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

Myocarditis-Pericarditis Etiology: cardiotropism Pathology Clinical features Diagnosis Immunity Epidemiology Prophylaxis and treatment

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

CMV and cardiovascular disease

Cardiac Malformations as Part of Rubella Embryopathy Etiology: vascular endothelial tropism

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

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

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

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

Circulation 89:2422, 1994

Inflammatory Cytokines Principal Cell of Origin Principal Action IL-2 Activated T cell Autocrine T-cell growth factor. Stimulates production of IL-2, TNF-a, 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- a 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.

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 

Signs and Symptoms of Viral Myocarditis 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

New England Journal of Medicine 343:1391 2000

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)

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

Noninfectious Causes of Pericarditis 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 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

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

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

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.

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.

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.

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

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

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

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

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

The Journal of Experimental Medicine 143:1239, 1976

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

Proposed Therapies of Postviral and Idiopathic Myocarditis Category Therapy Comment Conventional therapy of congestive heart failure Digitalis and diuretics Digitalis may decrease interleukin-1b and tumor necrosis factor-a Angiotensins-converting enzyme inhibitors and angiotensin-II receptor antagonists May have a direct immunomodulatory effect Bed rest, b-blockers Both beneficial and deleterious effects in murine models Immunosuppressive therapy Corticosteroids Documented use in humans Cyclosporine Azathioprine FK506 OKT3 Many others

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

Viral Infections with Involvement of the Hematopoietic and Lymphatic Systems

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)

New England Journal of Medicine 343:482 2000

New England Journal of Medicine 343:483 2000

JAMA 278:511, 1997

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

Pediatrics in Review 7:36, 1985

Clinical Findings in Heterophile Antibody-Positive Infectious Mononucleosis No. of Patients 270 56,200 100 Symptoms (% of patients) Sore throat 88 70 NS Malaise 50 43 76 Headache 62 37.5 55 Nausea, vomiting, anorexia 27 7.1 Myalgia 21 12.5

Clinical Findings in Heterophile Antibody-Positive Infectious Mononucleosis No. of Patients 270 56,200 100 Signs (% of patients) Fever 65 97.5 94 79 Lymphadenopathy >90 95 Pharyngitis 85 83 NS 91 Exudative 63 22 69 49 Splenomegaly 50 51 Palpebral edema 18 36 11 5 Palatal petechiae 47 25 13 Rash 3 15 12 Jaundice 10 8

Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis Number of Patients Malaise 9 Fever 8 Chills 6 Myalgia Sore throat 5 Headache 4 Anorexia 3 Abdominal pain 2

Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis Number of Patients Pharyngeal erythema 5 Lymphadenopathy Rash Splenomegaly 3 Hepatomegaly Exudative pharyngitis

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 Barré, Bell’s Palsy, meningoencephalitis) +++ Acquire agammaglobulinemia, aplastic anemia, lymphoma Lymphoproliferative lesions including lymphomas in renal and other organ transplant recipients ++ Tonsillopharyngitis Thrombocytopenia Pneumonia Reye’s syndrome Hemophagocytic syndrome + Acute arthritis

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 ++ Burkitt’s lymphoma, nasopharyngeal carcinoma Chronic mononucleosis or chronic (symptomatic) EBV infection Rheumatoid arthritis + Acquired immunodeficiency syndrome (AIDS) and AIDS-related complex

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

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

“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)

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

Timeline graph from 1800 to the present of other diseases with symptoms very similar to CFS Febricula, Vapors Neurasthenia Da Costa's Syndrome Chronic Brucellosis Hypoglycemia Myalgic Encephalomyelitis, Epidemic Neuromyasthenia Total Allergy Syndrome Chronic Mononucleosis, Chronic EBV Chronic Candidiasis Postviral Fatigue Syndrome Chronic Fatigue Syndrome 1800 1850 1900 1950 2000

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

Summary of the Working Definition of CFS Minor criteria Mild fever (37.5-38.0ºC 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

Summary of the Working Definition of CFS Physical findings (documented by physician at least twice ≥ 1 month apart) Low-grade fever (37.6-38.6ºC oral or 37.8-38.8ºC rectal) Non-exudative pharyngitis Palpable or tender anterior or posterior cervical or axillary lymph nodes (<2 cm diameter)

Epstein-Barr Virus, Infectious mononucleosis Laboratory diagnosis Blood smear with "atypical" lymphocytes Heterophile agglutination (nonspecific reaction with abs which   agglutinate HRBC or SRBC) Anti EB virus abs

Clinical and laboratory manifestations of infectious mononucleosis Clinical and laboratory manifestations of infectious mononucleosis. The predominant symptoms, signs, laboratory changes and EB virus-specific serologic findings during classic infectious mononucleosis are depicted in four panels. Arrow A indicates asymptomatic prodrome; arrow B, peak of clinical illness; and arrow C, early convalescence, during which the EB virus-associated neuropathies usually occur. Pediatrics in Review 7:37, 1985

Disorders Associated with >20% Atypical Lymphocytes EBV mononucleosis Viral hepatitis CMV mononucleosis

Disorders Associated with <20% Atypical Lymphocytes Infections Mumps Varicella Rubeola Rubella Roseola infantum (HHV6) Herpes simplex Herpes zoster Influenza Tuberculosis Brucellosis Toxoplasmosis Syphilis Smallpox Malaria Babesiosis RMSF Ehrlichiosis

Disorders Associated with <20% Atypical Lymphocytes Non-Infectious Drug hypersensitivity reactions Drug fever Dermatitis herpetiformis Radiation therapy Stress Lead intoxication

Interpretation of EBV Serology IgG-VCA IgM-VCA EBV Nuclear Antigen EBV Early Antigen No evidence of infection <10 <2 Acute infection >10 ≥10 ≥20 Convalescent infection Variable >2 Remote past infection ≤20

Bilateral posterior cervical/generalized lymph-adenopathy EBV Toxoplasmosis Rubella HIV CMV HHV-6 HAV/HBV Physical Findings Pharyngitis ++ (exudative/ non-exudative) + (non-exudative) ± Lymphadenopathy Bilateral posterior cervical/generalized lymph-adenopathy Unilateral single node involvement Occipital postauricular generalized lymph-adenopathy Localized node enlargement generalized lymph-adenopathy Bilateral posterior cervical/ generalized lymph-adenopathy Bilateral posterior cervical adenopathy None/mild general adenopathy Splenomegaly +++ - Lab Abnormalities Leukopenia Atypical lymphocytosis 20% <5% ≥ 20% <10% SGOT/SGPT Thrombocytopenia Mono spot -* *rarely false positive Mono spot test

Epstein-Barr Virus, Infectious mononucleosis Epidemiology: Children and young adults Droplet spread probably Communicability period and incubation period

Epstein-Barr Virus, Infectious mononucleosis Immunity: EB virus (or one closely related antigenically) might  operate in an opportunistic way whenever it finds  actively proliferating lymphocytes

Epstein-Barr Virus, Infectious mononucleosis Prophylaxis and treatment: Symptomatic and supportive Acyclovir Corticosteroids

Burkitt's disease African lymphoma starting as jaw or orbital tumor, then involvement of maxillary bones, kidneys, ovaries, thyroid, parotid Epidemiology Central Africa Case concentration: children 7-8 years old Associated etiology Herpes-group virus: EB virus (from cell line of a  Burkitt lymphoma  established by Epstein and Barr) DNA, 180 nm enveloped

Annual Review of Microbiology 31:424, 1977

Other HHV 6, HHV7, HHV8 Human Parvovirus B19: transient aplastic crisis Bone marrow failure Malignant association

Mechanisms of virus-induced bone marrow failure. EBV = Epstein-Barr virus CMV = cytomegalovirus CTL = cytotoxic lymphocyte HGF = hematopoietic growth factor HSC = hematopoietic stem cell Hematology of Infancy and Childhood 4th Edition Vol 1:222, 1993

Infectious Causes of Cancer Clinical Infectious Diseases 32:679, 2001

Established Association Between an Infectious Agent and a Malignancy Pathogen Malignancy Helicobacter pylori Gastric carcinoma Mucosal-associated lymphoid tissue Schistosoma haematobium Bladder cancer HTLV-1 Adult T-cell leukemia/lymphoma HTLV-11 Hairy cell leukemia HBV Liver cancer HHV-8 Kaposi sarcoma EBV Lymphoproliferative disorders Nasopharyngeal carcinoma Burkitt’s lymphoma HPV Anogenital carcinoma, cervical cancer

CMV and cardiovascular disease

Cardiac Malformations as Part of Rubella Embryopathy Rubella virus predilection for vascular endothelium: patent ductus arteriosus, atrial septal defect, ventricular septal defect, lesions of myocardial fibers, alterations in renal arteries, pulmonary artery stenosis, and also thrombocytopenic purpura