Systemic manifestations in COPD

Systemic manifestations in COPD - Extra Extra pulmonary...

Info iconThis preview shows page 1. Sign up to view the full content.

View Full Document Right Arrow Icon
This is the end of the preview. Sign up to access the rest of the document.

Unformatted text preview: Extra Extra pulmonary manifestations of COPD manifestations of COPD Implications in management DM seminar DR. Basanta Hazarika Senior Resident Resident Dept. of Pulmonary and critical care medicine PGIMER medicine, PGIMER Introduction COPD COPD is a chronic inflammatory disorder characterized by progressive expiratory airflow characterized by progressive expiratory airflow limitation limitation that is poorly reversible A substantial proportion of COPD patients have substantial extraextra-pulmonary symptoms and signs Common Common manifestations include skeletal muscle weakness osteoporosis cardiac arrhythmias weakness, osteoporosis, cardiac arrhythmias, ischemic heart disease, stroke, depression, and cancer The The presence of these extra-pulmonary extramanifestations of COPD increases morbidity and mortality mortality Inflammatory markers in COPD fl In In COPD ↑ levels of inflammatory cytokines, acute phase proteins, and markers of oxidant stress (Oudijk EJ, et al. Eur Respir J Suppl 2003;46:5s–13s) 2003;46:5s– Cytokines in COPD include TNF Cytokines in COPD include TNF-α, TGF-β, interferonTGF interferon γ, and ILs- 6 and 8 ILs(Wouters EF et al.Proc AmThorac Soc 2005;:26–33) 2005;:26– COPD COPD with lowest FEV1 have the highest levels of CRP, fibrinogen, and other systemic inflammatory markers while those with the highest FEV1 have the markers, while those with the highest FEV1 have the lowest lowest values (Circulation 2003; 107:1514–1519) 107:1514– Inflammatory markers in COPD fl ↑cytokines and CRP are associated with SMD, heart disease and atherosclerosis in patients with COPD disease, and atherosclerosis in patients with COPD (van Eeden SF, et al. Proc Am Thorac Soc 2005;:61–7) 2005;:61– CRP CRP and fibrinogen, are elevated in smokers, and ↑ fib fibrinogen levels in smokers are associated with ↓ lung function and function and ↑ risk for COPD for COPD (Dahl M,et al. AJRCCM 2001;164(6):1008–11) 2001;164(6):1008– ↑ CRP is an independent risk factor for CAD, CRP is an independent risk factor for CAD myocardial infarction and stroke (PRIME Study. 2003; 23: 1255–61) 23 1255– Systemic effects ff Skeletal Muscle Dysfunction in Skeletal Muscle Dysfunction in COPD COPD MA MA is associated with ↑ mortality risk independent of disease staging based on di i severity of airflow obstruction (Am J Respir Crit Care Med 2002;166:787–9) SMD SMD in COPD is characterized by a ↓ in strength and endurance of the muscle th th Skeletal Skeletal MA in COPD selectively affects the predominant glycolytic type IIA/IIX fibers (Eur Respir J 2003;46(Suppl):52s–63s) 2003;46(Suppl):52s– Skeletal Muscle Dysfunction in Skeletal Muscle Dysfunction in COPD COPD In In COPD, shift of muscle fiber type I to type II Type fibers resistant to fatigue type II, Type I fibers - resistant to fatigue, Type II fibers - more fatigable (Am J Respir Crit Care Med 2002;166:787–9) Respir Crit Care Med 2002;166:787 In In COPD Muscle glycogen content lower, and lactate concentrations are higher and lactate concentrations are higher (Am (Am J Respir Crit Care Med 1996;153:288–93) 1996;153:288– Elevated levels of inflammatory mediators Elevated levels of inflammatory mediators, such as TNF-α and IL-6, cause skeletal TNFILmuscle to atrophy muscle to atrophy Mechanism of skeletal muscle Mechanism of skeletal muscle weakness weakness Deconditioning Deconditioning is a major contributor to the muscle dysfunction in COPD patients dysfunction in COPD patients Inflammatory Inflammatory mediators in COPD may be responsible for weight loss and muscle wasting. Reduced Reduced levels of circulating hormone(GH, Test,) in COPD patients Ch Chronic steroid myopathy after prolonged pro administration administration of lower doses of corticosteroids Chronic hypoxemia or hypercapnia or the effects of Chronic hypoxemia or hypercapnia or the effects of cigarette cigarette smoking cause muscles damage Evidence of skeletal Muscle Evidence of skeletal Muscle Dysfunction in COPD Muscle Muscle atrophy Weakness Weakness Morphology changes * proportion of type I fibers proportion of type fibers * proportion of type IIb fibers * Capillarization Altered metabolic capacity * ↓ Intramuscular pH * ↓ ATP concentration * ↑ Muscle lactate concentration * ↑Iononine monophosphate monophosphate * ↓Mitochondrial enzyme activities (Maltais, F, et al. Clinics in Chest Medicine, 21:665-685, 2000) Structural alterations of SM in COPD Muscle massMuscle mass- ↓ Fat free mass Muscle fiber types and sizes- ↑ Type IIb Muscle fiber types and sizes Type IIb fibers fibers and atrophy of Type I and IIa fibers Numbers Numbers of capillaries per unit surface area in the vastus lateralis is 53% lower area in the vastus lateralis is 53% lower than than normal subjects Lower oxidative enzymes capacities in the th vastus lateralis Etiology of skeletal muscle Etiology of skeletal muscle dysfunction dysfunction Related Related to COPD-Hypoxia and COPDhypercapnia inflammation and chronic hypercapnia, inflammation and chronic malnutrition malnutrition Related to comorbid conditiononelectrolyte disturbances, cardiac failure, deconditioning, diabetes, and failure, hypertension Related Related to therapy- corticosteroids, β2 therapyagonist agonist Skeletal muscle atrophy Impacts on clinical outcomes Muscle Muscle weakness Decreased quality of life Decreased quality of life Lower Lower functional capacity Increased Increased mortality risk Accentuated inflammation and ROS Accentuated inflammation and ROS production production after exercise ( Respir Med, 94:859-67; 2000) Management of SMD Pulmonary Rehabilitation Exercise training – Upper and lower extremity endurance training, respiratory muscle training, strength training Ed Education – Self-management strategies Psychological and behavioral intervention – Support groups for stress management Oxygen Oxygen therapy LTOT LTOT in patients with COPD,improvement in skeletal muscle energy metabolism skeletal muscle energy metabolism (Jakobsson P et al. Respir Med 1995, 89:471-476) 89:471- During During exercise, supplemental oxygen to hypoxemic patients with COPD improved COPD aerobic aerobic metabolism (Respir Med 1995, 89:471-476) 89:471- LTOT LTOT could also help by allowing patients to be more active thereby reducing the effects be more active, thereby reducing the effects of of deconditioning. Anabolic Anabolic hormones GH GH exerts its effects primarily by ↑ levels of IGF GH deficient adults administration of GH muscle GH-deficient adults, administration of GH ↑ muscle mass mass and strength, and improves exercise performance (J Appl Physiol 1991, 70:688-694) (J Appl Physiol 1991 70:688 Patients Patients received GH plus exercise training increased lean body mass, whereas the group that received exercise training alone did not received exercise training alone did not (Am (Am J Respir Crit Care Med 1997, 155:A498) Significant Significant increase in weight and lean body weight with anabolic steroids as compared with a control group group (Chest 1998, 114:19-28) 1998, 114:19 28) Cardiovascular disease in COPD di di Mechanisms of Increased Risk of Mechanisms of Increased Risk of CVD CVD in COPD Cardiovascular disease in COPD Why Why COPD would predispose to cardiovascular events is largely a mystery di COPD COPD and CHD have shared risk factors including advancing age, cigarette smoking, includin and environmental air pollution However, However, even among relatively young nonsmokers, COPD is an independent risk factor for incident cardiovascular disease suggesting other mechanisms Cardiovascular disease in COPD In In COPD, persistent pulmonary inflammation promotes the release of pro-inflammatory chemokines roand cytokines into the circulation The systemic inflammation in turn adversely impacts The systemic inflammation in turn adversely impacts the the blood vessels, contributing to plaque formation and, to plaque instability and rupture (Si (Sin et al. Chest 127: 1952–1959.2005) Ch 127 1952 Hemostasis Hemostasis and thrombotic pathways may also play relevant roles in COPD and ischemic heart disease relevant roles in COPD and ischemic heart disease (Wu (Wu and Thiagarajan, 1996) Cardiovascular disease FEV1 FEV1 >50% of predicted, CVD account for approximately 50% of all hospitalizations and approximately 50% of all hospitalizations and nearly nearly a third of all deaths (Anthonisen et al.1994 Jama 272: 1497–1505) 1497– In In more advanced disease, cardiovascular events account for 20 25% of all deaths in events account for 20–25% of all deaths in COPD COPD (Sin et al. 2006Eur Respir J 28: 1245–1257) 1245– A RR of 2.74 for women and 1.42 for men RR who were in the lowest FEV1 compared to those in the highest (Speizer (Speizer et al. 1989Am Rev Respir Dis 140: S49–55.) S49– Cardiovascular disease The The AR of ischemic cardiac deaths from reduced FEV1 is 26% in men and 24% in women independent of the effects of cigarette men and 24% in women, independent of the effects of cigarette smoking smoking (Hole et al. 1996 Bmj 313: 711–715) 711– Patients Patients had both COPD and arrhythmias at baseline, the risk of coronary events increased by over two fold compared with subjects without COPD (Engstrom et al. Circulation 103: 3086–3091. 2001) et al Circulation 103: 3086 2001) For For every 10% ↓ in FEV1, all cause mortality ↑ by 14%, cardiovascular ortality by cardiovascular mortality ↑ by 28%, and nonfatal coronary event ↑ ardiovascular nd onfatal oronary vent by almost 20% (Anthonisen et al. Jama 272: 1497–1505 1994) 1497– Arrhythmias Arrhythmias in COPD Stable Stable COPD patients: 72 % of arrhythmias were ventricular in origin while 52 ventricular in origin, while 52 % were supraventricular were supraventricular (Kleiger, RE et al. Chest 1974; 65:483) Reduced Reduced FEV1 is an independent predictor of new onset onset atrial fibrillation in patients with stable COPD (Eur.Respi.J 2003;21.1012) Atrial fibrillation and ventricular arrhythmia were Atrial fibrillation and ventricular arrhythmia were independent independent predictors of death In In patients with acute respiratory failure, the presence of arrhythmia may be associated with increased mortality li Therapeutic Interventions and Modification Of Therapeutic Interventions and Modification Of Cardiovascular Cardiovascular Risk In COPD ICS ICS is a mainstay of COPD therapy for many years and there is some evidence showing years and there is some evidence showing they they ↓ exacerbation ↓ plasma CRP levels of COPD patients in plasma CRP levels of COPD patients in response response to ICS, suggesting that ICS may act to reduce systemic inflammation an important to reduce systemic inflammation, an important element element of cardiovascular pathophysiology (Man SF et al.Thorax 2006; 61: 849–53) 849– EUROSCOP EUROSCOP study use of budesonide in mild COPD found a reduction in cardiovascular adverse events in the treatment arm Therapeutic Interventions and Modification Of Therapeutic Interventions and Modification Of Cardiovascular Cardiovascular Risk In COPD TORCH TORCH study, a RCT which investigated whether combined ICS and LABA therapy improved mortality combined ICS and LABA therapy improved mortality compared compared with LABA or ICS alone, or placebo, showed no significant difference in all-cause or disease-specific alldiseasemortality with active treatment. HMG CoA reductase inhibitors in primary and secondary HMG CoA reductase inhibitors in primary and secondary prevention prevention of coronary heart disease A retrospective Norwegian study showed a reduction of retrospective allall-cause mortality in COPD patients on statin therapy who have had a recent exacerbation (Soyseth V et al. Eur.Respir. J. 2007; 29: 279–83) 279– Therapeutic Interventions and Modification Of Therapeutic Interventions and Modification Of Cardiovascular Cardiovascular Risk In COPD COPD COPD had improved cardiac, pulmonary and all-cause allmortality when receiving either statin therapy mortality when receiving either statin therapy, ACEI,ARB either alone or in combination (J. Am. Coll. Cardiol. 2006; 47: 2554–60) 2554– Infliximab Infliximab is a mAb that specifically inhibits TNFα, and therefore specifically inhibits inflammation TNF TNFα antagonists have been studied in COPD but showed no improvement in morbidity over a short followfollow-up period, although cardiovascular outcomes were not specifically assessed were not specifically assessed (Am. J.Respir. Crit. Care Med. 2007; 175: 926–34) 2007; 926– Therapeutic Interventions and Modification Of Therapeutic Interventions and Modification Of Cardiovascular Cardiovascular Risk In COPD BRONCUS BRONCUS study treatment with antioxidant NAC showed no improvement of lung function or showed no improvement of lung function or exacerbation exacerbation rates compared with placebo Use Use of antioxidant treatment in primary prevention of CVD in the general population showed no improvement in mortality improvement in mortality (Lancet 2003; 361: 2017–23) 2003; 2017– MRC LTOT study only showed survival advantage in MRC severe patients with resting pO2 < 7.3 or those with pO2 < 8.0 and evidence of cor pulmonale. Cardiovascular mortality was not specifically Cardiovascular mortality was not specifically assessed assessed (Lancet 1981; 1: 681–6) 1981; 681– Anaemia Anaemia in COPD WHO WHO defines anaemia as a haematocrit level <39%(13g%) in males and level , <39%(13g%) in males and <36%(12g%) <36%(12g%) in females Prevalence Prevalence of anaemia of 12.6% in males and and 8.2% in females (Chambellan A et al. Chest 2005; 128: 1201–1208) 1201– Putative mechanisms that are thought to Putative mechanisms that are thought to lead lead to ACD, namely: shortened RBC survival, iron homeostasis dysregulation and impaired bone marrow erythropoietic response Anemia Anemia in COPD Other factors such as nutritional disorders occult Other factors, such as nutritional disorders, occult blood blood loss, treatment with certain drugs (theophylline or angiotensin-converting enzyme angiotensininhibitors) and even oxygen therapy causes inhibitors), and even oxygen therapy causes anemia anemia in COPD (Similowski (Similowski T et al. Eur Respir J. 2006;27:390-6) 2006;27:390- Anemic Anemic patients had higher levels of EPO than nonnonanemic COPD patients as well as more ↑values of ILIL-6 and CRP (John M et al. Chest. 2005;127:825-9) 2005;127:825- Anemia Anemia in COPD ANTADIR study COPD receiving domiciliary oxygen therapy ANTADIR study, COPD receiving domiciliary oxygen therapy, demonstrated reduced hematocrit level was a strong predictor of mortality and was also associated with more frequent hospitalizations and a longer mean hospital stay (Chambellan A et al. Chest. 2005;128: 1201-8) 1201- In the ANTADIR study , haematocrit decreased with age and In with the degree of obstruction (FEV1/vital capacity) Patients with an average FEV1 of 37±2% predicted, the Patients prevalence of anaemia of 13%. (John (John M et al. Chest 2005; 127: 825–829) 825– Anemia Anemia in COPD Multivariate Multivariate analysis emphasised haematocrit as an independent and major predictor of survival independent and major predictor of survival BODE prognostic index, haematocrit was significantly higher in the patients who survived (42±5%) compared with those who died (39±5%) (Celli BR et al.N Engl J Med 2004; 350: 1005–1012) BR et al Engl Med 2004; 350: 1005 NETT, NETT, ↓ hemoglobin to be an independent predictor of mortality together with other variables, such as age, supplemental oxygen use, higher residual volume, and higher BODE score. COPD and Osteoporosis COPD and Osteoporosis Osteopenia Osteopenia is BMD between 1 and 2.5 SDs and osteoporosis is BMD of 2.5 SDs below the mean for young adults (Eastell R et al. N Engl J Med 1998; 338:736–746) 338:736– As As many as 35 to 72% of patients with COPD have been reported to be osteopenic, and 36 to 60% of patients with COPD have osteoporosis patients with COPD have osteoporosis (Incalzi RA et al Respir Med 2000; 94:1079–1084) 94:1079– Patients Patients receiving oral CS (average cumulative dose, 19.5 ± 24.8 g) have been found to have a 1.8-fold 1.8-fold (95% CI, 1.08 to 3.07) ↑ incidence of one or more vertebral fractures. (McEvoy C et al. AJRCCM 1998; 157:704–709) 157:704– Contributing Factors to Osteoporosis Contributing Factors to Osteoporosis in in COPD Smoking Increased alcohol intake alcohol intake Vitamin D levels Genetic factors factors Treatment with corticosteroids Reduced skeletal muscle mass and strength skeletal muscle mass and strength Low BMI and changes in body composition Hypogonadism yp Reduced levels of insulin-like growth factors Chronic systemic inflammation COPD and Osteoporosis Subjects Subjects with severe ↓in PFT requiring ICS (FEV1, 59 ± 3.7%) or OS (FEV1, 50.6 ± 2.8%) had a 9 fold ↑ risk of osteoporosis compared to the control group. In prospective study of 286 patients with COPD In a prospective study of 286 patients with COPD who who were randomized to inhaled budesonide (800 μg/d) or placebo, reported no significant change in BMD in either group after years BMD in either group after 3 years (N (N Engl J Med 1999; 340:1948–1953) 340:1948– Patients Patients with low dose of prednisone (ie, 2.5 to 7.5 mg/d) had mg/d) had a 1.77-fold ↑ risk of fractures, and fold risk of fractures and patients patients receiving 7.5 mg/d prednisone had a 2.272.27fold ↑ risk (J Bone Miner Res 2001;16:581–588) COPD and Osteoporosis Slemenda et al reported that lumbar spine BMD Slemenda et al. reported that lumbar spine BMD was was 12% lower in smokers who have smoked 20 packpack-years compared to nonsmokers. (J Bone Miner Res 1989; 4:737–741) Bone Miner Res 1989; 4:737 Risk Risk of vertebral fractures increases 2.3 fold among long term smokers long term smokers (Seeman et al. Am J Med 1983; 75:977–983) 75:977– In COPD BMI was the strongest predictor of In COPD, BMI was the strongest predictor of osteoporosis, osteoporosis, with a BMI ≤ 22 having an odds ratio 22 of 4.18 (95% CI, 1.19 to 14.71) (Incalzi RA et al. Respir Med 2000; 94:1079–1084) RA et al Respir Med 2000; 94:1079 Osteoporosis screening tool for Osteoporosis screening tool for COPD patients Three or more of the risk factors indicate high risk of osteoporosis Recommendations to Decrease Recommendations to Decrease Osteoporosis Osteoporosis Risk in COPD Measure BMD in the following high-risk patients at baseline: at baseline: Those on chronic oral glucocorticoids or high high-dose inhaled glucocorticoids inhaled glucocorticoids Postmenopausal women Premenopausal women with amenorrhea women with amenorrhea Hypogonadal men History of fracture of fracture BMI <22 (Diane M. et al. CHEST 2002; 121:609–620) Recommendations to Decrease Recommendations to Decrease Osteoporosis Osteoporosis Risk in COPD Follow BMD every 6–12 mo in those receiving oral glucocorticoids or every 12–24 12 mo in those not taking oral glucocorticoids Give supplements to daily intake of 1,000– 1,500 mg calcium and 400–800 IU vitamin D Encourage an exercise program to improve strength and balance (Diane M. et al. CHEST 2002; 121:609–620) Recommendations to Decrease Recommendations to Decrease Osteoporosis Osteoporosis Risk in COPD Gonadal hormone replacement to all postmenopausal women, premenopausal women with amenorrhea, and hypogonadal men (unless contraindicated) Consider bisphosphonates or calcitonin in patients with osteoporosis or in high-risk patients in whom HRT is not effective or indicated (Diane M. et al. CHEST 2002; 121:609–620) Cachexia in COPD Cachexia Cachexia is defined as excessive weight loss in the setting of ongoing disease, associated th di with with disproportionate muscle wasting Associated with poor functional capacity, reduced health status, and increased mortality mortality The prevalence of weight loss in COPD increases with COPD disease progression Cachexia in COPD COPD In In mild to moderate COPD, only 10 to 15% and severe COPD, nearly 50% of patients have significant weight loss (Creutzberg (Creutzberg et al. 2003 Eur J Clin Nutr 52: 396–401 ) 52: 396– COPDCOPD-related cachexia is an independent risk factor for morbidity and mortality. COPD COPD mortality was 2.2-fold higher with FEV1 <50% of 2.2predicted, who had a BMI <20 compared with those whose BMI was between 20 and 25 and over sevenBMI 20 25 sevenfold higher compared with those whose BMI was 30 or greater (Landbo et al. 1999,Am J Respir Crit Care Med 160: 1856–1861) 1856– Cachexia in COPD Cytokines, TNFCytokines, TNF-α, and INF-γ inhibit mRNA INFexpression for myosin heavy chain, leading to ↓ muscle protein synthesis Cytokines Cytokines may also directly or indirectly stimulate proteolysis of myosin heavy chains (Acharyya (Acharyya et al. 2004; Guttridge et al. 2000) COPD COPD patients frequently take inhaled or systemic glucocorticoids, which further systemic contribute to a catabolic state. COPD COPD and lung cancer COPD is not only risk factor for lung cancer but also COPD is not only a risk factor for lung cancer, but also for for death from lung cancer The The presence of moderate or severe airflow obstruction is a significant predictor of incident lung cancer cancer (Mannino DM et al. Arch Intern Med 2003;113:1475-1480 ) 2003;113:1475- Hypoxia-inducible transcription factors (HIF) may ypoxia-inducible promote angiogenesis and involved in both ischemic diseases and cancer (Constans A et al The Scientist 2004;18:20-21) et al The Scientist 2004;18:20 COPD and lung cancer Evidence suggests that angiogenic dysplasia is Evidence suggests that angiogenic dysplasia is a prelude prelude to invasive carcinoma (Keith RL et al. Clin Cancer Res 2000;5:1616-1625) 2000;5:1616- 49% of lung cancer patients have COPD and as many 49% of lung cancer patients have COPD and as many as as 12% of COPD patients between the age of 65–69 65– yrs die as a consequence of lung cancer (Vilkman S et al. Respiration 1997; 64: 281–284) 28 Predisposition Predisposition of COPD to lung cancer may be due to - impaired mucociliary clearance, genetic predisposition , oxidative stress-mediated di stress-me inflammation inflammation and carcinogenesis process (Cancer Detect Prev 2002; 26: 308–312) 308 Psychiatric disorders Prevalence Prevalence of psychiatric disorders in COPD ranged from 30 to 58% Depression Depression and anxiety appear to be the most commonly observed psychological problems in COPD The The prevalence of depression has been estimated as between 10 and 79.1% between 10 and 79 The pattern and extent of cognitive dysfunction reported in COPD vary across patients, and appear to be associated with disease severity (Hynninen KM et al.J Psychosom Res 2005;59:429–443) 2005;59:429– The The Cycle of Physical, Social, and Psychosocial Consequences of Psyc COPD COPD Psychiatric disorders Mild Mild hypoxemia may be associated with impairment in higher cerebral functioning, including abstract reasoning, auditory and visual attention verbal and nonverbal learning and recall and visual attention, verbal and nonverbal learning and recall, and reasoning reasoning and motor skills Improvement in visual memory verbal memory and motor speed Improvement in visual memory, verbal memory, and motor speed among among subjects with COPD after 6 months of continuous oxygen therapy. (Krop HD et al. Chest 1973;64:317–322) HD et al Chest 1973;64:317 Patients Patients with COPD after a 30-day exercise rehabilitation program 30that included instructional/educational components, psychosocial that included instructional/educational components, psychosocial counseling, counseling, and stress reduction Improved complex attention (Emery CF et al.Chest 1991;100:613–617) 1991;100:613– Psychiatric disorders Mortality Mortality is 3.11 times higher among severely depressed patients than non depressed th patients patients Greater mortality at years in depressed Greater mortality at 4 years in depressed patients, patients, even when there were no difference (Chest 2002, 121:1441-1448) 121:1441- COPD with anxiety or depression face greater COPD levels of cognitive decline, more functional limitations, lower self-efficacy, and more limitations lower self efficacy and more serious serious life events (Kunik M et al. Chest 2005; 127(4):1205-11) 127(4):1205- Conclusion COPD is a chronic inflammatory disease of the lungs Progression is often characterized by the is often characterized by the development of extra-pulmonary diseases These systemic manifestations contribute a great deal to reduced quality of life and increased mortality deal to reduced quality of life and increased mortality in COPD patients Systemic manifestations of COPD should be treated aggressively, as they add to the overall morbidity and mortality of COPD patients. In general, smoking cessation and pulmonary general, smoking cessation and pulmonary rehabilitation can be recommended to patients to modify some of these processes Take home massage COPD COPD must be considered a systemic disease disease, Extra Extra pulmonary manifestations must be considered in the evaluation of its be considered in the evaluation of its severity severity Treatment of these manifestations Treatment of these manifestations could could modify the prognosis of patients ...
View Full Document

This note was uploaded on 12/03/2011 for the course MEDICINE 350 taught by Professor Dr.aslam during the Winter '07 term at Medical College.

Ask a homework question - tutors are online