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

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


• 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


• 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 CytokinesCytokine 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.


• 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 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)

InfectiousCauses 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


• 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.


• 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.


• 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


• 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


• 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


• 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-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

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 Medicine343:482 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 Review7:36, 1985

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

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

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

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

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

Lake Tahoe CFS

? Stress + EBV-related

CEBV

Severe CEBV (high VCA, EA, absent EBNA-1

Antibodies)

CMVHIVHHV-6

Lyme disease

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

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


• 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


• 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)


• 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

IgG-VCA IgM-VCA EBV Nuclear Antigen

EBV Early Antigen

No evidence of infection

<10 <10 <2 <10

Acute infection

>10 ≥10 <2 ≥20

Convalescent infection

>10 Variable >2 Variable

Remote past infection

≥10 <10 >2 ≤20

EBV Toxoplasmosis

Rubella HIV CMV HHV-6 HAV/HBV

Physical Findings

•Pharyngitis ++

(exudative/

non-exudative)

+

(non-exudative)

+

(non-exudative)

±

(non-exudative)

+

(non-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% <5% - ≥ 20% <10% <5%

• SGOT/SGPT + ± - - + + +++

•Thrombocytopenia + - ± + + ± -

•Mono spot + -* -* -* -* -* -*

*rarely false positive Mono spot test


• Epidemiology:– Children and young adults– Droplet spread probably– Communicability period and incubation period


• Immunity:– EB virus (or one closely related antigenically) might

operate in an opportunistic way whenever it finds actively proliferating lymphocytes


• 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 Microbiology31:424, 1977

Other

• HHV 6, HHV7, HHV8

• Human Parvovirus B19: transient aplastic crisis

• Bone marrow failure

• Malignant association

Hematology of Infancy and Childhood4th Edition

Vol 1:222, 1993

Mechanisms of virus-induced bone marrow failure. EBV = Epstein-Barr virusCMV = cytomegalovirusCTL = cytotoxic lymphocyteHGF = hematopoietic growth factorHSC = hematopoietic stem cell

Infectious Causes of Cancer

Clinical Infectious Diseases32:679, 2001

Established Association Between an Infectious Agent and a Malignancy

Pathogen Malignancy

Helicobacter pylori Gastric carcinoma

Helicobacter pylori 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

EBV Nasopharyngeal carcinoma

EBV 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

Documents

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