turn around he gets better in the hospital but if we put him back out into the streets he will get sick again and it wont be a year this time it will be less. The likelihood of Fred making it to 70 is very unlikely with his lifestyle. He basically has two choices: 1. Die 2. Get a girlfriend The girlfriend takes him to church, he gets involved with meals on wheels (he is helping people eat well), he stops smoking, drinking, he is watching his diet, and his new wife is making him do all of these good things for him. He lives to be 85. When we are dealing with a chronic problem, we can only do so much clinically, but we have to communicate to the patient that there are more to it than drugs to get better. The drugs can only do so much. We need to communicate to people that their role in their lives and getting better is very important. They need to change their lifestyle (behavioral aspect can directly change the outcome of treatment). It centers on these things that are predisposing factors. What they are really doing is they are bypassing a defense system - they are stressing out the T-cells response so then you have lower T-cell counts and a lower antibody response. People do not see it that way. We want to activate cytokine production for good health. We want a good relationship with the people we are dealing with so that they listen to us. Types of Pneumonia: Alveolar Pneumonia (Lobar) we have a inflammation inside of the alveolar sac. Typically, this is going to be a phagocytic response inside of the alveolar sac the alveolar macrophages are going to be involved. It tends to be localized in the distal portions of the lungs the lobes the tips of the lobes. Now, the assumption that we are making here is that the person is up and walking around. If the person is lying flat on their back they are not going to have this. Walking around means that it will be in the lower portion of the lungs alveolar. This is typically bacterial. Interstitial Pneumonia involves the space between the alveolar sacs. In this setting we can see T-lymphocytes involved and macrophages involved. Interstitial is more likely to be viral or mycoplasma pneumoniae a bacterium. Most bacterial is going to be alveolar pneumonia, but mycoplasma is interstitial. We also classify them...
Pathological Classification ...as primary, secondary, metastatic, or aspiration pneumonia. Primary pneumonia is the primary site where the infection occurs it is caused by a single organism that we have. Secondary pneumonia we have a second invasion of an organism in the same site an example of that would be that we have a primary viral pneumonia (influenza virus) and we have a secondary bacterial pneumonia haemophilus influenza. So we at first see the viral infection with the influenza virus followed by a bacterial - haemophilus influenza. This secondary invader takes advantage of the fact that your immune system is down because of the invasion of the first organism. When this occurs, that secondary invader is much more aggressive than it would be by itself. Our immune system is already compromised. Sometimes the person just has a "super infection." It is this kind of situation that occurred with the epidemic that occurred right around WWI we had a worldwide pandemic upwards of 100 million people died it was a combination of both influenza and bacteria pneumonia (most likely haemophilus influenza) we are very concerned about that secondary infection (pneumonia) and that is bacteria. Another note on bacterial pneumonia if we have a patient that has multiple risk factors already and they get viral pneumonia we sometimes anticipate and prophylactically treat for a secondary bacterial pneumonia, so we have patients who have these factors or are immunocompromised in someway and sometimes we prophylactically use antibiotics not to treat the viral obviously, but to prevent the bacterial. There is risk factor analysis. If we can anticipate that a patient will get bacterial pneumonia, we try to prevent it because in the immulogical state the patient is in, it could have negative effects. Metastatic Pneumonia this refers to the fact that the organism has spread from one location to another organisms can spread from place to place - A patient may have an impacted wisdom tooth or a chronic sinus infection and that can in turn spread to the lungs or to the lining of the brain. So we start with one sight of the infection and we move to another site of infection. Aspiration Pneumonia This is caused by someone who aspirates fluid. Unlike the UPT which is 90% viral and 10% bacterial the LRT is 50% viral and fungal and 50% bacterial. It is an even split here. Again remember that a "super infection" is a combination of both a viral and a bacterial infection. We see a variety of agents that cause an infection in the LRT Agents of the LRT Influenza virus Coccidioides immitis called desert fever (fungal agent) also called San Joaquin Valley Fever fungal agent that affects the lungs Bordetella pertussis whooping cough (DPT) Chlamydia and Coxiella burneta are not that common although Chlamydia causing is psittacosis a Chlamydia that we get from birds. It has a bird origin it can be passed to humans (we can breathe it is), and humans can get effects of this. We are increasingly concerned about the low level of blood stream impact of this organism that may increase the risk of atherosclerosis. The data on this is still coming in. We can get pneumonia from this. We want to treat with antibiotics to get rid of the organism because we would like to prevent the atherosclerosis. We want to reduce the inflammation. Viral Agents: Influenza Virus In terms of the structure, we have on the surface (this virus is enveloped so the virus is released by budding), but we have on the surface of this structures Hemagglutinin and Neuraminidase. Hemagglutinin gets its name because this structure on the surface of the viruses can cause RBCs to clump HEM agglutinin so if we mix the virus and RBCs, we are going to see the clumping of RBCs. We will have an antibody response to Hemagglutinin (as well as for Neuraminidase) and the antibody will block that clumping phenomenon. So, what we do then in the lab is we put the virus together with RBCs and we see clumping and then we add different
dilutions of the patients sera to see how much blocking antibody they have. We will do it undiluted, 1:2, then 1:4 etc.; we will keep diluting out that sera until that clumping occurs so there will be no clumping when we have antibodies and when we lose the antibodies to block it then we have clumping. There will be no clumping when we have antibodies, and as we lose the antibody to block it, then we have clumping. We call this the HEM agglutination inhibition assay. So we can determine what you have been exposed to or what we need to immunize against and so on. We have an assay for Hemagglutinin agglutination. So we have these Ns and Hs. These are the basis of the serotyping that we do for epidemiological purposes. Lets look at the epidemiology Page 14 of notes We see the spread of the virus with the migratory bird route. We have this route from Northern China down to Australia (this is where we have the co-infections occur this is where we have the virus interacting with both human and animal cells, and we have the changing of the Ns and Hs resulting in the different serotypes of the virus. Since we have not seen this before (the new serotypes), we do not have the protective antibody and we will come down with the disease, and this will start an epidemic. This is a new variety that has not picked up much force yet so, if it does not pick up that much force they this is not going to be that big of problem because we can then do things to stop it. There wont be much of an epidemic then. We know that what is going on in Asia for the last month or two is likely to be the serotype that hits us come November and December so we analyzing what is going on on that side of the globe, so we can prepare for what is going to occur on this side of the globe. We can protect ourselves then. This works great for us but not so great for them. Page 14 of notes: Different Serotypes Spanish flu (N1H1) occurring right around WWI major pandemic upwards of 100 million people were killed. Sometimes we can more than serotype invading at the same time. So, when we hear about the Ns and the Hs this is the serotyping we are doing. Now, there are two types of changes shifts and drifts Shift a major change occurs every 8-12 years where we have BOTH the Ns and Hs change we definitely have not see this for awhile Drift a minor change that occurs every 2-3 years we have a constant change either an H OR an N changes we see this often If we have a change that we have not seen lately, we know that a great percentage of the population is going to be at risk. If we saw it last year, that means we are NOT at as great of a risk. Immunization - To make a vaccine, we need to have the proper Ns and Hs types of the virus to make the vaccine properly. When we do this, if it is something that we have seen repeatedly and we have worked with it for awhile there is a possibility of actually creating a genetic deletion so we can use a live, attenuated vaccine these tend to give us a better immune response because they cause a MINOR infection in the patient. We have to be careful with immunocompromised patients because they may come down with a more serious infection. We could also use a completely "kill" preparation this was previously killed. We take a growing virus and we kill it. The way we commonly grow the virus for this setting would be in a birds egg we know about co-infection it grows well in hens eggs. Now, when the virus is growing in a hens egg setting we basically just peel off the top, add the virus, and then harvest the virus from that egg a few days later. We can immunize a million eggs they have to be fertile eggs the virus is actually growing on the embryo it is growing on the LIVING embryo we have a cell culture on the inside of the egg. Now, it (the virus for the vaccine) is going to pick up egg protein, so if you are allergic this is going to be a problem. We also can have "kill" preparations that have in one way been purified this is called a "slip" vaccine. We chemically purify the virus so we have more of the virus and less egg protein or other protein (virus protein).
When we immunize people we try to immunize those that are greatest risk first we know these people because we have those predisposing factors. So, these people we do not want them to get the virus because then that will set them up for a secondary bacterial infection and that can kill them. If there is a major change and everyone is at risk, and we want to immunize the whole population as soon as possible especially those at the highest risk. In 1976, we had a problem. We thought that we were going to have another epidemic like the "swine" flu that we had before it is called "swine" because it is associated with flying barnyard animals and pigs. We had a co-infection with pigs. So, we thought that we were having a problem here it was coming from Asia, and we hurried up and made a vaccine. But the early information was a little foggy. We found the serotype, we were going to try to find the vaccine and prevent the disease in as many of people as possible. Somehow the virus actually was not that virulent it had receptor sites but it was not as virulent as it was once before thought. The admixture from the co-infection lost some virulence. So, the serotypes were there, but the virulence was not. Even though, the virus was not that virulent, it was an election year, and they went ahead and immunized millions of people. They messed up though, and people in our population were getting the "flu." So what happened was we learned more about Guillian-Barre Syndrome (about a dozen people got sick from this "flu"). This syndrome is an immune response to virus where you are infected with the virus or you are immunized with the virus this immune response is an immune response that attacks the myelin sheath of the CNS resulting in paralysis. So, we had a virus that if we had left ALL alone we would not have had any problems. But as it turns out, we immunized 100 million people so therefore, the cases of Guillian-Barre were associated with the immunization. There was nothing wrong with the vaccine. We had about 1100 people die of the problem. Some people just saw a weakness in an arm or a leg and it went away in a matter of weeks some people had trouble breathing because of the paralysis and so on now, remember that this virus without the vaccine was NOT virulent enough to cause any real problem to the people of the United States. The government then in the 1980s did not want to come under any scrutiny because of a mistake, so they just let the drug companies "hang" they did not help them out at all with the development of any vaccines. By the time the 1990s came around, it was hard to get even childrens immunizations. We did not have them. We needed to change this. We only let one or two companies make vaccines now so when they have a production problem we really do no have a significant amount of that vaccine out there. The government was trying to cover their ass. The vaccine committee of the world had to change how they were doing things. Things are not as they seem. When we look at vaccines, the problems all go back to Guillian-Barre so when we have a problem, it all goes back to this problem. There was nothing wrong with the vaccine, when they made it, it was fine. The problem was that when we made it, we did not understand it well enough that we actually exposed people who were not at risk, so the riskbenefit analysis was not properly calculated. Anytime you immunize, you are going to have this risk so when you are going to immunize you need to look to see if it is going to be a major problem. When need to know if this is going to be a major problem like an epidemic so that people are protected and if it is not going to be a problem, then we really should not do anything remember Guillian-Barre. We need to communicate to the public when it is going to be a treat or not because people will not know whether they are at risk or not.
Microbiology 6-17-05 We really need to know if the vaccine is going to be a problem or if the disease itself is going to be a problem. We are trying to stop at many problems as possible. So lets say that instead of 100 million people that are at risk of being infected, we only have 6 people that are at risk of being infected. If we only have a few people who are exposed to the virus because the virus is a fizzle, but we immunize 100 million people with immunizations, we still have 100 million people exposed they we have people who will come down with Guillian-Barre and we have a whole new problem.
Because of that in 1976, this made a cascade reaction mostly a political reaction the problem now, is that we have trouble keeping up with the demand and we have many companies that do not practice in the US that cannot make the vaccine anymore we have to get all of our vaccines not just our influenza vaccines but all of our vaccines from the regulated companies in the US (even the child vaccines), so that we have essentially a world-wide problem with the production of vaccines. With this particular agent, the serotypes are worldwide but we can imagine that if the serotypes are different in developing countries vs. nondeveloping countries so the undeveloped countries in the other part of the world does not have the capacity to make the vaccine they have their own serotype and basically, the developing world says that that is their own problem. We only make the vaccines for ourselves. We do not tend to share. Another possible problem that is associated with the exposure to influenza (this is an actual infection and we expose it to other viral agents such as chicken pox or mumps relates to the immune response the person has to the organism. This is called Reyes Syndrome now, we understand some of the mechanisms associated with the pathogenesis, but we do not understand the etiological start why do children get this? These patients develop an antibody and probably a T-cell lymphocyte response that destroys the capacity for functioning mitochondria and this is a problem of course because mitochondria are inside of the cell most immune responses particularly antibody responses are on the surface of the cell we are not sure how this comes about but what we do know is that there is diminished capacity in these patients and the immune response is related to it? How? That mechanism is not known. There is a lot of functions of ATP it triggers the body to do a variety of things some of them good and some of them not so good. One of the aspects is that the body will assume that there is not enough glucose that is why are not making enough ATP so the liver will go into gluconeogenesis. Now, the degree of gluconeogenesis is such that the patient develops fatty liver syndrome you can actually see big fat globules develop in between the cells of the liver we see this in other settings where the liver is exposed to its own toxin this fatty liver response, is not a good thing. So, now we have liver problems in the patient. The muscles will try to make up the difference by going into lactic acid fermentation we can only do a little bit of that because as we produce ATP through lactic acid fermentation the muscle tissue will be exposed to lactic acid fermentation and that of course will change the pH of the bloodstream as lactic acid gets dumped into the bloodstream the lowering of the pH of the bloodstream will then in turn (pH of the blood is directly related to the respiration rate Henderson-Hassalbalch the pH of the blood influences the respiration rate). This problem will increase the respiration rate. So, now we have the muscle not contributed right to the problem, and we also have the liver not contributing effectively to the problem. The next stage of problems is that the loss of ATP production extends to the lining of the brain usually when it goes to the lining of the brain it is easily treatable because antibiotics can cross the BBB so bacterial agents are not a problem but viral agents are - so what happens in this case is the loss of the functional ATP production that effects the lining of the brain and that results in the loss of the ability to maintain proper fluid balance so the brain begins to swell which is definitely not a good thing if this continues there is going to be massive brain damage because of the pressure on the brain so we initially put some holes in the skull to release some of the pressure sometimes we have to take out the skull cap to release the pressure we do end up putting this back on we have to watch out for infection. So a lot of these things are not good. It all began with the patients experience with influenza virus so the chicken pox virus or the measles or mumps and we realize that we have no idea how this mechanism works. We started to look at cofactors these cofactors seemed to be that we were giving an ASA or an ASA containing compound at the same time that we have the acute illness (fever) this problem starts to develop about two weeks after the disease so we begin to have an immune response two weeks after the initial problem developed, so when we look back at the patients history, we look back to the acute phase when they had a fever and they took an ASA containing compound and that compound seems to be a cofactor.
Other cofactors seem to include exposure to insecticides, herbicides (so people who are very into gardening and spraying everything under the sun), and also an individual who is working in a farming setting. Farmers are providing fertilized products. They are exposed to these chemical in high concentrations. They are exposed to the chemical when they are applying it to their crops, and they are also exposed when they are mixing it up before they apply it to their crops. People are not always aware of what they are doing. They are not always aware of what they are putting on their hands and then what they are putting in their mouths. They are inadvertently contaminating themselves. So this Reyes Syndrome is a significant problem, and it can result in the death of the patient. All we can do at this point is provide supportive care for the patient, such as relieving the pressure on the brain to do this supportive care actually involves a team of physicians a special crash team who is specialized in this particular disease. Each state has several centers for this. So, we have a few centers where we take the patient and they are treated by a series of physicians working in teams to treat the patient. We have a whole bunch of people working on the patient. We have developed a very aggressive campaign against this disease. We have really tried to get the word out about the avoidance of ASA or ASA containing products in children with a fever. Reyes Syndrome is why we developed this campaign, but we do not know exactly what caused Reyes Syndrome in the first place although some people think that they have done a great job with just recognizing that ASA is causing this the rest of the people are just not sure. It might be an irregular serotype of these viruses and since we stopped children from taking ASA it might be harder to figure out why when kids take ASA they could potentially get Reyes Syndrome we do not know the answer to this. So, the cases of Reyes Syndrome have gone down considerably. When something goes away that we do not know why it goes away or why it appeared in the first place, then we cannot predict the future very well, so we keep this on the back burner, and we are not really sure what is going on this is something that we need to be aware of Reyes Syndrome Cytomegalovirus (CMV) Where influenza virus affects us all, whether we are healthy or immunocompromised, the CMV causing pneumonia is going to be something that we see in immunocompromised patients. They will get a viremia, lung infection, and eventually encephalitis. We do not have good treatments for this we have some so fortunately there are only a few patients that will come down with this disease only a small group. It can also cause a viremia, and it can affect the eyes we can see a retinitis it can effect the eyes. So, CMV is something that we are going to potentially see in an AIDS patient immunocompromised patients get many lethal infections because of their compromised immune status. The patient can get CMV encephalitis, CMV retinitis, and CMV pneumonia. These particular agents by themselves can kill them. This virus is not as common as one. Transplant patients may also see this they are immune compromised as it is. Fungal Agents Coccidiodes immitis There are three different kinds of fungal agents that can cause three different problems in the lungs. The first one is Coccidiodes immitis. This fungal agent is also known a San Joaquin Valley Fever Agent "desert fever" in the places like California. They pump in lots of water from other places because there is NO water there Now, the interesting thing about San Joaquin Valley Fever is that people will inhale the spores a lung infection will ensue and most people tolerate this very easily they do not have much of a problem. They will have a strong Tcell lymphocyte response, and T-cells are part of what we call our cellular immunity or our cell mediated immune response our CMI so if we have T-cells directly in contact with the fungal
agent there will be the release of cytokines that will then directly kill the fungal agent this is a very efficient system. We will bring macrophages to the area, and the problem will be resolved. Now, a small number of patients, however, whose immune system is governed by a different set of immunogenetics the immune system is under a different genetic control a small set of patients will develop antibodies which is part of what we call humeral immunity (aqueous humor of the eye) so we have a humeral immunity where we are producing a lot of antibodies whereas when we produce T-cells - this is our cellular immunity so they are only producing antibodies and very little T-cell - CMI response. As a result, they may get very ill and they may die of pneumonia. Of course, the patient will respond by producing antibodies so we give the patient Amphotericin B (has very ill-effects on the kidney if taken for long periods of time). So, we hope that in the next few weeks, the patients immune system gets to where it can convert to a CMI response if the patient is able to do this the patient will recover if the patient does not do this the patient will die. So all we are doing with the Amphotericin B is buying time for the patient it is not effectively killing off the organism in great enough numbers for the patient to survive alone we have to have a conversion of the patients immune system now we are understanding more and more how this balancing act occurs between humeral immune response and cellular immune response. Now, we are not at the stage of clinical trials yet, this sets a conceptual foundation for this idea particularly cytokines those cells signals more specifically interleukins (which are a variety of cytokines coming from T-cells and T-cell macrophages) and these interleukins might be able to provide as amino-pharmaceuticals to allow the person to convert from this non-protective antibody response to this protective CMI response. We are on the verge of this concept we are not quite there yet. We will probably see this in the next five years or go if we know precisely what the problem is we know that they are not producing the right kind of immune response and we know that Amphotericin B does not do exactly what we are looking for BUT it does buy us time. If we monitor the patients immune response we know that the ones that are going to make it convert and those that do not convert to do make it. Cryptococcus neoformans This fungal agent has a very luxurious capsule it will cause pneumonia and meningitis particularly in children immunocompromised particularly in those children under five (after 3 months to those who are up to five). The other group who will be affected by this is the immunocompromised AIDS patients, leukemia patients and so on. You really to have some kind of immunocompromised index to get a better handle to see if a patient will fall in this category if they do fall in this category of someone who is immunocompromised we want to be concerned more with other diseases as well. If a patient actually comes down with Cryptococcus neoformans then this would give us some indication that our immune system is not working as well as it should be this should be a warning sign. Aspergillus Species This organism is an environment contaminant found in moist areas such as basements or flooded out areas a lot of reason as to why we just destroy homes after a flood or so on is not because the structure is unsound but because this organism will be found in the moist areas. By breathing in Aspergillus individuals can have an allergic in the lungs so we can breathe in the organism, and the organism will start to grow in the lungs just like the black mold growing in the corner of the room or something and this mold that is growing in the lungs will result in ??????itis, an allergic reaction in the lungs We have a broad category of these sorts of things; we sometimes call them farmers lung because farmers will be exposed to a variety of different fungal agents and so on associated with different kinds of grain and the storage of grain Aspergillus might be in this broad category. Aspergillosis is a reaction to aspergillum in the lungs this is more of an immune response more of an allergic reaction than it is an actual infection response to the organism the result is the same you will still have a problem with the lungs.
Bacterial Agents Streptococcal pneumoniae Haemophilus influenzae These two bacterial agents have the same general biology. They have a bacterial capsule made out of sugars the capsule is anti-phagocytic. You will find a capsule in Cryptococcus neoformans this capsule is also anti-phagocytic. Fungal capsules and bacterial capsules are both made out of sugar anti-phagocytic, hydrophilic layer. Then we have to have an opsonizing antibody that will then bind to that sugar-specific immune response creating a hydrophobic surface now that will be readily phagocytized. These organisms can cause URT problems. We will also see eye infections (pink eye); we will also see sinus infections of a chronic nature. We also saw these two organisms causing earaches. We see these organisms down in the throat, but that alone was not enough to get them in the lung we had to have a predisposing factor then we end up seeing these organisms in the lungs if a patient has these predisposing factors. We also talk about how streptococcal pneumonia or haemophilus influenzae can be secondary bacterial agent this is that "super-infection" kind of idea. The viral infection is fairly minor by itself (influenza virus) but getting one of these secondary infections can be major. The treatment for each of these secondary infections is going to be different they do not respond to the same cell wall synthesis inhibitors one is gram-positive and the other is gram-negative we have to be able to identify the organism for treatment which is gram positive and which is gram-negative and know the treatment because there are different degrees of resistance. But, the basic mechanism is going to be the same. Klebsiella pneumoniae This organism has less of a capsule, but it still has a capsule and it can be associated with the GI tract oddly enough (it is a gram-negative organism). If we have a Spinabifida patient (developmental problems maybe the mother did not get enough folic acid during pregnancy so we have an open spine). So, we have this opening in the spinal column base (because of the folic acid deficiency) called Spinabifida open spine. What happens then is we can have the contamination of this organism it can get into the spinal column, and it can cause meningitis and pneumonia a bacterial pneumonia obviously. This contamination is not a normal cause this is not something that we will find in a normal person with a normal immune system. In order to be affected with this organism, there has to be a few predisposing factors here because their immune system is otherwise normal in this case we have something unusual about the patient we have a Spinabifida patient. Pseudomonas aeruginosa This organism we will see again when we talk about wound infections this organism is a big problem. It is a gram-negative organism. It commonly has multiple R-factors that means it has lots of antimicrobial resistance. We tend to find this in a hospital setting, and it is very difficult to treat sometimes. Occasionally, there is an isolate where there is no known antimicrobial agent that will work. Fortunately, this isolate is very rare, but unfortunately, it is common that this organism will not be affected by many of the commonly used antibiotics so this organism really has a history of be very highly antimicrobial resistant. So, we will find this organism in a hospital setting. The other aspect about this organism is that it has lots of exoenzymes. It is very good at surviving. We can find this organism in soil very commonly. So, this means that in the hospital setting we will find this organism in very tough terrain that most other organisms find very tough to survive in. These pseudomonas organisms actually cause very big problems with burn victim patients the organism can survive very tough scrubbing so it will not go away very easily. The organism, in particular instance, kept causing deaths with burn patients, and the hospital staff
could not figure out how the organism kept getting into the patient. It turns out that the organism was brought into the hospital and introduced to the patients by the orange juice flaps. We open up the flap to put a straw in for the patient to drink, and the organism was found underneath that flap. It got in there and started the contamination of the patient. This contamination was of a soil source. Oranges come from the soil. We also find these organisms in the flowers that are brought into hospital rooms. We also find these organisms in the salads that are being served in the hospital cafeteria. Of all things, it can also be spread by the housekeeping staff. If they do not properly dilute their mop-cleaning solution, when they are cleaning the rooms, later the organism can actually be found growing on the mop (or in the bucket and they are spreading it everywhere when they clean). It is not necessarily their fault because they are not trained in this area. The organism can survive a very harsh environment because the dilution will still kill other organisms just not pseudomonas. They have also isolated pseudomonas from the distilled water reservoir on the roof of the hospital they may have some contamination of this reservoir and they have a little bit of algae growing in there and all of that is then filtered into the distilled water supply and it will get into the distilled water in the micro lab. Pseudomonas is growing using the little amount of calcium and so on that is found in this water, and the little bit of nutrient source that is found in the algae. Pseudomonas strains are also used to digest oil. They have also been known to clog the pipeline that goes from the shore out to the tanker it cant come to the shore so we have these pipelines that have oil flowing through them, and that oil flow can be occluded because of the pseudomonas growth. This is a pressure kind of situation also they can survive the pressure conditions. So, this organism will grow in really any kind of condition. It can also grow in a positive pressure breathing apparatus in a hospital. It is growing inside of the machine. A patient is getting some kind of inhalation therapy so if the respiratory therapist does not do their job by cleaning out the apparatus properly, that patient is breathing in pseudomonas. It is that kind of thing that will cause infections of pseudomonas. It is when you least expect it, because obviously NOTHING is supposed to or CAN grow there that you will get a pseudomonas infection situation because pseudomonas more than likely CAN grow there. So, with hospital acquired infections we have to be very careful and be good detectors to outsmart the organism. The organism only as a little bit of genetic information we should be able to figure out to stop it. We just have to be careful because if the organism can digest oil, it can digest the patient. This organism has also been known to grow on and contaminate soft contact lenses. It will grow on our soft contact lenses, and it will digest them. They are very nasty critters. This organism will grow in MANY places. We will see a pneumonia from this organism they are associated generally with invasive techniques, such as breathing in the organism in a positive pressure breathing apparatus (from respiratory therapy). This is a very unusual way for this organism to get into the lungs, but once it is there, the problems will be very bad. It is unusual to see this one in the lungs. Staphylococcal aureus This is a very unusual organism to cause pneumonia. S. aureus is usually found on the mucosal surfaces we will find this organism up in our sinuses it is an organism that can also cause wound infections in the hospital Staph infections ("Staff" infections) a patient could get a Staph infection post-operatively from the hospital staff we find the organism in our sinuses, and this is why the hospital staff wears masks. So, we have this organism in our URT in our sinuses and we generally do not see this organism in the lungs. But we will see this organism in the lungs of one particular patient this is the patient that has aspirated their own vomit. So, we have someone who has been unconscious (an alcoholic, etc) so, if we see someone with this organism in the lungs, we are then actually very suspicious that the person might have some of substance abuse problem. Most people, when they are conscious, when they vomit they vomit down. But when you are unconscious when you aspirate you may be on your back when you vomit, you may aspirate the vomit. If you do this, you asking for a ton of problems. The acid could affect your lungs, etc..., but not only these things, you are actually bringing an organism into your lungs this is an unusual thing.
So, when we see one of these unusual organisms causing something in an unusual patient, we have to take some precautions with the patient. So, if the organism that is causing the pneumonia is that of S. aureus we should immediately look for substance abuse in the patient. This is associated with binge drinking sometimes. Sometimes the patients will pass out, will vomit, will aspirate their own vomit, and sometimes they will die that way. Both other times, they will just get a nasty pneumonia. More Bacterial Agents: All of these agents are talking about are put into clusters because they are different. The first two agents on this next list are actually so different that we call them etiological agents of Primary Atypical Pneumonia (PAP). They have a specific designation. There is something dramatically different about the way these first two agents cause pneumonia. Mycoplasma pneumonia This one lacks a cell wall. It has a membrane that it gets from the host cell. It has a stable membrane it also has no shape it is pleomorphic. This organism can obviously cause a pneumonia and it is atypical because of it disease course the disease course can last for months most infections, the disease cause will begin in days after exposure and will climax after about 2 weeks or so. Here we have a situation where it is just beginning in two weeks. - We have a patient that has a dry, non-productive cough which can last for months. The patient can have a mild fever. But the fever is NEVER severe enough to warrant seeing a doctor, so the patient will just wait. Eventually, the patient will go to the doctor and will be prescribed a cell wall synthesis inhibitor (penicillin, ampicillin, cephalosporin, etc) which will do nothing. So, the patient will keep getting worse. The patient will then go back to the doctor the doctor will do a chest X-ray and we will see an interstitial pneumonia. We will see it widespread. We will not see a lobar pneumonia because that is caused by another agent we will see a widespread interstitial pneumonia not a viral pneumonia like other agents that cause pneumonia so the patient will be put on a protein synthesis inhibitor like erythromycin or something like that and then the organism is not going to be such a problem. This organism is a T-cell mitogen it makes T-cells divide earlier we talked about a B-cell mitogen with the EBV (which causes infectious mononucleosis) so the EBV stimulates B-cells which converts the plasma cells which makes the antibodies. This agent causes the T-cells to divide and as a result, we have an alveolar wall thickening from a single cell there may be 2 or 3 or 4 cell layers thick - and that is what will cause the breathing problems the respiration rate will drop which means that there is less oxygenation of the blood so that will result in fatigue. Finally, by the time we get rid of the stimulation of the mitogenic effect - getting the infection cleared up which can take up to six weeks after the organism is killed so the patient will be effectively treated and it will take weeks until the mitogenic effect will be over. Walking pneumonia is not a clinical entity, but it can be called this. AIDS patients are a concern because HIV is inserted into the T-cell lymphocytes when that Tcell is stimulated to divide it activates the virus the virus can activate itself, but at a much slower rate. We will see an accelerated conversion from HIV + status to full blown AIDS. It changes the kinetics of the reaction. If we have an AIDS patient, we want to immediately treat anything that it could be because of this. Generally speaking, people will always recover from this. It is just an unusual kind of problem. And a conceptual idea an organisms virulence can be dependent upon our immune response if an organisms weapon response over-activates our immune system. Legionella pneumonphila
This is another unusual agent this is another member of the primary atypical pneumonia group (PAP). The disease course of this organism could be rapidly culminating. That is to say that in 45 days the patient will be dead. The other organism we just talked about took a couple of weeks for the disease course, and the patient will end up getting better and with this one, we have just 4-5 days. 1976 epidemic in Philadelphia Legionnaires Convention This organism is associated with moist air. It is also associated with stagnant water, so it can easily be put in an air conditioning system associated with the cooling system of a new building. In the case of the Legionnaires epidemic in Philadelphia, we learned that with the convention being held in a new building Legionnaires was introduced into the AC when they messed up installing the system. The circulation was messed up, so they were breathing in a lot of wet, moist air and the Legionnaires organism was associated with that and they were breathing in the organism which was causing a big problem. We isolated the organism from hotels, etc; we also found this organism in fountains particularly indoor fountains so if you breathe in the mist of the fountain this could be a problem. So it is really associated with stagnant water. The other part of the story is that it is found in clusters people that are together are breathing in the same air and they are all getting the same problem because they are together. When we were going though the analysis of this organism, we found that because it has this rapidly culminating disease course, we were very suspicious that it might have an exotoxin related to it, and we found one. So this gram-negative organism has an exotoxin associated with this. Then after 1976, this wasnt as big of problem because we knew what was going. Now, we are seeing that the organism commonly found in the water is this legionella pneumonphila and there is no epidemic. And there is usually an epidemic. So, what we think is that a virus carrying the exotoxin (exoenzyme) comes in a converts it to a pathogenic organism because it obviously is not a pathogenic organism by itself. This is just like diphtheria toxin just like the beta-page of diphtheria. Now, this organism does respond to antimicrobial agents, but we have to catch this quick. This is rapidly culminating disease course. The last organism is not PAP. Mycoplasma pneumoniae
Microbiology 6-20-05 Mycoplasma tuberculosis This is an acid fast organism. We know that this organism is going to be readily phagocytized but not digested. We know that the immune response is going to be a cellular response not an antibody response and this T-cell lymphocyte cell mediated immune response CMI (T-cell immune response) this is not an antibody response not a humoral immunity response. And this T-cell response will wall off the organism and create a granuloma in which will essentially imprison the organism and slowly kill of some of them. But in that granuloma, viable organisms can be found in there for several decades. So, right away we have to understand that the organism frustrates the immune response, and that frustration begins with the basic biology of an acid fast organism. We can get the organism is our body by three different methods. The most common method is by droplet spread, so you inhale the droplet. We can also ingest the organism. Someone with TB may cough on a hot dog, and then you eat the hot dog. You can also get the organism through a wound site. We have the organism still viable in the sputum sample of an infected patient, so something like spitting could spread the organism to a wound. There are public health laws to help protect us. It can stay viable in a
sputum sample and say you cut your hand and inadvertently you touch that hand to someones saliva with the viable organism in it, they you could be infected. It will not penetrate intact skin it will not create a wound. Now, we have the organism in our body. It spreads to the lymphnodes. There are lymphnodes in your armpits, in the GI tract, and if you breathe it in it goes to the lungs. Once it is in that regional lymphnode system, it spreads to the rest of the body being picked up by the phagocytic cells of the immune system "taxicab" they are taking the organism from place to place. Areas of the body that have a high concentration of phagocytic cells are then going to concentrate the organism that is why the organism is found in the lungs and in the lining of the brain. These are the two critical areas where we will find TB. You can also find lesions in other areas of the body the kidneys would be a secondary site so a urine sample from a person who has TB could be something of concern you can find viable TB in the urine and this could cause disease. The T-cells will find the organism and will wall it off in a granuloma. These granulomas will calcify in a matter of weeks so 4-6 weeks after the granuloma forms we tend to see a radio-opaque area in lungs from a chest X-ray. We can also see a granuloma in the kidneys as well. What we look for in our staging of the disease is - is it in the lungs and is it only in the lungs? We can verify this by sputum samples and chest X-rays and we can use spinal taps and urine sample and so on to figure out if it is anywhere else. If the organism is only in the lungs, the treatment is a very short-course treatment six months of treatment. Because the organisms metabolism is very slow, the opportunities to get this with antimicrobial treatment do not happen very often. As a result this slow growing organism is isolated inside of this granuloma and it is hard to get at. So, our body is isolating it from spreading (it is almost like a cellular amputation), and it also isolates the blood-vascular system which will not help in bringing antimicrobial agents to the area. When we look at the susceptible population, all minorities have an increased risk of infection. One of the risk groups are immigrants from high concentration areas of the world with TB. Anyone that is immigrating from a high risk area, then it is possible for these immigrants to be a point of entry. Isoniazid (INH), sulfa-drugs, and rifampin can all be used to treat TB. We generally use a combination of at least two drugs and after two months we switch one to two drugs so we will have several drugs used in combination over a period of six months to minimize the selection for antimicrobial resistance. We do have areas in the world that are poorly treated. If a patient is UNTREATED, then we cannot select for antimicrobial resistance, but if you misuse an antibiotic, then you will be selecting for antimicrobial resistance. We saw a lot of this in the former Soviet Union because they do not use the antibiotics correctly. When people immigrated from the Soviet Union, we saw a high number of people infected with TB in the areas that they immigrated to (New York) and this was also the highly resistant form of TB because of the misuse of antibiotics. Now, prior to the use of antibiotics to treat TB, we simply isolated people who were infected. We actually kept people away from everyone else. When we started to treat, in a very short period of time, probably less than ten days of treatment will reduce the likelihood significantly of spreading the disease to other people remember the whole course of treatment is six months. The person will still be infected with the organism, but the sputum sample will come back negative the people will not be nearly as infectious. You have to go on treatment and stay on treatment and you can go out and be around people. If you refuse treatment, then you can be imprisoned, so you do not spread TB. We have a problem in terms of people maintaining the proper dosage for the proper amount of time on a worldwide basis we have selection occurring in other countries for antimicrobial resistance. We did have two sanitariums for people with TB. They can be forced to stay there until they are negative for the organism. If you are antimicrobial resistant, then you could be in there for a long time until we can find something to treat you. If you are properly treated, we can ultimately during that six month treatment penetrate that granuloma and kill the organism sterilize the granuloma. You can get rid of the viable organism by penetrating the granuloma.
If a person has been exposed to TB, there T-cell lymphocytes are going to be very reactive to the organism. We can also test for TB we take an extract of the organism known as a purified protein derivative of the organism PPD we take that extract of that organism and we can add it by a patch or by injection. The patch test is where you rub off the skin on the forearm and place something like a Band-Aid on the spot with the PPD on the little pad and after 48 hours if there is a red-reaction that means that the person has sensitized T-cells they have been exposed to the organism, and this means that they are skin test positive. A better test is called the Mantoux test with this, we inject a specific amount of PPD at a specific depth into the forearm in fact we can use different concentrations at different locations on the forearm then after 48 hours, we measure the size of the redness and swelling because there is a thickness of the skin in that area (if infected) it is not an actual swelling it is a thickness of the skin this area of induration can be measured. The larger the area of induration as compared to a smaller concentration of PPD the more reactive you are. So, smaller amounts resulting in a larger reaction indicates that you are very reactive. So, we have a subset of quantifying a degree of reactivity so, this Mantoux test can be used to quantify of the reactivity of the patient. This is quantitative yes/no. With a minor exposure, you will have some skin test reactivity so one concern we have are with people who have been immunized. If someone has been immunized, they may not have been exposed to the TB, but they will come up skin test positive. The immunizing agent is called Bacillus Calmette-Gurin BCG this is living organism that was passed through a lot of different organisms and such and is not viable anymore this organism has several chromosomal deletions we can chart the chromosomal deletions over time. Now, basically if you have an area with a high rate of TB endemic high rate of cases all the time not an epidemic it is just that everyone is exposed at a high rate all the time. If you live in places like Africa, where there are high rates of TB then you will be immunized against TB students, doctors, nurse, etc. These people then come to the United States and they are potentially exposed. They are potentially exposed say in a hospital setting. The question is - were they really exposed? If someone has not been immunized with BCG, they have the skin test done and it comes up negative they are okay. If it comes up positive, then they will undergo treatment. If someone has been immunized, and they come up with a red reaction is that red reaction because they were immunized or because they were recently exposed. The physician has to make a choice do they treat everyone (Isoniazid has some serious side-effects it could have a serious effect the liver and people are treated for six months) so we want to avoid that unnecessary exposure so someone who has been BCG immunized can do something like undergo a chest X-ray if they come up positive or they can use the information relative to the different concentrations of BCG given on the forearm of the Mantoux they can say their only reaction was with the highest concentration so that is probably a reaction left over from an immunization they once had when they were younger. If it is not indicative of a recent exposure and the chest X-ray is fine, they can come back then and get this done on a routine basis to make a compromise with the doctor instead of treating. If the chest X-ray keeps coming back fine, it is probably not a recent exposure and they do not need to be treated. We have to find a physician that will work with the patient because of the toxic effects of the drugs. When you become exposed to TB, it is not so much from the active organism from a recent exposure to TB; the risk usually comes about when the patient was exposed earlier 10 to 20 years earlier they have a granuloma, but they were never treated. Now, the patient develops an immunosuppressive problem they develop lung cancer. As the body responds to the tumor, the T-cells are moving away from the granuloma the granuloma works to contain the organism not because it is a physical barrier, but it is barrier to the organism on the fact that it is a constant cytokine release from the T-cells in the wall of the granuloma when they leave and go to find that tumor, then there is no one "guarding" the TB and out the organism comes. It goes into the lung. The person is coughing. It can be spread this way very easily. The patient is also being moved around the hospital a lot, so it can be spread to many people in a short amount of time. So, then we must skin test everyone, and one person has been immunized. What do you do? If you are immunized, does that mean that you are protected? Not necessarily. Sometimes it is not effective, but most of the time, it is effective. We really can be for certain if it is going to
work against the organism, or if it is just going to make a positive skin test. Liver damage is also a concern. If you were exposed once, you might be resistant to some degree but not necessarily full resistance. Our immune system does not work well with this organism. This is very hard to treat. It takes while for that granuloma to form you will not see it on the day that you were exposed. It takes several weeks to develop this granuloma, and it takes six months for treatment at least and the sputum sample must be negative for the organism to say that you are fine. You could also use Sodium Hydroxide (will not effect the organism) but it will thin out the secretion centrifuge it look for the pellet of organism and do the antibody testing. We have to have the sputum sample be negative, six months of treatment, and no extra body sites to be "cured" from this organism. If it has spread to the brain or the kidneys or if you still have a positive sample this treatment could keep going on for years certainly more than six months. You can also see meningitis. This is an interesting process. What is happening to the patient at this point, is we do a spinal tap on the patient for typical bacterial agents H. influenzae, N. meningitis we would find a decline in the glucose levels we would also find a rise in protein levels remember, the organism is a protein and we would also find PMN cells be high because they are part of the inflammation response. These would be for typical bacterial agents. Now, if we have TB, we are going to see no major changes in glucose (maybe a slight change), proteins may be normal or slightly elevated, but we do see the lymphocytes go up because this is a lymphocyte response to the organism. We are also going to see macrophages because wherever T-cells go they are going to attract macrophages. The first two levels are not good indicators of TB. So this is going to be a hint (if lymphocytes are up and macrophage numbers are up) that this particular response is unusual. So, if we can get the information from the micro lab in terms of these levels, we can get a hint of what kind of organism we are dealing with. We could also try to gram-stain the organism from the sputum sample or from the spinal fluid. If it is in the spinal fluid this indicates a meningitis problem not a lung problem. The other thing about the organism is we are extremely susceptible to infection resulting in skin test cross-sensitivity. Our granuloma approach is fairly effective. School Bus Example There are 30+ kids on a bus. The school bus driver has TB, and he is driving them to a field trip. A different bus driver drives them home that particular bus driver did not have any other contact with these students. This is a very defined exposure an hour and a half in an hour and half, all of the children were successfully converted to skin test positive not of the children end up coming down with TB they are just all converted. So, being skin test positive does not mean that you have the disease state, but it does mean that we are going to treat them. Now, when you get the actual disease, that means the organism is getting out of the granuloma and getting out into the lungs when that occurs it can destroy the lung creating sort of a spongy, cottage cheese-look to the lung tissue. This is called caseation. At this point and time, the patients immune system has released a wide variety of cytokines that result in significant weight loss in the patient. One of those cytokines is called tumor necrosis factor. This is found in the T-cells, and it results in significant weight loss in the patient. The old name for this disease was called "consumption." So, as the lung is being destroyed, the patient is losing weight, and in order to get more oxygen into the blood stream, they are breathing deeper and more irregular so they have an increased respiration rate they are trying to breathe in as much air as they can even though their vital capacity is not there anymore. As a result, the muscularity of the chest gets very well developed. We get a barrel-chested kind of look. This person gets a big chest and a withering body. TB affected the Europeans very heavily in the 1880s. They observed that they thought TB had some effect on the brain. They thought that these people had a greater ability to think. It was also seen that fashions changed. The size of what an ideal-woman should look like had changed to a VERY skinny, girlish figure, form a girl who was a size 18 or 20 from before. The disease impacted how we look at women even. It was because this disease affected so many people. So, we have the disease progressing, they may have meningitis, and they will begin to
waste away. We do not see this anymore because we treat the patients those who will die are those that are untreated or they have a very highly resistant form of TB. In Europe, the standard treatment is to remove the lung or the affected parts of the lung or remove the granulomas. The vaccine stimulates a T-cell response because our body in response to the organism creates a T-cells response, which creates granulomas very early in the patient to isolate the organism. Oral Cavity Associated Infections Acute Infection of the Oral Cavity Gum Disease Chronic Infection Dental Caries, but also disease into the gums and into the root itself and from the root to the jaw. If you have an abscessed root that is an infection in the root of a tooth and the infection breaks out into the jaw bone itself these can be long-term and serious. Local Tooth decay However, once we have the chronic infection of the impacted tooth, abscess the tooth, once we have that it can be a source of organisms to the bloodstream Systemic Infection There are two kinds of abscesses there is the "hot abscess" which hurts a lot. Then there is the "cold abscess." It does not hurt all of the time, but it hurts for awhile then it does not hurt so much. That pain is because of a pressure build up and there is some release of pressure somewhere in the area where the tooth is leaking out of the gum or an old filling or something it leaks out so the pressure goes away and then the pain goes away this is a much more efficient way to spread the organism a cold abscess spreads the organism more efficiently because the organisms are spilling out (leaking out) there is a constant source of organisms spilling out we can aspirate the organisms from that cold abscess and we could potentially get pneumonia the systemic problems are much more serious. Key Definitions Dental Plaque is when we have bacteria, food, and secretions trapping the organisms at the surface of the tooth that is plaque. As the organism (part of the food might be sugar candy), is growing, we have a source of glucose, the organism is growing (we have the fermentation of glucose) up against the enamel of the tooth the tooth cracks so as the trapped acid comes up against the enamel of the tooth, it erodes away the tooth. This is a pH dependent situation. If we lower the pH, we can demineralization the tooth. That area of demineralization is dental caries or tooth decay. The organism associated with these kinds of plaques leading to the acid production then leading to the dental caries is Streptococcus mutans. This is one of the organisms associated with tooth decay. Now, fluoride is very effective against these organisms effects. Fluoride will embed itself into the enamel of the tooth and into the bone, and so now it is scattered around the body and it has the ability to be solubolized and demineralized at a much lower pH. The fluoride makes the tooth much more stable at the low pH. It has nothing to do with calcium. The acidification of the organism is now not sufficient enough to create a dental caries. Fluoride treatments are given in the water supply. If you have well water you will have to supplement add fluoride to teeth or take orally or have mother take it while she is pregnant so the developing fetus will have fluoride. There is a concern of being over-fluorinated but you have to take a lot in order for this to happen. You would have to drink a lot or get too much from the dentist so in order to overdose you would probably have to take an oral supplement many times a day. This is not very likely to occur. If you did overdose, your teeth would be discolored.
Periodontal Diseases Gingivitis mild inflammation (redness, swelling, heat, pain), gum swelling, bleeding when brushing teeth your gums are a good indicator of overall mouth health and health of the patient bleeding gums are an early sign of nutritional problems. So if someone has bleeding gums, gingivitis, they might have some other nutritional problems. ANUG Acute necrotizing ulcerative gingivitis you will see some local lesions that have some depth to them. Necrotizing means that there is going to be the death of tissue these are going to be painful. This can also be called trench-mouth from the WWI era. This is a more invasive form of gingivitis. Chronic Destructive Periodontitis This will start to happen when a patient is in their late 30s and early 40s and continuing on later in life where gum disease results in the loosening of teeth and perfectly healthy teeth start to fall out. This is why we get cleanings every six months now. What we need to do is recognize: There is a pocket here and they will probe around the tooth to see the depth what will happen is we will start to see these calcium deposits calculus results in the mineral deposits building up around the sides of the teeth and will push the gum away causing the space to become deeper eventually loosing the teeth. When this occurs, we are actually exposing our teeth this lower portion now to antimicrobial attack and this results in gum disease, etc. and then the tooth will fall out because the organisms are attacking the gum tissue that is lower. So, what we can do is scrap the area and the gum will keep growing back and this protects the lower portion of the teeth. This cleaning of the teeth at the dentist is important to stop this from happening.
Periodontosis a gum disease resulting from malnutrition. We see this in early teenagers 1013 years old. They are losing the permanent teeth they are just getting. This is a dietary deficiency that can result in loss of permanent teeth. This is a more common childhood problem. The organisms associated with gum disease are the Actinomyces species these organisms are bacteria with a very strange morphology. The origin of these organisms is uncertain. They can be found in household pets although no one is for sure who this started with or where it started. Actinomycosis is a chronic bacterial disease. Localized swelling with suppuration, abscess formation, tissue fibrosis, and draining sinuses characterize this disease. Gram-positive, pleomorphic nonspore-forming, nonacid-fast anaerobic or microaerophilic bacilli of the genus Actinomyces and the order Actinomycetales cause actinomycosis. Actinomyces are very closely related to Nocardia species, and, at one point in time, both were considered to be fungal organisms
Microbiology 6-21-05 GI Tract Infections and Intoxications Infection means we have the growth of the organism occurring in the patient Intoxication we have toxicogenic effect of the toxin on the patient we could have multiple scenarios then:
We could have just infection the organism is growing and the growth of the organism is causing an infection of the patient it gets into the bloodstream and we see endotoxin and such. We can also see the other extreme in which the organism is in the food before we even prepare it we make the food that the organism was once in (and has since died), the only thing that is left in the food is toxin. Now, we eat the toxin and that would be a pure intoxication there is no infection at all. So we could have a pure infection where the organism is not producing a significant exotoxin and there may be an endotoxin involved if the organism gets into the bloodstream but that is not a significant part. So we have the growth of the organism being the primary problem, or we have the injection of an already made toxin and no organism that would be pure intoxication. We also have the possibility of both the organism is growing and producing an exotoxin in those settings we have two possibilities the organism is going to be growing and producing an exotoxin, but the exotoxin is not significant in its pathogenicity. So if the growth of the organism is the main problem we would say that would be essentially infectious it is essential in the fact that both are present but infection dominates. On the other hand, we might have the organism growing and producing a VERY potent exotoxin and that would be the main problem. This would be referred to as an essential intoxication. The pure forms are just that infection or intoxication where essentially both are present but one dominates and infection dominated in a pure infection and intoxication dominated in essential intoxication. This will help us with treatment so if we have a pure intoxication or an essential intoxication, then the problem with this is the patient may die unless we deal with this intoxication very quickly on the other hand, if we have a pure infection or an essential infection, we can treat these with antibiotics so with pure intoxications and essential intoxications, we must know how to deal with that toxin to save the life but with a pure infection or an essential infection, we can treat with antibiotics to save the patient. Etiological Agents: Bacterial Here we have four agents that are common agents of GI tract infections and intoxications now the first one Salmonella species there are many species of salmonella (80-100). The disease is called Salmonellosis there are basically three stages (and we can think of this like a pyramid) all 80+ organisms can cause the first stage that is a gastroenteritis it is generally a mild GI tract disturbance nausea, vomiting, loose stool, maybe diarrhea basically the person just does not feel to well. This is kind of like a "hangover." So, gastroenteritis is the growth of the organism in the GI tract so it would be a pure infection at this point Now if the patient is immunocompromised (this would include the extremes of age as well as those patients that are clinically immunocompromised like leukemia or AIDS or maybe they are immune suppressed because of the treatment of a certain disease or those patients that are transplant patients these people are all people that can progress to the next stage which is gram-negative septicemia the organism gets from the GI tract to the bloodstream. So, not many people go into the gram-negative septicemia but many people who are otherwise healthy will have the gastroenteritis this gastroenteritis is fairly common most individuals will get this three to four times per year the source of the organism is extremely common it is
found in the GI tract of chickens in many chickens and the way that we slaughter the chickens infects other chickens so it is basically found in chickens. We will also find these organisms in contaminated water supplies that are fecally contaminated (human or animal) and then we can get that contaminated water and in that contaminated water we put a pet turtle so a four-year-old child plays with that turtle, and he gets contaminated himself (he will get diarrhea or stomach upset and so on). Or you can get this by preparing chicken on the BBQ and many people do not take the precautions to clean them or use clean ways to prepare them. The organism will be on the surface of the meat so we need to properly cook the meat to kill the organism. The third stage that is possible is only associated with one organism Salmonella typhi also known as salmonella typhosa this third stage is known as typhoid fever (this is not the same as typhus typhus is caused by a rickettsial organisms) in this setting we have an essential infection because there are some toxins associated with typhoid fever they can effect the CNS and they can effect cardiac arrhythmias. But it is essentially an infection. Now, typhoid fever has something that we should be aware of and that is the carrier stage that is possible with this salmonella infection now the carrier is an individual who was previously exposed to the organism, came down with the disease and seemingly recovered but has developed sort of homeostasis with the organism. They do not continue to be ill, but they continue to have the organism the organism is often hidden away (hidden away in the case of salmonella in the gall bladder) so every time there is a secretion of bile in the GI tract and into the fecal material there is salmonella there. Now, these salmonella organisms are susceptible to our sanitation system gram-negative organisms such as Salmonella, Escherichia, and Shigella are all gram-negative organisms so they are very susceptible to chlorination so they will be killed by the chlorination and it is because of these organisms that we chlorinate our water we tend to stay healthier in this country not only for how we prepare out food and take precautions but because of our chlorination. If there is a problem with our sanitation then we see outbreaks of any of these organisms even of typhoid fever. Well water and holding tanks are a problem well water could have a septic tank leak into the ground and holding tanks could get a leak in them so it leaks into the ground. So, we have people in our general population otherwise healthy individuals who are carriers for typhoid fever there have been several epidemics will see outbreaks along the lake or in Boy Scout camps. This time of year we have a big thunderstorm tons of rain and there will be signs that will actually say do not touch the water what happens was when the sanitation systems were first built they were built to handle the rain water and waste water as cities grew we paved more roads and those areas that we paved could not absorb that water into soil so there was run off so the more we pave, the move run-off into the sanitation system. As a result, every time it came down all of that water had to come through the sanitation system and it simply could not handle it so it will back up our option was to put the run-off into the river. So, it will go into the lake so we have this constant flow of organisms. So, take this example there are about 5,000 people who live in this certain town their sanitation system can only work for those 5,000 people. Every year, they have this car show that brings 100,000 people into the town for three days what happens? The sanitation system is overwhelmed and all of that raw sewage runs off into the lake this is big problem. All of these organisms are very common to see in the lake. Any time there is a flood this is also the situation we are walking in sewage we are exposed to hepatitis etc. We really are only one minor disaster or big rain away from this situation in Big Rapids from being exposed to these things they ARE all out there. Just remember to keep your hands off the streets and out of the water when told so. We know these organisms caused disease. So, those sanitation systems in the major cities in the world are 100+ years old. There are wooden pipes still in some of these systems. We can expect to see more problems with these organisms over time because the structures are getting older and we are getting more populated.
So we have these organisms but they are not really a problem now, unless we directly exposed to them because chlorination helps good nutrition helps and our overall healthy lifestyle helps when you lose any of these you are just waiting for a disease. There are some organisms are not killed by chlorine and therefore are not killed by sanitation systems and they are a fungal organism that are not killed by chlorination called Kryptos spirillum associated with cows and horses and their fecal material when that gets into the water supply that is not killed by chlorination and this organism can cause human disease several people died from this when it was an epidemic elderly people, young people, HIV patients, immunocompromised patients they were at greatest risk to this EVERYONE was exposed. The spirillum is an example of a fungal organism that is not like salmonella, e. coli, or shigella it is not killed by chlorine it is not stopped by the sanitation (filtration system). It will live in water this is a relatively new phenomenon to be able to sell water because we are concerned with the quality of water so we sell water now. The more concerned we get the more we are going to sell water for. So, Salmonella three stages gastroenteritis gram-negative septicemia and only one organism can cause all three stages - gastroenteritis, gram-negative septicemia, and then it produces an exotoxin which will cause an essential infection (the exotoxin does not cause the problem) and that is typhoid fever. One odd thing is if you treat the organism in the gram-negative septicemia stage then treatment of the organism in a carrier you have to treat the carrier with a different set of antimicrobial agents we also remove the gall bladder of these patients so the question is whether or not this is a public health issue or a personal issue and who will pay the bill? Typhoid fever will always follow a gram-negative septicemia it always goes in this progression. Escherichia coli EHEC ETEC Enteropathic ------ E. coli First, we want to realize that this organism is a normal flora organism E. coli is a normal flora organism so we are talking about an organism that is causing a GI tract problem, we are talking about an organism that is not the normal flora organism that is causing this problem. It is the normal flora organism + "something" now that "something" is going to produce toxin. These toxins are plasmid related and for the most part they are NSRP related which means that they are spread by transduction for the most part. The first one that we are going to talk about is ETEC Enteropathic Toxigenic E. coli Enteropathic means that it is a variety of organisms that cause problems with the gut as opposed to normal flora organisms and toxigenic means that we have the production of a toxin. In fact, we have the production of several toxins and they all have the same general effect that is they cause diarrhea. This organism has many other different names (ETEC) there are the names that we use in the United States it is called "summertime diarrhea," "infantile diarrhea," "swimming-pool diarrhea (infected child is brought to the pool and has an accident the organism is very susceptible to chlorine)," and we also call this "travelers diarrhea." In the traveler setting, it typically effects all ages young children as well as adults so we see it in the US, we are going to see it in children and we see it outside "travelers diarrhea" so we go to Mexico it is not the citizens that live there that see themselves coming down with the problem they have the same age range remember, even children can get it. There is something odd going on. In the United States, we see children getting it and in Mexico, we also
see children getting it. And in Mexico, we see adults getting it, but not Mexican adults its travelers. So there is something about traveling that is causing this to occur. What is happening is this the organism stimulates a GI tract antibody known as secretory IGA immunoglobulin A. It is secreted on the surface of mucosal surfaces such as the lining of the gut it is like a wall that paints itself now this is protective a protective lining. The problem with this is the genetics of the immune response are unusual. Typically we are talking about a blood stream antibody and our first exposure to the organism produces a little bit of antibodies this is an IGM antibody you get this with the first exposure. And with subsequent exposures you will produce more antibody and faster this is an IGG response the first is known as your primary immune response the second is known as your secondary immune response the bloodstream is invaded by antibodies.
With respect to secretory IGA there is no memory response same lag time no increased amount no change in class (IGM-IGG) it remains IGA so there is no enhanced response or no quicker response - repeated exposures are repeated an no memory no effective memory response there is no genetic change. IGA is like a "perpetual virgin" each time is like the first time. What that means then is there is going to be a delay in the production of antibodies and the amount of antibodies produced is not that great. So, again, you are traveling down to Mexico, and while down there, you come down with travelers diarrhea you are down there with friends who live in Mexico and do not get sick at all. You eat all of the same things. Well, a week before you came they were also eating the same stuff that you ate before you came that is they were exposed to the organism daily so what their profile would look like then is something like this what you have then is constant low level exposure which results in constant low level protection. Last weeks exposure provides this weeks protection and this weeks exposure will protect them next week and so on. So, if you want to get back at them just fly them out to Big Rapids and give them chlorinated water for a week and then fly them back down to Mexico, and they will come down with diarrhea. So we need a constant low level exposure so adults do not come down with it because they have a constant low level exposure. If you come from a chlorinated area you are exposed for the first time, and you get the diarrhea now this is travelers diarrhea again, younger children are susceptible to diarrhea and the effects of dehydration. The elderly are also susceptible to both.
Dehydration does not mean that you are thirsty we are talking about kidney failure, death, etc. We used to think that when someone was dehydrated what they needed was water but then we realized that the person needed electrolytes to maintain kidney function properly. So when you are dehydrated because of a diarrheal disease we will give you fluid - water with electrolytes but even that does not work particularly well it is not transported very easily then we started working on children who were dying of this dehydration and the only way that we could save them was to stick an IV in their heads. This is a rather difficult thing to do, but we have a dehydrated person we have to do it though. This is very unsterile. We have to do this because there is no fluid in the body, and all of the veins have collapsed So from this we have developed oral rehydration combination of salt and glucose it turns out that we need glucose
to facilitate the uptake of the liquid and the salt this is the active ingredient. It is very INEXPENSIVE to make. Some who would die in the next hour or two because of dehydration will be turned around with oral rehydration. They will completely come back to life from a lifeless person "electrolytes" "pedialyte" In the US, we are well nourished and well hydrated so it is not as big of a concern then to get pedialyte into us it is not a life or death situation normally some children and some very old adults get very dehydrated and in those cases pedialyte would be appropriate but the average person will be okay. EHEC Enteropathic Hemorrhagic E. coli hemorrhagic is referring the fact that we have the destruction of the kidneys so what begins as a GI tract infection gets into the bloodstream, goes to the kidneys and results in kidney failure this occurs in the US in children under the age of 18 (from about 8 to 15 years typically) so what is happening here is the organism is producing a different toxin, and it is much more serious as far as hospitalization and so on. The organism of E. coli that is associated with the production of this hemorrhagic form is associated with a particular serotype H7O157 there is nothing about the flagella (H) or the O-Ag side chain (O) or the genetic information that produced that it is not directly related to the problem we think that it is associated with an inherited cofactor that is a linked area of genetic information so it is linked to it, but it is not positive. The other information is linked to it genetically. The link tends to be accentuated by enabling the organism to have a certain set (we not yet classify them) they are the common pili so we see common pili being pretty much the same as well as the H7O157 the common pili are attached to the intestinal tract of cows. In the US, many of the cows have the same father artificial insemination and as a result, the genetic diversity of the feed stock is not very broad so we have the same varieties of cow and they all seem to share the high-frequency receptor sites for that one particular kind of pili that is linked with H7O157 so we have it sort of stuck in our system. So besides needing to have a little more diversity in our feed stock (beef cows), we also need to improve more on our sanitation. The organisms get into the food that we eat the beef that we eat and remember it is coming from the intestinal tract of the cows (remember that chickens got contaminated during slaughtering) the same happens with cows steaks are fine only on the center ground beef more of a risk of infection here more surface more organism in the middle of the hamburger. We must cook hamburger all the way through. We can also make things better system of slaughtering animals and try not to contaminate the center of the meat we need to have some standards. So, there IS a certain level of contamination that is allowable tolerable we are not eating sterile meat. The key would be zero. With ETEC, it usually does not get into the bloodstream whereas EHEC WILL get into the bloodstream now obviously if we have an immunocompromised patient we can get ETEC into the bloodstream, but this is usually not the case. Usually, ETEC is in the gut and EHEC is usually in the bloodstream. So, each of these types has a different age range that it effects and different scenarios overall. Shigella species This species has 30 or more types and one of the more common ones is called Shigella dysentery this is obviously involved with dysentery. There are two general kinds of dysentery one is called bacillary dysentery associated with a bacillus shaped bacteria bacillary shigella. The other one is called amoeboid dysentery caused by amoebas not a bacterial organism so there are two forms of dysentery and what we will be talking about is the bacillary dysentery which is caused by rod-shaped bacteria Salmonella, E. coli, and Shigella are all rod-shaped bacteria they are also gram-negative organisms what one looks like they all look like? In the case of shigella, the organism generally invades the GI tract and erodes away the lining the intestinal tract and it can get into the bloodstream and cause gram-negative septicemia and it
may in fact be the worse form of E. coli diarrhea more severe form of E. coli! Another bacterial organism that is noteworthy at this point - causing more severe diarrhea is entero-cholera cholera organism are an essential intoxication and a pretty interesting one. The organism produces a toxin called cholera toxin or choleragen affects the intestinal lining of the small bowel once it gets inside of the cell, it activates adenylyl cyclase which increases the intercellular levels of cAMP. So we have the toxin activated adenylyl cyclase converting ATP to cAMP so the levels of cAMP rise in the cell and in that particular cell, when you raise the concentration of cAMP, it reverses the function of that cell the function of the cell normally is to uptake fluid and electrolytes so now with the higher levels of cAMP, the cell actively pumps out fluid and electrolytes. In this case, the fluid loss is amazing. A patient can lose 10 to 20 L of fluid a day that is 2040lbs a day. So in 2-3 days of this they have lost so much that they are so weak, and they cannot get out of bed they can not get out of bed to go to the bathroom so we have a cot with a bucket for these people called a cholera cot and by the second day, or maybe even after the first day you have lost so much fluid that your fecal material will be grainy, starchy (that kind of material that kind of color) that is exactly what it is like there is also no odor it is just fluid and electrolytes. Oral rehydration works slowly so the main approach would be IV antimicrobial treatment takes too long it may 4-6 days to kill off the organism. So we need to get IVs into the patient plus oral rehydration if we catch this early enough we can save the patient the big thing is to get fluids into the patient. These four agents are all gram negative organisms and from recent genetic analysis we see that they are not that much different.
Microbiology 6-22-05 The four agents that we talked about yesterdays lecture are all gram negative. And through genetic analysis, we see that Salmonella, E. coli, Shigella, and Cholera organisms are probably all subspecies of something since, they are all gram-negative rods they are all susceptible to chlorine. Staphylococcal aureus This organism is a gram-positive organism (staphylococcal). With this staphylococcal aureus situation, we have additional virulence factors provided by bacterial viruses bacteriophage these are usually on NSRP so the amount of exotoxin produced is dependent upon the number of plasmids a particular strain has. So, if a particular S. aureus organism has a low amount of exotoxin because it does not have any SRP or there could be a range of production depending upon the number of SRP the organisms have. We talk here about vomiting and diarrhea. It has an abrupt onset. Its severity and quickness of onset depends upon how much toxin you have ingested so in addition to having a variable relative to how much toxin is produced by a specific organism you also have the variable of how much was in the food that the person ate. So, if the person liked the dish, they will have a more rapid onset of symptoms. So that means that it could occur in a matter of an hour or two or it could take 8-12 hours but once it starts its an abrupt onset and by abrupt onset it means that one minute you are fine, and the next instant you are projectile vomiting. The abdominal cramping is so severe that it is just you see in the movies (the person projectile vomiting). It is shooting out 1 or 2 feet from the person. The person just isnt feeling a little sick; with salmonella they feel a little sick; with this they ARE sick. The patient will also have diarrhea. The abdominal might be so severe they you actually will not "spill" a drop. But you will be vomiting. The amount of fluid loss is so great, that eventually w/i a half hour or so, you cannot lose anymore fluid. Then you will be experiencing dry heaves. People are throwing up and gagging, but nothing is coming out. There is no fluid left. The abdominal cramping can continue even when you are done with all the vomiting and diarrhea this can result in an acute dehydration the loss of fluids and electrolytes.
S. aureus can also cause wound infections. You can contaminate food by a cut in your hand with S. aureus. The very young and the very old are most affected by dehydration. There was a cut on one individual who inoculated the food source, incubated it, and it released its toxins. The toxins allowed it to have immediate effect. This is an essential intoxication it can be a pure intoxication, but physically the organism is present in very small amounts (it does not take much) so it is an essential intoxication. We can phage-type S. aureus that is we can take S. aureus from a pure culture, and then expose a lawn-streaked plate to an antimicrobial disk but you add a particular bacteriophage and if it is a living bacteriophage, it will create a clear area called a plaque where you added that drop that is because there is a surface structure that matches that particular bacteriophage that surface structure is of course genetically decided by the organism. As a result of this, a person might have a phage-type of 16, 19, and 27, and someone else might have 15, 34, and 56. They have different phage types, which are analogous to serotyping. We do not serotype this organism, we phage type this organism. So, if we have an outbreak, and we want to know whether it is a common source outbreak lets say that three different fast food restaurants had the same outbreak, the same problem at the same time. The question is, is the problem that the fast food place had poor hygiene and did not wash their hands and it just so happens that it happens to three places OR is it because the essential supply was infected with all of the same phage-types it was just a random thing that the same phage-type went to three different stores. The same thing happens with patients in the hospital with wound infections. For epidemiological purposes, we phage-type the Staphylococcal organisms. See page 21 and 22 for graphs and notes. More Bacterial Agents Clostridium botulinum This organism produces an endotoxin (it is an gram-positive rod organism. It is a CNS toxin. So the symptoms of botulism have nothing to do with vomiting and diarrhea as our other organisms do We are going to see CNS problems so a patient who has botulism is going to have a difficulty swallowing, maybe even drooling, they may have difficulty focusing their eyes (double vision), they may have a headache, they may be light sensitive photosensitivity is really a good indicator that something is going on up there. They will eventually develop cardiac difficulties or cardiac arrest respiratory arrest and die. There are two basic forms of the problem: Adult form The adult form is a pure intoxication you eat only the toxin. The botulism toxin was produced in the food by the organism the organism died and the toxin remained. Then you eat the toxin and you get the intoxication the pure intoxication. Infant form With the infantile form we have an essential intoxication the child eats the organism in the food the organism grows in the GI tract of the child and the toxin produced by the organism causes the problem. With the infantile form, the organism is GROWING in the GI tract. **With the adult form, the organism is not growing in the GI tract** To understand this more completely, we have to realize that the organism is very sensitive to a low pH. The organism will not grow at a low pH. The toxin, however, is stable at a low pH. We also have to realize that the GI tract of a new born up to the age of six months is at a more neutral pH. The GI tract of the new born is still developing. The baby needs to drink milk (all different kinds) and most of that is quickly absorbed into the bloodstream. There is NOT much in the way of digestion. There are no enzymes helping with digestion. It goes from the gut to the bloodstream.
This is why of course when you change the diaper of a newborn there is not much in there but when they reach about six months of age they get a real human dump Something has happened in that first six months part of it is there was the maturation of the gut that means that when the organism gets into the low pH the organism gets killed. The organism cannot survive the pH but when it is the stomach of a young child it grows. We have to understand the developmental physiology of the GI tract of the child to see why sometimes it is a pure intoxication and in other cases it is an essential intoxication when we eat the organism we kill it no problem. Adult Form Case Study We have a 73-year-old Italian woman who lives in Chicago. She is known for her sweet, red sauce she makes it from the Italian tomatoes. SWEET means no acidity it is a very neutral acidity. So she made her spaghetti sauce with very little acid in it everyone liked it that way. She stored it in the basement. She skipped church and she was cooking her sauce, she tasted it, and while everyone was away at church. She passed away. She was found dead on the floor of the kitchen. They called the hospital, and she had died of cardiac arrest. She died of a heart attack. So, they have the funeral then they have the party afterward and everyone eats Grandmas special sauce. Now, we have several people watching each other having double vision and having trouble swallowing. They know that something is going on there, so they all go to the ER to be treated --- with an ANTITOXIN. And at the same time, they did some research into the sweet sauce to see if it was Grandmas sweet sauce that caused the problem. It was the problem, so it really was not cardiac arrest that killed Grandma it was botulism. Things to think about Sweet sauce things can grow in here especially organisms especially botulism. A lot of times when people make these "sweet" spaghetti sauces they will add a little bit of lemon or citric acid to the recipe they just add a little bit so the organism can not grow in the recipe. So having an acid deficiency will let the organism grow. But just by adding a little bit of acid into the recipe, if the organism does happen to get in the food the organism will not be able to survive the low pH. We want to food to have a low pH, otherwise if a spore does get in there and the pH is higher than it should be, the spore will germinate; it will grow, produce a toxin and then die. So the high pH of the food is the problem. We see a lot of botulism problems with home canning and cooking. This is where we see the most instances. Commercial establishments have a lot system where every lot is identified on the basis of when it went through the autoclaving procedure. We keep the records of the temperature, the time, etc. and this is a particular lot. If there is a problem with anything in that lot we can go back to the records to find out whether or not it was due to improper procedure, etc. If it was then we can "call" that lot. We do this for the public health concern. Also, businesses must follow the procedure because they will go out of business if they are not careful because their customers got botulism from their restaurant. They are VERY careful about all of these things on the other hand, people who do their own canning tend not to follow the rules so in this case Grandma did not add the lemon juice to her recipe, which left conditions that were NOT acidic and that led to the organism being able to grow, produce its toxin and die. The second part of this is the initial index case Grandmother was the first one to die because no one was particularly looked for this to happen. We will see a "cluster" with intoxication just like we see a cluster with infect. The index patient is likely to have the worst intoxication - the index patient is going to have the worst symptoms and in this case Grandma dies. The more people who have the intoxication after the index patient has the intoxication the more likely that the rest of the people will be okay. Early treatment is through the use of serotype specific antitoxin now we have antitoxin for some of the toxins, but not for all serotypes of the
toxin if someone has a rare toxin, we probably will not have that antitoxin. Most of the toxins are covered we should have more but we do not. There are just too many. The most common ones are covered. When you start to have the symptoms, lets say that you have difficulty swallowing, etc. we can administer the antitoxin IV what happens is it will neutralize any free toxin in your body or we could pump your stomach that stuff is already bound and it is already causing symptoms and it is not going to be reversed by administering the antitoxin. The antitoxin does not have any effect on bound toxin. This is not an instantaneous process if give someone the antitoxin, it will take hours to neutralize so you will probably get sicker for a few hours after administration before you stabilize. At that point, we can put you on respirators or other ways to maintain normal body functions and the toxin has a biological decay that releases it from the nervous system at a certain rate so you will get worse after we give you the antitoxin we are then going to stabilize you and allow you to have a normal recovery which could take weeks (worse case scenario). This is because of that biological decay we have no way of accelerating that process. Infantile Botulism Case Study In California, a few years ago, we had a sudden surge of infant deaths due to Sudden Infant Death Syndrome (SIDS). SIDS is largely unexplained there are several different theories probably a multiple-cause problem obviously because it is the sudden death of an infant. This is usually a very young infant and we do NOT know why. There are many possible causes but we have no idea what is causing this. However, in CA, the health department did figure out that it was honey based. All of the children had recently had honey added to their cereal. Well, the bad thing is that the honey was NOT pasteurized and this allowed the organism to grow (allowed spores to grow in the children) and in some cases the vegetative state of the organism would then grow in the belly of the child, as it grew (the pH of the belly was neutral), it produced a toxin and the toxin caused CNS problems resulting in cardiac arrest, respiratory arrest, and death. This is not to say that all SIDS is the result of the botulism so this particular outbreak was helpful in the fact that now we know not to give our kids raw honey. We basically just do not want to give honey to those children who GI tracts have not yet changed if we have a matured gut then we will not have that problem. With the ingestion of that organism growing in the intestinal tract will cause that problem the organism will then produce a toxin so we have essential intoxication not pure intoxication. Pasteurization is able to handle the organism not the spores. In an adult, the spores will be killed in their GI tract the adult GI tract will be able to handle the organism because of the GI tracts low pH. It is all a matter of pH. The stomach will kill the organism off before it can reach the lower intestines which have a higher pH. PPIs might also increase the risk of Clostridium botulinum because those will raise the pH of the stomach. Camphylobacter fetus This organism is a gram-negative organism which causes a recurrent, relapsing bloody diarrhea. Once we have determined what you have, you will continue to have it without significant immulogical protection, and the infection can last for years actually decades. Certain parts of the world, certain parts of the US (rural areas in particular) individuals who get these bloody diarrhea episodes once or twice and month, and they once thought that it was associated with just growing old "old people get this." The organism causes an ulcer in the intestinal tract these abscessed or ulcerated areas cause a source of organism when the ulcer or abscess ruptured the ulcer in the lining of the GI tract and that then leads to the organism we then have diarrhea, and because of that ruptured abscess we have blood in the diarrhea. This occurs over a period of about a week to ten days there is a secretory antibody response which clears up that particular infection only to have an
abscess released which leads to another infection, another secretory response week after week, month after month, and year after year. One of the fundamental flaws of our immune response here is the lack of a good memory response (just like with travelers diarrhea) so have that constant first time each time situation. We do not have a protection against this agent. It is not an everyday experience but you will have the response get rid of this episode then we will forget out to do this again then we will get infected again. This organism can cause a lot of problems because of how it acts its disease course. This organism can cross the placenta the child can be born with this organism it can be born with camphylobacter fetus or another subspecies camphylobacter jejuni invading the common area of the intestinal tract this organism likes to cause gastric problems it attacks the lining of both the small and large intestines. The fetus part means that we can have a child infected with this disease we say transplacental infection the child is infected in-utero it is born then with the infection. (Infants can be exposed to an organism at the time of the vaginal delivery, or they can be infected in-utero) This is an example of an in-utero transplacental infection not at the time of delivery.
Besides C. jejuni, other species of Campylobacter bacteria may also cause illness. One species is Campylobacter fetus (C. fetus), which looks like C. jejuni but usually attacks newborn babies or people with weakened immune systems. C. fetus also causes a more severe illness, which typically requires prolonged treatment with antibiotics.
Camphylobacter is not too difficult to treat. It really was once thought that this infection was just a sign of aging. This was a normal thing. They just thought that getting old meant that you could not control your bowels. So, generally we are going to use nothing that is too unusual. We are going to use tetracycline or any other variety of antibiotics because this is NOT difficult to treat at all because there is little antimicrobial There resistance. seems to be a reservoir in barnyard, farm animals chickens being a key one but not the only one. They actually did rectal smears on chickens, and those chickens that were otherwise healthy had camphylobacter. So, the bottom line is this is fairly common, and exposure to people who live on farms with chickens was a very common way to spread this disease. The organism was also found throughout the bloodstream of the animal, and therefore it is often associated with different body parts of the animal particularly animals parts that you would eat raw you may not think that you ever eat chicken raw but there has been instances with liver pt. So, if you go to a fancy restaurant, you could get camphylobacter. Helicobacter pylori This organism has an interesting history, and we are learning about it all the time. This organism is the etiological agent for most gastrointestinal tract ulcers. We did not know this for a long while and this caused us to have a paradigm shift for what actually caused ulcers. We assumed that ulcers are caused by pH secretions in the GI tract so therefore we put people on bland diets, told them not to drink alcohol, etc. These are not bad things to do anyway, but these are not the right treatments for people who had ulcers. We suggested things like Tagamet so we sold a lot of Tagamet. Tagamet treated the symptoms. It was once thought that ulcers are caused by stress. To finally figure out what ulcers are caused by, a scientist deliberately gave himself helicobacter pylori which gave him an ulcer, and he then had to be treated for the infection. The treatment is not too complicated; we can give the patient something like Pepto Bismol and give that in combination with some antimicrobial agents sulfa drugs, etc. This would generally take care of the problem in a couple of weeks. Whereas when we were Tagamet, we were taking a lot more
and we basically had to take it for the rest of our lives. As soon as this approach to ulcers came out, we got rid of about 90% of people who had ulcers. There are still a small percentage of people who do not respond to this kind of treatment. But this is a small percentage. Tagamet lost a lot of money. This organism has some gaps as far as our understanding of it as an etiological agent. How does this actually cause disease? If order for it to cause the lesion (the ulcer) there has to be a fissure or an opening in the GI tract. It is uncertain as to whether the organism itself can cause that fissure. There may be some cofactors, but we just do not know. Once it gets into that fissure though, it does a good job at causing the ulcer but also we are learning now that it can stimulate a mitogenic activity that is associated with GI tract cancer so we have a microbial source that we can link at this point to a cancer. There are clinical trials of a vaccine in fact. But certainly we CAN PREVENT cancer by appropriate treatment with antibiotics. This is not a firm link yet, but the link is growing the link to helicobacter pylori and to GI cancer. The problem is this mitogen stimulating cells to divide which will then trigger the possibility of a tumor forming. Page 23 of notes There are different agents that could cause botulism. The thing to notice here is that there is wide variety of foods and these different foods are associated with different serotypes of botulism toxin. The fish products are those rare products associated with a toxin that we have an antitoxin. Etiological Agents Viral Rotavirus This virus is very similar in complications to something that see in the veterinary world called parvovirus. Parvovirus in puppies is a lethal, bloody diarrhea. The good thing about this is that there are only a few serotypes of this virus, so the puppies can be saved. We can develop a vaccine. When we looked into rotavirus, we realized that there were also only a few serotypes of that so we were able to make a vaccine. We now have a vaccine for rotavirus. HOWEVER, the vaccine has a problem. We had to take if off the market a few years ago because of a handful of cases probably less than five cases out of hundreds of thousands of those who were vaccinated. We had five cases of a telescoping ,,in of the intestinal tract. The intestinal tract would literally move into itself. This telescoping in - the intestinal tract telescoping in to itself caused it to be blocked. Now, in these cases that this occurred in we did an analysis to see what was going on and this resulted in an interesting solution simply touching the area would bring it back out again. So, we just had to look at it to solve the problem. In the US, rotavirus causes diarrhea and dehydration we can counteract that very easily because we are a society that is well hydrated, well nourished, and we do have some oral rehydration solutions (fluids such as Pedialyte). So, we have alternative ways of dealing with this infection. Because our population is very healthy, this is not a life-threatening situation unlike with puppies and parvovirus. Rotavirus normally does not kill people So, in a risk-benefit analysis even though there were only a handful of cases that had adverse outcomes the vaccine was not worth the risk-benefit, so it was pulled off of the market, and the vaccine is now reformulated. The most likely answer to this other problem is that it is NOT even associated with a rotavirus immunization this is the most logical outcome for what was studied. We have changed the format of the vaccine we have three different formats now. They are in clinical trials now and we can expect them in about three months.
Microbiology 6-23-05 Rotavirus
Rotavirus vaccine We were talking about a potential problem with the rotavirus vaccine as an international agent. This issue with rotavirus came up at an international meeting we found that what we do as a country interacts with the rest of the world at any level. In the case of rotavirus, in the area around the equator is called the diarrheal belt. There are many diarrheal diseases (E. coli and so on), but rotavirus is number one. And in this area of the world tens of thousands of children die every year so the numbers are very great. They decided NOT to immunize with the rotavirus vaccine even though in their country because of generalized malnutrition and poor hydration mortality rate is significant with rotavirus particularly because the patient could have MANY diarrheal diseases. We most likely will not get a pure culture then so they will have several things all at the same time - each one increasing the likelihood of dehydration and death. So, if we can knock off one or two of these agents or more the better we are. These countries are not using the rotavirus vaccine because we are not using it. They other countries do not want to be our guinea pigs. They do not want to expose their children to because we are not exposing our children it. This makes some sense politically, but it doesnt make medical or scientific sense. The risk-benefit analysis is very much so in favor of using rotavirus vaccine. Many parts of the world will not use it because it was taken off of the market in the US. Hopefully, we can try to convince them of the good it will actually do. Most of the problem is the government and politics of other countries. It would be very hard to try to convince these countries that it is okay. So, many children are dying because the vaccine is not being used. Now, again we have redone the vaccine and we have three different companies working on it, and it looks like the situation of the telescoping in of the intestinal tract was NOT caused by the vaccine it DID occur at the same time, but the vaccine did not cause this problem. So really we do not see this as being a problem. We are also going to change the age-group that we give this to children to be a little later we are going to let the intestinal tract to develop a little more. This is, however, a risk worth taking if death is an outcome. In the US, death is not an outcome because we have good nutrition and good rehydration. So, again the idea of the use of a vaccine or of the use of a drug, we have to consider the side-effects and then look at the big picture to see if it is worth it. What might be good for one person might not be good for another. We also have to deal with "non-science" all the time. Thimerosal is associated with autism. Thimerosal is a mercuric-based compound that is used as a bactericidal agent stabilizing agent for certain vaccines. We have taken it out of and do not use it in vaccines anymore so we do not have it in vaccines anymore. People had thought that because they immunized their children at a certain date (when Thimerosal was still in the vaccines), and then a period of time after that, the children began to experience all of these problems. So, we have now a lot of non-science types are making a big deal about that agent in vaccines when there is no evidence actually linking the two at all. In fact, the evidence that we do have with autism is that the brain change that we do have with autism, can be observed even in-utero certainly LONG before ANY immunizations. So science and politics come together with an ODD result with rotavirus children are being exposed to something that WILL kill them when there is a vaccine that will help them. Epidemic Acute Gastroenteritis Virus We see this virus sporadically as the name suggests, and we have many cases at one time (epidemic); the name also suggests that is occurs rapidly. Other names of the same virus are: the Norwalk Agent and this virus is the virus that we have heard about lately with tour boats and such everyone on the tour boat gets diarrhea it is quite likely that the source of this is probably a crew member. This virus can cause epidemic-like diarrhea, vomiting, rapid onset, and it is spread primarily through fecal oral contact (poor hygiene). It will affect ALL age ranges because there are multiple serotypes. Now, remember that rotavirus only had a few serotypes so we could develop a vaccine but it also meant that it actually affected for children because once you have seen it, you tend to have a good, long immune protection to it. With this virus, we see multiple age ranges with MANY serotypes.
The course of this virus is usually 24-48 hours. The treatment for this is basically supportive treatment there really is nothing that we can do. We treat the diarrhea with electrolytes and fluids. The people with the greatest risk are the young and the old and those who are immunocompromised and even those who are under hydrated or malnourished. Hepatitis A Hepatitis is basically an inflammation of the liver. There can be many causes to that inflammation. Certainly, there are many non-microbial causes chemicals, anesthetic gases that we use in the hospital (this can induce hepatitis). Then we have viral hepatitis. There are many viruses that can cause hepatitis EBV this can cause a mild hepatitis. Hepatitis A and E viruses these are spread through a contaminated water supply. Typically Hepatitis A is more common in the US in other parts of the world (Middle East and Eastern Europe) we tend to see more of this Hepatitis E. Both A and E are a contaminated water and food problem. Hepatitis B, C, and D viruses there are a blood and sexual transmission route. So, we are just going to mention Hepatitis A-E, but there are many other kinds of Hepatitis out there. There are a variety of others, but these are just the most common. Comparing Hepatitis A and E besides the fact that they are spread through contaminated water and food they are generally milder forms of Hepatitis as compared to B, C, and D meaning that kinds of Hepatitis are only going to last about 4-6 weeks whereas Hepatitis B, C, and D can easily last 4-6 months, and there are situations where you can have a 7-12 type of infection. Hepatitis A and E generally result in a full recovery not always but that is the expected outcome. Hepatitis B, C, and D can lead to other problems including liver failure and death or liver cancer and death. We just want to recognize here which are spread by food and water and which are spread by other routes. Dont eat raw oysters during certain times. The risk of getting Hepatitis A is an increasing problem and it really is best NOT to eat raw oysters. Polio Virus This virus is also associated with contaminated water and so on. We do not think of this as a good poisoning but the entrance to humans is through a contaminated water supply there are only a few serotypes of it it is a relatively simple RNA virus (we know its replication cycle already). We have even developed a vaccine for it. We have had problems with the vaccine to it. The two primary vaccines for polio are the "kill-preparation" known as the Salk vaccine, and the Sabin which is a live, attenuated type. So we have had two types of problems with these vaccines. The first problem that we had was with the Salk vaccine in which to grow the virus we had to use the kidneys of a monkey for the cell culture. Now, as we talked about before when we have something like this that we are dealing with viruses and we use other living things we have the possibility of contamination. The first group of people to receive the early vaccine received an extra added agent they were given something called Simian Virus #40 it turns out that this virus causes cancer in monkeys we found that this virus is also susceptible to?????, but we did immunize hundreds of thousands of people with a virus ("a killed-virus") that caused cancer in monkeys we found this out 15 years later. We dodged the silver bullet. Then, when it came to the Sabin vaccine, currently this vaccine has been pulled off of the market; the problem that we see with this vaccine is called vaccine related polio and this was occurring because we are giving a live, attenuated virus with a genetic deletion in it but the problem is in the childs diaper because they will shed the virus for anywhere from 4-6 days to probably two weeks It is very common to see a fully virulent virus in the diaper of a child who
was vaccinated with this vaccine. Now, if the people around the baby were immunized, they will just get a "booster shot" but if the person who is changing the diaper has never been immunized or is immunocompromised they could come down with fully virulent polio. This is not a good thing. What we thought was increasingly rare was not so rare. Therefore, because we found fully virulent virus in the diapers of children who were immunized with the Sabin vaccine (live attenuated strain), we have pulled it off the market for now. We may see it back once it has been modified, but for now it is gone. So, we do see some problems with the polio vaccine.
Microbiology 6-27-05 Wound Infections Etiological Agents: - Aerobes (require oxygen) or Facultative Anaerobes (can live with or without oxygen sometimes organisms will under aerobic respiration or fermentation) - Anaerobes (obligate or strict anaerobes no oxygen) With wound infections, we need to know their metabolism in order treat the disease that the organism causes. Aerobes or Facultative Anaerobes: Staphylococcus aureus This agent has already been described to us as an agent of food poisoning. This organism has an interesting relationship relative to bacteriophages we indicated that we could do phagetyping, so if we wanted to know more about the etiological agents of food poisoning we would not do serotyping, but we would do phage-typing. The same is true here with wound infections. If we want to know more about the epidemiology, and about the actual source of the infection, we would do a phage-typing. As we should recall, we take a pure culture of the organism, streak it on a plate (make a bacterial lawn just like what you would do if you were doing an antimicrobial susceptibility test, but instead of adding disks with antibiotics on them we add drops of raw bacterial viruses. These drops then if the organism has a matching receptor site will result in a lytic infection and there will be a clear area or a plaque where we added that particular bacteriophage. We can add dozens of these to the surface of the plate and we will know which ones are where, we can then say that the phage-type is 7, 14, 19, 22, etc. Those are the areas that are relative to the areas of the plaques. This is the area of the lytic infection. If a bacterial cell wall does not have the receptor site for #19 then it does not cause a lytic infection. So, we can do this for epidemiological purposes again, for food poisoning or a wound infection. Now, S. aureus, in addition to having a receptor site matching relationship to viruses it has a very strong relationship to viruses relative to transduction. And this transduction brings to it a variety of elements most often associated with NSRP this gives it a wide repertoire of potential exoenzymes. It is also found that transduction results in inserting into the main chromosomes as a result, this organism has a wide range of potential, optional, kind of setting relative to exoenzymes. Depending upon what collection of exoenzymes it has, it can cause different kinds of problems. We will start with the more common enzymes, and then we will move to the more unusual ones: Coagulase This causes plasma to clot. The organism uses this to wall itself off from our immune system as seen through our blood vessels. So, the blood vascular system carrying antibodies and phagocytic cells and lymphocytes and so on, will be barred from entrance where the organism is, and the organism will wall itself off by causing our plasma to clot the organism is using part of our system to protect itself against our immune system. So, the organism causes our plasma to clot coagulate. This walled off area that the organism creates is called an abscess. Abscesses can be small the size of hair follicles or a little pimple or something or
we could have a large abscess that is several centimeters across. We could also have internal abscesses which are very large sometimes abscesses can produce sometimes a liter or more of pus so in a surgical setting we might open up a lesion to drain it and we literally get a bucketful of pus out of that. Pus cells are just dead phagocytic cells. So, once we have the area walled off, we have in essence captured some of the immune system cells in this walled off area exoenzymes are directed towards those which are trapped inside, so that they are killed off and get pus or dead phagocytic cells. Such things as leukociden a general name for a compound that would be killing WBC if it is given a very unique phospholipid to target then that enzyme is called a sphingomyelinase these two agents destroy specifically WBC resulting in pus. So, the organism is growing quite well. It is growing in the log phage it uses up its available nutrients it enters into the stationary phase and that stage is generally where it is at during the abscess. Now, when we drain the abscess (simply squeezing the pimple on your nose) either surgically or physically, what we are doing is taking the remaining organisms are sending them back into the log phase so it went from lag, log, stationary, and back to log and of course as we know that makes it more susceptible to penicillin. So, when we drain the abscess and treat it with a cell wall synthesis inhibitor we are treating it in really two ways. So, if we simply added the cell wall synthesis inhibitor to the abscess without draining it, it would really have no effect. It would not affect the organism in the stationary growth phase. Now, the abscess is going to get bigger (pimple on nose when from a hair follicle to a big pimple) now, what happens here is the organism also has an enzyme that breaks down clots. We call that enzyme staphylokinase this has an interesting history because we were trying to find a product that would digest clots in patients staphylokinase was one group and streptokinase (from the strep. pyogenes organism) was another group. Streptokinase is not a major pathogenic agent from strep. pyogenes, but it is produced by the organism nonetheless. So, both staphylokinase and streptokinase have the same effect in that they breakdown clots. S. aureus uses it so that it can enlarge the abscess it breaks down the wall and adds an addition. As it turns out one of the groups developed the streptokinase first and they were giving it as shots if someone was have an MI or a clot in the heart we would inject it in the blood vessel, a recombinant DNA product, which is really a streptokinase and not a staphylokinase, but it is the same kind of thing. Now, we have the enlarging abscess it breaks down the "clot" to be able to enlarge the abscess. The organism can find its way into a major blood vessel at this point, and if it is enlarging it can leak out a major number of organisms which can leak out into the body we can say that it has metastasized and it can spread out all around the body which can cause other lesions around the body. These new lesions can be anywhere in the body. They can be in the lungs, brain, and other major organs. One of the structures that they can get into that will cause a lot of problems is the bones it which case they are causing a disease called osteomyelitis. So, now we have the bone which is basically a hollowed out structure and the blood vascular system runs through it and obviously, there are a lot of "caves" as the osteoclasts break the bone down and hollow out the bone and the bone is lighter. So, we can have the organism causing an abscess inside of the bone causing this osteomyelitis which is VERY difficult to treat. We have the natural fortification of the bones, and it is walled off and it is also not well vasculated as compared to soft tissue so as a result of this, it is hiding in a cave of some kind. So, the only thing that we are successful with this is in the long run is a very long term treatment 5-10 years or more and our concern here is the development of antimicrobial resistance where S. aureus would have lots of R-factors associated with it. Alternatively, we can open up the bone, scrap it out, and replace that area with a large amount of antimicrobial agents right in the bone structure, and then we seal it all up again. Now, one of the problems that we see in a hospital acquired infection (nosocomial infection) with this organism is a post-surgical abscess. This is a S. aureus infection caused by the hospital staff. The "Staph" infection has a double meaning and a double spelling. So, a person is in the operating room and someone sneezes or drops and instrument on the floor (using a non-sterile technique), or if someone is having staples, screws, rods, etc, - and if those things are contaminated, we are adding in organisms that will grow in the wound. So, say it is a hip replacement the organism is going to be growing in that hip joint which is then going to
weaken the bone structure and the reason that they had the hip replacement was because they had a weaken bone structure to begin with so we end up with a very delicate situation where the structural nature of the bone (integrity of the bone) is being compromised by infection. This is a serious problem. So anytime we are adding this ,,hardware, there is always this potential risk so obviously we need to be cautious, especially when they are splattering blood everywhere. A major concern for surgeons is this "post-surgical problem". We can also get a post-surgical problem in the intestinal tract. One early approach was to load the patient up with a lot of antibiotics before the surgery to prevent this from occurring and when they did that it actually made it worse. What happens is S. aureus has natural competitors as part of its normal flora. If we use a lot of antimicrobials pre-op we will lower the number of normal organisms in the intestinal tract, and if we lower it too much if there is a contamination in the intestinal tract - we will not notice it until maybe three or four days post-op. The first 2-3 days of it, the patient will complain of abdominal pain, and the response to that is that the patient just had surgery of course they are going to hurt. The real problem with the patient, however, is not pain after surgery but that their intestinal tract is being attacked internally from S. aureus. So, after about day 4 or 5, when they should be getting better, and they are not, the doctor goes back in and sees that because we took away so much of the normal flora that when S. aureus got in there, we actually made a bigger problem (from losing all of the normal flora) and a large section of the intestinal tract has been eroded away by the organism. So, this is another post-surgical problem. Where does the organism come from? The organism can be found on our hands (normal flora on our hands). It is also normal flora in our sinuses and in our URT and that is why nurses and doctors wear masks and gloves. Now, we had an interesting problem a few years ago with Munson Medical Center. They actually tracked down an individual nurse by going through the work schedule, and they found that she was the one that was always associated with postoperative problems associated with S. aureus. They could not figure out exactly what was going on because everywhere they swabbed her the organisms of S. aureus that they found did not match the phage-type. They just knew that she was the problem. They ended up finding the problem in her vagina. So, basically, everyone is the hospital has to wear pants no skirts, and they HAVE to wear underwear. So, basically pants, gloves, masks all of these are the result of different organisms which occupy the mucosal membranes, the skin, etc. We are a source of organisms to the patient. So, post-surgical Staph infections major problems are coming from the staff of the hospital not from outside clearly this is nosocomial and therefore, the organism is selected for antimicrobial resistances so we have lots of antimicrobial resistance associated with the nosocomial variety whereas with a community acquired infection, it is not so much of a problem. That makes a lot of sense because we are not selecting for resistance with a community acquired infection. S. aureus may also cause other problems. Those problems will be caused by additional exoenzymes that it may have. One is called TSS Toxic Shock Syndrome. With TSS, the organism was first associated with the use of long-lasting tampons those that are designed to absorb lots of moisture and so on and in this case, the organism was initially growing on the tampon. After extensive testing, we found out that the organism is not using the tampon as a media source in any way. The actual connection is that the normal flora organism will not produce the toxin if there are divalent cations available. It uses these divalent cations in the media in this case the vaginal flora to produce a repressor protein that blocks the operon that encodes for the production of the toxin. So, if you have divalent cations you have an active repressor you repress that section of DNA and therefore the organism does not produce the toxin this is a normal flora organism. In the presence of the highly absorbent tampons, the divalent cations will be lowered below that threshold so without the availability of a sufficient amount of divalent cations the repressor protein was not made and the toxin was made. Typically, now we know what is going on TSS is not completely unheard of it is just not as common as it once was because we know what is happening.
Here is another problem caused by additional exoenzymes that S. aureus may have. The problem is called SSSS Staphylococcal Scalded Skin Syndrome. This affects neonates (newborn) generally under one month of age. The infection generally starts at the umbilical site. The can get this in the hospital, or they can get it from their parents or something like that but if the umbilical cord starts to turn red, be sure to get the child to the doctors office or the Emergency Room as soon as possible. This can be very serious. It begins with the redness of the umbilical cord and spreads across the belly, down to the groin, and then down to the leg, and then finally to the rest of the body. It looks as if someone poured hot coffee on the child it looks like child abuse scalded skin syndrome. What it is is an exfoliating toxin which means that the skin layers separate and boil up. There are large blisters that occur the outer layers of skin slough off, and the remaining surface of the epidermal surface is very, very red. So, when the parents bring the child to the ER it looks like child abuse because the initial stages of the infection look like child abuse. The big concern here is because we are dealing with such a young child, and the child could have a major area of skin loss which will result in a major dehydration, and the fatality rate for something like this could be as high as 70%. So this is very serious because of the dehydration it is essentially like a bad burn there is such a loss of skin dehydration. So, we need to deal with this early on when it is at the umbilical cord not when it is rapidly spreading around the body. These are all of the different stages of S. aureus. It takes on all manners of different kinds of rapidly, culminating disease courses depending on the exoenzymes that it has. We can expect to see new clinical entities associated with S. aureus. Streptococcal pyogenes We have talked about S. pyogenes associated with a sore throat. We have also talked about it associated with childhood problems of impetigo in which the kid will scratch the infection and add S. aureus to it so that we have both organisms present. Most often impetigo is a mixed infection with a lead organism of S. pyogenes. S. pyogenes will also cause - with the addition of an exoenzyme a disease that would scare the general public called necrotizing (referring to the dead skin) fasciculitis (refers to the fascia layer below the skin almost like tissue-paper looking skin). The general public just decided to call this the "flesh-eating virus (its not a virus) or bacteria (which is closer)." What is happening here is the organism essentially under minds the dermal layer. So, it is growing laterally away from the relatively seemingly small initial wound site. So, you could have a wound site the size of a dime, but the organism is really spreading beneath that in all directions, and it could easily be an area of 6 or 8 inches in diameter and only look like something the size of a dime. As it then continues to spread through the fascia which is basically a collagen so the enzyme there is collagenase an enzyme that breaks down collagen and so, it is basically spreading through the fascia or collagen material. It will eventually it will then destroy the blood vascular system that supports the tissue above it. When that occurs this dime size area can enlarge at the rate of an inch per hour. So, in six hours, it could be six inches across. This is a very serious problem. It requires a somewhat courageous surgical team to recognize exactly what the problem is and to realize that the problem is MUCH worse than it looks. To get a good outcome with this, there is the need for significant and highly invasive surgery because you cant just deal with the dime-sized area; you have to deal with the six-inch sized area. And of course by the time the visible wound is six inches the damage is really twenty inches so we are going to carve up an arm or a leg very severely maybe even thinking of amputation. Now, there has been a nosocomial effect of this. Fortunately, this is relatively rare but this is very, very serious. This organism can even chew up internal organs. In the hospital, a small lesion could introduce this organism to the inside of your body, and you will die because of
its negative effects. So, this is a very NASTY bug. All in all, this organisms effects are very rare. The nosocomial infects are VERY rare, and really, the regular infections of this disease are also pretty rare. It just that when the media becomes aware of something that it seems like this turns into a very big deal it is really not that big of a problem. They just make an appearance of an increased incidence. There is no real increase.
Escherichia coli E. coli can also cause wound infections. We know from before that E. coli can use UTIs (flagella and pili). Klebsiella pneumoniae can also cause UTIs. Pseudomonas can also cause UTIs. Generally these gram negative organisms can cause UTIs. But in terms of a wound infection, we have to realize that E. coli is a normal flora (when we do have it as non-normal flora the Enteropathic strains that we talked about EHEC and ETEC); but generally, the normal flora organism of the intestinal tract is being shed all the time. E. coli is everywhere because we shed the organism constantly. So what happens then is if a patient has a lesion somewhere on the lower portion of their body so say the patient has an ulcer on their foot (we will talk about diabetic wounds later) it is quite common/natural to find that wound to be a mixed infection with an organism such as E. coli being involved with that infection. So, It can get out and it will get out and it can be part of a mixed infection of a wound on the lower portion of a patients body. Klebsiella pneumoniae The same thing is going on here we will find this organism also in wounds in the lower portions of the body here again, it is shed from the intestinal tract. This organism complicates things a little bit though that means that we have a mixed infection so we have a lead organism and another organism that follows we have to take that into consideration with how we are going to treat it and which drug that we are going to use. We want to kill all of the bugs not just one, so that means that we need a broad spectrum agent or we may need multiple agents, or so on. Pseudomonas aeruginosa This bacterium also has a very healthy relationship with bacterial viruses. These viruses have exoenzymes associated with them. These viruses are associated with both the main chromosome as well as NSRP they exchanged their information by transduction most likely. They contain a lot of exoenzymes. The organism is naturally found in the soil, so if you dig in the dirt, you will find pseudomonas most likely. In that environment then, we have a lot of exoenzymes in the bacteria that allow them to break down the environment. Remember that the purpose of exoenzymes is to break down the environment (secreted by the organism) these organisms are going to break down the environment and match the transport system that is going to bring stuff in the nutrients the organism needs. Now, since it lives in the soil, it is designed to have a lot of exoenzymes. It can break down oil this organism was also found growing in the kerosene that WWII fighter pilots used for fuel and the organism clogged the fuel injection ports and the engines actually shut down midair. There was nothing wrong with the engine other than the fact that pseudomonas got into the fuel supply and clogged the fuel injection ports. So, in terms of wound infections, it is growing in a patient. The particular wound infection here is a burn wound. The organism has a slightly blue-green pigment to it this pigment is produced by the organism. We are sure about this exactly but we think this is genetic linking. Pigment production is associated with the ability to cause disease it is NOT the color - but it probably a link to a genetic enzyme. The organism has the ability to digest things so it can
digest the patient in the wound setting. This digesting can cause serious eye infections the organism can digest a soft contact lens. It can digest the contact lens in such a way that the patient may not think the contact is working just quite right. In fact, the digestion if it is not figured out the doctor will just change the prescription. This situation can also inoculate your eye. So, if someone has soft contact lenses and they are cleaning them in the palm of their hand, and they do not have the best sterility and they stick the contact into their eye the organism may have contaminated that contact and now that organism will contaminate the patients eye. Blindness could occur in this situation. We can have the organism even come from our hair and contaminate our eyes. This infection will be a chronic infection until it is properly treated. There was an instance where a woman has a chronic sinus infection she drooled at night. The organism got on her hair and was then transferred to her eye. We can get rid of the eye infection which would be a GOOD thing as to not cause blindness, but it is a different story of trying to get rid of the chronic sinus infection. So, this organism can cause SERIOUS eye infections. So, in burn wound settings, we can see that blue-green haze as a film on the wound when this happens this is not a good sign. The organism gets into the bloodstream of the burn patient, and once this happens it is 90% fatal. So, if it is growing in an open wound, it does not take much for it to get into the bloodstream so it is a major problem. Most of the time, these infections are hospital acquired. We will have burn victims in the hospital fighting for their lives and three to four weeks in to recovery, they then develop a pseudomonas infection and they die. We have tried many things, and we have stumbled upon the answer. We tried the vaccine we developed a vaccine called "Pseudogen." This worked great. It provided a strong immune response that was protective in non-infected people. But when we tried it in burn patients they responded very poorly to the vaccine their immune response was very muted. So, we wanted to figure out what was going on so we studied the biochemical reactions occurring in the patient and basically a burn wound (which could be a chemical burn or a thermal burn) is a shock to the metabolism of the patient such that they go into a nitrogen imbalance. They are cannibalizing themselves. The patients are breaking their own tissue down. So, in the process of breaking their own tissue down, they are not producing new proteins as in the form of antibodies. So, we found that we can overcome that by force-feeding them (just as we would do with a patient who was in a coma) we give them a high-protein flurry we are going to force-feed them so that they can overcome the nitrogen imbalance - their own immune system then without needing the "Pseudogen" - is quite effective at fighting off the infection. So, this vaccine was put back onto the shelf. We really do not it if we have strong, healthy, balanced nitrogen production of proteins. So, we do have to understand what those burn patients are going through besides all of the pain and debridement of the wound and all of that but that the patients are in metabolic shock and once we know that and are able to overcome that then the patient will be able to survive. Pseudomonas organisms because of their ability to survive extreme conditions we have isolated the organism in the salads in the cafeteria of the hospital; we have also isolated it on the flap of the orange juice container; we have also seen it on the flowers that people have brought in for the patients; we have also found it on toys that children have in the hospital. It is because of pseudomonas that we shut down the patient sometimes (so that they have very minimal access not just family and friends, but also limiting the hospital staff) so in burn units we sometimes do not allow multiple patients in the same burn unit we do not want to treat them in the same area because we might spread organisms from patient to patient. We also do not allow flowers or balloons. We also monitor their food and no not allow them to have salads or vegetables, etc. All of these things could cause the patient to die. Anaerobes These are the organisms that are killed by oxygen. This is a pretty wide group. The first five organisms on the list on page 25 of the notes are all associated with gangrene also known
as gas gangrene the lead organism here is Clostridium perfringens. So, all of these organisms are gram-positive organisms. Clostridium perfringens produces a spore so spores can be part of the pathogenicity of these particular problems. But this is the lead organism. And if this one is present other organisms will grow. The key in understanding this is that you must have anaerobic conditions in the tissues. Without the anaerobic conditions, these organisms are killed. If you injected any of these organisms into healthy tissue they would be killed because of the oxygen content in the tissue. They could be killed in a few minutes. So, even though these are serious infections, we have to take into consideration the underlying cause is the anaerobic conditions. Then we will have a better understanding of how to treat the patient. These anaerobes respond fairly well to antimicrobial agents. These are not difficult to treat generally. There are some resistances that we do tend to see sometimes, but treatment is generally not a problem. The problem actually is the underlying conditions. We can see that sometimes it is the normal flora that ends up overgrowing because of some underlying condition. See page 26 of notes for normal flora organisms that are found in the GI tract. These anaerobic infections are most often mixed infections. See page 26 (second picture) bacteremias, brain abscesses, bite wounds (people bites and animals bites), PID, sinusitis, and dental abscesses are all caused by anaerobic organisms Microbiology 6-28-05 Clostridium perfringens We are talking about anaerobic infections. Clostridium perfringens is the lead organism. We must remember that this is going to be a mixed infection. It is going to involve the various other anaerobic organisms that we find on page 25 of our notes. We must also realize that the anaerobic condition maybe deep in the wound, and that there may be aerobic conditions on the surface of the wound (so there maybe be aerobic and facultative anaerobic organisms on the surface of the wound) we when we talking about a mixed infection, we can infect have aerobic and anaerobic conditions in the same wound site (so we can have aerobes, anaerobes, and facultative anaerobes all in the one site). We must have anaerobic conditions at some point in the wound cycle so that we can have anaerobic organisms present. This anaerobic condition is essential for an anaerobic infection. We could take Clostridium perfringens and inject it into our skin the oxygen tension in our tissue would be sufficient to kill the organism. So, lets think about the kind patient that might have problems with these types of organisms. Diabetic Foot Ulcer The diabetic patient is going to be a critical patient to have a complete understanding of their potential health problems. It is very involved disease. Obviously there is a glucose and insulin problem. Insulin itself is a growth factor and therefore we can see that that by itself can have a profound effect on a patient. We try to counter that by having only having only a specific small amount of insulin being given to the patient. BUT, it is still a growth factor; we are still giving it exogenously; and we normally do not have to control what the body does normally, but now we do so, therefore excess amounts of insulin can be a problem. The diabetic patient also has the glycosylation of the RBCs glucose sticks to in a sense it adheres (a chemical bound) of glucose to various structures (proteins and the like). So we will have RBCs being glycosylated and we will have an index of that glycosylated Hb and we will do an index to see how much glucose is sticking to things we do this as a good indicator of how well a diabetic is taking care of themselves and this is good indicator of their general care. We also have a problem with the repair of the blood vascular system. The blood vessels start to close down and stop functioning the damage is not being repaired. As we will see, as the wall of the blood vessel changes it moves the phagocytic cells out through that wall a process known as Diapedesis which is a process of extra vascularization this is a process of moving a
phagocytic cell between the epithelial wall cells this occurs between the cells at the intracellular junction until the phagocytic cells on the inside of the blood vessel pushes the junction between the alveolar wall into the surrounding tissue. This process of going outside of the blood vessels is impaired if you have glucose stuck everywhere. That means that the phagocytic response (PMN cells and macrophages) are going to be impaired in the case of the diabetic which means that part of their immune system is not going to work well. This loss of blood supply will result in problems to the eye; will result in problems to the kidney; erectile dysfunction in males, etc. There is just a major lack of blood flow. We also have anaerobic conditions in the extremities (hands and feet but not exclusively) so the conditions are proper now for the anaerobes to begin the infectious process because of the lack of blood flow. We have a poor immune response a weakened immune response there is also poor blood flow to the area so there is poor oxygenation of the tissues so what begins as a relatively minor injury (ingrown toenail, a blister, etc.) it is this kind of issue results in a major infection because the organism has gotten IN. Now, the next stage would be pain. Usually this would hurt, but in the loss of blood flow to the extremities we also have peripheral neuropathy that is the peripheral blood system failing which will result in the failure of the peripheral nervous system. So, what should be painful on the foot so what really should be painful on the foot really is NOT painful on the foot at all because you cant feel it. When we walk, we walk normally because we can feel where our feet are. We feel the contact of our foot with the ground we do not necessarily have to look to see it happen. If someone was to lose peripheral nerve endings and there is damage down there that person would not be able to feel it. In fact, the patient will often develop the "diabetic stomp." The person will make an extra hard foot strike, so that they can feel it up the calf because that is the last part of their leg that they still have feeling in so as the peripheral neuropathy continues, you will have to go further and further up the leg for feeling the feeling of the foot strike is then compensated with a heavier step. Diabetics have a heavier step. This heavy step is a clue that the person has peripheral neuropathy (plus tripping, etc). So, they have this damage done, and now they have the beginnings of an ulcer this will be a defection in our skin. The ulcer may be small or large. It is a sore that does not heal. It does not heal in part because the immune system is impaired it does not heal properly because the blood vascular system is impaired so then we have the anaerobic conditions. Now, it gets worse. This ulcer on the foot (on the lower part of the leg), starts to get larger it looks like a big hole in your foot this should hurt very badly, but because of the peripheral nerve damage it does not hurt them much at all. To the patient, this is not as BIG of a deal because the wound does not hurt that much. And indicator to us that something is seriously wrong is when something really hurts. Diabetics are missing that really important signal. Well it should hurt, but it does not because of the same reason that you have the problem in the first place this is the peripheral neuropathy and the loss of blood supply as so on the anaerobic conditions in the skin. If this diabetic foot also problem continues, ultimately we will have to do amputation. We have talked about amputation and debridement with the whole situation of reducing equivalents and so on. So, now we have to cut something. We also cant just cut off the infected area we have to cut and get a stump that will ,,heal. This means that we need a stump that has a good blood supply It does not do any good to cut something off right above the ankle when in fact there is not good blood supply until the calf. Then you will just have a stump that will not heal. So what we need to do is look at our blood vascular system and get a good area with good blood supply. We could even reroute blood vessels to get blood to the tissues. This will help so the stump of today, if done properly might actually be right above the ankle. Then we can get an artificial foot or something like that. This is what we can do today however, the same underlying conditions of diabetes will continue. Then later on - the area of good blood flow will change. It will move to above the knee, and then it is above the knee, etc. (to get an area of good blood supply).
Now, the diabetic problem actually began in part when we stressed the pancreas, and we do that in part by diet (will adult on set diabetes). We can then compensate with diet. We can then compensate with diet and exercise early on, so we do not get to this part of the road of this disease this fast. These are long term chronic diseases. So, when someone has one of these long-term diseases, then the patient can be depressed. And of course a depressed patient is then not a cooperative patient, and they do not do what they are supposed to do. So, a patient will come in, and they have not been following the things that they should have been doing, but they know that they should have. They try to self-treat their foot problems they may put a bag over their foot because they smell or something (anaerobic infection/conditions), and they may have even lost a toe because of this because it was mummified. So, this loss of blood supply aggravated by the patient not knowing what the problem is and putting a plastic bag over the foot, etc, etc, etc ... will cause problems. This is a problem that will begin the late teens and early 20s, and it will just continue on. How you end up is directly related to how well you took care of yourself all of these years. It will depend on if you watched your weight, exercised, etc. Now, some of these problems are really related to the different degrees of diabetes that you may have, but a patient factor (how the patient is acting) will be significant relative to the outcome to all of these problems. If you do not deal with this disease properly, you could see a forty year old with no arms and no legs. So, we just make these patients realize that they have a chronic illness, that they can get depressed about their illness having to deal with it (they will get tired of being sick and testing their glucose they just plain tired of having to deal with it) what we need to do is boost their self-confidence somehow. This will help to have them hold themselves together as long as possible. Once the let themselves go it is very to get them back. There are many drugs that these patients can be on to HELP not cure but they need to contribute. So, we can see blindness, kidney failure, amputation, etc, can all happen. A big role in all of this is the patient understanding their condition and understanding how it is that they can survive living with this disease and not dying of it. This psychological aspect is very important. So, we have this anaerobic infection. We can also have an anaerobic infection due to clostridium perfringens in a crush wound. Crush wounds have their own set of nasty characteristics. Once we take the crushing thing away, we have a nasty metabolic breakdown which can then rush through your system and that alone can kill you. So, relieving the crushing thing improperly after it has been trapped for awhile will release metabolic products on the other side of that boulder which will result in heart failure, kidney failure, and ultimately death. So, certainly this crush wound can be another way to have tissue that does not have a good oxygen supply which is great for anaerobes. We can also have GI problems. We can see appendicitis (page 27 of notes). The appendicitis with peritonitis can result with an attack on the ovaries and a variety of other things. These infections can lead to a lot of secondary infections. So, we have to maintain that good awareness to keep ourselves healthy. You might also develop a lung abscess from a collapse lung a lung that is no longer functional a pneumothorax for example where we have poor oxygenation of the area. In all of these setting we have a poor blood supply poor oxygen supply. Dental Abscess When you get your wisdom teeth removed, some people experience something known as a "dry socket." This is an anaerobic infection. At first we did not know that these dental abscesses were an anaerobic problem. We tried to grow them in an oxygenated area. The anaerobes will not grow in an oxygenated area. They thought that they had a real problem because they had this abscess, but they could not grow anything they called this a "sterile abscess." Obviously there is no such thing as a sterile abscess so realized later that this thing was an anaerobe. So, anaerobic infections are common, and the good thing is that they are
easily treatable. We do not have a lot of concern with antimicrobial resistance. They are easily dealt with and do not cause a huge problem Clostridium perfringens (disease course) But first we are going to look at what Clostridium perfringens does. It will begin as a ulcer, smaller in size, and it will be red around the wound. The ulcer may get bigger, but it is still red around the wound this is called a simple wound infection. The next stage that we are going to see is an enlargement of an area of cellular destruction which will result in exoenzymes being released by the organism so it is still growing basically in that wound site but the exoenzymes are spilling out into the tissue around it causing a destruction of the tissue and necrosis. So, this next stage is going to be wound infection with necrosis. And this tells us that we have these exoenzymes having an effect now; increasingly distal to the actual site of the lesion. It is getting further and further away. The next stage is that these enzymes will be dumped into the major blood supply to be carried around the body. This will result in multi organ system failure (which can ultimately cause death). This is sometimes called gas gangrene because in the stage of mild necrosis, we often have a gas that is given off and the outer layer of skin sort of looks like fried chicken it becomes a little translucent and hard. And the gas is then trapped (this is where it gets its name gas gangrene) it sort of bubbles up a little bit. So, the skin becomes more translucent a little tougher and then we see that bubbling (which is the trapping of that gas). The presence of gas itself is not a critical factor it can be very serious without this bubbling but it can happen. This becomes serious when it spreads systemically, and it goes throughout the body. In very, very prime conditions, this process can go from initial injury, to simple wound infection, to necrosis (gas gangrene), and systemic spread and death in 96 hours if all of the conditions are perfect for the organism. The person will ultimately be dying for kidney failure or heart problems. Now, when we intervene, as we often do, we will use hyperbaric oxygen chambers to treat this; we will use antimicrobial agents to treat this; we will use would debridement to take away the dead and dying tissue to stop the use of reducing equivalents this process can be extended for months when we try to treat. It is the SAME PROCESS. It is just going much more slowly. So, one of the clinical determinations that has to be made, is when do we stop treatment of this kind of infection with all of these treatments, and when do we stop cutting off legs and arms (amputation). Because once you amputate someones leg, that completely changes that persons lifestyle. It makes them obviously much more sedimentary they do not move around as much then so that can cause more problems. This is big step. We want to try to avoid this big step because it is life-altering. We want to ultimately save the leg, but we only want to save that leg if that patient is going to survive. We do not want to try to save it for so long that the infection goes systemic and the patient dies. This is a very delicate call. Obviously, we want to treat this with antibiotics, but we have to remember that this organism is not necessarily going systemic the ENZYMES are going systemic. So, the organism is growing and growing (this is true) but there is probably more local damage to the surrounding area and the wound is getting bigger but our problem is going WAY beyond that because these exoenzymes are secreted and we have this problem because we have this effect distally. We may have a problem in our leg, but then we will have kidney failure, etc. Clostridium tetani This organism is also associated with Clostridium perfringens because these anaerobic infections are generally mixed infections. This organism is associated with tetanus. This could be an intoxication. It is usually an essential intoxication. We have the actual grow of the organism, but we have the production of the toxin. The toxin is tetanospasm, and tetanospasm unlike botulism toxin (which develops in a classic paralysis weakness trouble swallowing, etc) this is a contractile situation a tightening. People dying of tetanus are in a spasmodic type of shape. Sometimes that flaccid vs. contractile kind of outcome is used on standardized exams in terms of describing these two toxins affects. So, this organism will produce toxins in a wound
site. There are about 1000 cases of tetanus each year associated with trivial wounds (that is paper cuts or a minor cut walking barefoot we get a little cut in the bottom of our foot). So, 1000 cases of tetanus each year are from trivial wounds. It does not have to be a major injury to have a problem. Now, we have resolved this problem in the US by immunizing everyone with DPT diphtheria (this is toxiod), pertussis (this is a whole organism) (whooping cough), and tetanus (this is also a toxoid). So, the proper immunization is used frequently in the US and it is very effective. So, if you have a minor wound of any sort and you go to the ER for that wound and regardless of that answer, you WILL get a tetanus shot. They are very aggressive with this kind of immunization and this is a good practice to have because it is much easier to deal with using out immune system to come back with a memory response because in our four days you will have high levels of antibodies to the toxin and you will not have any risk at all of developing tetanus in a clinical setting, so it is very, very effective. "Emergency room conflict" It is very common in the US to be immunized with DPT but not all of us have the same background. We have people in the US that may not have all of the proper papers importing people from other countries to work. But what is happening is that these individuals may not speak English, and they may be concerned about being deported. So, therefore they may not treat an infection of this sort early. So, they have a simple wound infection and it goes 14 days without any serious treatment occurs. It takes that long because we have this spore which is what gets in the wound it germinates - in as short as about 4-5 days, but it could take months to germinate (by germination we mean going from the spore stage to the rod-shaped organism stage). Now, the rod-shaped organism is what is producing the toxin. So, we go from the spore, to the vegetative stage, to the rod-shaped organism (toxin production), and once we have toxin production, it is going to take several days for sufficient levels of the toxin to have any kind of clinical effect. So, if we add up all of this time, we have 2 weeks that we do not have to worry about this right away. So, if someone has been immunized frequently and recently, we clean up wound, give them some antibiotics, give then the tetanus toxoid, and the patient is good to go. We have no real concern at all for this. On the other hand, with someone who has NEVER been immunized, and that wound has been around for a couple of weeks then we have a problem. Now there may be home remedies. Different cultures use different ways of treating these kinds of things folk remedies like kerosene for this. They will clean their arm with kerosene. So, basically, they have cleaned the wound out and we are going to treat it with antibiotics, but now we have a concern. It is possible that this person already has toxin production in the lesion. In which case, they may develop tetanus from the tetanospasm toxin produced from the organism. So, what we want to do is neutralize the toxin we do this by giving an antitoxin. So, we use antitoxin and that will take care of their IMMEDIATE problem. But it will not provide them protection next week or in two weeks because the antitoxin that is given is an already made protein which will degrade at about 50% every 20-30 days, and as a result, it is not long-term protection. It WILL take care of this initial problem you will not get tetanus if you are treated with this and do not have any symptoms yet. But what we dont know is what will happen in six months when the patient hurts themselves again. So, ideally, what we should tell them is come back in two weeks we will take a look at the wound everything should be okay but we are going to give you the tetanus toxoid (the booster) when you come back in those two weeks. The problem is that those people will not come back in two weeks. So, under the assumption that they are not going to come back, we treat the wound add the antimicrobial agent and if we think that we are in danger of infection, we will inject the area of muscle around wound site, neutralizing that toxin that may be released in that wound. Now, remember this person DOES not have any symptoms yet, but then
in the other arm we are going to give the tetanus toxiod. Now, what is going to happen is the antibodies that find any toxin is going to neutralize that toxin but as the antibodies move away, and the toxin circulates around the body it is going to neutralize the antibody that it has just made. So, it is not going to be as good of an antitoxin effect as it would be otherwise. But we will now have the advantage of having the beginnings of their own immune system producing its own antibodies to subsequent exposure. This is the best we can do, but it demonstrates the difference between theoretical medicine and practical medicine. This is an example of what is actually done. It is not as good to use both antibody and antigen at the same time, but that is what we have to do, and it will eventually work, just not as good right away. Now, if the patient actually develops signs of tetanus we can of course give the antitoxin and we ARE NOT going to let this person go because they are showing signs of the infection. We are going to put them in a room that is away from the main part of the hospital so that they do not hear a lot of sounds and such (it is not that they are contagious or anything) it is that they are going to be very reactive to the light and other simple stimulation. They become more sensitized to their surrounds when they are infected with this (they can hear a toilet flushing on the third floor of the hospital when they are on the first). These patients often have to be tied down and sedated. And we basically have the same procedure as before; we give the antitoxin which will neutralize the toxin, but it will not affect the ALREADY BOUND toxin. So, the person will get a little worse until they stabilize we have to actually add the antitoxin (they will get a little worse because it does not immediately neutralize the toxin all at once) so that before every molecule of toxin is neutralized some of the toxin is going to bind to the target and as a result, we are going to see an additional stimulation, so it is going to seem worse. So, after several hours 6-8 hours the patient should be stabilized they should not get any worse we will then sedate them and hope for the best. This treatment is fairly effective if you get it early enough it the patient is far enough along that they are having full body systemic effects there is not much we can do to save the patient at this point because we cannot reverse the effects of the bound toxin. A lot depends on how far along the patient is in the infection. Sexually Transmitted Diseases Generally Considerations A general term for this variety of organisms is a venereal disease or VD (Venus "God of Love") - and in a very strict sense this meant a microbial infection that can only be spread through sexual contact. The term STD is a more comprehensive term. A sexually transmitted disease is a term that the organism may cause infection through sexual transmission, but you could also get this same infection by other means. You may get Hepatitis B through sexual transmission, but someone else may get Hepatitis B from their mother who had it while you were a fetus it crosses the placenta. Or someone may get is from a contaminated supply of blood or from artificial insemination. So, it may be sexually transmitted but it MAY be from other means. There are many organisms that can be associated with an STD. There are bacterial agents, fungal agents, viral agents, as well as parasites that will cause STDs. So, someone who has an STD quite commonly does not get it in a pure culture form. Most commonly STDs are mixed infections. There are a couple of things that we need to be aware of in terms of these mixed infections. The first thing is treatment. We may choose a broad spectrum agent even though a specifically identified organism might be treated by a narrow spectrum agent. The idea is that something else may be lurking so a broad spectrum agent will get it all. If a person comes down with an STD that is relatively not a problem, but it is enough for us to do additional testing to see what else they may have been exposed to. These are usually mixed infections, so if we find one of these organisms our index of suspicion increases that there may be something else involved. We dont want to scare the patient, but these things usually do not come in PURE CULTURES.
Neisseria gonorrhoeae This organisms virulence factor is the common pili - remember that Neisseria meningitidis caused meningitis and that also has a different virulence factor and that is a capsule. This organism has the common pili, and they bind to receptor sites wherever there is that receptor site match, the organism will cause infection. It generally does not spread from one site to another that is we may get it from one site in the blood stream, but once it is in the blood stream it does not pop out in other sites. So, our first area of infection would be a good tip off to what you did to get the infection. We find the organism in the oral pharynx (sore throat); we can see the organism in the eye; we can have the organism causing rectal lesions; male/female urethritis; the male can also see infection in the epididymis or in the prostate or the female will have an infection of the cervix or of the fallopian tubes and beyond causing PID. About 1/3 of all PID infections are caused by this organism. There are other organisms that cause PID, but 1/3 of them are STDs. N. gonorrhoeae is an anaerobic infection. So, once we have the organism in the site depending upon what that site is we are going to have a better understanding of what the reaction is going to be in terms of the patient whether they are going to know about it or now because the asymptomatic state of the infection site can result in someone giving this to someone else without knowing it. This is the gift that keeps on giving. The sore throat is relatively minor. If someone has N. gonorrhoeae infection of the throat; they probably will not know that they have it. The eye infection is rather dramatic. Their eyes will be blood shot; there will also be swelling; there will be tenderness; and there will be a lot of pus associated with this kind of infection. This is going to alert the patient to see a doctor, so these eye infections are treated very commonly. The rectal lesion is generally asymptomatic. The urethritis of the male/female; there is going to be a discomfort, and the patient may or may not seek treatment. The male will not know whether or not the epididymis or prostate is involved, but if they are involved, then we are going to have a urethritis that is going to be lasting a lot longer than it usually should. It is going to last several days as opposed to one or two days. The male will also start to see an exudate after he urinates. There will be ooze, a thicker liquid that will come out and the patient will notice this also in his underwear it will build up in his underwear. The patient will then know something is WRONG. At this point, the male will seek treatment. He probably did not seek treatment with the initial urethritis. In the female, if they have a cervical infection, it will be asymptomatic. They will not know that they are infected. If the infection is in the fallopian tubes, the female will probably still not know that they have a problem. It is until the patient has PID when she has abdominal pain, does she start saying that something is wrong. At this point, however, the infection could have been going on for weeks. So, depending upon the body part that is affected, we have different kinds of clues to signal the patient that something is wrong. The sooner the patient seeks medical attention, the sooner that the patient will receive antimicrobial treatment, and the better the outcome will be. If these are sites that are asymptomatic in some respect, these tend to be a bigger problem when they finally are discovered. In the case of the PID, we could have a 14year-old girl with gonorrhea and it may have progressed so far that the only thing left to do might be a hysterectomy. It could go that far. Now, the response in the body with these infections is probably also related to the common pili in that it stimulates a T-cell response. And that in turn will result in a much more dramatic inflammation. There will be lots of phagocytic cells (macrophage and PMN cells initially there will be lots of PMN cells and eventually macrophages) and the destruction of the phagocytic cells in the process, as they die, will elicit an overwhelming response to a minor problem and what happens then is it clears the organism, but the scarring of that area of the body may be significant. In the case of the urethra in the males (prostate is involved so there is a longer infection extended infection), so we will see a closing down of the urethra in the male and scar tissue will build up and that is called a stricture formation. The scar tissue builds up inside of the urethra closing down the urethra. Now, additionally with the immune response
although it is effective with getting rid of the organism after several weeks - there is no development of long term protection. So, you can get the infection over and over again, and each infection is going to result in the narrowing down more scar tissue and eventually the urethra will become smaller and smaller because more and more scar tissue and the patient will become "super male" he can stand further and further away from the urinal than anyone else. There is a much narrower stream. But this wont last very long because eventually, it will close down to the point, where ONLY when the male has a full bladder will he be able to even have small trickle of urine come out. And as the bladder empties out a little bit, there is not enough urine in the bladder to open up that urethra so with probably ths of the bladder still full, he cannot go anymore. We can solve this problem short term with a catheter. But we must solve this problem long term is that we are going to go in and surgically strip that scar tissue and the bodys response to this kind of procedure is scar tissue. So this often has to be done several times before we can maintain an opening. The female, with ascending infections into the fallopian tubes, also results in scarring. We could see this infection go as far as PID, so we have to have a full hysterectomy. But with this infection of just the fallopian tubes, we could have the closing down of the fallopian tube which will result in infertility. The woman is still fertile. She has eggs, but they cannot get out of the tube. This stricture formation results in infertility. The tube has closed down. At first all we could for this is diagnose this and just have to let it go. The woman would just eventually become infertile. We then developed a surgical procedure that we took functional portions of either side and make a fallopian tube that worked. This was just a little bit of transplanting, but it worked and women were able to become pregnant. All we need is one functional tube. So, if we catch this soon enough, we will not have to have a hysterectomy otherwise we will have to take out EVERYTHING and the woman will have to be on HRT for the rest of her life. Early is better. We want to treat with antimicrobials. In terms of treatment, we have seen increasing amounts of resistance. PAGE 29 OF NOTES - We can see that we went from virtually no problem to a significant problem. We used to use Penicillin the resistance to Penicillin went from virtually nothing to 8% resistance. Since this resistance is so high, we use other things than Penicillin now to treat this infection. The N. gonorrhoeae organisms have penicillinase producing plasmids, so we have to use other antimicrobial drugs. Transmission of N. gonorrhoeae to Children If we have an infected mother; how will the child contract this disease? The child will be infected at the time of the vaginal delivery. The most likely site of infection is the eye. As a result, state law requires treatment of ANY child on the assumption that ALL women are infected with gonorrhea. So, all mothers are assumed to have gonorrhea, so that all children are treated at the time of birth. So, at the time of delivery are given some kind of antimicrobial treatment in their eyes. We do treat the child to prevent the infection. Basic Message One of the other factors that will stress now is that with all of these STDs (gonorrhea, syphilis, HIV, etc.) there is major behavioral factor that is involved with the sexual spread of these diseases. Now, the child cannot do much about these diseases. We can only treat the child at the time of birth and hope that they will be okay. But the mother is a different story. Generally speaking, your frontal lobe does not start to develop until your early 20s. So, the ability to understand the consequences of your actions really does not develop until then either. So people who are age 14 to 23 are going to be risk-takers. They are going to take risks they may not think that they are taking risks, but they are. So, really they are not thinking at all. We are not really able to understand the consequences of our actions until about the age of 23
with the development of the frontal lobe. We have to understand that young people really have a behavioral disease in this case this one treatable - the sooner the better. Some of the other STDs (like HIV) are not treatable (curable). We have difficulty getting the message across to younger people about STDs. The best way is to avoid sexual contact; the second best way is to use some sort of barrier technique. Condoms, for example, are a good barrier, but are not that effective at preventing disease if used improperly. And who is going to use these improperly? The younger people are going to use them improperly. They are going to be hard to get through to. Condoms are highly effective if used properly. We must know the consequences of our actions we also must be prepared to tell teenagers about 100 times the consequences of unsafe sex.
Microbiology 6-29-05 N. gonorrhoeae There are about 1 million cases per year, but this is not necessarily a true number because there is the very great chance of reinfection (also there are many people who just do not report that they have the infection. The same person can get the infection over and over again. Repeated infections can be a problem. The stricture formation can be a big problem with blockage of the urethra and fallopian tubes. The big thing is that we have REPEATED infections so there is not a good memory response to this infection. The big thing also is that we have an exaggerated immune response which will result in a stronger inflammation and more scarring. The numbers every year have fluctuated because of the concern for HIV. People at one point were taking more precautions, so the numbers of STDs in general dropped. But now, the numbers of HIV have dropped, and people are starting to care less and less so the numbers of STDs in general are on the rise again. There are many agents of disease that can be spread the same way, so we use a broad spectrum agent that will affect this organism and say also Chlamydia. This idea of mixed infections tells us to use a broad spectrum agent to treat the problem because there might be something else that is an underlying problem. The after effects of the infection are the scar tissue (stricture formation) in both males and females; it can result in PID (severe in some women) if it is not treated early (hysterectomy); and we will also see some immune complement disease ICD but we will see this it is an immune complex of antibodies activating complements that get trapped in various parts of the body. We most commonly see this with N. gonorrhoeae in the joints. So, we joint pain and joint swelling with repeated infections of gonorrhea. Again these are immune complexes of organism and antibody activating these complements (immune response?) Treponema pallidium This organism has a long history with lots of generalizations made about it. Treponema (threadlike) pallidium (pale) so it is a pale threadlike organism. It is not gram +/-, however, it does have characteristics of a gram organism, but it does not stain gram -. Biochemically, there are a lot of similarities. In the 1400s, this was very much a very lethal disease. Most of the people who got this disease died of it. We used to use compound 606 to treat the lethal STDs that were of that time, however, since that time, the organism has modulated. The disease has become much milder and prolonged. It is either the organism adapting to us or us to them it is probably the organism adapting to us. As a good parasite-host relationship the parasite does not want to kill the host. So, if the organism is able to stay alive in the patient for a longer amount of time, this is a good thing. If the organism kills off the patient too soon, this is not good for the organism. If the organism rapidly kills the patient, then it wont spread too many people. This would not be a good bacterium then because if it kills the patient too fast it will not have the chance to spread. We want to keep the viable population happy and growing this organism is a
good spreader because it is staying around longer, and it is able to be spread to more people. So, it is adapting to us. It is not as lethal as it once was, so we tend to have more chronic diseases. Syphilis was named after a boy in a poem. Fracastoro wrote this poem, and he named the organism. The shepard boy in this poem had this particular agent that Fracastoro (Italian) he wrote a poem about the seeds of disease and he wrote about how it possible for an organism to go from person to person and grow within them like a plant and then they will seed and spread small objects (that you could not see) from person to person so if you looked at someone wrong you could give them the disease. Fracastoro was looking for an entity that caused disease rather than an evilness that was not well defined. More important than this, he was smarter than we first recognized him to be. Once we had HIV problems, we realized just how SMART he was. He named the disease Syphilis (the name of the Shepard boy who had this disease). Now, the naming of the disease will impact greatly how the treatment of the disease will come about. In the case of an entity that was an evil thing spread from person to person then that is hard to treat. But IF IT IS A THING (they are not bad people; they are just sick people) then it is a completely different way of looking at it. They once thought HIV was a punishment from God before they knew what it was so it was pretty hard to treat a punishment from God. Now, we have an organism, so this is different. You are no longer a bad person; you are just a sick person. So, we still found some problems with the naming of the AIDS virus because initially the early stages were called age related complex ARC you didnt have AIDS yet, but you had ARC. People were then under the assumption that they were okay then at this point they didnt have AIDS yet. Then, we called the early stages HIV+ - people were under the assumption here that they were also still okay because the person only had HIV+ - not AIDS. We were treating these things all differently as if they were all different. Finally, the UN said that we are just ultimately going to call this HIV and then we are NOT going to make a distinction between HIV/AIDS so now, we talk about them together. It really is JUST one entity. HIV will turn into AIDS eventually. So, the naming of a disease has social and medical impact on how something is treated. By naming syphilis, it became something that we could deal with and treat. It is not a something evil, and the person is not a bad person. Syphilis The organism begins as the first of three stages we call this a hard chancre which is a raised button-like lesion (about the size of shirt button underneath the skin) it is red and it is not tender (it does not hurt) but it is early friable (easily broken). This lesion appears at the point of entry three to five days after the initial contact. Now, the point of contact can be many different places because there are many different ways in which you can get this. Dentists and dental hygienists often get lesions on their hands because they have their hands in the mouths of many patients. The dentist could get cut from braces, and therefore the organism could get in this cut. The organism will not invade intact skin so a cut or small abrasion (only the size of a pin) is necessary for this organism to get in, but intact skin will not let the organism invade. However, it can invade intact mucosal tissue. Also small cuts on the shaft of the penis, the labia, etc. are good places to get the organism in. We can also see it in the vaginal wall or on the cervix. We can see around the anal opening; on the lips; and even on the left tonsil much more commonly found there than on the right tonsil. So, when a dentist is checking your mouth, part of what they are looking for are these hard chancres. They are looking for Primary Syphilis this hard chancre. Now, we said this hard chancre was easily friable which means that it is a good source of organisms because within the first few days before the lesion occurs the bloodstream of the patient is teeming with organisms lots of organisms. The organism is in high concentrations in the bloodstream before that lesion occurs. So, when a lesion occurs and it is easily broken open that is a source of organisms to other people. Now, the organism is going to continue to invade the body (spreading itself throughout the body, but there is only going to be that one chancre there is only going to be that one primary lesion at the point of entry.
After about 5-10 days, this hard chancre will disappear so it will just go away. When something that the patient is concerned about just goes away this is a good thing for the patient because then they do not have to worry about it anymore because it went away. This is a good thing for the organism. This is the period known as the first latent period which lasts anywhere from 5-20 days in which there are no signs or symptoms. Then we begin Secondary Syphilis we will have a secondary lesion. The secondary lesion is a rash now this rash is not the normal kind of rash. It begins on the palms of the hands and the soles of the feet. It does not begin in an area of the genital region or something like that. So, we have syphilis beginning in these two areas and it will then spread to the arms and the legs and to the rest of the body. This rash is just the opposite kind of rash most rashes spread from an area that is moist on the body (groin, armpits, etc) and then spread to the rest of the body (so the arms and the legs are last). So, when we are talking about rashes we want to know where this rash began. This will help with treatment so now we have this secondary lesion and eventually the person will be completely covered with this rash. The rash will then begin to fade and after about 5-10 days the rash will be faded almost completely, and the patient will then enter another latent period the second latent period. This can last anywhere for 10 days to 20 days on the short side to many years 5 -15 years or more. During this period of time, this organism will most likely be killed in the body. The next stage is then the Tertiary Syphilis. With Tertiary Syphilis, we have a T-cell immune response we have a cell mediated immune response (CMI T-lymphocytes) we will have this response to ,,parts of the organism (debris). Because the organism was in very high concentration in the bloodstream, and then it will be killed off there are body parts of Syphilis everywhere in the body floating through your bloodstream. And they tend to get caught or trapped and embedded in certain parts of the body for example wherever there is a major blood vessel like the aorta where blood is going to the right or to the left at the point where it decides to go right or left it spins around and it goes to the right or the left when it spins around it drops down to zero velocity (think physics and vectors) and anything that it might be carrying is dropped out of the blood so the organism is dropped out. So, in terms of blood vessels, we have the deposition of the organism. So, now we have the organism deposited in those vessels then we have the T-cells attacking those organisms and this results in the weakening of the wall of the blood vessel where the organism was deposited. Because the BP is equal everywhere in the closed system if we have a weakened spot, then it is going to balloon out this is called an aneurism. So, the patient can have cardiovascular syphilis an aneurism from the weakening of a blood vessel in the circulatory system. If the patient is going to be undergoing surgery particularly a surgery that might put stress on the cardiovascular system (fluid forced stress) we want to know whether you had syphilis or not. We need to know so that we do not have an surprises when we are doing surgery we do not want to blow a blood vessel during surgery without any warning beforehand. We want to know what the risks are. Something else that may occur in Tertiary Syphilis is neurological syphilis. Here we have the deposition of the organism in the brain and it can be randomly put in the brain but now we have the T-cells destroying brain tissue because they are trying to destroy the parts of organism that have been deposited in the brain and in the process they are destroying brain tissue. Something that you should remember is that the organism was thought to be gone at this point. We just have parts of the organism left. In this case, the neurological findings are unusual. There is no pattern to it the fact that there is no damage to the neurological damage is a clue to the neurologist that syphilis might be the cause. Other damage has an explanation. In this case, we have all of these pieces of neurological discrepancies we have a weakness of the right leg, or right arm, blindness in the left eye, etc. There are a lot of weird things going on that do not add up in any kind of single event trauma and therefore is fits the "pattern" to the neurologist that we may have neurological syphilis (tertiary syphilis).
So, we have stages of syphilis. We have the organism around for quite sometime. We are infectious to other from the first few days on if untreated six weeks or longer 8 weeks. So, we are infectious before primary syphilis, during primary syphilis, after primary syphilis, during the first latent period, during the rash, and then during the second latent period (when the rash disappears) so we then begin this second latent period and at some point in time during this period, the organism is going to be killed off (this could be several years) but we are still infectious until it is gone. We are still going to be infectious in the beginning of the second latent period. Now, when someone is diagnosed, for the first time of having syphilis and this first diagnosis is during tertiary syphilis, we will treat with antibiotics, but we do not expect anything to happen. But just to be on the safe side, we will treat it with antibiotics. Now, the staging of this has to do in part with our immune response to the organism and it is unusual. The organisms surface is unusual it is not gram +/- - it is a highly adsorbent surface so it will coat itself with our proteins. So, about two weeks into the disease, you will produce an immune response to the organism, but the target of that initial immune response is coated with our proteins. So, the antibody response cannot find the target it covers itself up. However, if during that time (after the first two weeks of that initial infection) you are exposed to syphilis again, your immune response that was triggered by the first exposure that was not protective is protective against a second infection we call this concominent immunity. It is an odd thing. By being infected, you are protected against being infected again. That same protective response that works on the second attack does not work on the first attack. This is very weird. We see this concominent immunity also with parasitic infections round worm, flat worm, etc. These organisms generally have structures that function in the way as those proteins that cover the surface. Eventually we will kill the organism off, but this will take a long time this is concominent immunity a very odd thing. Now, we can treat this patient and penicillin works (also other penicillin-like compounds) there are other compounds that we can use that will work. This is not difficult to treat generally, and there is not a lot of antimicrobial resistance. So, treatment is not a problem. When we first treat with a bactericidal agent, the organism will release endotoxin-like compounds that will trigger a fever in the patient. This is called a Jarish-Herminer reaction which is a fever and chills that we will see in a patient being treated with a bactericidal agent like penicillin. So, if the patient gets a fever and chills that is consistent with the fact that we are on the right track with treatment we expect this to happen if we are on the right track. And this will go away in a matter of hours this is NOT a long-term thing. The other thing about the treatments is that we will stop the progression of the next stage. So, if we treat primary syphilis, we will not go to secondary and tertiary syphilis, etc. This is a good thing. Also this organism is capable of crossing the placenta and invading the fetus if the mother is in the first trimester (first three months) of pregnancy the baby is killed over 90% of the time if we are treating a baby this is exposed in the second trimester it drops down to about 40-50% fatality and if exposed in the third trimester there is only about a 20% fatality rate. The fatality rate goes down if the baby is infected later during development in utero there are problems with the child, however. The child once infected will show signs of being infected. Depending upon the stage of development at the time of infection various kinds of things can be problematic. The child may be born without cartilage or some of the cartilage which means that there may be no ears or malformed ears, maybe there is no nose, and sometimes in the joints the cartilage will be missing (esp. the knees). We also can have problems with the jaw line children infected in utero will sometimes we born with a Vshaped jaw line vs. a U-shaped jaw line the child infected in utero may also have a reduced jaw so their face may be distorted. The teeth may also be out of alignment. Also, the shape of the teeth may be malformed - the front teeth (look like shovels) hollowed out in the back and they may be pointy and the molars come in as a bunch of little bumps little teeth they are not a real good molar. There can also be CNS problems blindness, deafness, and mental retardation. This will all happen to those children that survived getting the infection in utero, but
now they will have to deal with all of these other life-altering problems. The problem with the cartilage is the formation of the cartilage in utero in will not form in utero. So, even though the survival increases as we go from 1st, to 2nd, to 3rd trimester so too does the problems associated with this infection. The good news is if we treat the mother not only do we prevent the mother from going on to the next stage of syphilis we also stop the spread to the child. So, early treatment is extremely important to prevent the spread to the child. Early treatment is major for the child. Part of the diagnosis is the physical diagnosis. We know what happens in each stage and what signs and symptoms there are to look out for. We know all of the signs and symptoms to look out for and if a patient seems to exhibit some of these signs and symptoms then we do the testing. These symptoms are pretty indicative of a syphilis infection, so then the search for a definitive test for syphilis was needed. The search for this test was on. There were some very interesting findings. We could not and still cannot grow the organism in an artificial media so to develop a source of antigen, we went to a source that was plentiful and unfortunately that was with stillborn children we took the organs of stillborn children ground them up and that was the antigen. This is really gross stuff. This became the antigen for the organism. Then we found a cross reacting control that turned up an interesting observation someone used the control of a beef heart instead of a human heart and it worked just as well. So we used cow parts. Why would we have an immune response to cow heart? We realized that our first test is to figure out if you could possibly have syphilis but those immune responses are not specific to the organism. This first test will POSSIBLY indicate that you have the infection. And extraction of the cow heart found something called cardiolipin cardiolipin is a phospholipid found in beef heart and also in the syphilitic child. So, now we are going to purify that. We want to see what is going on we are getting an immune response to cardiolipin well, we also find cardiolipin in our own membrane. Now, the plot thickens! So, cardiolipin is a lipid found on the inside of our cells membranes and not on the outside so each time we have a strong inflammatory disease we could have an immune response to this particular compound called cardiolipin. So, lets say that someone has malaria they will have a positive test for the antibody to cardiolipin. We call this a biological false-positive so a person that has syphilis has antibodies to cardiolipin, but also other kinds of diseases some autoimmune diseases (lupus patients) may have a positive test for the antibody to cardiolipin. Also, a person with malaria may have an antibody to cardiolipin so someone with a chronic disease having this antibody is VERY possible. And syphilis CAN be this chronic disease. So, we have a nonspecific test. We have different kinds of nonspecific tests the big test now is the VDRL. The VDRL is a flocculation test venereal disease research lab test (this is just a redeveloped cardiolipin antigen test). This is another non-specific test. So, therefore we often do (actually this is much less commonly done now), but in the past in the hospital, everyone that came into the hospital had the VDRL test done this made a lot of money for the lab actually because not many of these tests actually came up positive certainly though - any patient that is going to undergo some kind of cardiovascular surgery is going to undergo this VDRL these antibodies will last for decades so you know if you have had this response. Now, it does not tell us if you have had syphilis for sure, so the logic here is if you have had syphilis, you will have a positive VDRL. But IF you have a positive VDRL, you may not have syphilis. You may have malaria, lupus, etc. So, what we need then is a follow up test. We use the VDRL as a screening test. Then we need a follow-up test to confirm the fact that the reason you had an antibody to cardiolipin is that you had syphilis. So, what we did was we developed a fluorescent antibody absorbed sera-test. Now, to do this we take the patients antibodies (who has secondary syphilis) and we take the patients sera who has secondary syphilis and in that sera we have the antibodies and we add some antigen so we are going to add non-treponema pallidium antigen - other agents that might give you a positive test there are similar agents that will cause a similar response there are other spiral - shaped organisms that are just like treponema pallidium antigen and when we add the
non-TPAG and if you have any antibodies to those those antigens will bind creating an immunecomplex (antigen-antibody complex). After we have added the non-TPAG, we will then centrifuge it, and the complex will make a little pellet at the bottom leaving any antibody that is TP alone it leaves the free antibody alone this is what we refer to as being adsorbed sera. So, now if you have TP you didnt have the other spiral organism diseases then your antibody is still free unbound antibody basically we take the adsorbed sera and add it to a slide that has on it TP antigen so we add this sera (the patients antibodies) and what will happen then is we will have this slide the antigen and the patients antibody. And then what we are going to do is add a goat anti-human (IgG memory response) so we are adding a goat antibody to a human antibody so an antibody to enable a protein an antibody is a protein so we can take a human antibody and inject it into a goat and the goat will produce antibodies to it. Those antibodies to human antibodies are called "uncle-bodies" so an "uncle-body" is antibody to an antibody but this goat antibody to an antibody has a fluorescent dye to it. So, wherever it goes it glows. So, this antibody (the goat antibody) is going to glow it is going to bind to the human antibody that is bound to the antigen that is stuck to the slide. So, this is the fluorescent antibody absorbed sera-test. This is a fairly easy test to do, but it is VERY specific. Again, we take the patients sera which may or may not have antibodies to syphilis which may or may not have antibodies to any other spiral organism (and other treponema organism) and we mix that sera in with antigens that are not treponema pallidium in nature so we mix those in which will create an antibody-antigen complex we then spin that down and take the pellet away we want to use the supernate which will have the unbound antibody which may be to syphilis we then add the TP-AG to the slide and we then add the patients sera. We then add the goat antibody which has the fluorescent antibody to it those are anti-human bodies (uncle-body) and now we look under a microscope and if it is glowing they bound then you have syphilis. Now, this test is much more expensive so we use a screening test first. If you have a positive VDRL we will do this. If you have a negative VDRL we will not do this. We use a pretest that is not specific for TP. We have an antibody for cardiolipin that we first look for then we have an antibody that we are looking for that is specific to TP. (With mono we look for antibodies to something else; not to EBV) This is an antibody this is specific for the organism so this is the fluorescent antibody absorbed sera test that allows us to say that a patient for sure has syphilis. Tuskegee Experiments We have this town Tuskegee, AL, in about the 1940s 1970s, black males who were identified to be in their 40s and 50s were deliberately not treated for syphilis to just see what will happen if we do not treat. How many people will develop what? Who will develop what? What exactly will they develop? What kind of neurological problems will they have? These men were not told anything they were just told to keep coming in to the doctor to get regular checkups. They were diagnosed with syphilis and deliberately not treated because we needed ,,data. We ALREADY had plenty of data to look at esp. before penicillin. We had the first public apology about these experiments in the 1990s! We also used to use infectious diseases on prisoners of war we did lots of these "studies." This is our government doing these horrible things to people and they did these horrible things to people and then they did not want to talk about it. Lyme Disease This is not an STD. Lyme disease is caused by an organism named Borrelia borgdorferi it is also a spiral organism. The agent is spread by wood ticks (there are other way) and there is a lesion at the site of entry there is a very specific lesion. There are also stages to this disease and the lesion is often referred to as a bulls eye lesion this is a migrating erythema that is it moves as a red area so you can see a small spot in the middle a dark red color and then there is a white area then there is another layer of redness the more white and this
"bulls eye" can get to be three to four inches across or more. So, we have this characteristic lesion at the site of entry. (Primary Stage) We then have a latent period during this time of bulls eye period the latent period the organism is in the bloodstream we then develop a rash (this is like the Secondary kind of stage) again it will cover the entire body. Other symptoms include generalized fatigue, headache, stiff neck, muscle aches, and joint pain. Then we go into another latent period and then we can see some neurological problem: one is known as Bells Palsy which is a facial paralysis (this will go away but once a patient has it, it tends to return especially when the patient is fatigued this can come and go for decades there are also other organisms and other causes to this paralysis). This is where may be one side of the face drops down. (Chronic Stage Tertiary) This can also be associated with the influenza virus. There is some debate about this but there is evidence that this can cross the placental barrier and infect a newborn in utero. This kind of infection also responds to antimicrobial treatment it will respond so we can stop the spread to the next stage or we can stop the spread to the growing fetus. It can also be confused with other chronic diseases such as Hodgkins or leukemia if it is not caught early in the third stage. So, there are a lot of similarities in these two spiral organisms they are not the same they are NOT both STDs but there are a lot of similarities between them. When we are dealing with a spiral organism infection we should think as a model that there will be stages to the disease there will probably be a rash, a lesion, latent periods, or a chronic disease stage. There are a variety of similarities between these spiral organisms. In ALL cases, if we treat them, they will stop the spread to the next stage or to the fetus. So, Lyme disease is not an STD! This could be confused with multiple sclerosis. It was in the past but then they saw that it could be treated with antibiotics so it must be caused by an organism Microbiology 7-8-05 Haemophilus ducreyi Haemophilus ducreyi is sometimes called soft chancre disease or chancroid. There is a lesion that is associated with this which is more of an open sore - whereas with syphilis there is a just the raised "button" chancre. The open sore results from the organism growing in high numbers in the lymph system. This organism will be growing in such high numbers that it will block the lymph system. What it causes is the closing down and constriction of the lymph system and upstream from that constriction we will see a swelling. The swelling will appear often in the groin area, and it will appear as about the size of your index finger and it will be a raised bump in your skin from the surface. This is called buboe(s). An this buboe is an enlarged lymphnode, and because this organism is involved with this, it erodes away at the surface so you have essentially what starts as a spot and it enlarges, and then along the top of that enlargement the skin erodes away so that we have an open sore and is known as the chancroid. Now, for reasons that we do not really understand, even though it is an STD, it is almost exclusively seen in warmer climates. So, we will see this in the Mediterranean or in South Africa and also in Southern Asia. We do not really understand the climate aspect of this organism. This is another one of those diseases that is easily treated, and the earlier that you treat it the better the outcome. There is no particular spread to the child in utero, but the child may be contaminated at the time of delivery because of the proximity of the vaginal opening vs. the lymphnodes in that area. The possibility for contracting this one is not as great as contracting others, but there still is the possibility.
More Bacterial Agents Most of these agents are unusual in their general biology. Chlamydia trachomatis is an organism which requires a cell in which to grow. It is a prokaryotic bacterial form that is not free living it will not grow in our artificial media. It must grow in a cell culture. It must grow inside of a cell. Now, this agent can cause a prostate infection in the males and a vaginal infection in females. The number of people that are infected by this organism is upwards of about 50-100 million. There are a lot of infections. The vast majority of cases are asymptomatic (99%) so if you are infected you probably do not know. The most common possibility of a problem associated with Chlamydia in terms of a clinical problem would be PID a female infection. Occasionally, the prostate gets infected to the point where it needs to be treated in the male. This is relatively rare. The most common problem associated with Chlamydia is infertility NOT sterility but infertility. The female produces eggs and the male produces sperm, but they do not come together. This means infertility whereas sterility means lacking egg or sperm production. Infertility just prevents them from coming together somehow someway. In some way, in which we are not sure of a Chlamydial infection of the egg and sperm prevents the sperm and the egg from coming together (prevents fertilization). About 10-14% of couples have problems having children. So, when a couple cannot have children this will result in the couple going to the doctor they will have a full exam to check hormone levels, etc. and a microbial checkup is also done when everything else is done. When the results come back from this workup, it is very common to see a Chlamydial infection in one or both of the partners. It is VERY common. The good thing is this is very treatable in terms of the outcome for fertilization. The lower the levels of organism (tetracycline, etc.) uncomplicated treatment to lower the levels of the organism and the couple will be able to have a child. One of the problems, however, is that this organism does not generally totally clear up from the prostate. This results in the prostate becoming spongy a chronic infection. The organism inside of the prostate does not totally clear up. The infection does not get cleared up. A prostate infection will be chronic in the male. Also, there are usually no symptoms but it will be there. So treatment can occur though and conception can occur, and a few years later, they go to have another child and the male is infertile again because of the chronic prostate infection. It will keep coming back and getting worse it just needs to keep getting treated. This can be suspicious to the female however because the male WAS treated he shouldnt have it again but we have to understand that the infection went too far to the prostate. When the treatment occurs, it is likely to be very effective they are likely to have conception but you are also likely to get reinfected when you stop taking the antimicrobial agents. It asymptomatic infection so many people will not know that they are infected and the male will be the reservoir. Every time they want to conceive the male will have to be treated for this infection. Chlamydia can also cause an eye infection. With a vaginal delivery the child could be infected at the time of delivery but will not be infected in utero. The patient can have Chlamydial infections, and they can have an endogenous source of organisms from their hands to their eyes, for example we can get a Chlamydial Conjunctivitis this is very common among sexual active young adults. People who have the eye infection will more than likely have the genital infection (asymptomatic). The correlation was very high. The eye infection will result in dryness of the eye, itching of the eye, redness around the eye these symptoms will alert the patient to go get checked out. It is very easily treated. There is not a lot of antimicrobial resistance. In other parts of the world, the seriousness of the eye infection is not that great. They do not treat the eye infection like we do here in the US it should be but it is not (there are much more pressing problems) as a result scarring occurs on the inside of the eyelid and the scarring on the back of the eyelid will cause scratching on the cornea which will result in blindness so it is one of the leading causes of blindness from a microbial point of view worldwide. This is called trachoma. Trachoma is the world's leading cause of preventable blindness. Trachoma is caused by the bacterium Chlamydia trachomatis which can be spread easily by hands, clothing, or flies that have come in contact with discharge from the eyes or nose
of an infected person. The disease generally occurs in poor countries where people have limited access to water and health care. This can be serious but it has to go untreated for months or years to be a problem and in the US we treat this early on. It is best to treat every disease early for best results. Ureplasma urealyticum The last part of this organisms name suggests something about its structure. This organism lacks a cell wall it is in the same general category as mycoplasma called Ureplasma so this organism lacks a cell wall, so we have to take this into consideration when attempting to treat this kind of infection. We have to pick the right drug. Like Chlamydia, this infection is generally asymptomatic. We do no have a good idea of the Ureplasma infection. This organism can also lead to infertility again so it tends to be a mild urethritis a prostate infection a possible fallopian tube involvement a possible fallopian tube disease. There is a LOW incidence rate of this infection (esp. with PID), but it is all possible. You would be more likely to get PID from gonorrhea. The leading agent for PID would definitely be N. gonorrhoeae. But it is still possible for this organism to cause PID. There is such a low incidence rate that this organism will spill out of the fallopian tube to cause PID. The most common problem with Ureplasma urealyticum is going to be infertility. This could be another one that will pop up in the work up in a couple who is trying to conceive. Treatment for this organism is NOT a problem once you actually know what the organism is. Fungal Agent: Candida albicans The organism can be considered an STD, but this organism can infection someone by other means than by sexual contact. This is called the common yeast infection. Now, fungal organisms will tend to grow when different kinds of growth conditions dominant the microbial flora of the vaginal area. The vaginal microbial organism may include a LOW level of Candida albicans but if we change something about the environment, it will become a dominant organism and overflow. For example, if we treat the patient with antibiotics and kill off the bacteria we will allow the organism to grow. So, if patients are on long-term treatments of antimicrobial agents they have an increased risk of getting this kind of infection we can an overgrowth of a small percentage of a normal population we will allow this yeast to thrive because we kill off all of the other normal flora (other bacteria for the yeast to survive). Patients that are diabetic tend to have an increased risk of yeast infections because they will have the presence of glucose in their secretions. Patients who are on certain BC preparations the hormonal preparations can result in the changing of the secretion pH which will also allow the organism to dominant the normal flora. The secretion pH tends to become more neutral normally the bacterium in the vagina is acidic. By changing the secretion pH, we will create an environment for this organism to grow. Generally teenagers and those in their early 20s (females) will get a feeling that they have to be "clean" all of the time. They have to get very clean on the inside, so they do a lot of douching. We do not want to strip out the mucosal lining that mucosal lining is protective and it is thicker in the vaginal wall than other places but if it is a thicker secretion, we do not want to have to dilute it out because the more you dilute it out, the more you open it up for more kinds of infections. So, too much rinsing out is NOT good. Then we have what you rinse out with we want to use something that is slightly acidic such as vinegar and water (natural douche). We should try to avoid fragrance, etc. (irritation). When you rinse too much, these are the types of problems that can arise. If you use something with glucose in it, you are just asking for a yeast infection; also if you use something that is not acidic. Some of these cases what is being done to an extreme is actually causing the problem. So, when the patient has a yeast infection once a year or twice a year this is normal, but when a patient is having repeated vaginal yeast
infections several times a year then we will start to think about some underlying causes maybe the person is diabetic or the person is improperly douching or if the person is on multiple antimicrobial agent (or long-term) and we select for it or is the patient on a newer formulation of a BC pill so the vaginal secretions have changed. One big thing that should be brought to our attention is that there are OTC treatments for vaginal yeast infections that are sometimes advertised as you know what you have because you had it before, and you used our product before so use it again. The OTC meds usually try to tell you that you do not have to go to your doctor. So the selling of these OTC products for occasional yeast infections is okay but if we have repeated yeast infections that is a tip-off that something is NOT right and just because you are using the same OTC product again because it worked last time, this is not good. There will be a point where this will not work anymore a doctor should be seen. So, we have to be careful about the patients misuse of OTC products because there may be some underlying issue that needs to be addressed. The other thing of course is that if we have a teenager who is 12-14 years old and they are having MULTIPLE infections we need to start thinking about sexual activity other agents that they might be exposed to and even other STDs. Even though, it is a relatively uncomplicated situation, and it is a very common problem it still deserves some additional looking to see what the underlying problem is. A child could be being treated for acne with tetracycline, etc. and they then will be getting multiple yeast infections. Candida albicans can also cause thrush which is a mouth infection in immunocompromised patients. We also see this in younger children because their immune system has not developed yet. We will most commonly see thrush as a mucosal candidiasis which is a generalized infection of the mucosal membrane and in the case of AIDS patients for example, we can basically know if they are infected because with them it will be a really bad infection. So, thrush is not the normal kind of vaginal yeast infection this is a mucosal membrane infection which is fairly severe in immunocompromised patients but more normal in babies Thrush in an adult would be an indicator that something else is wrong. This can also be spread to other mucosal membranes it can be spread from the mouth to the anus for example. Viral Agents Herpes simplex There are two serotypes of herpes simplex, and they is some epidemiological distinction, but it is not a biological distinction by that we mean that serotype 1 is most common around the oral cavity on the mucocutaneous junction (between the lips and the skin) right on the edge of your lip is where you are going to have that infection occur. And it is going to appear as a blister. And there are going to be some early symptoms there is going to be a burning and an itching around that location about 48 hours before that blister will occur. The first time you get a herpes simplex infection, it is accompanied by the release of cytokines that are associated with flu-like symptoms aches, pains, and maybe even a fever this is the initial infection. This initial infection results in an attack of the nervous system at this point it attacks the trigeminal nerves around the mouth and such. After that, the endogenous source of the organism in the nervous system results in repeated infections. By the time you are 15, 85-95% of individuals have been seroconverted meaning they have antibodies to herpes simplex type 1. Many people were infected very early on for example, your aunt kissed you as a baby and she inadvertently infected you. And for most people (by the way, the % that did not contract and didn't produce antibodies does not mean that they were not exposed and infected it just means that they did not produce antibodies not everyone responds to the exposure if they are exposed) so the other 15-20% were most likely infected but only a few people will actually have repeated outbreaks. So, actually, the infection rate is very high, but the repeated outbreak cases are not very high.
Repeated outbreaks are directly related to a drop in T-cell immunity CMI response that can be resulting from a concurrent/concominent infection this is an infection occurring at the same time so we could see a viral URT tract infection, and then we would see a cold sore. Or we could have a fever blister, or we could have a fever that results from some kind of infection and that concominent infection triggers the response. The drop in the T-cell immune system allows the virus to become activated out of the nerve and it comes to the tip of the nerve and that is where it spreads to the skin so when you feel that burning sensation, you will already have virus at the site. After several days, T-cell response catches up resulting in a blister so the blister that you see is really a CMI response. It is more like a hypersensitivity (kind of like a poison ivy reaction) but it is a cellular response the blister is not caused by the organism. It is caused by the immune response to the organism at that site. A person is infectious from the time that they feel that first burning sensation, during the eruption of the blister, and you will be shedding for about 10 days after the blister disappears. There is about a 1% breakthrough virus that does not result in a blister. So, when you are otherwise healthy 1% of the time it is possible that you could be shedding virus that is how you probably were first exposed to it as a young child. So, remember after the 10 days after the blister disappears about 1% of the time, people will still be shedding that virus. This is type 1 which is typically found around the mouth Type 2 is generally associated with genital herpes. So, with genital herpes we will see a small rash of about four or five blisters or so it is not uncommon to have several blisters. In this general area there is a large amount of vascularization and innervation on the shaft of the penis and on the labia there a just a LOT of never endings to keep popping out the virus. One the mouth we just see one. There are the same general symptoms the burning sensation will occur, the blister formation (will take 4-6 days) and then we will have the shedding of the virus for 10 days afterwards. We will also see that 1% breakthrough shedding here also. So, because this is T-cell dependent there is an interesting link between psychology and the persons sense of themselves and the T-cell response. If you are very, very concerned about herpes and spreading it to your partner if you are very concerned about it, there is very increased risk that you will have a blister. Because you are worried about it, that stress will put a hormonal change in and that will affect the CMI response so prior to the discovery of HIV and other infection there used to be support groups for those who have herpes. Treatment We commonly use Acyclovir (an analog of guanine) to treat herpes infections. Basically acyclovir interferes with the metabolic function of the virus. Acyclovir is most effective if it is given IV it is somewhat effective (but must less effective) if taken orally and it is relatively ineffective when it is administered as an ointment topically. The use of the oral medication is dependent upon the immune status of the patient remember that this whole thing occurs in the first place because of a lowered CMI response so depending on the immune status of the patient this can be somewhat effective but it is not super effective. For example, if the persons blister on average lasts six days the drug will bring that time down to 4.5 days and if we usually shed for 10 days then the medicine will probably shorten our time to 7 days. It is not that great of results for a VERY expensive drug. It is a toss up for treatment. In the case of an immunocompromised patient though a herpes infection can get very bad they will generally go to the blood stream causing a viremia which then can cause an infection in the brain (an encephalitis) a meningoencephalitis (both infections together) it can cause a retinitis (an eye infection which can lead to blindness) so with immunocompromised patients (AIDS etc) IV use of this medication is very important, and it is very effective. If we give them a high dose IV the infection will clear up very quickly. So, the patient is in very bad shape, and in a week to 10 days they are much better off. The problem that occurs in these patients tend to have repeated infections and repeated infections mean that over the next 3 years they would have half a dozen of these infections. What we did in the first four or five dose like how much we gave or how long we used it for each outbreak the longer we used the drug, the more we select for resistant forms and generally
after several years that drug will not work anymore. So we end up with various kinds of analogs of these anti-viral drugs and eventually not work anymore. So, we have to keep developing new drugs so it is an ever-kind of catch up game. So, initially it is very effective but eventually we begin to select for the resistant forms of the organisms and then we have to go to an alternative form of the drug which then organisms will develop resistance to that so when we are dealing with a long-term chronic infection there is still an organism that we have to deal with that will become resistant to the drugs that we are using, and we will have to keep finding new drugs. It is easily treated right away. This is not a protective CMI immune response it is more of an allergic response so the lymphocyte response is not a protective response. This is an STD it can be spread by many different ways you can get this sexually and non-sexually so you can get this by direct contact the virus is stable on inanimate objects for days so in swimming pools and hot tubs we can isolate the virus but again the virus will not invade intact skin areas but it can invade the mucosal membrane another thing to think about this is this typing Type 1 above the waist and Type 2 below the waist this was one thought. The type of infection depends in large part on the kind of sexual practice that you engage in if you are involved with a lot of oral, sexual contact, you can easily get type 2 orally and type 1 genitally. It is not a biological limitation of serotype matching and receptor site matching it is more of a way it is just common spread so most type 1 is oral (commonly 70%) and most genital is type 2 (commonly right around 70% - but these numbers keep dropping) because the infections are going to other places oral-sexual contact. The other thing to be aware of about this is that the child can be infected at the time of vaginal delivery generally not in utero the infection can be very much asymptomatic and unlike bacterial infections like gonorrhea where we just assume the mother is infected we do not do this with herpes we do not treat at the time of delivery this will result in a tough call later on the tough call is when "do we think that the infection is now systemic and it is going to cause possible brain damage to the child or encephalitis and we have to intervene with acyclovir (to the child)." This is really a tough call and rather than even getting to this possible situation if the mother has a history of vaginal herpes then the mother is a good candidate for a Csection so rather than expose the child to a vaginal delivery, we would much rather just perform a C-section so we try to prevent this from occurring at all. We do not make any exceptions like if they are not feeling the burning it is okay to deliver vaginally because there may by shedding so we are now at the point where a little C-section could solve a lot of problems if the mother has a history of repeated infections even though the mother does not have repeated infections now we want to make this determination early in the pregnancy so that whenever she delivers it is going to be by C-section regardless of what she feels or does not feel we want to prearrange a C-section. Because once the baby begins to be delivered the water is breaking the baby is exposed to the virus so we do not want to do a C-section after the placenta ruptures (its already exposed) whats the point? We have kind of lost all of our advantage by doing this. We are probably going to do a C-section anyway, but we want to do the C-section before the actual "water breaking." We want to avoid that initial eye infection it can lead to a viremia blindness meningioencephlitis which can lead to mental retardation we can use acyclovir in the child at this point but there is already damage done. We need to catch things like these early. Treat the child early. These studies have even lead us as far as seeing that children infected at birth will even have trouble reading because they were infected with this virus at six months. They did not receive treatment until they were six months old. It is important to treat early.
Microbiology 7-11-05 Hepatitis A & E
These types of hepatitis are most commonly spread by a fecally contaminated water supply. Hepatitis A is much more common in the United States than Hepatitis E (more common in Eastern Europe and certain parts of Asia) so we have these fecally spread the fecal-oral route. One thing that we should notice is that there is not a chronic state for Hepatitis A & E. So basically, you can get this illness which can last for quite awhile it is not the common cold kind of thing but nonetheless there is not chronic state that we can find. What does this tell us about the virus host-cell interaction? If it does not go chronic what does this tell us? The virus does not integrate into the genome so it may be something that we could ultimately find soon good antiviral drugs for. If the virus integrated antiviral drugs would not do much good. Immunization We also have immunization both pre- and post-. Pre meaning that we can give you antibodies pre-exposure. So, for Hepatitis A we can give pre-exposure antibodies that IGG class of antibodies that is given to someone who has been immunized we use their serum as a source of protection for you. So, if you are going to a country where the chance of infection is high we will give you the pre-immunization immunoglobulins the antibodies. We could also immunize you, so if you plan to travel to an area that is of high risk of Hepatitis A or even in the US (if you are in waist-deep water helping flood victims that means that the sanitation system which is generally below ground is now mixed with the water on the surface and people are now walking through fecally contaminated water and Hepatitis A is a possibility) so we do have that group of people in that are in this special category (where it be travel or occupation) and we can immunize them against Hepatitis A which we would be giving the person antigen so that they can make their own antibodies (this would be long-term) we also have a short-term preexposure you know that you are going to be going to a place where the risk is high and we will give you some antibodies ahead of time. Or there is post-exposure where you ate a restaurant somewhere and later find out that there was a Hepatitis A exposure possibility so you will be given antibody post-exposure but it is recent exposure (yesterday) and we will give you antibodies that will bind to the free virus and this will reduce the chance of the virus to invade out liver. Now, there is already an exposure risk (it has been in the body for 12 hours) so there is a possibility of getting Hepatitis, but we can reduce that possibility by giving you already made antibodies. Remember that antibody will probably last six-weeks or so in your body (giving an antibody ahead of time, etc). This is not long-term protection whereas if we give you the antigen this will be long-term protection. Notice, that with Hepatitis E there is not much that we can do to prevent this it is not common in the US but if you travel elsewhere there is that possibility and we do not have any way of preventing it. Hepatitis B, C, D First, we must note that these are all transmitted by blood/blood products sexual transmission is possible with B, C, and D also can be spread by artificial insemination, tissue transplant, etc. As far as with transmission, it can go through openings in the skin; it can go through membranes a chronic stage is possible for all three of them. For Hepatitis B, we know that we have a vaccine that can be given. It is a recombinant DNA vaccine with the Hepatitis B surface antigen. We also have a post-exposure immunization and by post exposure that means that we are going to give antibodies so if you got a needlestick or something you could get antibody to Hepatitis B this is short-term (post exposure) again, this is not a perfect system, but it is better than nothing. You have probably had the virus in your body for awhile and the virus has already had a chance to bind to the liver depending upon the dosage that you got of it it might be too late but this is better than nothing there is at least something that we can give you.
Hepatitis C There is not much concerning prevention with this virus other than conventional ways of behavioral modifications, blood donor screening, safer sex, etc. But we do not have anything for the patient specifically. There is not pre/post exposure immunization. There is no antibody or antigen. Hepatitis D There is nothing here again specifically for pre/post exposure but there is actually a sort of pre/post exposure immunization that can be given it is just kind of tricky. D is a defective virus by preventing B you will prevent D. So, if you have been immunized against Hepatitis B, then you are protected against Hepatitis D. We do not have a D vaccine specifically. Page 32 of notes Chart Estimates of Acute and Chronic Disease Burden for Viral Hepatitis, United States It is possible to die of Hepatitis A there are a number of fulminant deaths per year which means as a result of the acute infection now these patients that actually died of Hepatitis A most likely were immunocompromised and their immune system could not handle the infection. The percentage that actually dies is not that great. There are a small number of people that actually die from B and so on. Hepatitis A is not chronic but with HBV, HCV, and HDV the chronic cases are significant this is a major problem. Then you can see the number of deaths per year from chronic liver disease per year. Geographic Distribution of HAV Infection Hepatitis A is definitely warned to travelers. The high rates are in Central and South America, Asia, Africa, etc. Hepatitis A Virus Transmission - Close personal contact close household contact (this is probably going to be associated with having a hygiene problem in your family sharing razors, toothbrush, no washing hands, contaminated silverware, etc this is common with people in small quarters (dorms even) if one person gets it other people will get it) - Sexual contact this is a very special situation it is possible but it is not going to happen and it will not happen for exam purposes (but what is happening here is anal intercourse followed by oral intercourse fecal-oral contact) - Children are at risk also again, this is a personal hygiene problem we have kids in diapers in daycare centers - Contaminated food, water (infected food handlers someone in a fast food place does not wash their hands and raw shellfish bottom feeders the sanitation system goes out to the shoreline of the ocean and the shellfish will get contaminated the shellfish will concentrate the organism than in the water around it) - Blood exposure (rare) this is a very UNCOMMON way of getting this and we will not include this as a spread for our multiple choice questions for the exam. (If someone has Hepatitis A and then they are a drug user (transfusion) it can be spread BUT if you said this since it is so rare, youd have to say that ANYTIME you are sharing your blood you could get any disease that anyone has) This is theoretically possible but NO!
Hepatitis A Clinical Features Incubation period: Average 30 days; Range 15-50 days Jaundice by Age Group: We are going to expect to see jaundice with Hepatitis A in different involvement with different age groups this is bilirubin build-up in the whites of the eyes (all races predominately in Caucasians) and skin. < 6 years, <10% - so children in the daycare center do not develop jaundice. 6-14 years, 40-50% - so the older you are, the more likely that you are going to develop jaundice. We are seeing a symptom that has an age factor to it this is not an unusual observation we should keep this in mind. > 14 years, 70-80% Complications: These are the situations that result in the death of the patient from Hepatitis A the patient could have an underlying problem with their liver maybe they have a gall bladder problem, and they already have an underlying problem with their gall bladder so that is a problem. - Fulminant hepatitis - Choiestatic - Hepatitis - Relapsing Hepatitis we are really not sure what this is it is possible of this happening maybe with multiple exposures Chronic sequelae: (A pathological condition resulting from a disease) NONE (IMP!!!) Hepatitis A Virus Infection Page 34 of notes
Typical Serologic Course
With Hepatitis A, we are going to look at the titer (this is an indication of the concentration) this a reciprocal of the highest dilution that gave us a positive test the further you can dilute something out that means the original blood had a very high concentration. The higher the titer the higher the amount of the virus or antibody depending on what we are looking for. ALT is a transaminase, and we will see this transaminase rise up at about 3 weeks (it is element independent) so this basically indicates liver cell destruction in a broad sense transaminases are a link to other cells so it is a factor but not a unique factor because if someone is having a heart attack they will have muscle cell damage in their heart and they can have a rise in transaminases as well. So, we are going to see an elevated transaminase commonly and then that will drop off about a month after exposure. So, we have two different kinds of antibodies we have IgM anti-HAV (anti-Hepatitis A virus) and this IgM is our first antibody so we produce that early on maybe after about a month and then your lymphocytes will switch and we will produce a memory response which is going to be IgG. The difference then between the IgM line and the total line is the amount of IgG so initially, we will only have IgM and then it gets to the place where we will see IgG (and that is the difference between the two lines) and after six months or so it is all IgG IT DOES SAY TOTAL but the difference between the total line and the IgM line is IgG the memory response.
So, when we are testing someone, we can find the antibody to the virus in their fecal material beginning about 2 weeks and lasting to about 6 weeks after infection. This means that the patient is shedding virus before they see any symptoms. They are shedding virus at two weeks they do not know it yet but it is easily transmittable right now (sharing a spoon for example) you can get the virus when someone is shedding it. The elevation of transaminases occurs before any symptoms start also. Then there are the physical symptoms (for all varieties of Hepatitis actually they are pretty much the same): vomiting, abdominal pain, fever, and jaundice (these will vary from person to person). If the vomiting lasts for several weeks this is obviously not good you should get checked for this. How do we handle this epidemiologically? Hepatitis A Vaccination Strategies Epidemiologic Considerations - Many cases occur in community-wide outbreaks (we want to look at community protection people changing diapers, daycare, etc.) - No risk factor identified for most cases - Highest attack rates in 5-14 years old - Children serve as reservoir of infection - Persons at increased risk of infection - Travelers (highest risk) 99% - Homosexual men 0.5% - Injecting drug users 0.5% Hepatitis E Virus The outbreaks here are in the European areas, etc. Page 36 of notes Hepatitis E Clinical Features Incubation period: Average 40 days; Range 15-60 days (similar to A) Case-fatality rate: Overall, 1-3%; Pregnant Women, 15-25% - We are not exactly sure why on this one It might have something to do with the immunocompromised status of pregnant woman the mothers immune system is a little out of sorts during pregnancy because of the baby so therefore if she is infected during pregnancy she is of greater risk to die for this. Illness severity: Increased with age Chronic sequelae: None identified Hepatitis E Virus Infection Typical Serologic Course We see kind of the same thing here as with Hepatitis A, we see the viral shedding that occurs with the symptoms, but IT ALSO occurs before the symptoms occur we have to remember that is someone develops the symptoms they have been shedding the virus for a period of weeks before that we see the elevated transaminases again we also see IgM and IgG. Hepatitis B found early in mental institutions actually We find this infection high in the costal regions Greenland area, we see it near the equator in Brazil, Africa, and other parts of Asia these are all high risk. These are areas where 8% of the population or greater are infected.
Risk Factors for Acute Hepatitis B United States These are kind of standard ways to be infected: heterosexual activity, homosexual activity, IV drug use, household contact, health care workers, etc. But there is a large (31%) percentage that is unknown. We do not know what that group is but we do suspect that these are the people that do not want to admit that they fall into another category people who are having multiple sex partners, etc. This is not really a whole new category these are just people who do not want to admit that they got Hepatitis B a certain way. Multiple partners is a term that is not limited to multiple partners at the same time we are talking about people who have had multiple sexual partners in their life. Hepatitis B Clinical Features Incubation period: Average 60-90 days (much longer); Range 45-180 days Clinical Illness: Jaundice the younger you are, the less likely you will see jaundice so if a child is born to a mother with Hepatitis B the child will get Hepatitis B in utero this is very common reason why so many people have Hepatitis B because they got it from their mother. The older you are, the more likely you are going to see jaundice, but it is still not that great. < 5 years, <10% > 5 years, 30-50% Half the people who have Hepatitis B will not show jaundice, so people may not know because they do not have physical symptoms. But you can have Hepatitis B without having jaundice. Acute case-fatality rate: 0.5-1% (fatality rate) Chronic Infection: The younger you are the more likely you are going to be chronic so those that are born with Hepatitis B they are in the 90% range of becoming chronic. So, all of those people who are born with Hepatitis B (especially in Africa and Asia) are born with a chronic infection they will have it their entire life and can spread it to other people that entire time children are a good reservoir. < 5 years, 30-90% > 5 years, 2-10% Premature mortality from chronic liver disease: 15-25% Someplace between 10-12 years or so after you have had the acute infection, you will die of liver disease. This liver disease can be of one of two varieties this can be a liver cancer or it can be a total collapse of the liver (liver failure). So, this is a fairly significant figure in terms of chronic Hepatitis deaths. This is why we immunize.
Outcome of Hepatitis B Virus Infection by Age at Infection Page 39 of notes We can see with this chart that if you were born with Hepatitis B, 90% of the people who were born with Hepatitis B who got it from their mother will have a chronic case of Hepatitis these
people also often will have no symptoms at first. On the other hand, the older you are, the chance of developing a chronic infection will go down. Now, there are several ways that the Hepatitis B virus can interact with our bodies THIS IS GOOD EXAM MATERIAL Acute Hepatitis B Virus Infection with Recovery We are going to begin talking about symptoms that you can actually see and those are going to start around 2-3 months and they will last for about 4 weeks or so this is the vomiting, fever, abdominal pain, and maybe jaundice. Then we can take a look at our serum, and we can find a variety of things both antigens and antibodies first we will look at HBsAg (Hepatitis B surface antigen) we assume this to be the virus we can isolate the virus about a month after you were exposed which would be before the symptoms occur, and you were definitely infectious early on in the disease process you were infectious before the symptoms occur. We then have a peak of this HBsAg at about 3 months and the HBsAg starts to disappear. (We see this on the left side of the chart) On the other side of the chart, we have this antibody to HBsAg. This is the immune response (anti-HBs). The antigen disappears, and then the antibody appears. Why is the antigen disappearing? (Its not because the virus is being cleared from the body integration can occur with this virus also but this not why it is disappearing). The antibody begins being produced earlier than when we are actually seeing it on the graph so as the antigen is declining, it is declining because it is creating an immune-complex, and we have antigen/antibody complexes in that "dead space." So, the antigen disappearing corresponds with the production of antibodies it is only when you have gotten rid of the free antigen that you start developing free antibodies. We learned this the hard way with blood donation we thought that if we didnt find the antibody or the antigen then we were okay to use the blood but what happened was we didnt know about the "immune-complex" status the serological tests for FREE antibody/antigen were all coming up negative when the antigen and antibody are in a complex so this person is actually fully infectious at this point but we missed them. So we gave this blood to someone thinking that it was okay and the recipient came down with Hepatitis. When we have this period of time where there is no antigen present (surface antigen) and no antibody present we call this the window period. So, now we have a different system we do look for the antigen for HBsAg but we do not look for the antibodies we look for the antibodies to "core." Now, we have IgM anti-HBc (so this is an antibody to the Hepatitis B core) and then we have the total and of course the difference between the total and the IgM is the IgG (memory). So, we will look for antibodies to (Hepatitis B core Ag) which are anti-HBc and we will look for the HBsAg (Hepatitis B surface antigen) so we look for the antibody to core and the surface antigen for Hepatitis B. If we look for these things we are really covered from about four weeks on. We start out with the antigen (HBsAg) and as this antigen lowers down because of the immune complex, the antibody to core is there. And these antibodies are carried out for many months. So, now our only problem is knowing what that person has been doing for the last 3-4 weeks. They do not have symptoms yet. We want to try to find those people who fall in this early category of Hepatitis B by asking lots of questions about behavior, travel, etc. So, we also have this antigen it is the Hepatitis "e" antigen and this appears early on.
Progression to Chronic Hepatitis B Virus Infection Typical Serologic Course
This HBeAg appears about the same time that we find the HBsAg, and then we will pick up an antibody to HBeAg (anti-HBe). Now, this HBeAg and anti-HBe is going to be important in determining the chronic infection. The patient who will develop the chronic infection generally does not produce the antibody to HBeAg. A patient who will fully recover (no long-term effects) is going to develop this antibody to HBeAg. Everything will work out for this patient (there is not integration and there is no chronic disease). This is very good because this patient will only be sick with the initial effects of Hepatitis B. So, we will look for this anti-HBe as a marker for chronic infection if you do not develop antibody to HBeAg this is not a good sign. Page 40 bottom graph Here is someone who is moving towards a chronic infection. This patient at 6 months to several years still hasnt developed anti-HBe. Only later (this might be 10 years later or it might NEVER occur) will they develop the antibody to HBeAg. The chronic patient also has HBsAg and they do not develop the antibody to it. So, there is no antibody to HBsAg there is no antibody to HBeAg. This is not a good sign. We do develop antibody to core both the IgM and the total and IgG is the difference. There is not antibody to HBeAg or HBsAg and what we are going to look for in these patients is this antibody to HBeAg. With a chronic infected person, they will produce antibody to the core both IgM and IgG. So, what if a person was immunized against Hepatitis B? What would it look like? What were you immunized with? We were immunized with a recombinant DNA product manufactured in a yeast organism where we make these genetic deletions to the virus HBsAg and we take this genetic information and inject it into a yeast organism and take that organism and introduce it to HBsAg no virus just the surface antigen. This is what you have been injected with just the HBsAg. So, we will produce antibody to the surface antigen. So if you want to know the difference between someone who has been immunized and someone who has been infected we can look for certain things. If you only have antibody to HBsAg and no other antibodies or antigens then you have been immunized. Based on antibodies and antigens we can have a sense of past infection (anti-HBe, anti-HBc, and anti-HBs), current infection (HBsAg, anti-HBc, HBeAg), chronic state (anti-HBc, HBeAg, HBsAg) or immunized state (ONLY anti-HBs). Know these. We should know what kind of antigen/antibody levels mean what know general time frame for immunization times and length of disease in general B, C, D have longer incubation times, length of infections, and a higher rate of chronic problems. Just have a general idea of the incubation period. Age at Acquisition of Acute and Chronic HBV infection Acute infections are more common in adults, and chronic infections are less common in adults. Children are much more likely to become chronically infected. Concentration of Hepatitis B Virus in Various Body Fluids It is low/not detectable in urine, feces, sweat, tears, and breast milk. If there are other options available, it is probably safer NOT to breastfeed even though the levels are not detectable or very
low. If the milk is safer though because of cleanliness then breast milk is safer than the water to make formula. There is high risk of the virus in blood, serum, wound exudates (fluid), semen, vaginal fluid, and saliva. Immunization and Number of Cases The number of cases dropped significantly when we started immunizing. Infant immunization was very important. Chart on page 42 of notes. The younger children are at the greatest risk of getting the chronic infection they are also then a reservoir of the virus in the population that is why we want to immunize these children first. Then these children become adolescents and we can "boost" their vaccine. It is ideal to "boost" around 12 years of age or so or at least before college. We want to do this before you get too sexually active. So, really this vaccine stops an STD, and it prevents cancer. So, it is a really good thing. Also, this vaccine also prevents against Hepatitis D. Elimination of Hepatitis B Virus Transmission in the United States - Prevent prenatal HBV transmission - Routine vaccination of all infants - Vaccination of children in high-risk groups - Vaccination of adolescents - All unvaccinated children at 11-12 years of age - "High-Risk" adolescents at all ages - Vaccination of adults in high-risk groups Hepatitis D (Delta) Virus This virus is often referred to as the defective virus. The Hepatitis D virus will only replicate in liver cells that are already infected with Hepatitis B. This is where the defective part comes in. Hepatitis D Clinical Features - Co-infection - Severe acute disease - Low risk of chronic infection This co-infection is an important aspect of this infection. - Super-infection this person already has a chronic Hepatitis B infection, we add a second agent that becomes chronic HDV infection. So, we are putting the liver under a lot of stress. The liver is an amazing structure it takes a lot of abuse. It can regenerate itself, but we are putting a lot of stress on our livers when we drink because we are inducing those enzymes it is an inducible system. This will result in some liver damage. So, if you have degree of liver damage already and then you add more by this virus there is a very high risk that the patient will develop a severe chronic liver disease LIVER FAILURE. If you have one of these infections, you have to give up drinking, etc. because you have to be careful with whats left of your liver so maybe you can outlive the infection. HBV-HDV Co-infection Page 44 of notes Typical Serologic Course We look for the HDV RNA the genetic information for that virus we also look for the HBsAg. We also look for the anti-HBs.
HBV HDV Super-infection Page 45 of notes Typical Serological Course We will see the HBsAg and no antibodies we will see HDV RNA. Without that antibody to the antigen you know that this patient is going to be a chronically infected patient. What other antigen should we find in this patient w/o an antibody to it we should expect to find HBeAg without an antibody to it. These things are all consistence with someone having a chronic Hepatitis B infection and we find the HDV RNA so we know we have a co-infection going on, and the liver is under even greater stress. Again, the liver is going to try to repair that damage by regenerating more cells and the result of that is going to be additional liver damage and we have erosion of the liver and scarring of the liver and hardening of the liver etc. There will be antiHDV IgM and IgG. Hepatitis C Clinical Features There is a 1% prevalence of Hepatitis C in the United States Incubation period: Average 6-7 weeks; Range 2-26 weeks Jaundice (clinical illness): 30-40% (20-30%) Not a good indicator of Hepatitis Chronic Hepatitis: 70% There is no protective antibody response there is no vaccine Persistent Infection: 85-100% Immunity: No protective antibody response identified Persistent Infection means that the virus has integrated into the host cell genome we cannot get rid of this one. Risk Factors for Acute Hepatitis C in the US This is a major concern of ours because we have a vaccine for Hepatitis B not for Hepatitis C and there is a lot that goes with this! IV drugs users, STDs, household, transfusions, occupations, etc. There is a big unknown here. There is no rational basis for this socioeconomic status. With this category we really do not know if these unknowns are in other categories or if they are really unknowns. We do have a way to prevent the spread through transfusions. By doing this, we stop the spread the first test was good the second test was better. This is one mechanism of spread that we can minimize. We do not know all of the mechanisms of spread, so this one is tough to stop. We do know how to protect ourselves sexually though. Hepatitis C Virus Infection Typical Serological Course Because of this persistent infection, we are going to see various rounds of damage done. So, we will see the transaminases elevate and then come down and then they go up and down and up and down they tend to go all over with persistent type infections. We do develop an antibody to the virus but that rises very slowly. It occurs over years. See Page 48 of notes to counsel on HCV These people will be Anti-HCV positive.
The treatments for Hepatitis are not all that great we use interferon treatments for some of them there are not great anti-viral drugs those that we do have are not that effective. We really do not want to use anything that will put pressure on the liver esp. a TB patient know whats going on. Viral Agents: Cytomegalovirus (CMV) This is referred to as "mini-mono." The symptoms are similar to mono in terms that we have a fever, swollen glands, and fatigue these symptoms are so similar that when people are feeling this way they may think that they actually have mono but the mono test comes up negative. It does not do what mono does. This particular agent involves the liver. People think that they have mono and do not they have CMV. It is a sexually transmitted disease so it is common in college-aged students 14-25 years. Most people tolerate this without any problems. But if you are immunocompromised this can be a much more serious infection it can involve a brain infection it can involve a retinitis so this is much more of a serious infection for immunocompromised people. If an average person gets this (they probably got it by sexual transmission) and they are usually not immunocompromised this occurs in normally healthy people and has NO serious outcomes. People who are transplant patients are on immunosuppressive drugs, so the transplant that they just received is not rejected by their body immunocompromised. Actually, these patients that are immunocompromised are much more likely to have the virus spread to the bloodstream so then we have a systemic spread of the virus to the bloodstream it then invades the brain causing encephalitis and a retinitis. This virus is actually one that we have found on the death certificate of AIDS patients obviously contributing to the cause of death (there are a lot of viruses in the blood of an AIDS patient its hard to say what killed them).
Microbiology 7-12-05 Human Papilloma Virus (HPV) This virus is often known as the genital wart virus. Genital warts can be found on the labia, shaft of the penis, on the cervix, around/on anal openings they usually start with a really small blister maybe 1mm or 2mm across like a little water blister basically just like a wart that you would get on your hand or something. There can be one or several. There can be a cluster or "rash" of them 5 or 6 of them all together. If left alone, they generally get bigger unlike a wart that you would see on your hand. In extreme settings, they could be as much as 2cm off of the skin and as much as a couple centimeters across it can sort of look like cauliflower because of this uneven bubbling on top of itself. It wont be a blister it will be a rough uneven growth that is just like cauliflower. The typical situation is that they can be removed by nitrogen (burn them off), cut them off this is largely cosmetic, but you really do not get rid of them although there probably is some kind of reduction of the virus in the area but it is nothing that can result in any real significant outcome or change. So, people who have these will tend to keep them. So, we can remove them before they get too big but they will come back. These warts, in large part, are more of a nuisance than anything else. However, obviously they are spread sexually. If the mother has the release of the virus during a vaginal delivery the child can be exposed, and we will see a growth on the vocal cords which usually is not noticed until about two to six months after delivery this is something that a physician will
look for in a normal workup of the child like at their physical or for their immunizations or something. What will happen is that little nodules will grow on the vocal cords. These can be easily removed surgically. Something of grave concern is that a few of the 80+ serotypes about 3 are associated with cervical cancer so now we have a cancer that is spread sexually (Hepatitis B is also a cancer that is spread sexually). Now, there are only a few serotypes and typically in a clinical setting we do not determine the serotype. We observe that you have the genital warts and we remove them. But we generally do not do additional biological testing to determine the serotype of it because it is expensive and there is no certainty that you will obtain a pure culture so that means that a sampling of one part of the cervix does not mean that another part of the cervix does not have that particular serotype that causes cancer. This could result in false hope or in a false promise. It is too hard because you cant swab every area on the cervix or you could pick up some other serotype or some other disease along the way. So, therefore even though there are only a few serotypes associated with cervical cancer any woman that has genital warts is going to have an increased frequency of pap smears done. If there is any dysplasia or anything unusual, it is going to be looked at with a little more curiousness if there is a history of HPV. Now, there is some good news there is a vaccine that has been developed and it is effective it is highly effective in preventing the initial infection. They didnt even continue the trials because the vaccine was so effective and so safe. It has come into a snag however with the CDC they were afraid that if they made the vaccine readily available to pre-teens (8-12 year olds) that they would give them some sense that they could have the liberty to have unprotected, premarital sex. So, because this group thought that it might increase sexual activity among the younger population, this vaccine was not put out and made readily available. This is very shocking because we actually have a vaccine that can prevent cervical cancer it is a no-brainer scientifically to use it and everyone should be immunized against this. It could be given to both males (so they dont spread it) and females to PREVENT cervical cancer. This is what we want so why dont we use they dont make the same claim about Hepatitis B even though that is an STD also (this vaccine prevents and STD AND prevents a cancer also). So, we really do not understand what is going on because it is readily available it is just not regularly advertised. So, hopefully, this will change because it is sad that so many women will develop cervical cancer, and it could have been prevented. They will probably develop cervical cancer when they are 27 or 32 because they contracted this virus when they were probably 14 or 15 and this all could have been prevented. HIV-1; HIV-2 Notice that we have numbers associated with the letters. We are going to talk a little about some serotyping, but to fully understand that we are going to take a look at the overall classification of viruses. Retroviruses We have this general category of viruses called retroviruses of which there are three categories: Oncovirus in cell culture this stimulates the proliferation of cells (stimulates cells to divide) Spumavirus which in a cell culture is called a cytopathic effect (CPE) in a cell culture this is causing the destruction of cells they round up they change their shape from the normal flat shape to a rounded shape they fall off the monolayer (normally they grow there) they will lose the ability to have contact inhibition normal cells will come up to one another and not grow on top of each other this CPE will allow the cells to clump the cells will die etc. So, obviously these will damage the cells.
Lentavirus associated with a slow viral destruction Lentaviruses have several different members: - Lentaviruses are all associated with the ability to bind to and infect T-cell lymphocytes so: - HTLV I (Human T-cell Lymphotropic Virus) this is associated with adult T-cell leukemia - HTLV II associated with hairy cells leukemia Worldwide, we do have tests for these but in general, the US does not test for these viruses in the blood supply so we do not know who has these viruses, and we do not know who got this from a transfusion, for example. Since we do not test for these agents this fits out concern that we do not give transfusions without a GOOD reason. The best transfusion is no transfusion the next best transfusion is our own blood but this is not always possible. - HIV 1 (HTLV III) this is an immunodeficiency virus which initially we called HIV-1 and 2 which initially corresponded to the early classifications (HTLV III and IV) - HIV 2 (HTLV IV) We do not worry about these classification systems anymore because they have fallen apart we do look at what called clades clades are a cluster of serotypes and we have a clade analysis, and the clades are given letter names so A, B, C, D, and so on it is not a single epitope it is not a single antigen it is not a single serotype but they are clusters that we put into groups? so we cluster them. The reason for this initially is so that we can develop vaccines for the appropriate clade variety (serotypes) that would be associated with the population to be immunized. So, then we found, for example that A and B clades were found in the US and Europe so to make a vaccine for the US and Europe we just put those clades in there. This obviously did not work. This idea fell apart for many reasons because the virus kept changing all of the time and spreading around the world so if you look at the millions of people who are infected the mixtures of clades are common now so a clade that was once unique to China is popping up in Chicago now - etc. It is mixing up. The bottom line is that we are dealing with a ssRNA virus it is single-stranded therefore it makes multiple mistakes and therefore it changes and there is no way to fix it. So, the virus is constantly changing even within a patient from their early infection throughout their entire infection their serotypes will change so that makes it more difficult to develop a vaccine. The serotypes are just too far ahead of us. So, then what we did was we looked for a conserved region of the genetic information an area that did not change much and we used that as our basis for a vaccine it was found in all clades (in HIV-1 and HIV-2). The problem with that particular vaccine approach was that sure enough you did produce antibodies to it so the vaccine was sort of a success BUT it did not influence the outcome of exposure because the antibodies were not protective. We are really not working on this vaccine anymore. A clade is a cluster of serotypes it was an attempt to get a handle on these ever growing varieties of antigens from the surface of the virus and so we grouped them into clades so if we have a certain glycoprotein we will call that clade A so there will be different groups of glycoproteins that we might call "789" but there are different clades. The problem is that the variations are far greater than we ever thought that they would be. They are not stable. When we make vaccines for most viruses we are using one surface antigen this is one thing we know what the virus is we respond to it we are protected from it then we are done. With HIV, this is not the case so although we have HIV 1 and HIV 2 and although we have these clades we do not worry about these things anymore because there are just too many different varieties.
See page 50 of notes to see the numbers for HIV infection There may be 40-50 million people living with AIDS worldwide now. The epidemic began in SubSaharan Africa the infection started out greatly with male homosexuals, but it very quickly evened out in the population. It spread out into the general population. The number of people who have died from the beginning of the epidemic to 1999 is about 16.3 million not it is probably close to 30 million. The US probably gets about 45,000 new cases of HIV every year. It fluctuates a little bit when everyone is concerned then the numbers start to drop. People controlled their sexual behavior. Now, the only people who do not have any kind of control of contracting this are children whose mothers are infected so if a child is born to a mother with HIV, there is a 30% chance the child will be infected if we give the mother AZT during the pregnancy the numbers will probably drop down to 5%. HIV/AIDS Global Pandemic Beginning in the of this pandemic, in the early 1980s it took 7 years for the first 50,000 to die then it took 17 months to get the next 50,000 etc. so the epidemic nature of the spread of the disease is pretty clear. All of the advertisement about AIDS has saved lives. Schematic of the Course of the Disease The time following exposure in the first six months you are going to be symptom-free maybe even 10 months but then you are going to have a period of up to 3 years you are going to have a fever and maybe some swollen glands you wont start seeing any real effect on your immune system until after 3 years 6 years and that can lead to an increasing amount of normal infections. So, we start developing normal diseases that increase in frequency. Then after about 5 years, we start to see an increasing number of opportunistic infections. These are not totally unusual infections, but we wouldnt expect them in normally healthy people thrush in the mucosal membranes all over. Then we have the collapse of the immune system which will result in death. If we look at our lymphocytes we then the counts go up and down and first then down, down, down, etc. We can see the normal range on the chart then the significantly decreased T-cells (depressed) and then severe T-cell depletion. The dotted line is viral RNA copies per mL. So, notice that early on in the infection, we have a high amount of virus in the blood stream then it will start to stop down but then it will start to rise again to get to the first amount of the virus in the blood. So you actually have the highest amount in the early stages, and then you WILL gradually get back to that level again but not for many, many years later with the collapse of the immune system. Lets talk about the CD4 these are you T-cell lymphocytes (your helper T-cells) the CD4 count normally runs about 550 to 600 or above we will diagnose you will AIDS now if you have the virus in your bloodstream, and you have low T-cells 500> count. So, what we have done is we have set guideline to a person having AIDS. Once you are HIV + and you actually develop AIDS we have no way of stopping the process of this disease developing. It will continue on. So eventually we just say HIV/AIDS they have the disease. So, we are able to (with the name change) to say a person right away has AIDS allows the federal government to allow money to buy the drugs that people need prior to this they had to wait until people actually were declared that they had AIDS and by that time, they were 72 month along and those drugs were not going to help. So, we are treating people earlier we are defining the patient as that they have what they have earlier and that is probably for the good in terms of the patients long-term care. The drugs are very expensive though. See graph on Page 52 of notes. Immunization of HIV
So, in our efforts to figure out how to make a vaccine we began that process and we found many potential targets for a potential vaccine. Reverse transcriptase was something that we needed to look at for either a vaccine or a drug we could also test for the viral RNA. We started to look at glycoprotein 120 (which is sometimes put together with 160) but we have a glycoprotein on the surface that we were going to try to use for the vaccine. We have analyzed the genetic information to try to see what we could use glycoprotein 160 is precursor to glycoprotein 120. These were the targets for our initial vaccine. The importance of the 120 is that it interacts with the surface receptor site of CD4 found on the helper T- cells, and it is also found on macrophages so this was a good thing then because this was a natural receptor site interaction so it made natural sense to develop an antibody to this to block the receptor sites and we could then develop a vaccine. So the vaccines are not going to be all that effective, so we are going to have to develop appropriate antiviral drugs. We are concerned about this virus in the bloodstream spreading from person to person during transfusions so we have developed testing. The testing is a test for the antibody. We are testing for the antibody we can test for other things (antigen) but when we are testing the blood stream, we are testing for antibodies. These antibodies to not develop to detectable levels in all patients until as much as six months after infection so we do not get over 90% of the production of antibodies until six months after the infection. If you were exposed and you do not develop antibodies when we test yet it does not mean that you are not infected it just means that you arent positive you just dont have the antibody. If you are exposed, you will have to wait at least 6 six months before you know anything. The six month window starts every time you are exposed. Serological Testing There are two basic tests we first do a screening test (Elisa) and then we have a confirming test. We can adjust the reagents and the concentrations so that the screening test is made with a high degree of sensitivity meaning that we will have very few false negatives and we may have structured in some false positives so the first test that we do is going to have very few false negatives (it will pick up all of those that are positive for the antibody and maybe a few extras that are false positives). The second test is screwed in the other direction by adjusting the reagents, the Western Blot is skewed in such a matter to reduce the number of false positives so that we can kind of clarify the situation. With any given test, there are some terms that we need to understand completely Sensitivity: Likelihood of +ve person testing +ve for test results Specificity: Likelihood of a ,,ve person testing ,,ve for test results And a key term is called a Positive Predictive Value: the likelihood of a positive test being a true +ve in a given population. Is it positive or false positive this should help. Now, notice that we now have a new factor in a given population we must have an UNBIASED population so we have a better chance of coming up with reasonable numbers. If were to test all new army recruits, we would have a higher incidence of false positives because we did not pre-select them in any manor than if we were testing people in an STD clinic. The first screening test is designed to give us more positives by eliminating any false negatives only if you are positive on the first test will you need to be tested with the second test. So, we have two tests the Elisa and the Western Blot. So, when we talk about the positive predictive value the patient population is a factor in determining the effectiveness of what that positive test means.
Microbiology 7-13-05 Serological Testing The ELISA test is the Enzyme-Linked Immunosorbent Assay, and as a result what that does is basically we will have a prepared antigen the patients sera will provide the antibodies and we will then use an "uncle-body" (an antibody to an antibody) that is internally linked to an enzyme.
We have the prepared antigen and then we add the patients antibody and to that we add a reagent "uncle-body" (anti-human IgG) and then we have this "uncle-body" complexed with an enzyme. So, we have an antigen there; we add the patients sera; and then add the reagent of "uncle-body" with the enzyme and we finally add the substrate and there is usually a color change so we can read it. We can also read it in terms of HOW MUCH color is there a quantified reading as well as a qualified reading did it turn color or not? So, we can read this several different ways. With the substrate-enzyme complex, there is often a color change and the only time there is a color change is if the enzyme is there and the enzyme will only be there if the "uncle-body" has found a target. This is an odd complex of things. We also talked about an "uncle-body" in terms of the fluorescent antibodies. So, with the ELISA test there are several different enzymes that we use. The "uncle-body" is important because we have to understand the parameters of the test and we are only going to look for patient IGG. And then we have the antigen and this is an area that we have to address in more detail. We are going to look at the ELISA test in terms of these "uncle-body" reagents. It was brought to our attention by a group of people that they have discovered some children whose mothers were HIV+ -who were HIV+ at birth but about three to six months after birth they were cured. This was very interesting. They thought that there was a natural response to the organism that results in protection this is a so-called correlative immunity these children are somehow fighting the virus. So, we asked the people doing the study how they did the test so they used the "unclebody" to IgG we know that only 30% of the children born to a positive mother are going to be positive and the rest (70%) of the children are going to have maternal antibody that crosses the placenta and that declines with age so the mothers antibodies are going to disappear at about 50% every 30 days so it will keep declining and as it declines this test is going to recover less and less positives THIS BABY WAS NEVER INFECTED. We are looking for maternal antibody that is disappearing we are not looking for the IgM what the baby would use produce if the baby was infected they would have had to use a reagent that has an "unclebody" to look for human IgM NOT the standard reagent which is usually used against IgG. So, they re-did the test, and they saw the error that they made. The standard reagent looks for IgG which is what we would expect to find in a patient who is positive. They used it as a research tool without thinking. 70% of those children were never infected and all of them at birth will have antibodies from their mother. Only 30% will have IgM their own antibodies. We need to understand the reagent. The other thing to think about is the antigen on page 56, there are a variety of antigens that we are looking for remember that we said that we are dealing with an ssRNA virus and that this virus has lots of mutations so there are a lot of antigens that change (the glades and the serotypes all fell apart). So, for vaccine purposes, we want to look for a consistent or conserved
region of nucleic acid that would produce a consistent protein and we found the glycoprotein 160 (120) and we tried to use that for a vaccine, but it did not result in protection but it DID produce antibodies. Well, we have this same sort of problem when we talk about testing what antigens do we test for? So, what we do is we test for more than one thing. As we can see on the diagram on page 56, we can see a variety of gene products that we can use on page 57; we can see some of the strips that we can use. All of these strips had more than one antigen on the strip. So, when we put the "prepared" antigen on the plate to add the patients antibodies to we are really talking about antigens. So, we when we do the ELISA we actually have several antigens on the strip (five for our example) we needed to make a determination and say that a certain number of those have to be positive in order for you to actually be positive. So, if you are positive on the screening test for only one or two of the antibodies then you are probably negative for the test. But we will probably test you further. If you are positive for three or four of these then we are a little more concerned and we will put you into the indeterminate status (we cant say youre positive but we will probably do more testing). But if you are positive for all of them then you are positive for the test. So, not only do we have to deal with the idea of false positives, but we have to deal with the idea that we have more than one antigen that we are looking for. So, there is a gray area some other infection or some other immunization have made them more sensitive to the test we are talking about those people who were first immunized with the Hepatitis B vaccine which actually contained the AIDS virus. We actually isolated Hepatitis B from the sera of people infected with Hepatitis B to make the vaccine. Those people were mostly male homosexuals, and they had HIV also. We have to watch these people because they will light these antigens up even though they are NOT positive. They have been exposed to killed viral proteins, but they have NOT been infected. Because of that exposure, they produce a wide range of antibodies to HIV as if they were infected, but they werent. They will have a very weird reaction. This is the reason why we all receive recombinant DNA vaccines so we can avoid these kinds of problems. We do the ELISA test first then we do the second test the Western Blot. The Western Blot is a separation of proteins so we have this test for all of those who were initially positive and this will tell us how many of them are truly positive. This is a double-screening procedure. Remember to think of the population being tested. If you were selected because you have other STDs, then youre positive will more likely mean it is a positive if you were selected as part of a general screening then in that particular setting has less of a chance of that initial positive actually being positive. Know the circumstances for why you are being tested. So, if the first test comes up positive it is imperative to wait until the second test is done to make sure that you really are positive. HIV patient Now, HIV patients will also see a drop in their CD4 levels so they will be more prone to certain infections. They are going to be sicker more often. These CD4 cells are those T-helper cells so we are going to see a drop in that and we are going to actually see more of those opportunistic infections occurring these agents do not generally cause infection in an otherwise healthy individual. Now, this is not going to be a hard and fast line. The history of this patient is going to be that their T-cells decline and they are going to have more COMMON infections than normal, but an individual infectious agent by itself is not abnormal. But if a patient has shingles (reactivation of chicken pox) along with mycoplasma pneumonia infection (stimulates T-cells to divide) a history of repeated infections is going to tell us that something is NOT quite right so the actual infectious agent is not unusual it is the frequency. Then we get the opportunistic infections and we have this history of repeated infections, and now we are coming down with unusual agents (Candida albicans, RSV, etc will start popping up even TB most people exposed to TB will come up skin test positive, but the will not actually get the disease if you get the disease this should be a red flag). ( do AIDS tests for these diseases if you come down with one of these)
So, between the ages of 14-25 years old, there is a greater frequency of multiple sexual partners and as a result that age group is more inclined to get an STD, and if they get an STD they should be tested for HIV. If a person is HIV + and their immune system is declining, we should expect that they might run into these diseases, and we want to prevent them from getting one of these diseases. We will be on the alert for these diseases early pneumonias one agent that we should particularly look out for is Pneumocystis carinii pneumonia (opportunistic infection parasitic organism) this something that we will only see in very immunocompromised patients this agent is actually part of the normal flora (it is present in individuals on and off without causing any disease not everyone has this but some people do and it causes no problems). (Sulfa drugs treat this organism). Most people who come down with this pneumonia are going to be those that have HIV. The labs then started to culture HIV once they put the ideas together. Natural Process of HIV This takes about 10-14 years. If someone were to get about 13-14 times the amount of HIV present in a normal patient this process would only take about 3 months. The natural process goes from one to another to another etc. so this takes about 10-14 years to develop. You may not be diagnosed until about 2 years before you will die but it was probably going on for a long time before that. If we intervene if we come with lots and lots of virus all of the cells are probably going to be infected all at once. So, the initial dose influences the outcome. The virus is going to go inside of the CD4 cell which is going to be macrophages and T-helper cells it is going to get integrated in there and it is going to stay there with a slow viral infection only to come periodically and invade (make multiple copies) other cells. It takes years before there is enough of a decline in your T-helper cell function that you see an increased risk of disease and this is a gradual kind of thing first, there is an increased frequency of normal diseases and then you come down with opportunistic infections. If you have a larger inoculum or because of the number of sexual partners that you have or because of the IV that you are sharing you will increase the likelihood that you will get to the end faster because there is more virus added from the outside. Treatment - Vaccine We need to intervene somehow. The vaccine is not working and there is no hope of really developing one anytime soon we cannot see to develop an immune response. The vaccine does not work in any population there were antibodies produced from this vaccine, but there was no immune response. In developing a vaccine, the first stage is that it does not do any harm the HIV vaccine didnt do any harm stage 2 is does it produce an immune response yes it did stage 3 did it protect NO!!! There is one glimmer there is a group of long surviving (without treatment) HIV+ patients that have never converted to flow blown AIDS they actually are prostitutes in Africa. We do not know how to explain this. Are they being exposed to constant low levels of the virus? Is that doing something? Is it something about their genetics and their immunogenetics and control of their immune response that they somehow are different than everyone else? We just do not know. The background science we dont know. Something that may be possible that we have BOTH helper cells AND suppressor cells and it is possible that we need to look at increasing a suppression response and keeping those particular infected T-cells quiet. So, they may have a different balance in their suppressor/helper population of T-cells such that they are suppressing those T-cells from activity so we may have to develop a system of suppression rather than a system of prevention.
The other thing that we may have to start looking at is a vaccine that is not used as a prophylactic agent but as a treatment agent following this idea of expression we may immunize these people who are already infected in such a manor to modulate their immune response so that they turn off those cells and do not activate them remember that mycoplasma pneumoniae would be a T-cell mitogen which would stimulate the T-cells to spread the virus quicker so maybe if we immunize patients we could suppress as opposed to the mitogenic effect we want to suppress the infected T-cell so that it does not activate. This is a possibility. There is no actual vaccine yet for this. Treatment Drugs AZT AZT alone does not successfully extend the life of a patient it does seem to extend the period of time that the patient is reasonable healthy but when the end they died faster they went downhill faster they came down with MORE severe opportunistic infections and sort of still died "on time" - but they felt better longer. The most IMP advantage of AZT is that it significantly reduces the spread from the mother to the child the infection is in utero It is spread through the bloodstream. The normal rate of infection is 30% which has now gone down to a 5% infection rate. This is a good way to stop the spread of infection unfortunately, we are going to have to let the infected people die we cant do anything for them but we can stop the spread to the next generation by way of the children. If we have limited resources we could just focus AZT on pregnant women and therefore decrease the number of children infected with HIV. This is will slow down the pandemic. We also will have to educate people on sexual practices. There are also various analogs of AZT available now also. There will be resistance developed here also with viruses, so we will have to keep changing drugs. Protease Inhibitors This is a category of drugs that we can choose from. Protease inhibitors significantly decrease the free virus load in the patients body. This is in their serum and in their fluids and MOST LIKELY decrease their infectivity to some effect to others. It will not decrease the infectivity to others completely, but it is going to decrease it to some extent. If we do not have the virus in the bloodstream, then we do not have the free virus in body fluids (semen and vaginal wall secretions) but we still have the virus in the cells (think ping-pong ball). The person is NOT free of the virus because the virus is still in the cells. They are free of the virus in the bloodstream but that is not the same as being free of the virus in the body. Protease inhibitors do not decrease the number of cells actually infected in anyway. Now, if you think about the spread of HIV body fluids are a mechanism that we can spread the virus but we have to realize that bodily fluids CAN contain cells. Some of these cells are macrophages macrophages are CD4 + cells so any kind of open wound that has pus cells in it (phagocytic cells) are going to have CD4 positive macrophages in it and that is going to spread from person to person. In fact, the virus in the bloodstream is very fragile so the most efficient way of spreading the virus from person to person is inside of a cell so although we can say that protease inhibitors decrease free virus in the bloodstream and possibly has some effect on the infectivity to others IT DOES NOT PREVENT THE SPREAD TO OTHERS AND IT DOES NOT CURE THE PATIENT. So, what protease inhibitors do is it slows down the process of infectivity to other cells (it acts as a sponge to the "ping-pong ball" so it can not set off anymore "traps") so the spread seems to be slowed down. So a protease inhibitor as part of the cocktail does seem to have the potential of extending a persons lifespan. This is very hard to know because it is all so new! Drug Cocktail This ssRNA virus has a lot of unique targets. There is a complex cocktail that we use in these patients to try to treat this virus because of all of these different targets. There are a whole bunch of drugs some of these drugs are taking care of the side-effects because they are so serious
(nausea, diarrhea, etc.). We take all kinds of drugs to neutralize the side-effects of the drugs that we take. Then of course the virus develops resistance to these drugs so we have to keep changing the cocktail of drugs all of the time. It is complicated to following these drugs. These drugs are also VERY expensive (AZT, protease inhibitors, etc). We already have problems with healthcare and the longer these people stay alive the more these drugs are going to cost. The availability of treatment and cost and who can pay for it all is a very big problem. See chart on Page 58 of notes Protozoan Agents: These organisms are not solely spread by sexual transmission. If you get one of these agents, you should be checked for other diseases. These are a good indicator of sexual activity. Trichomonas vaginalis Giardia lambia Ectoparasites: These organisms are associated with crabs, body lice, etc. They grow on pubic hair and underarm hair, etc. These can also be spread by non-sexual means. Phthirus pubis Sarcoptes scapes The key is here that is people start getting these we should start thinking and looking more into this than just treatment.