27 - Respiratory viruses 1 Categories of Respiratory Viruses • Orthomyxoviridae Influenza virus • Paramyxoviridae Parainfluenza virus Mumps

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Unformatted text preview: Respiratory viruses 1 Categories of Respiratory Viruses • Orthomyxoviridae: Influenza virus • Paramyxoviridae : Parainfluenza virus; Mumps virus; Measles; Respiratory syneytical virus • Togaviridae: Rubella Virus • Coronaviridae: Corona Virus; SARS virus • Adenoviridae : human Adenovirus • picornaviridae: Rhino Virus; 2 • Reoviridae: Influenza virus Orthomyxoviridae: Influenza virus Influenza is a disease caused by Influenza virus ,a member of the Orthomyxoviridae. 3 Genome of Influenza virus • 8 negative sense RNA nucleocapsid segments • The 'RNP' (RNA + nucleoprotein) is in a helical form with the 3 polymerase polypeptides associated with each segment. • The segmented genome promotes genetic diversity caused by mutation and reassortment of segments on infection with two different strains 4 Virion • spherical/ovoid, 80120nm diameter, • The inner side of the envelope is lined by the matrix protein, stable typespecific. 5 Virion • The outer surface of the particle consists of a lipid envelope from which project prominent glycoprotein spikes of two types, the haemagglutinin, ~135Å trimer (HA), and neuraminidase, ~60Å tetramer (NA). 6 Haemagglutinin (HA) • Encoded by RNA segment #4 • Can agglutinate red blood cells ­ hence the nomenclature • Cleavage by host­cell protease is required (resulting in HA1 and HA2) for infection to occur • Hemagglutinin glycoprotein is the viral attachment protein and fusion protein , and it elicits neutralizing , protective antibody responses 7 Neuraminadase (NA) • Encoded by RNA segment #6 • Enzyme that uses neuraminic (sialic) acid as a substrate • Important in releasing mature virus from cells 8 ORTHOMYXOVIRUSES HA - hemagglutinin NA - neuraminidase helical nucleocapsid (RNA plus NP protein) lipid bilayer membrane polymerase complex M1 protein type A, B, C : NP, M1 protein sub-types: HA or NA protein 9 Influenza virus A 10 Replication • Influenza transcribe and replicates its genome in the target cell nucleus • assemble and buds from the plasma membrane 11 Influenza virus 12 Antigen • Soluble antigens: include ribonucleoprotein and M protein which are much stable in antigenicity. • Surface antigens: include HA and NA which are much variable in antigenicity. 13 Types • Influenza viruses are divided into 3 groups determined by the ribonucleoprotein (RNP) antigen and M antigen: • Group A ­ This group is the cause of epidemics and pandemics and has an avian intermediate host (IH) Group B ­ This group causes epidemics and has no IH Group C ­ This group does not cause epidemics and causes mild disease 14 TYPE A severity of illness animal reservoir human pandemics human epidemics antigenic changes segmented genome amantadine, rimantidine zanamivir surface glycoproteins TYPE B TYPE C ++++ yes yes yes shift, drift yes sensitive sensitive 2 ++ no no yes drift yes no effect sensitive 2 + no no no (sporadic) drift yes no effect (1) 15 Subtypes • According to antigenicity of HA and NA, influenza virus is divided into subtypes such as HnNm( H1N2, et al ) 16 Variation and Epidemiology Antigenic drift: median or small epidemic. Antigenic shift:large scale epidemic. 17 Antigenic Shift Of Influenza virus • Reassortment of genes is a common feature of Influenza A, but not B or C • When two different "A" viruses infect the same cell, their RNA segments can become mixed during replication • New viruses produced in this way may survive due to a selective advantage within the population 18 Antigenic Drift of Influenza Virus • Constant mutations in the RNA of influenza which lead to polypeptide mutations • Changes are less dramatic than those induced by Shift • If these mutations affect HA or NA they may cause localized epidemics 19 20 Epidemic 21 where do “new” HA and NA come from? • 13 types HA • 9 types NA – all circulate in birds • pigs – avian and human 22 where do “new” HA and NA come from? 23 why do we not have influenza B pandemics? • so far no shifts have been recorded • no animal reservoir known 24 Resistence • The particles are relative labile ,not resistant to drying, etc. 25 Pathogenesis • Influenza is characterised by fever, myalgia, headache and pharyngitis. In addition there may be cough and in severe cases, prostration. There is usually not coryza 鼻鼻 (runny nose) which characterises common cold infections. • Infection may be very mild, even asymptomatic, moderate or very severe 26 Transmission • Source of infection: patients and carriers. • AEROSOL – 100,000 TO 1,000,000 VIRIONS PER DROPLET • 18-72 HR INCUBATION 27 Aerosol Inoculation Of virus 28 NORMAL TRACHEAL MUCOSA 3 DAYS POST-INFECTION 7 DAYS 29 POST-INFECTION SYMPTOMS • • • • • • FEVER HEADACHE MYALGIA( 鼻鼻 ) COUGH RHINITIS( 鼻鼻 ) OCULAR SYMPTOMS 30 PULMONARY COMPLICATIONS • CROUP (YOUNG CHILDREN) • PRIMARY INFLUENZA VIRUS PNEUMONIA • SECONDARY BACTERIAL INFECTION – Streptococcus pneumoniae – Staphlyococcus aureus – Hemophilus influenzae 31 NON-PULMONARY COMPLICATIONS • myositis (rare, > in children, > with type B) • cardiac complications • liver and CNS – Reye’s syndrome • peripheral nervous system 32 33 Immunity 34 Lab Diagnosis • Viral detection: Respiratory secretions ( direct aspirate , gargle , nasal washings ) 1. Cell culture in primary monkey kidney or madindarby canine kidney cells 2. Hemagglutination (inhibition) Hemadsorption (inhibition) 3. IFA/ ELISA 35 • Serology hemagglutination inhibition Hemadsorption inhibition ELISA immunofluoresence complement fixation. NT. 36 Prevention • Vaccines at best give about 70% protection. They may sometimes not be effective against the most recently evolved strains because the rate of evolution outpaces the rate at which new vaccines can be manufactured. • This constant antigenic change down the years means that new vaccines have to be made on a regular basis. 37 Types of Vaccine • Killed Whole Virus Rather pyrogenic, not used today. • Live Virus Attenuated strains were widely used in Russia but not elsewhere. • Virus Subunit HA extracted from recombinant virus forms the basis of today's vaccines. For example, the WHO Recommendation for Influenza Vaccine, 1995-1996, contains two A strains and one B strain:-[A / Singapore / 6 / 86 (H1N1)+A / Johannesburg / 33 / 94 (H3N2) +B / Beijing / 84 / 93 ] • Synthetic Much research is being done to try and find a neutralising epitope that is more stable, and can therefore be used for a universal vaccine. 38 CDC 39 PB2 PB1 PA HA NA NP M NS Attenuated Donor Master Strain Attenuated Vaccine Strain: Coat of Virulent strain with Virulence Characteristics of Attenuated Strain X PB2 PB1 PA HA NA NP M NS PB2 PB1 PA HA NA NP M NS New Virulent Antigenic Variant Strain 40 Treatment • Amantadine and rimantadine are active against influenza A viruses. The action of these closely related agents is complex and incompletely understood, but they are believed to block cellular membrane ion channels, and inhibit an uncoating step and target the M2 membrane protein 41 PREVENTION - DRUGS • RIMANTADINE 鼻鼻鼻鼻 (M2) • type A only • AMANTADINE 鼻鼻鼻鼻 (M2) • type A only • ZANAMIVIR (NA) • types A and B, not yet approved for prevention but studies show effective • OSELTAMIVIR (NA) • types A and B 42 TREATMENT - DRUGS • RIMANTADINE (M2) • type A only, needs to be given early • AMANTADINE (M2) • type A only, needs to be given early • ZANAMIVIR (NA) • types A and B, needs to be given early • OSELTAMIVIR (NA) • types A and B, needs to be given early 43 OTHER TREATMENT • REST, LIQUIDS, ANTI-FEBRILE AGENTS (NO ASPIRIN FOR AGES 6MTHS-18YRS) • BE AWARE OF COMPLICATIONS AND TREAT APPROPRIATELY 44 Paramyxoviridae 45 Paramyxoviridae • Genus • Morbillivirus • Paramyxovirus • Pneumovirus Human pathogen Measles virus Parainfluenza viruses, Mumps virus Respirtory syncytical virus 46 Virion • Large virion consists of a negative RNA genome in a helical nucleocapsid surrounded by an enevlope containing a viral attachment protein • HN of paramyxovirus and mumps virus has hemagglutinin and neuraminidase. • H of measles virus has hemagglutinin activity • G of RSV lacks these activities 47 PARAMYXOVIRUSES pleomorphic HN/H/G glycoprotein SPIKES F glycoprotein SPIKES helical nucleocapsid (RNA plus NP protein) lipid bilayer membrane polymerase complex M protein 48 PARAMYXOVIRUS FAMILY properties of attachment protein GENUS GLYCOPROTEINS TYPICAL MEMBERS Paramyxovirus HN, F HPIV1, HPIV3 Rubulavirus Genus HN, F HPIV2, HPIV4 mumps virus Morbillivirus genus H, F measles virus Pneumovirus genus G, F respiratory syncytial virus genus 49 50 Replication , Pathogenesis and Immunity • Virus replicates in the cytoplasm • Virions penetrate the cell by fusion with the plasma membrane • Viruses induce cell-cell fusion, causing multinucleated giant cells • Paramyxoviridae are transmitted in respiratory droplets and initiate infection in the respiratory tract • Cell-mediated immunity causes many of the symptoms but is essential for control of the infection 51 MMR vaccine • Composition : live attenuated virus Measles / Mumps / Rubella • Vaccination schedule: at 15-24 months and at 4 to 6 years or before junior high school • Efficiency: 95% lifelong immunization with a single dose 52 53 Measles virus (((((( 54 Pathogenesis and Immunity • Childhood infection almost universal, protection resulting from this is probably lifelong. Both man and wild monkeys are commonly infected • In culture, produces characteristic intranuclear inclusion bodies and syncytial giant cells. • Transmission and initial stages of disease similar to mumps, but this virus can also infect via the eye and multiply in the conjunctivae. Viraemia following primary local multiplication results in widespread distribution to many organs. 55 Pathogenesis and Immunity • After a 10-12 day incubation period • Dry cough, sore throat, conjunctivitis (virus may be excreted during this phase!), followed a few days later by the characteristic red, maculopapular rash and Koplik's spots • Towards the end of the disease, there is extensive, generalized virus infection in lymphoid tissues and skin. 56 viremia 57 DISSEMINATED SPREAD • LONGER TIME FOR SYMPTOMS • IMMUNE RESPONSE • IF SYMPTOMS DUE TO IMMUNE RESPONSE, USUALLY INFECTIOUS PRIOR TO SYMPTOMS 58 Adapted from Mims, Playfair, Roitt, Wakelin and Williams (1993) Medical Microbiology MEASLES - Koplik’s spots 59 Murray et al. Medical Microbiology Koplik's spots 60 MEASLES - RASH CDC - B.Rice 61 Murray et al. Medical Microbiology DISEASE • FEVER • RESPIRATORY TRACT SYMPTOMS • rhinorrhea, cough • KOPLIK’S SPOTS • MACULOPAPULAR RASH • T-cells ->endothelial cells • CONJUNCTIVITIS • epithelial cells 62 MEASLES GIANT CELL PNEUMONIA Murray et al. Medical Microbiology 63 Mims et al., Medical Microbiology 1993 64 MEASLES ENCEPHALITIS • 1/1000 cases • sequelae – deafness – seizures – mental disorders 65 SSPE • sub-acute sclerosing panencephalitis – inflammatory disease – defective virus • early infection with measles is a risk factor • rare (7/1,000,000 cases of measles) • decrease since vaccination program 66 67 68 Treatment • No 69 Prevention • Both live and killed vaccines exist. Vaccination with the live attenuated vaccine has been practised since the 1960's with a dramatic decline in the incidence of the disease . • Trivalent live attenuated vaccine (MMR) usually given - all of these viruses best avoided during pregnancy! 70 Mumps virus ((((((( 71 Mumps virus • Droplets spread the infection via saliva and secretions from the respiratory tract. • Incubation period of 2­3 weeks 72 Mumps virus • Malaise and fever is followed within a day by painful enlargement of one or both of the parotid (salivary) glands • A possible complication in males after puberty is orchitis ­ painful swelling of one or both testicles. • Inflammation of the ovary and pancreas can also occur. • Disease is usually self­limiting within a few days • Aseptic meningitis (usually resolving without problems) or postexposure encephalitis (can prove fatal) are the most serious complications associated with mumps. 73 Prevention and treatment • Treatment: none (passive immunization has been used). • Prevention: one invariant serotype therefore vaccines are viable - both formalininactivated and live attenuated exist, the latter now being widely used- see MMR. 74 MUMPS CDC - B.Rice 75 76 Mims et al., Medical Microbiology 1993 Mims et al., Medical Microbiology 1993 77 Parainfluenza virus ((((((( 78 Important Characteristics • Typing: Four types (1-4) : distinguished antigenically, by cytopathic effect, and pathogenically • Hemeagglutinin and fusion F protein is found in the envelope 79 Pathogenesis and Immunity • Cause acute respiratory infections of man ranging from relatively mild influenza-like illness to bronchitis, croup (narrowing of airways which can result in respiratory distress) and pneumonia; common infection of children. • Transmitted by aerosols. 80 Lab Diagnosis • Nasopharynx specimen is culture in a surrogate cell line in AGMK. Infected cell are detected by hemeadsorption or DFA • DFA also can be done rapidly to identify the agent in direct specimen • Serotypes 1-3 are comfirmed by hemeagglutination inhibition using standardized antisera 81 Treatment • No antiviral therapy is available • Nursing the patient in a humidified atmosphere was commonly advised • Dexamethasone 鼻鼻鼻鼻 and budesonide 鼻鼻鼻 have been approved ( for outpatient treatments) 82 Prevention • No, vaccines is not available 83 Respiratory syncytial virus ((((((((( 84 Important Characteristics • RSV is highly infectious, transmission by respiratory secretions. • Primary multiplication occurs in epithelial cells of URT producing a mild illness. In ~50% children less than 8 months old, virus subsequently spreads into the L.R.T. causing bronchitis, pneumonia and croup. • Has been suggested as a possible factor in cot death and asthma. 85 Pathogenesis and immunity Disorder Bronchiolitis pneumonia, or both Febrile rhinitis and pharyngitis Common cold Age Fever, cough, dyspnea, and cyanosis in children younger than 1 year Children Older children and adults 86 Lab Diagnosis • DFA • Cell culture of nasopharyngeal specimen • A rise in antibody titre using ELISA 87 Treatment • Ribavirin aerosol( 鼻 ( 鼻 ) 鼻鼻鼻 , 鼻鼻鼻 ) is recommended for pneumonia in infants • RSV - IGIV has been approved for infants born prematurely • IFN 88 Prevention • Currently no effective vaccine! Also, infection does not result in lasting protection (c.f. mumps, measles) therefore repeated infections ('colds') occur throughout life usually without serious consequences in adults. 89 Adenoviruses ((((( 90 General Concepts • Most Adenovirus infections involve either the respiratory or gastrointestinal tracts or the eye. Adenovirus infections are very common, most are asymptomatic. Most people have been infected with at least 1 type at age 15. 91 Adenovirus 92 Important Characteristics 93 94 Replication 95 Pathogenesis and Immunity • • • • • • • Disease: Acute Respiratory Illness Pharyngitis Gastroenteritis Conjunctivitis Pneumonia Keratoconjunctivitis At Risk: Military recruits, boarding schools, Infants Infants All Infants, military recruits All • Acute Haemorrhagic Cystitis Infants • Hepatitis Infants, liver transplant patients 96 swimming pool conjunctivitis ( 鼻鼻鼻鼻鼻鼻 ; 鼻鼻鼻 ) • Eye infections characterized by a mild conjunctivitis "swimming pool conjunctivitis" are caused by adenoviruses and have been linked to transmission in contaminated swimming pools. 97 swimming pool conjunctivitis 98 Lab Diagnosis • Isolation of adenovirus can be accomplished in cell cultures derived from epithelial cells • Immunoassays, including fluorescent antibody and enzyme-linked immunosorbent assays, PCR can be used to detect and type the virus in clinical samples and tissue cultures • Serological assays such as CFA, HI, EIA and neutralization techniques have been used to detect specific antibodies. 99 Treatment • No 100 Prevention • Inactivated vaccines have been developed and are routinely used for military recruits in some countries 101 Rubella Virus 鼻鼻鼻鼻鼻鼻 102 General Concepts • Viruses have enveloped single stranded positive-sense RNA. • Replication in cytoplasm and bud at plasma membrane • Cause Rubella( german measles, 3-days measles) 103 Epidemiology • Occurrence: worldwide in prevalence( in winter and spring) • Reservoir: Humans • Mode of Transmission: Vertical transmission in case of CRS/ Infection in nonimmune children is usually transmitted by droplet spread or by direct contact with patients • Who is at risk: Non-immunized children are at risk • Incubation period: 2-3 weeks 104 Pathogenesis Virus Rubella enters and infects the nasopharynx and lung and then spreads to the lymph nodes and reticuloendothelial system. The resulting viremia spreads the virus to other tissues and the skin. Circulating antibody can block the transfer of virus at the indicated points. In an immunologically deficient pregnant woman, the virus can infect the placenta and spread to the fetus Congenital infection 105 EFFECTS ON FETUS • HEARING LOSS • CONGENITAL HEART DEFECTS • NEUROLOGICAL – PYSCHOMOTOR AND/OR MENTAL RETARDATION • OPHTHALMIC – CATARACT, GLAUCOMA, RETINOPATHY 106 EFFECTS ON FETUS • • • • • • thrombocytopenia hepatomegaly splenomegaly intrauterine growth retardation bone lesions pneumonitis 107 EFFECTS ON FETUS • First trimester – 65-85% of neonates have sequelae 108 EFFECTS ON FETUS • 1964 – 20,000 infants with permanent problems – 6,000 to 30,000 spontaneous abortions – 5,000 therapeutic abortions • 1969 to present – maximum of 67 cases congential rubella/yr • usually fewer than 10 109 CONGENITAL INFECTIONS • SHED VIRUS FOR A YEAR OR MORE AFTER BIRTH – nasopharynx, urine, feces 110 CONGENITAL INFECTIONS • EYE PROBLEMS • GLANDULAR COMPLICATIONS – diabetes, – thyroid problems – deficiency growth hormone 111 CONGENITAL / VERY EARLY INFECTIONS • PROGRESSIVE RUBELLA PANENCEPHALITIS 112 Lab Diagnosis • Current rubella infection, in pregnant women can be confirmed by 4-fold rise in specific antibody titer between acute and convalescent-phase serum specimens by ELISA • The Dx of CRS in the newborn may be confirmed by the presence of specific IgM antibody. 113 Treatment • There is no antiviral therapy available 114 Prevention • A single dose of live, attenuated rubella vaccine elicits a significant antibody response in approximately 98%-99% of vaccinated individuals • It should not be given to immunocompromised patients 115 Coronavirus (((((( 116 Important Characteristics • Virion: Spherical, 80-160nm in diameter, helical nucleocapside • Genome: +ssRNA, linear, nonsegmented, 27-30kb, infectious • Proteome: two glycoproteins and one phosphoprotein. Some viruses contain a third glycoprotein (hemagglutinin esterase) • Envelope: contains large, widely spaced, club-or petal- shaped spikes. crown-like 117 Virion structure • S-Spike glycoprotein: receptor binding, cell fusion, major antigen • M-Membrane glycoprotein: transmembrane budding & envelope formation 118 Pathogenesis and Immunity • These viruses infect a variety of mammals & birds. The exact number of human isolates are not known as many cannot be grown in culture. • They cause: common colds and have been implicated in gastroenteritis in infants. • Transmitted by aerosols of respiratory secretions 119 Rhinovirus ((((( 120 Important Characteristics • Rhinoviruses are picornaviruses similar to enteroviruses but differ from them in having a buoyant density in cesium chloride of 1.40 g/ml and in being Acid-labile • Rhinoviruses are isolated commonly from the nose and throat but very rarely from feces. • These viruses cause upper respiratory tract infections, including the common cold 121 Reovirus ( ((((( ) 122 Important Characteristics • Virion: Icosahedal, 60-80nm in diameter, double capsid shell • Genome: dsRNA • Envelope: none • Diseases: Acute respiratory tract infection and Gastrointestinal infections 123 ...
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This note was uploaded on 12/27/2011 for the course STEP 1 taught by Professor Dr.aslam during the Fall '11 term at Montgomery College.

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