Viral Infections In Which Cardiovascular Manifestations Predominate

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. 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 Viruses That Have Been Shown to Cause Myocarditis

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

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. 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 Signs and Symptoms of Viral Myocarditis

14. New England Journal of Medicine 343:1391 2000

15. 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) Infectious Causes of Pericarditis

16. 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 InfectiousCauses of Pericarditis

17. Collagen vascular diseases Rheumatic fever Rheumatoid arthritis Scleroderma CREST syndrome Systemic lupus erythematosus Sarcoidosis Sjögren's syndrome Mixed connective tissue disease Vasculitis, including temporal arteritis Polyarteritis Drug-induced Minoxidil Bleomycin Procainamide Hydralazine Azathioprine Inflammatory bowel disease Ulcerative colitis Crohn’s disease Noninfectious Causes of Pericarditis

18. Neoplastic Primary (benign or malignant) Metastatic to pericardium Other Fabry’s disease Uremia Löffler's syndrome Thalassemia Acute myocardial infarction Kawasaki’s Disease Dissection aortic aneurysm Post-radiation Pregnancy Other Myxedema Dego's disease Cardiac Injury Traumatic Dressler’s syndrome Stevens-Johnson syndrome Polymyositis Dermatomyositis Behçet's syndrome Addisonian crisis Gout Whipple’s disease Noninfectious Causes of Pericarditis

19. 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 Criteria for Diagnosis of Myopericarditis

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 • *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

32. Proposed Therapies of Postviral and Idiopathic Myocarditis

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

41. Clinical Findings in Heterophile Antibody-Positive Infectious Mononucleosis

42. Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis

43. Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis

44. Clinical Disorders Associated Etiologically with Epstein-Barr Virus

45. Clinical Disorders Associated Etiologically with Epstein-Barr Virus

46. Neurologic Meningoencephalitis Aseptic meningitis Guillain-Barré 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 Complications of Infectious Mononucleosis

47. Cardiac Myocarditis Pericarditis Respiratory Pharyngeal edema with airway obstruction Interstitial pneumonia Pleuritis Hepatic Cholestatic jaundice Massive hepatic necrosis causing liver failure Splenic Rupture Complications of Infectious Mononucleosis

48. Signs and Symptoms of Hemophagocytic Lymphohistiocytosis

49. 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) “Chronic Mononucleosis”Clinical Findings and Reported Complaints Among 39 Patients with Suspected Chronic Infectious Mononucleosis

50. CFS due to stress and unknown factors ? Stress + EBV-related CEBV Lake Tahoe CFS Severe CEBV (high VCA, EA, absent EBNA-1 Antibodies) CMV Lyme disease HIV HHV-6