1.Viral Infections In Which Cardiovascular Manifestations Predominate OST 524 Cardiovascular System M. J. Patterson, MD, PhD

2. Myocarditis-Pericarditis Etiology: cardiotropism Pathology Clinical features Diagnosis Immunity Epidemiology Prophylaxis and treatment 3. Viral Infections with Involvement of the Hematopoeitic and Lymphatic Systems Epstein Barr Virus (EBV): Infectious mononucleosis EBV: Burkitt's lymphoma Human herpes HHV6, HHV7, HHV8 Human Parvovirus B19: transient aplastic anemia Bone marrow failure Malignant association - other 4. CMV and cardiovascular disease 5. Cardiac Malformations as Part of Rubella Embryopathy Etiology: vascular endothelial tropism 6. Myocarditis - Pericarditis Etiology Virus should always be part of the differential diagnosis of primary acute myocarditis Clinical evidence suggesting involvement of the heart has been reported for essentially all known viruses Cardiotropism: viral receptor substances 7. Myocarditis - Pericarditis Etiology Most commonly incriminated viruses: enterovirus 30 nm, RNA: Coxsackie B, Coxsackie A, ECHO, polio Cox B esp 2,3,4,5 Cox A ECHO Occasionally myopericardial involvement in course of any viral infection often manifested only by EKG modification does not necessarily imply an anatomic alteration of the myocardium 8. Viruses That Have Been Shown to Cause Myocarditis Common Coxsackievirus A Coxsackievirus B Echovirus Human immunodeficiency virus Influenza Less Common Adenovirus family Arbovirus Epstein-Barr virus Herpes simplex virus type 1 Human cytomegalovirus Measles virus Respiratory syncytial virus Rubella virus Varicella-zoster virus 9. Myocarditis - Pericarditis Pathology Relatively nonspecific Cardiac lesions: dilation and hypertrophy, esp. of left ventricle, edema, interstitial infiltrate of mononuclear cells, isolated necrosis of myocardial fibers, inflammation and necrosis resulting in foci for sclerosis Diffuse cellular necrosis in other organs in coxsackie infections Pericarditis rarely occurs without clinical or histologic evidence of myocarditis Immune-mediated pathology 10. Circulation 89:2422, 1994 11. Inflammatory Cytokines Cytokine Principal Cell of Origin Principal Action IL-2 Activated T cell Autocrine T-cell growth factor. Stimulates production of IL-2, TNF-, Activates natural killer cells IL-1 Activated macrophages, endothelial cells Stimulates T-cell activation. Induction of inflammatory metabolites. Activates endothelial cells and stimulates cytokine production. IL-6 Monocytes, macrophages, T cells, endothelial cells Stimulates differentiation of B cells. Stimulates production of plasma proteins by hepatocytes. INF Activated T cells Activates monocytes. Increases production of oxygen radicals by macrophages. Increases expression of MHC class I and II antigens. TNF- Activated macrophages Activates endothelial cells. Stimulates production of cytokines. Can induce direct lysis of some cell types. IL-8 Activated macrophages, lymphocytes, endothelial cells Chemo-attractant for neutrophils and causes neutrophil stimulation. 12. Myocarditis - Pericarditis Clinical features: relatively rare form of heart disease in U.S., generally acute and benign Occurrence - a disease of newborns and infants; sometimes older children, occasionally in adults Antecedent URI---1-30d before symptoms refer to heart subacute or chronic cardiopathy 13. Signs and Symptoms of Viral Myocarditis Symptoms Fatigue Dyspnea Palpitation Chest pain Syncope Signs Pericardial rub Sinus tachycardia Atrial or ventricular arrhythmias Conduction disturbances Cardiomegaly Right or left S3 or S4 gallop sounds Congestive heart failure 14. New England Journal of Medicine 343:1391 2000 15. Infectious Causes of Pericarditis Bacterial Actinomyces Bacteroides fragilis Borrelia burgdorferi Brucella Campylobacter Chlamydia Enterococcus sp. Escherichia coli Fusobacterium nucleatum Haemophilus influenzae Klebsiella pneumoniae Legionella Listeria monocytogenes Mycobacterium avius-intracellulare Mycobacterium tuberculosis Mycoplasma pneumoniae Neisseria gonorrhea Neisseria meningitis Nocardia asteroides Peptostreptococcus Pseudomonas aeruginosa Prevotella sp. Salmonella Staphylococcus aureus Streptococcus pneumoniae Streptococcus (group C) 16. Infectious Causes of Pericarditis Viral Adenovirus Coxsackie A Coxsackie B Cytomegalovirus Echovirus Epstein Barr virus Hepatitis B Herpes simplex HIV Influenza Mumps Varicella Zoster Fungal Aspergillus Blastomyces dermatitidis Candida Coccidioides Immitis Cryptococcus neoformans Histoplasma capsulatum Parasitic Entamoeba histolytica Schistosoma Toxocara canis Toxoplasma gondii 17. Noninfectious Causes of Pericarditis Collagen vascular diseases Rheumatic fever Rheumatoid arthritis Scleroderma CREST syndrome Systemic lupus erythematosus Sarcoidosis Sjgren's syndrome Mixed connective tissue disease Vasculitis, including temporal arteritis Polyarteritis Drug-induced Minoxidil Bleomycin Procainamide Hydralazine Azathioprine Inflammatory bowel disease Ulcerative colitis Crohns disease 18. Noninfectious Causes of Pericarditis Neoplastic Primary (benign or malignant) Metastatic to pericardium Other Fabrys disease Uremia Lffler's syndrome Thalassemia Acute myocardial infarction Kawasakis Disease Dissection aortic aneurysm Post-radiation Pregnancy Other Myxedema Dego's disease Cardiac Injury Traumatic Dresslers syndrome Stevens-Johnson syndrome Polymyositis Dermatomyositis Behet's syndrome Addisonian crisis Gout Whipples disease 19. Criteria for Diagnosis of Myopericarditis ECG manifestation ST-T or T wave changes or Low QRS voltage or A-V conduction defects or Intraventricular conduction defects Plus 2 or more symptoms Precordial left-sided chest pain Signs and symptoms of congestive heart failure Cardiomegaly Fever Pericardial friction rub 20. Myocarditis - Pericarditis Diagnosis Appropriate specimens for viral diagnosis Isolation of agent: pericardial fluid, T.S., R. S. first few days of illness, heart tissue at autopsy or biopsy Serology: 4-fold rise in titre by neutralization, complement fixation, hemagglutination inhibition; allows identification of a specific recent infection which is circumstantial evidence with a high index of suspicion when correlated with clinical findings. Etiological diagnosis of viral carditis is difficult 21. Disease Category: Myocarditis-pericarditis Source Viral Agents Usually Sought Throat Swab Rectal Swab CSF Urine Pericardial Fluid Other Enterovirus ++ +++ - - ++ * Myxovirus +++ - - - ++ * Paramyxovirus +++ - - - ++ * *Because it is frequently very difficult to isolate and/or associate these agents with the disease in question, it is emphasized that serological tests are particularly important to insure a diagnosis. N.B. In general, it is important to remember that viral shedding often diminishes rapidly after the onset of illness; therefore, it is important to attempt to collect specimens as early as possible - including an acute serum sample. 22. Criteria for Viral Myocarditis High-order association Isolation of virus from myocardium, endocardium or pericardial fluid or Demonstration of viral antigen in the myocardium endocardium or pericardium by immunofluorescent or immunoperoxidase assay, etc. 23. Criteria for Viral Myocarditis Moderate-order association Isolation of virus from pharynx or feces, and a fourfold rise in type-specific neutralizing, hemagglutination-inhibiting or complement-fixing antibodies or Isolation of virus from pharynx or feces, and a concomitant titer in serum of 1/32 or more of type-specific IgM-neutralizing or hemagglutination-inhibiting antibodies. 24. Criteria for Viral Myocarditis Low-order association Isolation of virus from pharynx or feces. A fourfold rise in type-specific neutralizing, hemagglutination inhibiting, or complement-fixing antibodies A single serum with a titer of 1/32 or greater of type- specific IgM neutralizing or hemagglutination inhibiting antibodies 25. Histologic Criteria for the Classification of Viral Myocarditis (Dallas Criteria) Initial Biopsy Active myocarditis with or without fibrosis Presence of inflammatory infiltrate and damage of adjacent myocytes Frank necrosis that may consist of vacuolization, irregular cellular outlines, and cellular disruption with lymphocytes closely applied to the cell surface Uninvolved myocardium often appears normal Borderline myocarditis (may require biopsy) Inflammatory infiltrate or myocyte damage not seen on light microscopy Diagnostic changes evident on additional cuts of original biopsy, which suggest active myocarditis and do not require a repeat biopsy No evidence of myocarditis 26. Histologic Criteria for the Classification of Viral Myocarditis (Dallas Criteria) Subsequent Biopsies Ongoing myocarditis Degree of abnormality is equal to or worse than that of the original biopsy Resolving myocarditis Inflammatory infiltrate is less and repair is evident Resolved myocarditis No remaining inflammatory infiltrate and no evidence of persistent cellular necrosis 27. Myocarditis - Pericarditis Immunity: Need to see 4-fold rise due to ubiquity of the agents and persistence of titers Chronicity postulated due to lesions representing an immune response 28. Myocarditis - Pericarditis Epidemiology: Season: random through year Spread: fecal-oral and respiratory Age Other factors: Physical exercise Nutrition Volume load on circulatory system Pregnancy Sex Corticosteroids Diabetes 29. The Journal of Experimental Medicine 143:1239, 1976 30. Myocarditis - Pericarditis Prophylaxis and treatment: Chronic sequelae constitute an argument for search for specific treatment and prevention Controlled studies of effects of therapeutic measures are needed Bed rest and supportive therapy 31. Proposed Therapies of Postviral and Idiopathic Myocarditis Category Therapy Comment Conventional therapy of congestive heart failure Digitalis and diuretics Digitalis may decrease interleukin- 1 and tumor necrosis factor- Angiotensins-converting enzyme inhibitors and angiotensin-II receptor antagonists May have a direct immunomodulatory effect Bed rest, -blockers Both beneficial and deleterious effects in murine models Immunosuppressive therapy Corticosteroids Documented use in humans Cyclosporine Documented use in humans Azathioprine Documented use in humans FK506 OKT3 Documented use in humans Many others 32. Proposed Therapies of Postviral and Idiopathic Myocarditis Category Therapy Comment Immunomodulatory therapy Gamma globulin Documented use in humans Coxsackie B3 vaccine FK565 Immunostimulant action inhibits replication Immunoadsorption Antiviral therapy Ribavirin Interferon Anticytokine therapy Anti-tumor necrosis factor antibody Vesnarinone One of several phosphodiesterase inhibitors that inhibit cytokine release Amiodarone Miscellaneous Margatoxin One of several T-cell potassium-channel blockers Calcium antagonists May prevent microvascular spasm N-monomethyl-l- arginine Inhibition of nitric oxide synthesis may prevent myocyte injury and reversible depression 33. Viral Infections with Involvement of the Hematopoietic and Lymphatic Systems 34. Epstein-Barr Virus, Infectious mononucleosis EBV herpes group virus, lymphotropic 1889 Pfeiffer - "drusenfieber" - glandular fever 1968 - Henle's: after long history attributed an essential virus role in the disease to a virus of the herpes group EB virus = Epstein Barr virus, a herpes type virus named for cell line in which it was first detected Transforms (i.e., releases from normal regulatory control) human B lymphocytes which then interact with the T lymphocytes (atypical lymphs of mono) 35. New England Journal of Medicine 343:482 2000 36. New England Journal of Medicine 343:483 2000 37. JAMA 278:511, 1997 38. Various Forms of Infection by EB Virus in Man Productive replicative infection Virus replication leading to cell death (as in the oropharynx of some infected individuals) Nonproductive infection Can be activated to productive cycle Latent infection Virus genome express to give LYDMA and EBNA (as in peripheral B cells of all infected individuals) Malignant transformation Virus genome expressed to give early antigen and cell changes of malignancy (as in BL showing LYDMA, EBNA, EMA, and NPC showing EBNA) In marmosets EB virus certainly induces malignant transformation with EBNA expression to give malignant lymphomas 39. Pediatrics in Review 7:36, 1985 40. Clinical Findings in Heterophile Antibody- Positive Infectious Mononucleosis No. of Patients 270 56,200 100 100 Symptoms (% of patients) Sore throat 88 70 NS NS Malaise 50 43 NS 76 Headache 62 37.5 NS 55 Nausea, vomiting, anorexia 27 7.1 NS 43 Myalgia 21 12.5 NS NS 41. Clinical Findings in Heterophile Antibody- Positive Infectious Mononucleosis No. of Patients 270 56,200 100 100 Signs (% of patients) Fever 65 97.5 94 79 Lymphadenopathy >90 100 94 95 Pharyngitis 85 83 NS 91 Exudative 63 22 69 49 Splenomegaly 50 NS 63 51 Palpebral edema 18 36 11 5 Palatal petechiae 47 25 NS 13 Rash 25 3 15 12 Jaundice 10 8 8 0 42. Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis Symptoms Number of Patients Malaise 9 Fever 8 Chills 6 Myalgia 6 Sore throat 5 Headache 4 Anorexia 3 Abdominal pain 2 43. Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis Signs Number of Patients Pharyngeal erythema 5 Lymphadenopathy 5 Rash 5 Splenomegaly 3 Hepatomegaly 0 Exudative pharyngitis 0 44. Clinical Disorders Associated Etiologically with Epstein-Barr Virus Primary infection Evidence for etiology (+ to ++++) Infectious mononucleosis ++++ Congenital infection with fetal abnormalities ++++ Acute neurologic disease (Guillain Barr, Bells Palsy, meningoencephalitis) +++ Acquire agammaglobulinemia, aplastic anemia, lymphoma +++ Lymphoproliferative lesions including lymphomas in renal and other organ transplant recipients ++ Tonsillopharyngitis ++ Thrombocytopenia ++ Pneumonia ++ Reyes syndrome ++ Hemophagocytic syndrome + Acute arthritis + 45. Clinical Disorders Associated Etiologically with Epstein-Barr Virus Reactivated infection Evidence for etiology (+ to ++++) Lymphoproliferative lesions including lymphomas in renal and other organ transplant recipients ++ Burkitts lymphoma, nasopharyngeal carcinoma ++ Chronic mononucleosis or chronic (symptomatic) EBV infection ++ Rheumatoid arthritis + Acquired immunodeficiency syndrome (AIDS) and AIDS-related complex + 46. Complications of Infectious Mononucleosis Neurologic Meningoencephalitis Aseptic meningitis Guillain-Barr syndrome Facial or other peripheral nerve paralysis Transverse myelitis Optic neuritis Seizures Coma Acute psychosis Acute cerebellar ataxia Hematologic Autoimmune hemolytic anemia Thrombocytopenic purpura Granulocytopenia Pancytopenia DIC 47. Complications of Infectious Mononucleosis Cardiac Myocarditis Pericarditis Respiratory Pharyngeal edema with airway obstruction Interstitial pneumonia Pleuritis Hepatic Cholestatic jaundice Massive hepatic necrosis causing liver failure Splenic Rupture 48. Signs and Symptoms of Hemophagocytic Lymphohistiocytosis Organ System Clinical Findings Laboratory Findings General Fever, edema Bone Marrow Anemia Hemophagocytosis, cytopenia 2 lines Immune system Splenomegaly, lymphadenopathy Natural killer cell activity, serum cytokines, soluble IL-2 receptor Liver Jaundice, hepatomegaly Triglycerides, fibrinogen, ferritin, LDH, coagulopathy, transaminases, bilirubin, DIC Lungs Cough Infiltrates on chest x-ray Skin Generalized maculopapular rash CNS Irritability, stiff neck, seizure, CN palsy, ataxia Protein in CSF, hemophagocytosis in CSF 49. Chronic Mononucleosis Clinical Findings and Reported Complaints Among 39 Patients with Suspected Chronic Infectious Mononucleosis Complaint Patients No. (%) Fatigue 29 (74) Nervous system 28 (73) Depression 27 (70) Pharyngitis 25 (64) Fever 24 (63) Lymphadenopathy 23 (59) Myalgia 21 (56) Complaint Patients No. (%) Dyslogia 20 (53) Arthritis/arthralgia 19 (51) Splenomegaly 9 (22) Weight loss 9 (22) Rash 5 (12) Hepatomegaly 4 (10) 50. CFS due to stress and unknown factors Lake Tahoe CFS ? Stress + EBV-related CEBV Severe CEBV (high VCA, EA, absent EBNA-1 Antibodies) CMV HIVHHV-6 Lyme disease 51. Timeline graph from 1800 to the present of other diseases with symptoms very similar to CFS 1800 1850 1900 1950 2000 Chronic Fatigue Syndrome Postviral Fatigue Syndrome Chronic Candidiasis Chronic Mononucleosis, Chronic EBV Total Allergy Syndrome Myalgic Encephalomyelitis, Epidemic Neuromyasthenia Hypoglycemia Chronic Brucellosis Da Costa's Syndrome Neurasthenia Febricula, Vapors 52. Summary of the Working Definition of CFS Major criteria Persistent or relapsing fatigue or easy fatigability that does not resolve with bed rest and is severe enough to reduce average daily activity by 50 Satisfactory exclusion of other chronic conditions, including preexisting psychiatric disease 53. Summary of the Working Definition of CFS Minor criteria Mild fever (37.5-38.0C oral if document by patient) or chills Sore throat Lymph node pain in anterior or posterior cervical or axillary chains Unexplained, generalized muscle weakness Muscle discomfort, myalgia Prolonged ( 24 h) generalized fatigue after previously tolerable levels of exercise New generalized headaches Migratory, noninflammatory arthralgia Neuropsychologic symptoms: photophobia, transient visual scotomata, forgetfulness, excessive irritability, confusion, difficulty thinking, inability to concentrate or depression Sleep disturbance Patient description of initial onset of symptoms as acute or subacute 54. Summary of the Working Definition of CFS Physical findings (documented by physician at least twice 1 month apart) Low-grade fever (37.6-38.6C oral or 37.8-38.8C rectal) Non-exudative pharyngitis Palpable or tender anterior or posterior cervical or axillary lymph nodes (20% Atypical Lymphocytes EBV mononucleosis Viral hepatitis CMV mononucleosis 58. Disorders Associated with