Correspondence

Immunosuppressive Therapy for Myocarditis

N Engl J Med 1995; 333:1713-1714December 21, 1995

Article

To the Editor:

Mason and colleagues report the results of a clinical trial of immunosuppressive therapy for myocarditis (Aug. 3 issue).1 Ventricular function improved to the same extent among the patients randomly assigned to receive conventional therapy plus immunosuppressive treatment as among those who received conventional therapy alone. McKenna and Davies, in an accompanying editorial, observe that many patients with dilated cardiomyopathy have immunohistochemical evidence of inflammation, even though they may not meet the Dallas criteria for the histologic diagnosis of myocarditis, and the authors allude to the question of a potential role for immunosuppression in the treatment of dilated cardiomyopathy.2

Six years ago in the Journal we reported the results of a randomized trial of prednisone for dilated cardiomyopathy,3 which are clearly germane to the diagnostic and therapeutic issues raised by McKenna and Davies. Of the 102 patients with dilated cardiomyopathy in our trial, only 2 met strict Dallas criteria, but another 58 had cellular infiltration with fibroblasts or lymphocytes (or both) or other potential indicators of inflammation (immunoglobulin deposition detected on endomyocardial biopsy, positive gallium scans, or elevated erythrocyte sedimentation rates). These findings, especially given the problematic variability between observers and the empiricism of the Dallas criteria,4 underscore the clinical inadequacy of the current nosology of myocarditis and dilated cardiomyopathy. As McKenna and Davies imply, there may be subgroups of patients with dilated cardiomyopathy who could benefit from immunosuppression, but we have no definite means of identifying them.

Forty-nine of the patients in our trial received conventional therapy plus prednisone (60 mg daily for three months), and 52 received conventional therapy alone. Among these patients (as among those described by Mason et al.), ventricular function improved regardless of whether they received immunosuppressive therapy. After three months, the left ventricular ejection fraction had increased slightly more in the prednisone group (from 17.9 to 22.2 percent) than in the control group (from 17.1 to 19.3 percent, P = 0.054). In the prospectively defined subgroup of 60 patients with some evidence of myocardial or systemic inflammation, the left ventricular ejection fraction had increased (i.e., risen 5 percent or more) in 67 percent of the patients given prednisone but in only 28 percent of the controls (P = 0.004). These data emphasize the need for further research to identify subgroups of patients with dilated cardiomyopathy who may benefit from immunosuppressive therapy.

Robert E. Cunnion, M.D.
National Institutes of Health, Bethesda, MD 20892

Joseph E. Parrillo, M.D.
Rush–Presbyterian–St. Luke's Medical Center, Chicago, IL 60612

4 References

1
Mason JW, O'Connell JB, Herskowitz A, et al. A clinical trial of immunosuppressive therapy for myocarditis. N Engl J Med 1995;333:269-275
Full Text | Web of Science | Medline

2
McKenna WJ, Davies MJ. Immunosuppression for myocarditis. N Engl J Med 1995;333:312-313
Full Text | Web of Science | Medline

3
Parrillo JE, Cunnion RE, Epstein SE, et al. A prospective, randomized, controlled trial of prednisone for dilated cardiomyopathy. N Engl J Med 1989;321:1061-1068
Full Text | Web of Science | Medline

4
Shanes JG, Ghali J, Billingham ME, et al. Interobserver variability in the pathologic interpretation of endomyocardial biopsy results. Circulation 1987;75:401-405
CrossRef | Web of Science | Medline

To the Editor:

“Cardiac inflammation is difficult to diagnose and even if diagnosed, can we then treat it more effectively?” This could be the conclusion of the Myocarditis Treatment Trial but was actually written 223 years ago by Jean Baptiste Sénag, physician to Louis XV. Since then, too much has changed for us to accept willingly the negative results of this trial.

The criteria for the diagnosis of myocarditis were based solely on the results of light microscopy. Today even Billingham, from the Dallas panel of pathologists, states that “these criteria have been misrepresented as a classification that is used as a sine qua non of the histological diagnosis of acute myocarditis.”1 Advances in immunohistochemistry (the identification of lymphocyte subpopulations, expression of major-histocompatibility-complex antigens, adhesion molecules, and immunoglobulin binding in biopsy specimens) have greatly increased specificity and sensitivity.2 Light microscopy is no longer the standard. It may even identify the wrong patients in the florid viral phase of myocarditis. In addition, necrosis, which is indispensable for the diagnosis of active myocarditis, is almost impossible to detect in a tiny biopsy specimen, and its use as a diagnostic criterion may have excluded patients with chronic forms and autoreactive features, who might have profited most from immunosuppression.3

Other diagnostic tools used in the trial were inadequate as well. The presence of enteroviral RNA or DNA from adenovirus, cytomegalovirus, Epstein–Barr virus, and influenza virus in the biopsy specimens was not determined. Their presence would rule out immunosuppressive therapy,4 since mortality in coxsackievirus-B3–infected animals with persistent virus is increased exponentially.3

In addition, the duration of the immunosuppressive treatment was too short. An extrapolation of the data in Figure 2 of the article by Mason et al. shows that there were nine deaths in the control group and four in the immunosuppression group at six months, when treatment was discontinued. The positive trend was already obvious at this time. Moreover, not all immunosuppressive agents are alike. Reviews of controlled trials3,4 suggest that azathioprine and prednisone are more beneficial than other agents.

Bernhard Maisch, M.D.
Philipps University, D-35033 Marburg, Germany

Fulvio Camerini, M.D.
Ospedale Riuniti, I-34100 Trieste, Italy

Heinz-Peter Schultheiss, M.D.
Benjamin Franklin University, D-12200 Berlin, Germany

4 References

1
Billingham ME. The histopathological diagnosis and morphological features of acute myocarditis. In: Banatvala JE, ed. Viral infections of the heart. London: Edward Arnold, 1993:32-58.

2
Kuhl U, Noutsias M, Seeberg B, Schanwell M, Welp LB, Schultheiss H-P. Chronic inflammation in the myocardium of patients with clinically suspected dilated cardiomyopathy. J Card Fail 1994;1:13-25
CrossRef | Medline

3
Maisch B, Herzum M, Schonian U. Immunomodulating factors and immunosuppressive drugs in the therapy of myocarditis. Scand J Infect Dis 1993;88:149-162

4
Maisch B, Schonian U, Hengstenberg C, et al. Immunosuppressive treatment in autoreactive myocarditis -- results from a controlled trial. Postgrad Med J 1994;70:Suppl 1:S29-S34
Web of Science | Medline

To the Editor:

Mason et al. conclude that immunosuppression is not an effective treatment for lymphocytic myocarditis. We are concerned that readers may falsely conclude that endomyocardial biopsy has no role in cases of suspected myocarditis.

Giant-cell myocarditis may resemble lymphocytic myocarditis on presentation. Giant-cell myocarditis usually begins with congestive symptoms during a period of several weeks to months, often with ventricular arrhythmias, but has a worse prognosis than lymphocytic myocarditis.1 There is usually a rapid progression to cardiogenic shock and death, unless a heart transplantation is performed. The diagnosis can be made only by endomyocardial biopsy.

We established the Multicenter Giant Cell Myocarditis Study Group in January 1995 to address the many unresolved questions about this rare and rapidly fatal disease. We have enrolled 50 patients with giant-cell myocarditis from U.S. and international medical centers in this ongoing study and have reported on the first 5.2 We know of several cases of giant-cell myocarditis that responded to treatment with cyclosporine, including two cases reported in the literature.3 The only well-documented treatment for giant-cell myocarditis remains heart transplantation. Of the 14 patients in our study who received heart transplants, 9 are well up to 11 years after transplantation.

Giant-cell myocarditis should be suspected in patients with rapidly progressive, refractory heart failure and ventricular arrhythmias. We recommend a heart biopsy as part of the evaluation. Patients should be placed on waiting lists for heart transplants as soon as the diagnosis of giant-cell myocarditis is established.

Leslie T. Cooper, Jr., M.D.
Ralph Shabetai, M.D.
University of California, San Diego, Medical Center, San Diego, CA 92103-8411

3 References

1
Davidoff R, Palacios I, Southern J, Fallon JT, Newell J, Dec GW. Giant cell versus lymphocytic myocarditis: a comparison of their clinical features and long-term outcomes. Circulation 1991;83:953-961
Web of Science | Medline

2
Cooper LT Jr, Berry GJ, Rizeq M, Schroeder JS. Giant cell myocarditis. J Heart Lung Transplant 1995;14:394-401
Web of Science | Medline

3
Desjardins V, Pelletier G, Leung TK, Waters D. Successful treatment of severe heart failure caused by idiopathic giant cell myocarditis. Can J Cardiol 1992;8:788-792
Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with Cunnion and Parrillo that there is no gold standard for the diagnosis of myocarditis. They cite the study by Shanes et al. as evidence of interobserver variability and the empiricism of the Dallas criteria. That study was flawed by technically inadequate histologic preparations and lack of training of the observers in the use of the criteria. Our pathology panel reported excellent consensus using the Dallas criteria.1 The criteria were developed to define myocarditis rigidly for our trial. The internal consistency of the study population is a hallmark of a meaningful clinical trial. The biopsy criteria were not intended to define myocarditis exclusively, since it has many potential histologic, immunologic, and clinical manifestations.

We also agree with the primary point that Cooper and Shabetai make about giant-cell myocarditis. With the help of Dr. Shabetai, a coinvestigator in our trial, we designated giant-cell myocarditis as a criterion for exclusion from enrollment and a form of myocarditis to which the results of the trial do not apply. We have previously pointed out the differences between lymphocytic myocarditis and giant-cell myocarditis, as well as the need to consider immunosuppressive therapy for the latter.2 We do not agree, however, that a biopsy should be performed to rule out giant-cell myocarditis in all patients with heart failure of uncertain cause, because it is a rare entity that will declare itself in its rapid progression. It is also not clear that transplantation is the best treatment, since giant-cell myocarditis may recur in the graft.3

Maisch et al. point out the conundrum that myocarditis can be diagnosed by multiple means because its pathogenesis is unknown. However, they imply that their methods constitute a new standard for the diagnosis of this disorder. We disagree. Standard diagnostic criteria for myocarditis (which do not yet exist) should identify one or more disease entities, each with uniform clinical characteristics and responsiveness to therapy. Thus far, light microscopy has not met these requirements, but neither have any of the new techniques cited by Maisch et al. Our experience with such techniques, which were not available when the trial was initiated, in a subgroup of our patients justifies tempered enthusiasm.4,5

Maisch et al. also suggest that there was a trend toward the efficacy of immunosuppressive therapy in the trial. At six months the difference between the two groups was not significant, and the effect did not persist. But we accept the possibility that a longer period of immunosuppressive therapy or use of other immunosuppressive drugs and doses might have yielded different results.

Jay W. Mason, M.D.
University of Utah Medical Center, Salt Lake City, UT 84132

John B. O'Connell, M.D.
University of Mississippi, Jackson, MS 39216

Bruce M. McManus, M.D., Ph.D.
University of British Columbia, Vancouver, BC V6T 2B5, Canada

5 References

1
Aretz HT, Billingham ME, Edwards WD, et al. The utility of the Dallas criteria for the histopathological diagnosis of myocarditis in endomyocardial biopsy specimens. Circulation 1993;88:Suppl:I-552 abstract.

2
Mason JW. Distinct forms of myocarditis. Circulation 1991;83:1110-1111
Web of Science | Medline

3
Kong G, Madden B, Spyrou N, Pomerance A, Mitchell A, Yacoub M. Response of recurrent giant cell myocarditis in a transplanted heart to intensive immunosuppression. Eur Heart J 1991;12:554-557
Web of Science | Medline

4
Tracy S, Chapman NM, McManus BM, Pallansch MA, Beck MA, Carstens J. A molecular and serologic evaluation of enteroviral involvement in human myocarditis. J Mol Cell Cardiol 1990;22:403-414
CrossRef | Web of Science | Medline

5
Weiss LM, Movahed LA, Billingham ME, Cleary ML. Detection of Coxsackievirus B3 RNA in myocardial tissues by the polymerase chain reaction. Am J Pathol 1991;138:497-503
Web of Science | Medline

Citing Articles (7)

Citing Articles

1
Bernhard Maisch, Michel Noutsias, Volker Ruppert, Anette Richter, Sabine Pankuweit. (2012) Cardiomyopathies: Classification, Diagnosis, and Treatment. Heart Failure Clinics 8:1, 53-78
CrossRef
2
Bernhard Maisch, Sabine Pankuweit. (2010) Therapie der fortgeschrittenen Herz - insuffizienz: medikamentös, Resynchronisation (CRT), Operation. Herz 35:2, 94-101
CrossRef
3
Lori A. Blauwet, Leslie T. Cooper. (2010) Myocarditis. Progress in Cardiovascular Diseases 52:4, 274-288
CrossRef
4
Michel Noutsias, Sabine Pankuweit, Bernhard Maisch. (2009) Biomarkers in Inflammatory and Noninflammatory Cardiomyopathy. Herz 34:8, 614-623
CrossRef
5
(2006) Im Fokus: Inflammatorische Kardiomyopathie. Der Internist 47:9, 970-973
CrossRef
6
Günter Hufnagel, Sabine Pankuweit, Bernhard Maisch. (1998) Therapie der dilatativen Kardiomyopathie mit und ohne Entzündung. Medizinische Klinik 93:4, 240-251
CrossRef
7
Matthias Eck, Axel Greiner, Reinhard Kandolf, Bernd Schmauer, Alex Marx, Hans Konrad Müller-Hermelink. (1997) Active Fulminant Myocarditis Characterized by T-Lymphocytes Expressing the Gamma-Delta T-Cell Receptor: A New Disease Entity?. The American Journal of Surgical Pathology 21:9, 1109-1112
CrossRef