Diagnosing and Managing Fulminant Myocarditis

Fulminant myocarditis (FM) remains one of the biggest challenges in critical care cardiology, and one of rare but highly morbid cardiac conditions in which diagnostic strategies and clinical decisions in medical therapy remain largely empirical. The latest AHA Scientific Statement on FM has sought to provide a much-needed expert review and summary of the latest evidence, with an emphasis on the prompt recognition of this rapidly progressive syndrome in the differential diagnosis of cardiogenic shock or refractory arrhythmia. Specifically, the writing group has highlighted several new causes of FM, (including sudden death presentations of athletes or adverse effects of cancer immunotherapies), importance of recognizing key clinical subtypes, and pearls and pitfalls in the management of FM. The prevailing clinical strategy, as emphasized by the writing group, remains to be heightened vigilance with FM being an important differential diagnosis in patients presenting with sudden and severe cardiovascular compromise, and the anticipation of prompt and higher levels advanced circulatory support and expertise that these patients invariably may need. Yet many of the age-old questions are still highly debated, as outlined below:

How Does Myocarditis Become “Fulminant”?

One of the biggest challenges remain the lack of a clear distinction between “fulminant” and “non-fulminant” myocarditis, as these conditions are often discussed interchangeably. The original 1991 Lieberman criteria for FM is largely based on clinicopathological assessment excluding giant-cell and eosinophilic myocarditis – a concept that has evolved over time with advances in diagnostic tools and treatments. Most clinicians are able to recognize hemodynamic instability when it happens – the “crash and burn” nature of FM. Yet, their rapid progression can be daunting even for the most seasoned cardiologist. Indeed, initial presentations of chest pain, shortness of breath, hypotension/shock, heart block, and arrhythmia can rapidly deteriorate into FM despite initial supportive care, and often can be difficult to distinguish from other common causes of cardiogenic shock like acute coronary syndromes or stress-induced cardiomyopathy. We still do not know how some individuals present with FM even with the same etiology (e.g. viral myocarditis), although it has been largely attributed to more aggressive host inflammatory responses to the potential culprits. Invariable, cardiac dysfunction is present in FM even when driven by incessant tachyarrhythmia and complete heart block. However, we still have very limited insight into when there are distinct inflammatory process (i.e. leukocyte infiltration) or drivers that contribute to the development of FM. Meanwhile, the broader concept of “inflammatory cardiomyopathy” as a spectrum rather than distinct histopathologic conditions have been entertained, which may be key to unravel potential treatment strategies rather than considering FM as a distinct clinical entity.2

How to Best Diagnose Fulminant Myocarditis?

The broader adoption of advanced multimodality imaging has been fueled by increasing availability and refinement of various advanced imaging techniques at the bedside. The updated Lake Louise Criteria has largely emphasized the presence and degree of myocardial edema and non-ischemic myocardial injury by cardiac magnetic resonance imaging (CMR).3 However, imaging data so far have primarily focused on identifying the presence of myocarditis, not necessarily defining their “fulminant” nature or origin. Especially in the setting of FM, profound hemodynamic instability as well as potential contraindications (such as temporary pacing or metal contents from implanted temporary MCS devices) may preclude prompt acquisition of CMR at the time of initial presentation. Nevertheless, many CMR features linger on following hemodynamic recovery, and can effectively guide clinical advice by monitoring disease progression or resolution (as in the case of returning to training for athletes). The prospects of adopting CMR-based evaluations in FM may someday provide clinically relevant endpoints for conducting rigorous prospective therapeutic studies.

To Biopsy or Not to Biopsy?

A common dilemma is the decision to confirm the diagnosis of FM with endomyocardial biopsy (EMBx) or not. Despite a relatively safe procedure by experienced hands, the invasive nature and vulnerability of a critically ill patient with profound hemodynamic instability can still challenge clinical judgment of “do no harm.” About two decades ago, a single-center cohort from Johns Hopkins reported that despite their dramatic presentation, patients with FM may have better outcomes than those with acute non-FM.4 This observation is now been challenged, as the findings have led to the belief and reassurance that aggressive temporary circulatory support without the need for EMBx confirmation. For example, a two-center Italian cohort observed that patients with FM had more severely impaired left ventricular ejection fraction on admission, and despite steeper improvement during hospitalization, remained lower than those with non-FM that corresponded to poorer long-term outcomes.5 These findings were confirmed with a newer report from a large international registry confirming higher rates of cardiac death and heart transplantation both in the short- and long-term in patients with FM vs non-FM.6 Hence, most experienced centers have adopted a more aggressive approach, especially when establishing the diagnosis of FM can lead to better treatment planning and earlier mobilization of advanced support strategies. The revised EMBx guidelines relevant to this topic are currently under development.

Should Viral Etiologies be Evaluated in (Fulminant) Myocarditis?

Invariably there is an inertia in clinical practice whereby any clinical suspicion of viral myocarditis will be accompanied by large panels of viral serologies. In some European centers, there is also a strong belief that viral causes of myocarditis should be worked up and routinely treated with antiviral therapy. Potential benefits of such proactive anti-viral approaches have not been replicated in rigorously conducted clinical trials, hence they have not been broadly adopted. The AHA statement clearly outlines the uncertainty of clinical value in routine viral serologies (or even viral genome analyses) due to the lack of specificity. In practical terms, results of most serological testing (except for rapid tests such as influenza) often return weeks later after the onset of FM and may have little to no relevance to diagnostic and therapeutic decision-making. That being said, positive results may serve some degree of confirmation in identifying the potential causes of FM. With more rapid turnover they may yield key insights if targeted therapeutic approaches are available in the future.

Should Empirical Immunosuppression Therapy Be Given?

After almost 2.5 decades since the publication of the landmark treatment trials for myocarditis, clinicians still do not have consensus in whether to administer steroids or other immunomodulatory therapies in the setting of FM. It is important to highlight the fact that the large majority of patients enrolled in these studies may not necessarily experience FM since their inclusion criteria largely involved the presence of cardiac dysfunction and histologic demonstration of lymphocyte infiltrations. The large majority of treatment decisions are largely empiric in nature, often driven by anecdotal experiences of individual clinicians. In general, intravenous corticosteroid therapy is relatively benign and low cost (in some ways, the safety of steroid use has been demonstrated in the Myocarditis Treatment Trial even though it did not show incremental benefit).7 Likely the threshold of initiating steroid therapy is inversely related to the clinical severity of FM and lack of treatment options in a rapidly deteriorating patient. It is interesting to note that clinicians have been very comfortable in the non-FM setting to give high-dose corticosteroids or immunosuppressants as in the case of cardiac sarcoidosis, lupus carditis, or acute post-transplant cellular rejection – much of which have also been empirical, and some with successful recovery albeit testimonial in nature. In fact, the presence of systemic or myocardial eosinophilia has even been associated with more favorable steroid responses from expert opinions.

How to Decide for the Best Mechanical Circulatory Support Device Strategy?

The AHA statement did not go into great details regarding how the underlying etiologies and clinical progression of FM can impact the choice(s) of percutaneous mechanical circulatory support (pMCS). For example, isolated left ventricular unloading strategies such as Impella®, while suitable for primarily left ventricular insufficiency (e.g. giant cell myocarditis with refractory tachyarrhythmia) may be inadequate in supporting FM due to systemic processes that invariably may lead to biventricular failure (e.g. influenza myocarditis). Clearly the profile and invasiveness of temporary or permanent mechanical circulatory support has to be taken into account including the risks/benefits as well as downstream treatment options. With a more systematic approach to cardiogenic shock, there is likely going to be a refinement in the selection criteria for the best pMCS strategies.

What are Promising Future Developments?

Fortunately, cases of FM remained relatively rare, although the potential of underdiagnosis exists as many unexplained cardiac deaths or events may have underlying FM. Despite the above-mentioned clinical challenges, the prospects of better definition of FM are good. The age-old Dallas histopathologic criteria are likely going to be refined with promising insights from gene expression and proteomic analyses of EMBx (so-called “molecular microscopy”) that may imply biological subtypes of myocarditis that can potentially benefit from a stratified medicine approach. New machine-learning recognition of histologic features may provide a more consistent interpretation of EMBx samples. Thanks to rapid advances in the fields of allergy/immunology and rheumatology, we now have an unprecedented number of novel biologic therapies that can be leveraged for targeted immunomodulatory approaches. Advances and broad clinical adoption of temporary MCS devices and maturation of the discipline of critical care cardiology also provide great opportunities to define the most appropriate diagnostic and management strategies for FM. Improved pharmacovigilance for FM as serious adverse effects of immunotherapies has provided much needed safeguards in clinical drug development. There is much to learn.