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
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 892422, 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
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 3431391 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
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

17
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
• Crohns disease

18
Noninfectious Causes of Pericarditis

• Neoplastic
• Primary (benign or malignant)
• Metastatic to pericardium
• Other
• Fabrys disease
• Uremia
• Löffler'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
• Behçet'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

• 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 1431239,
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 343482 2000
36
New England Journal of Medicine 343483 2000
37
JAMA 278511, 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 736, 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
Complications of Infectious Mononucleosis

• Hematologic
• Autoimmune hemolytic anemia
• Thrombocytopenic purpura
• Granulocytopenia
• Pancytopenia
• DIC

• Neurologic
• Meningoencephalitis
• Aseptic meningitis
• Guillain-Barré syndrome
• Facial or other peripheral nerve paralysis
• Transverse myelitis
• Optic neuritis
• Seizures
• Coma
• Acute psychosis
• Acute cerebellar ataxia

47
Complications of Infectious Mononucleosis

• Hepatic
• Cholestatic jaundice
• Massive hepatic necrosis causing liver failure
• Splenic Rupture

• Cardiac
• Myocarditis
• Pericarditis
• Respiratory
• Pharyngeal edema with airway obstruction
• Interstitial pneumonia
• Pleuritis

48
Signs and Symptoms of Hemophagocytic
Lymphohistiocytosis
49
Chronic MononucleosisClinical Findings and
Reported Complaints Among 39 Patients with
Suspected Chronic Infectious Mononucleosis

• Complaint Patients
• No. ()
• Dyslogia 20 (53)
• Arthritis/arthralgia 19 (51)
• Splenomegaly 9 (22)
• Weight loss 9 (22)
• Rash 5 (12)
• Hepatomegaly 4 (10)

• 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)

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
51
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
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 (37.5-38.0ºC 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

54
Summary of the Working Definition of CFS

• Physical findings (documented by physician at
  least twice 1 month apart)
• Low-grade fever (37.6-38.6ºC oral or 37.8-38.8ºC
  rectal)
• Non-exudative pharyngitis
• Palpable or tender anterior or posterior cervical
  or axillary lymph nodes (lt2 cm diameter)

55
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

56
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 737, 1985
57
Disorders Associated with gt20 Atypical
Lymphocytes

• EBV mononucleosis
• Viral hepatitis
• CMV mononucleosis

58
Disorders Associated with lt20 Atypical
Lymphocytes

• Brucellosis
• Toxoplasmosis
• Syphilis
• Smallpox
• Malaria
• Babesiosis
• RMSF
• Ehrlichiosis

• Infections
• Mumps
• Varicella
• Rubeola
• Rubella
• Roseola infantum (HHV6)
• Herpes simplex
• Herpes zoster
• Influenza
• Tuberculosis

59
Disorders Associated with lt20 Atypical
Lymphocytes

• Non-Infectious
• Drug hypersensitivity reactions
• Drug fever
• Dermatitis herpetiformis
• Radiation therapy
• Stress
• Lead intoxication

60
Interpretation of EBV Serology
61
rarely false positive Mono spot test
62
Epstein-Barr Virus, Infectious mononucleosis

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

63
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

64
Epstein-Barr Virus, Infectious mononucleosis

• Prophylaxis and treatment
• Symptomatic and supportive
• Acyclovir
• Corticosteroids

65
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

66
Annual Review of Microbiology 31424, 1977
67
Other

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

68
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 1222, 1993
69
Infectious Causes of Cancer
Clinical Infectious Diseases 32679, 2001
70
Established Association Between an Infectious
Agent and a Malignancy
71
CMV and cardiovascular disease
72
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