—  SPECIALTY CONFERENCE  —

Cardiovascular Pathology

Case 2 - Viral Myocarditis

Bruce M. McManus
University of British Columbia
Vancouver, British Columbia


Click on each slide thumbnail image for an enlarged view
Clinical Summary - Case A
A 54-year-old female dentist had a 5-day history of 'flu-like' symptoms (including cough, fatigue, shortness of breath chills and malaise). On admission to a local hospital for shortness of breath and inability to sleep, she was found to have left ventricular failure, cardiogenic shock and marked hypoxemia. She then developed uncontrollable cardiac arrhythmias and later that day, was transferred to St. Paul's Hospital for further care. The differential diagnosis was viral myocarditis, acute coronary syndrome, and / or sepsis. Investigations for pulmonary embolus and cardiac tamponade were negative. She was transferred to the intensive care unit, intubated, and given oxygen and inotropic support. She became profoundly hypotensive with severe arrhythmias, terminating in ventricular tachycardia on the same day.

This patient had hypothyroidism, treated effectively with Synthroid. Autopsy examination of the heart revealed fulminant lymphocyte-predominant myocarditis.


Slide 4 - Hematoxylin and eosin stained slide from the lateral left ventricular free wall which exemplifies the heavy infiltrates and damage seen throughout the myocardium (X125).
Slide 5 - Higher power of the same area showing myocyte necrosis and a cellular infiltrate (X250).
Slide 6 - Immunohistochemical stain for muscle-specific actin showing widespread myocyte loss (X250).

Clinical Summary - Case B
A 27-year-old female admitted to hospital with a 5 day history of exertional chest pain and dyspnea. Her presumptive diagnosis was acute myocardial infarction with NYHA Class IV heart failure. No prior cardiac disease or significant coronary risk factors were known. Her initial ECG demonstrated ST elevation in the anteroseptal leads, ST depression laterally, complete atrioventricular block and frequent ventricular premature complexes. Troponin I was markedly elevated at 41.7 ug/L . She was transferred to St. Paul's Hospital where cardiac catheterization revealed normal coronaries with mildly depressed LVEF of 54% and hypokinesis of anterior and posterior LV wall. Endomyocardial biopsy revealed active lymphocyte predominant myocarditis. Viral serology was positive for Cytomegalovirus, Herpes simplex and Varicella Zoster virus. She clinically deteriorated during the first 48 hours with hypotension and worsening heart failure requiring inotropic support and intubation. Drug therapies resulted in improvement of the patient's condition 6 days after initial presentation. A repeat endomyocardial biopsy 5 weeks after presentation showed late-healing myocarditis. Her heart function-related symptoms improved to NYHA Class I and a repeat echocardiogram showed an LVEF of 50%.


Slide 7 - Hematoxylin and eosin stained slide showing features of a widespread cellular infiltrate with myocyte loss and degeneration (X500).
Slide 8 - Another biopsy fragment from this patient showing features as above (X500).

Diagnosis
Viral myocarditis

Definition of Myocarditis
According to the Dallas Criteria, myocarditis is a non-ischemic primary inflammatory disease of the myocardium. The diagnostic hallmarks of myocarditis are inflammatory infiltration and myocyte necrosis in endomyocardial biopsy (EMBx) specimens. The causes of inflammation may or may not be known.

Causes of Myocarditis
Myocarditis is commonly caused by infection by viruses, bacteria, rickettsia and fungi, as well as toxic and allergic effects, hypersensitivity responses, and endocrine and immune disorders. Due to the possibility that drug hypersensitivity and direct toxicity may cause myocarditis, a complete clinical history including medications should be obtained with each biopsy. The most common viruses associated with myocarditis include picornaviruses, influenza viruses, human immunodeficiency virus (HIV), herpesviruses such as Epstein Barr Virus and cytomegalovirus, and adenoviruses. Among the most prevalent enteroviruses in the picornavirus family that cause myocarditis coxsackieviruses groups B and echoviruses are notable.

Differential Diagnosis
Clinically, myocarditis may present with diverse, nonspecific and variable manifestations including shortness of breath, chest pain, life-threatening arrhythmias and sudden heart failure. Particularly if viral in origin, patients may also have severe flu-like symptoms. However, acute myocardial infarction, dilated cardiomyopathy, valvular heart disease, sepsis, and hematological malignancy may mimic myocarditis. Microscopically, infarcted myocardium exhibits primarily coagulation necrosis, whereas myocyte injury associated with myocarditis is characterized by sarcoplasmic vacuolization as well as coagulative effacement and contraction band formative disruption. Idiopathic dilated cardiomyopathy is commonly associated with myocyte hypertrophy and heterogeneity, and interstitial fibrosis, although focal mononuclear inflammation may also occur.

How Does One Really Make the Diagnosis?
Clinical diagnostic approaches include peripheral blood leukocyte count, chest radiography, electrocardiogram, echocardiography, serum creatine kinase and troponin, viral serology, and fecal isolation of virus or genome (Figure). Endomyocardial biopsy (EMBx) of the right ventricle is the gold standard for the diagnosis of myocarditis in the pathology laboratory. For suspected myocarditis, it is recommended that 5-10 biopsy samples be examined at multiple levels. The first EMBx will distinguish myocarditis, borderline myocarditis and no myocarditis based on degree of inflammation and myocyte injury. Lymphocytic and phagocytic infiltration, and associated myocyte death that is discrete and multifocal or diffuse and abundant are clearly abnormal. However, there still exists some debate about the diagnostic meaning of infiltrates that are diffuse and sparse. The presence or absence of fibrosis must also be considered. Fibrosis should be designated according to localization (endocardial versus interstitial), extent (mild, moderate or severe), and type (perivascular, pericellular and replacement). Similarly, the inflammatory infiltrate should be described according to extent (mild, moderate and severe) and type (lymphocytic, eosinophilic, neutrophilic or mixed, granulomatous, giant cell). However, a temporal analysis of myocarditis would be inappropriate for the first biopsy.

A subsequent biopsy is necessary to establish the status of ongoing, resolving or resolved myocarditis based on comparisons with the previous biopsy(ies). Ongoing (or persistent) myocarditis indicates that the inflammatory process is either as extensive, or more so, than in the previous biopsy. Resolving myocarditis suggests that inflammation and necrosis are still present but are improving. Resolved (or healed) myocarditis indicates that the inflammation has abated. "Resolving or resolved" is not restricted to healing by resolution, but also includes healing by organization with fibrosis.

Although the cause of myocarditis is often idiopathic, there are common causes that are associated with certain types of inflammation. Lymphocytic myocarditis is most often associated with virus infection, 'autoimmunity', polymyositis, sarcoidosis, Lyme disease and drug toxicity. Eosinophilic myocarditis is associated with hypereosinophilic syndrome, restrictive cardiomyopathy, asthmatic bronchitis, parasitic infestations and drug hypersensitivity. Neutrophilic or mixed myocarditis is associated with general infection, myocardial infarction, bacterial or fungal infections, and drug toxicity. Giant cell myocarditis is commonly associated with cancers such as thymomas, sarcoidosis, rheumatic disease, other granulomatoses and drug hypersensitivity.


Figure: Clinical Diagnosis of Myocarditis.
Ish: In-situ Hybridization. PCR: Polymerase chain reaction. IHC: Immunohistochemistry.

Diagnostic Techniques Aimed at Etiologic Diagnosis
There are several diagnostic techniques that a clinician may use to determine a viral etiology. The benefits and drawbacks to each assay include sensitivity, specificity, reproducibility, costs, timeliness, quantitation and localization. Such techniques include RT-PCR, Nested PCR, ISH, IHC and Plaque Assay. A rough estimate of the value of each technique is portrayed. Ultimately, a definitive diagnosis will often include use of several of the above techniques depending on the stage of myocarditis and the patient's clinical course.

  RT-PCR Nested PCR ISH IHC Plaque Assay
Sensitivity + + + + + + + + + + + + +
Specificity + + + + + + + + + + + + + + + + +
Reproducibility + + + + + + + + + + + + +
Economy (financial) + + + + + + + + + + +
Economy (time) + + + + + + + + + + + + + +
Quantitation + + + + + + + + +
Localization + + + + + + + + + + + +
Suggested "ideal" application and valueDetection of acute viral infectionDetection of persistant viral genomeLocalization of viral genome and replication in tissues and cellsLocalization of viral capsid proteinsDetermination of virulence

Table: Comparative Value of different Methods in
Detection of Cardiotropic Enterovirus in Fluids, Cells and Tissues.
 (+ = perhaps least value, + + + + = most value).

Sources of Error in Biopsy Diagnosis
Myocarditis, by nature, may often be expressed as focal lesions, diffusely scattered. Thus, as eluded to earlier, the main caveat in using the EMBx for the diagnosis of myocarditis relates to false negative results due to sampling error. Typically there are false negative results in approximately 50% of cases. Thus at least five biopsies should be taken. A negative result should not be used in the "non-diagnosis" of this disease. Although the lesions are focal, they tend to be spread throughout the myocardium and thus a biopsy of the right ventricle is usually an appropriate tool for diagnosis. There are myocarditic entities which involve predominantly the base, left ventricular free wall and subepicardial regions.

As mentioned above, the criteria for diagnosis of myocarditis include myocyte necrosis and inflammatory infiltration. In some instances, clusters of fibroblastic and myofibroblastic cells or thickened small vessels may appear to be mononuclear infiltration. Common artifacts in the EMBx include myocyte contraction bands and small vessel intussusception. Other 'normal' features include right ventricular adipose tissue and a certain small assembly of sentinel myocardial mononuclear cells, mast cells and fibroblasts. Myocyte disarray is not uncommon if the EMBx is taken from the junction of the right ventricular free wall and the septum or at a previous biopsy site. In consideration of such caveats, it is critical for the pathologist to be aware of all clinical information before making the diagnosis.

There is an approximate 1% complication rate with the use of EMBx including pneumothorax, vasovagal reaction, transient nerve palsies, infection, atrial arrhythmias, ventricular perforation, air embolism and embolism of mural thrombotic materials.

References

  1. Aretz HT. Myocarditis: the Dallas Criteria. Hum Pathol. 1987. 18:619-24.
  2. Chow LH, Radio SJ, Sears TD, McManus BM: Insensitivity of right ventricular endomyocardial biopsy in the clinical diagnosis of myocarditis. J Am Coll Cardiol 1989, 14:915-20.
  3. Chow LH, Ye Y, Linder J, McManus BM. Phenotypic analysis of infiltrating cells in human myocarditis. An immunohistochemical study in paraffin-embedded tissue. Arch Pathol Lab Med. 1989. 113:1357-62.
  4. Cooper Jr., LT, Editor, Myocarditis from the Bench to the Bedside. 2002. p.621.
  5. Edwards WD. Endomyocardial biopsy and cardiomyopathy. Cardiovasc Rev Rep. 1990. 11:26-43.
  6. Hauck AJ, Kearney DL, Edwards WD. Evaluation of postmortem endomyocardial biopsy specimens from 38 patients with lymphocytic myocarditis: implications for role of sampling error. Mayo Clin Proc. 1989. 64:1235-45.
  7. Mason JW, O'Connell JB, Herskowitz A, Rose NR, McManus BM, Billingham ME, Moon TE. A clinical trial of immunosuppressive therapy for myocarditis. The Myocarditis Treatment Trial Investigators. N Engl J Med. 1995. 333:269-75.
  8. McManus BM, Kandolf R. Myocarditis. In Atlas of Cardiovascular Pathology for the Clinician. Editor McManus, BM. Current Medicine, Philadelphia. 2001:168-83.
  9. Veinot JP. Diagnostic endomyocardial biopsy pathology-general considerations and its use for myocarditis and cardiomyopathy: A review. Can J Cardiol. 2002:18:55-65.
  10. Winters GL, McManus BM. Myocarditis. In Cardiovascular Pathology, 3rd Edition. Editors Silver M, Gotlieb AI and Schoen FJ. Churchill Livingstone, London. 2001:250-84.
  11. Wu LA, Lapeyre AC III, Cooper LT. Current role of endomyocardial biopsy in the management of dilated cardiomyopathy and myocarditis. Mayo Clin Proc. 2001. 76:1030-8.