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| PARACLINICAL PAGES |
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| Year : 2015 | Volume
: 1
| Issue : 2 | Page : 161-167 |
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Myocarditis: Pathologist's perspective
Sudheer Arava1, Ruma Ray1, Sandeep Seth2, Firdaus Ali1, Parul Jain1
1 Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
2 Department of Cardiology, All India Institute of Medical Sciences, New Delhi, India
| Date of Web Publication | 30-Sep-2015 |
Correspondence Address:
Dr. Sudheer Arava
Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi - 110 029
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/2395-5414.166330
Myocarditis is a challenging diagnosis for both clinician and pathologist due to the extreme diversity of clinical presentation and low sensitivity of detection of myocarditis in the endomyocardial samples. The exact incidence of myocarditis is still not known as endomyocardial biopsy (EMB) is not performed in all suspected cases of myocarditis in majority of the centers. Identification of Dallas criteria in EMB is still considered as a gold standard in the diagnosis of myocarditis. Viral myocarditis is one of the most common causes of myocarditis next to idiopathic or primary myocarditis. Virtually any type of virus can affect the heart. Idiopathic myocarditis should be categorized depending upon the histopathological findings and clinical features as fulminant, chronic active, eosinophilic, granulomatous, or giant cell myocarditis. Hence, a thorough basic set of all relevant investigations including molecular study should be carried out in the evaluation of clinically suspected viral myocarditis patients to identify the active phase of the viral disease process which ultimately helps in the determination of treatment protocol and prognosis. Keywords: Dallas criteria, endomyocardial biopsy, myocarditis
How to cite this article:
Arava S, Ray R, Seth S, Ali F, Jain P. Myocarditis: Pathologist's perspective. J Pract Cardiovasc Sci 2015;1:161-7 |
| Introduction | |  |
Myocarditis is defined as an inflammatory process of the myocardium with associated cardiac dysfunction that is, diagnosed by established histopathological, immunological, and immunohistochemical criteria.[1] It can be associated with any of the following conditions such as viral infections, autoimmune diseases, hypersensitivity/hypereosinophilic syndromes and sarcoidosis, etc. After excluding all the known causes, a large and more important category of myocarditis is labeled as primary/idiopathic (possibly postviral) myocarditis. The exact incidence of myocarditis is still not known as an endomyocardial biopsy (EMB) which is the gold standard for the histological diagnosis is not performed in all suspected cases of myocarditis in the majority of the centers.[2] Myocarditis is a challenging diagnosis for both clinician and pathologist due to the extreme diversity of clinical manifestations and low sensitivity of detection of myocarditis in the EMB sample.[3] Clinical symptoms may vary from asymptomatic patients to dyspnea, chest pain, heart attack, arrhythmias, or sudden cardiac death.[4],[5] A proper and methodical evaluation of the clinically suspected myocarditis patients is necessary because up to 30% of the biopsy-proven myocarditis patients progress to dilated cardiomyopathy (DCM) which is associated with poor prognosis.[3]
| Endomyocardial Biopsy | | |
EMB has an important role in the evaluation of a patient with unexplained myocarditis and acute heart failure (HF).[6] It is still considered as a gold standard method in the definitive diagnosis of myocarditis.[7] Routine indication of EMB in myocarditis is still a matter of debate. Although it is claimed as the ultimate diagnostic tool for myocarditis, its low sensitivity, low availability, and risk of an invasive procedure have led many clinicians to avoid performing it. The biopsy sample is usually taken from the lower half of the right interventricular septum and rarely from the left ventricle.[8],[9] It is performed by a cardiac bioptome with minimal risk to the patient.[6],[8] According to the International Society of Heart and Lung transplantation (2004) grading system, adequacy of the EMB is categorized as follows [Table 1].
| Processing of the Endomyocardial Biopsy Sample | | |
Depending upon the clinical indication and suspicion, EMB sample should be processed separately as shown in the flow diagram [Figure 2].
For routine microscopy, EMB fragments should be sectioned at various levels with a thickness of 3–4 microns and stained with hematoxylin and eosin stain (H and E). This will help to increase the sensitivity of the detection of myocarditis in the given sample.
All H and E sections (first, fourth and seventh sections as mentioned above) at various levels should be examined thoroughly for any evidence of myocarditis/myocyte damage. Depending on the level showing prominent findings, neighboring unstained slides should be used for further workup like special histochemical stains or immunohistochemical analysis. Some of the commonly used special histochemical and immunohistochemical stains with their importance are mentioned bellow [Table 2] and [Table 3].
| Approach to Myocarditis on Biopsy Samples | | |
Histologically, myocarditis is defined as inflammation with associated myocyte damage/necrosis which should not be characteristic of an ischemic event.[5],[10],[11] This was originally proposed in Dallas (1986) as Dallas criteria.[11] Borderline myocarditis is defined as inflammatory infiltrate without any evidence of myocyte damage/necrosis.[7] When inflammation is confirmed on biopsy, depending upon the type of inflammatory infiltrate, myocarditis should be labeled as follows [Figure 3].[11]
In spite of the development of various diagnostic modalities, early, and definitive diagnosis of myocarditis still depends on the detection of inflammatory infiltrate in the EMB sample according to Dallas criteria.[4] Presently, Dallas criteria are reported to have less importance in the diagnosis of myocarditis because of the following reasons (death of Dallas criteria).[2],[7],[11]
- Sampling error: Chow et al.[12] and Hauck et al.[13] on postmortem heart samples of myocarditis patients demonstrated histological evidence of myocarditis in only 25% on single biopsy and nearly two-third with five biopsies favoring the fact that increasing number of sample increases the sensitivity [Table 4]. This study also showed that earliest myocardial abnormalities were evident in the lateral wall of the left ventricle, and only these sites revealed histological evidence of myocarditis. However, most commonly EMB samples are taken from the right ventricle. Hence, the detection of inflammation at this site is rare. As the disease process is patchy, biopsy specimen with absent Dallas criteria will not exclude the disease.[14]
- Variation in interpretation: Interobserver variability is most commonly noted in cases of borderline myocarditis. In order to standardize, following criteria have been developed [Table 3]
- Noncellular inflammatory disease process cannot be detected by this criterion. Number of investigators has demonstrated presence of viral pathogen without Dallas criteria of myocarditis, this indicates virus can exist in the myocardium in the absence of myocardial inflammation, and it may adversely affect the outcome [11]
- Presence or absence of Dallas criteria has no significant difference in the myocarditis treatment protocol
- No significant difference in 1–5 years survival or ejection fraction in patients with Dallas criteria of myocarditis treated with immunosuppressive therapy or placebo [11]
- Even in positive Dallas criteria myocarditis, response to treatment is influenced by the presence of virus or immunological response to infection [11]
- Dallas criteria myocarditis does not identify patients who respond to immune modulation therapy.[11]
| Etiopathogenesis | | |
There is little difference in opinion regarding the indication of carrying out EMB between European and American cardiology groups. European cardiology working group, on myocardial diseases recommends EMB should be performed for all suspected cases of myocarditis including acute and chronic DCM patients. American Heart Association recommends it should not be performed in the routine evaluation of patients with HF.[3] Thorough literature review reveals that for proper diagnosis and management of myocarditis, EMB should be performed in patients with acute cardiac deterioration of unknown etiology and in patients who are unresponsive to medical therapy.
Depending on the causative factor and histopathological findings myocarditis can be classified as shown below [Figure 4] primary or idiopathic (postviral) myocarditis should be further sub categorized depending upon the histopathological findings as fulminant, chronic active, eosinophilic, granulomatous, or giant cell myocarditis.[5] This histological characterization is important because treatment and prognosis varies between these subtypes.
| Viral Myocarditis | | |
Viral myocarditis is one of the most common causes of myocarditis which ultimately leads to DCM in 30% of patients. Many studies on animal models have proposed this hypothesis. Virtually, any virus can cause myocarditis, but most common cardiotropic viruses documented in the literature are hepatitis C virus (HCV), Epstein–Barr virus (EBV), cytomegalovirus, parvovirus B19 (PVB 19), human herpesvirus 6 (HHV 6), adenovirus, enterovirus, and coxsackievirus (A and B).[1],[5],[7] Association of the particular virus causing myocarditis is largely dependent on their geographical distribution.
Knowledge regarding the pathophysiology of viral myocarditis is important because viral serology, histopathology, treatment, and prognosis vary according to the stage of the disease progression. Pathogenetic mechanisms of cardiac damage are explained by two important methods: (1) Direct virus mediated myocyte injury as a part of their cytopathic effect and (2) autoimmune-mediated destruction of cardiac myocytes by circulating autoantibodies. During the course of progression, activation of host immune response attenuates the viral replication and protects against virus mediated myocyte damage. Pathophysiology of virus-mediated myocardial injury consists of four phases:[1],[15]
- Phase 1: Initial period involves viremia during which cardiotropic virus binds to its receptor on cardiomyocyte and leads to receptor-mediated endocytosis followed by viral replication and translation of viral protein in the myocardium, which leads to cellular dysfunction and apoptosis.[15] There will be increased levels of cardiac biomarkers at this stage due to myocardial damage. Viral culture and tissue polymerase chain reaction (PCR) will give positive results. Viral autoantibody levels will be negative, and EMB usually do not reveal any histopathological evidence of myocarditis (negative Dallas criteria). This is mainly due to the noninitiation of host antibody response to the specific virus
- Phase 2: In this phase, viral proteins start expressing on the cell surface of cardiomyocytes which leads to inflammation and myocarditis with an increase in various cytokine levels.[15] There will be increased cardiac biomarker levels, increased cytokine levels, a gradual mild increase in viral specific autoantibody levels. Viral culture, and PCR may be positive. EMB may or may not reveal significant inflammation
- Phase 3: This phase is characterized by further activation of cell-mediated immunity and recruitment of immune-mediated cells. Antigen-specific T-cells are recruited into the infected myocardium to clear the virally infected cells. T-cell activation further causes lysis of the virus infected cells.[15] There will be the development of antiviral and cardiac autoantibodies by activated B cells which causes a detrimental effect on myocyte signal induction. At this stage, there will be elevated cardiac biomarkers, viral specific autoantibody levels; viral culture and PCR results are usually negative due to the rapid clearance of the virus from the blood. EMB if taken at proper site usually reveals presence of inflammation and myocyte damage (positive Dallas criteria)
- Phase 4: Final (resolution) phase: This is the last phase in which properly developed host defense mechanism clears the virus effectively, and the myocardium starts healing. There will be a resolution of inflammation.[15] Damaged myocytes are ultimately replaced by fibrosis. Cardiac biomarkers, cytokine levels will be towards normal levels. Viral culture, serology, and PCR results usually become negative. EMB sample shows decreased inflammatory infiltrate with varying amount of fibrosis that depends on the severity of myocardial damage.
A thorough basic set of all relevant investigations should be carried out in the evaluation of clinically suspected viral myocarditis patients to identify the phase of the viral disease process. This is because: (1) Identification of the replicative virus in the myocardium with evidence of viral persistence implies worse prognosis (2) it will help to identify patients who fail to respond to immunosuppressive therapy (3) administration of immunosuppression in active viral replicative phase is harmful to the patient.
Primary/idiopathic (postviral) myocarditis: It is called postviral because the majority of these cases are thought to be due to postviral immune-mediated damage.[10],[11] It is classified according to the clinical and histopathological findings as follows:
- Fulminant myocarditis: It has a distinct short history of onset with profound left ventricular (LV) dysfunction without ventricular dilatation. Microscopic examination of the biopsy sample commonly shows multiple foci of active inflammation and myonecrosis.[15] Clinicopathological identification of this entity is important because the patient may die or recover within 2 weeks with complete histological and functional recovery of the myocardium in survivors.[11] If it is quickly recognized and patients are given aggressive treatment, more than 90% will make a full recovery with minimum long-term sequelae. Although viral etiology is thought to be responsible for the majority of cases, viral genome is identified in only 10–20% of patients with active myocarditis [11],[15],[16]
- Chronic active myocarditis:Clinically, it is characterized by the gradual onset of clinical symptoms with mild to moderate ventricular dysfunction. EMB usually reveals active or borderline myocarditis with varying degree of fibrosis.[10] These findings indicate ongoing inflammation which ultimately leads to fibrosis resulting in restrictive cardiomyopathy [11]
- Eosinophilic myocarditis: It is characterized by allergic reactions (drugs/toxins) or hypereosinophilic syndrome with associated LV dysfunction/failure. EMB sample usually reveals moderate to marked infiltration of eosinophils with myocyte damage/necrosis.[10] Identification of this entity is important because these patients respond to treatment of eosinophilic disorder and/or withdrawal of the offending agent [11]
- Sarcoidosis: It is an immune-mediated systemic disorder occasionally presents with HF due to cardiac involvement.[2],[9],[17] Cardiac involvement in sarcoidosis varies from 10% to 58% with the highest incidence seen in Japanese individuals. In sarcoidosis, the sensitivity of EMB in detecting granuloma is very low. However, if seen, it shows the presence of tiny nonnecrotizing epithelioid cell granulomas consisting of lymphocytes, epithelioid histiocytes and multinucleated giant cells [Figure 1]f.[18] When giant cells are more, it should be differentiated from giant cell myocarditis. On special histochemical stains, these granulomas will be reticulin rich and are negative for acid-fast bacilli stain. PCR samples will be negative for mycobacterium bacilli. Identification of granuloma is very important because it indicates poor prognosis and these patients respond to high dose steroids. Recurrence of sarcoidosis in the allograft is a concern in cardiac transplant recipients
- Giant cell myocarditis: It is a very aggressive form of myocarditis. Patients clinically present with rapid deterioration characterized by HF, ventricular arrhythmia or heart blocks. Biopsy reveals mainly multinucleated giant cells and active inflammation. This entity has to be identified at the earliest because, despite institution of medical therapy, these patients continue to have HF or ventricular arrhythmias. Untreated patients will die within 6 months.[11] These patients may sometimes respond to aggressive immunosuppressive therapy. Giant cell myocarditis has highest 1-year mortality and heart transplant rate of 70% with recurrence in up to 25% in the allograft heart. EMB is highly sensitive and specific for the diagnosis of giant cell myocarditis (80–85%) but sensitivity for lymphocytic myocarditis is very low (10–22%).[15]
 | Figure 1: Endomyocardial biopsy: (a) Adequate biopsy with more than 50% of the area is occupied by myocytes (b) inadequate biopsy containing mainly blood clot with few myocytes (c) borderline myocarditis without myocyte necrosis (d) myocarditis with myocyte damage (positive Dallas criteria) (e) myocarditis with positive Dallas criteria and marked replacement fibrosis (Grade 3) (f) granulomatous inflammation with Langhans type of giant cell (sarcoidosis).
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 | Figure 3: EMB classification according to the type of inflammatory infiltrate
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| Diagnostic Tests | | |
Clinical signs and symptoms can vary from subclinical disease to fulminant HF, hence, proper evaluation with supportive diagnostic modalities should be carried out to know the exact etiology of myocarditis, as it influences the management and prognosis of the patients. Diagnostic tests include both noninvasive and invasive procedures which are mentioned bellow:
- Electrocardiogram (ECG): ECG findings are usually abnormal, but they are neither sensitive nor specific [7]
- Echocardiography: It is also not specific, but it is of helpful in excluding the other causes of HF. It is of more use in identifying the chamber size, wall thickness and ventricular function [7]
- Cardiac magnetic resonance imaging: It is currently considered as the most accurate noninvasive imaging modality for the diagnosis and follow-up cases of myocarditis.[6] In suspected myocarditis, this will helpful in the localization and quantification of tissue injury including edema, hyperemia and fibrosis. By Lake Louis criteria [19],[20] the diagnostic accuracy is nearly 78%. It should be carried out in all clinically stable suspected cases of myocarditis prior to EMB
- Cardiac biomarkers: Sensitivity of theses markers varies depending upon the time of myocardial injury and onset of clinical symptoms, but they may help in the diagnosis of myocarditis. Elevated erythrocyte sedimentation rate and C-reactive protein are nonspecific lab findings in suspected myocarditis.[3],[6] Elevated cardiac troponin (I and T) are more sensitive than creatinine kinase levels in acute myocarditis. However, normal values do not exclude myocarditis.[6],[7] However, increased cardiac troponin levels have been shown to be of prognostic significance
- Viral culture: Viruses are difficult to isolate and cultivate. Virus isolation from the blood sample is useful for providing evidence of systemic infection but not for providing information on specific organ disease.[4] Hence, viral culture is seldom successful
- Viral serology: It has very limited utility in the diagnosis of viral myocarditis due to the high prevalence of circulatory immunoglobulin (Ig) G antibodies to cardiotropic viruses in the general population without any evidence of heart disease [4],[6]
- Endomyocardial biopsy: Discussed above
- Immunohistochemistry: As Dallas criteria have limited role in borderline myocarditis due to high interobserver variability, application of certain immunohistochemistry (IHC) markers will be of more use in confirming the diagnosis.[5] IHC is helpful in the differentiation and characterization of inflammatory cells, especially from fibroblasts.[6] After this technique, sensitivity, and specificity of detecting myocarditis have been markedly increased. Some of the commonly used immunohistochemical markers in the evaluation of myocarditis are mentioned in [Table 3].
- Molecular biology: Development of molecular techniques such as PCR, gene sequencing, reverse transcription-PCR, and in situ hybridization has significantly increased the specific diagnosis and sensitivity in detecting the infective organism. These techniques allow detection of low copy of viral genomes even from an extremely small amount of tissue such as EMB samples and also gives information between viral replication and latent persistent of viral genome which is of help in appropriate treatment and prognosis.[4],[5] These should be applied routinely in all cases of suspected myocarditis. Positive PCR sample should always be investigated on a blood sample collected at the time of biopsy. Gene sequencing is the most informative in the characterization of the infective cardio virulent agent.
| A Clinicians Perspective to Myocarditis | | |
Myocarditis is an inflammatory disease of the heart frequently resulting from viral infections or postviral immune reactions. Diagnosis involves cardiovascular magnetic resonance (CMR) imaging and EMB. There is some evidence that immunosuppressive and immunomodulating therapy is effective for chronic, virus-negative inflammatory cardiomyopathy. Further studies are needed to definitively determine their role in the treatment of myocarditis.[7]
Myocarditis is regarded as a precursor of DCM. With the development of new molecular techniques, the spectrum of frequently detected viruses in EMBs has shifted from classic enteroviruses and adenovirus to mainly PVB 19 and HHV 6. Biomarkers (such as troponins or creatine kinase) lack specificity but help to confirm the diagnosis. Virus serology in patients with suspected myocarditis remains of no use because most viruses involved in the pathogenesis of myocarditis are highly prevalent in the population.
CMR imaging has evolved as a valuable tool for the diagnosis of myocarditis. The T2-weighted edema imaging shows the presence of “acute myocardial inflammation.” T1-weighted late gadolinium enhancement images demonstrate the presence of typical late gadolinium enhancement in the subepicardium of the walls.
| Treatment of Myocarditis | | |
Most patients with acute myocarditis do not require therapy. Patients with LV dysfunction or symptomatic HF should follow current HF therapy guidelines, including the administration of diuretics and angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Beta-blockers can be used.[21]
Specific types of myocarditis due to autoimmunity like giant cell myocarditis or cardiac sarcoidosis are treated with immunosuppression. In acute myocarditis, avoidance of physical activity is indicated in addition to pharmacological therapy. More than 20 trials have been reported, using immunosuppressive, immunomodulating, or anti-inflammatory agents as well as immunoadsorption therapy. One of the largest trials, the Myocarditis Treatment Trial, failed to show a benefit from immunosuppressive therapy additional to HF therapy. Intermediate data from the European Study of Epidemiology and Treatment of Inflammatory Heart Disease showed that inflammation was eradicated in 59% of the patients treated with immunosuppressive agents; however, it vanished spontaneously in 40% of the placebo group. Ig in viral myocarditis is used for their antiviral and immunomodulating effects. In a trial with idiopathic cardiomyopathy and EMB-proven high PVB19 viral load, intravenous immunoglobin (IVIG) therapy resulted in significant decrease of PVB19 viral load; LV ejection fraction (LVEF) improved significantly at 6 months after IVIG therapy. IVIG is given as 1 daily infusion at 0.4 g/kg for 5 days. Trials in children with acute myocarditis showed an improvement of LV function and survival in the 1st year after treatment. Treatments with immunosuppressive in acute myocarditis have shown controversial results. The immunosuppressive therapy in patients with virus-negative inflammatory cardiomyopathy studied all EMB for inflammation by histological and immunohistological criteria. Molecular analyses were performed in all biopsy specimens to exclude viral infection. A significant improvement of LVEF and a decrease in LV dimensions resulted from immunosuppressive therapy with prednisone and azathioprine. Antiviral drugs have been tried from the knowledge that most common cases of myocarditis are induced by viral infections. In the multicenter Betaferon in patients with chronic viral cardiomyopathy study, 143 patients with inflammatory DCM and confirmed myocardial viral infection were treated with Betaferon (interferon-beta-1b) versus placebo. Treatment with Betaferon reduced significantly viral load (enteroviruses) in the myocardium; however, complete viral elimination (PVB19) was not achieved in all patients. The New York Heart Association functional class and patient global assessment improved among various assessed parameters.
| Summary | | |
- Myocarditis is a challenging diagnosis for both clinician and pathologist because of variable clinical symptoms and low sensitivity of EMB
- Primary (postviral) myocarditis is the largest category thought to be resulting from viral mediated immune injury to the cardiac myocytes. Treatment strategy should be based on etiology
- Sequential histopathological section analysis with a panel of immunohistochemical markers and molecular tests are mandatory in all suspected cases of myocarditis for a definitive diagnosis and proper treatment
- Dallas criteria are still helpful in distinguishing lymphocytic myocarditis from other entities, such as giant cell myocarditis, eosinophilic myocarditis, or sarcoidosis, which may guide treatment and prognosis
- In all suspected viral myocarditis patients common viral panel consisting of most common 8 viruses HCV, EBV, PVB 19, HHV 6, adenovirus, enterovirus, and coxsackievirus (A and B) should be carried out.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]
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