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

Cytokine IL-2 IL-1 IL-6 INF TNF IL-8 a Principal Cell of Origin Activated T cell Activated macrophages, endothelial cells Monocytes, macrophages, T cells, endothelial cells Activated T cells Activated macrophages Activated macrophages, lymphocytes, endothelial cells Principal Action Autocrine T-cell growth factor. Stimulates production of IL-2, TNF a , Activates natural killer cells Stimulates T-cell activation. Induction of inflammatory metabolites. Activates endothelial cells and stimulates cytokine production.

Stimulates differentiation of B cells. Stimulates production of plasma proteins by hepatocytes.

Activates monocytes. Increases production of oxygen radicals by macrophages. Increases expression of MHC class I and II antigens.

Activates endothelial cells. Stimulates production of cytokines. Can induce direct lysis of some cell types.

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

• Symptoms – Fatigue – Dyspnea – Palpitation – Chest pain – Syncope • Signs – Pericardial rub – Sinus tachycardia – Atrial or ventricular arrhythmias – Conduction disturbances – Cardiomegaly – Right or left S 3 sounds or S 4 gallop – 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 Viral Agents Usually Sought Enterovirus Myxovirus Paramyxovirus Throat Swab

++ +++ +++

Rectal Swab

+++ -

Source CSF Urine

-

Pericardial Fluid

++ ++ ++

Other

* * *

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

Proposed Therapies of Postviral and Idiopathic Myocarditis

Category Immunomodulatory therapy Therapy Gamma globulin Comment Documented use in humans Antiviral therapy Anticytokine therapy Miscellaneous Coxsackie B3 vaccine FK565 Immunostimulant action inhibits replication Immunoadsorption Ribavirin Interferon Anti-tumor necrosis factor antibody Vesnarinone One of several phosphodiesterase inhibitors that inhibit cytokine release Amiodarone Margatoxin Calcium antagonists N-monomethyl-l-arginine One of several T-cell potassium-channel blockers May prevent microvascular spasm 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 Symptoms (% of patients) •Sore throat •Malaise •Headache •Nausea, vomiting, anorexia •Myalgia 270 56,200 100 100 88 50 62 27 21 70 43 37.5

7.1

12.5

NS NS NS NS NS NS 76 55 43 NS

Clinical Findings in Heterophile Antibody Positive Infectious Mononucleosis No. of Patients Signs (% of patients) •Fever •Lymphadenopathy •Pharyngitis •Exudative •Splenomegaly •Palpebral edema •Palatal petechiae •Rash •Jaundice 270 56,200 100 100 65 >90 85 63 50 18 47 25 10 97.5

100 83 22 NS 36 25 3 8 94 94 NS 69 63 11 NS 15 8 79 95 91 49 51 5 13 12 0

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

Symptoms and Signs in Nine Patients with Spontaneous Cytomegalovirus Mononucleosis Signs Pharyngeal erythema Lymphadenopathy Rash Splenomegaly Hepatomegaly Exudative pharyngitis Number of Patients 5 0 0 5 5 3

Clinical Disorders Associated Etiologically with Epstein-Barr Virus Primary infection •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 Evidence for etiology (+ to ++++) ++++ ++++ +++ +++ ++ ++ ++ ++ ++ + +

Clinical Disorders Associated Etiologically with Epstein-Barr Virus

Reactivated infection •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 Evidence for etiology (+ to ++++) ++ ++ ++ + +

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 General Bone Marrow Immune system Liver Lungs Skin CNS Clinical Findings Fever, edema Anemia Laboratory Findings Hemophagocytosis, cytopenia  2 lines Splenomegaly, lymphadenopathy Jaundice, hepatomegaly ↓ Natural killer cell activity, ↑ serum cytokines, ↑ soluble IL-2 receptor ↑ Triglycerides, ↓ fibrinogen, ↑ ferritin, ↑ LDH, coagulopathy, ↑ transaminases, ↑ bilirubin, DIC Infiltrates on chest x-ray Cough Generalized maculopapular rash 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. (%) Complaint Patients No. (%) Fatigue Nervous system Depression Pharyngitis Fever Lymphadenopathy Myalgia 29 (74) 28 (73) 27 (70) 25 (64) 24 (63) 23 (59) 21 (56) Dyslogia Arthritis/arthralgia Splenomegaly Weight loss Rash Hepatomegaly 20 (53) 19 (51) 9 (22) 9 (22) 5 (12) 4 (10)

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

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. 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

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

EBV Toxoplasmos is Rubella HIV CMV HHV-6

Physical Findings

•Pharyngitis •Lymphadenopathy •Splenomegaly

Lab Abnormalities

•Leukopenia •Atypical lymphocytosis •  SGOT/SGPT •Thrombocytopenia •Mono spot ++ (exudative/ non-exudative) Bilateral posterior cervical/genera lized lymph adenopathy +++ + (non exudative) Unilateral single node involvement ± + (non exudative) ± (non exudative) Occipital postauricular generalized lymph adenopathy Localized node enlargement generalized lymph adenopathy + (non exudative) Bilateral posterior cervical/ generalized lymph adenopathy ± + (non exudative) Bilateral posterior cervical adenopathy ± + 20% + + + <5% ± -* ± <5% ± -* + + -* + ≥ 20% + + -* ± <10% + ± -* HAV/HBV ± (non exudative) None/mild general adenopathy <5% +++ -* *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 4 th 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 Helicobacter pylori Malignancy Gastric carcinoma Helicobacter pylori Mucosal-associated lymphoid tissue Schistosoma haematobium Bladder cancer HTLV-1 Adult T-cell leukemia/lymphoma HTLV-11 HBV HHV-8 EBV EBV EBV HPV Hairy cell leukemia Liver cancer Kaposi sarcoma Lymphoproliferative disorders Nasopharyngeal carcinoma Burkitt’s lymphoma 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