Eosinophilic myocarditis

Article written and reviewed by Dr Luca Moretti

Eosinophilic myocarditis is a histopathologic syndrome in which infiltration of the myocardium by eosinophils is not an incidental finding, but contributes to cardiomyocyte necrosis and cardiac dysfunction. This definition encompasses different mechanisms: drug reactions, DRESS syndrome, eosinophilic granulomatosis with polyangiitis, clonal or reactive hypereosinophilic syndromes, parasitic infections, neoplasms and forms in which the cause remains undetermined. Identifying the mechanism is essential, because the histologic label alone does not determine the duration and intensity of treatment.

The clinical course ranges from focal infiltrates detected incidentally to fulminant necrotizing myocarditis with biventricular dysfunction and shock; the peripheral eosinophil count is useful, but does not have sufficient sensitivity to exclude cardiac involvement, particularly at presentation or after corticosteroid treatment. Similarly, rash, fever and liver abnormalities suggest systemic hypersensitivity but are not mandatory, while an exclusively cardiac presentation may precede the other manifestations.

The systematic review of histologically proven cases published by Brambatti and colleagues described peripheral eosinophilia in approximately three quarters of patients and an associated condition in approximately two thirds, but these figures derive from selected reports and do not represent a population incidence. The high in-hospital mortality observed in the same series underscores the severity of recognized forms, without allowing individual prediction independent of shock, etiology and timeliness of treatment.

The central clinical concept is therefore diagnostic discordance: a severely inflamed heart may be accompanied by only modest eosinophilia, whereas marked eosinophilia may not yet have caused myocardial injury. Diagnosis requires linking the cardiac phenotype, hematologic trend, exposures, multiorgan involvement and tissue findings, avoiding both automatic treatment of every eosinophilia and waiting for an extreme value before protecting an unstable patient.

A useful classification must distinguish the eosinophilic finding from the process that generates it. The same tissue appearance may require simple withdrawal of a drug, immunosuppressive induction for vasculitis, targeted hematologic therapy or an antiparasitic agent, with completely different prognoses and follow-up. For this reason, histology defines the type of lesion, whereas the final clinical diagnosis retains the cause, phase and organs involved.

Published series aggregate different presentations and causes and are influenced by preferential publication of fulminant forms, so mortality and response percentages cannot be applied mechanically. The most credible prognostic information comes from the mechanism, shock, extent of necrosis and the possibility of removing the trigger before thrombosis and fibrosis become self-sustaining.

Etiology, Pathogenesis and Pathophysiology

In hypersensitivity forms, drug antigens or their metabolites activate a predominantly type 2 immune response, with production of interleukin 5, eosinophil recruitment and tissue degranulation. Antibiotics, anticonvulsants, anti-inflammatory drugs, diuretics, psychotropic drugs, vaccines and numerous other products have been reported, but the breadth of the list requires caution in causal attribution. A consistent temporal relationship, regression after withdrawal and systemic manifestations increase plausibility, whereas deliberate re-exposure is inappropriate when the injury has been severe.

DRESS syndrome combines a drug reaction, eosinophilia and internal-organ involvement, with a latency that is often longer than that of an immediate allergy. The heart may be involved while the skin and liver dominate the clinical picture or after initial systemic improvement, so troponin, ECG and echocardiography should be reassessed if dyspnea, pain or hypotension develop. Some necrotizing forms progress rapidly and require a low threshold for biopsy and intensive care.

In eosinophilic granulomatosis with polyangiitis, cardiac involvement may result from both eosinophilic infiltration and small-vessel vasculitis. Asthma, nasal polyposis, neuropathy, pulmonary infiltrates and purpura establish the clinical context, while ANCA negativity does not exclude the diagnosis and is common in cardiac phenotypes. Treatment must control the entire vasculitis, not only ventricular function, through a pathway shared with rheumatology.

Hypereosinophilic syndromes include clonal myeloid, lymphocytic, familial and idiopathic forms. Genetic rearrangements and other hematologic markers may identify a population responsive to targeted therapy, making a peripheral blood smear, tryptase, vitamin B12, flow cytometry, molecular testing and sometimes bone marrow assessment essential. The absence of a reactive cause does not justify defining eosinophilia as idiopathic before this evaluation.

Parasites with tissue migration, some fungal infections and other infectious conditions can cause eosinophilia and myocarditis. Travel, food, animal contact, immunosuppression and geographic origin guide targeted testing, because corticosteroids given without coverage in unrecognized strongyloidiasis can cause hyperinfection. Etiologic investigation must nevertheless proceed in parallel with stabilization, without delaying support for shock.

Eosinophils release major basic protein, eosinophil cationic protein, peroxidase and lipid mediators capable of damaging cardiomyocytes, endothelium and the microcirculation. Injury depends not only on the number of circulating cells, but on their activation state, migration into tissue and duration of exposure. Edema and contractile depression may be reversible, whereas extensive necrosis and disruption of the extracellular matrix prepare the substrate for a permanent scar.

In persistent eosinophilic disease, a continuum between a necrotic phase, a thrombotic phase and a fibrotic phase has been described. Endocardial injury promotes apical and subvalvular thrombotic deposits, followed by organization and fibrosis that may entrap the valvular apparatus and reduce ventricular compliance. This evolution, traditionally associated with Loeffler endocarditis, can lead to restrictive cardiomyopathy even when active inflammation has subsided.

An eosinophilic component may also occur in giant-cell myocarditis or other forms of myocarditis, but this finding does not make the diseases equivalent. Scattered giant cells with aggressive necrosis, organized granulomas or vasculitis alter diagnosis and treatment; the pathology report must therefore describe architecture, cell populations and the type of lesion, rather than merely count eosinophils.

The necrotic, thrombotic and fibrotic phases are not mandatory, perfectly separated stages. An already fibrotic apex may contain a recent thrombus, while the basal myocardium retains edema and an active infiltrate; different therapeutic targets can therefore coexist in the same patient. Imaging must simultaneously assess inflammation, endocardial anatomy and thrombosis, linking each finding to the decision it can actually change.

Clinical Manifestations

Dyspnea, reduced exercise tolerance, orthopnea and edema reflect ventricular dysfunction or restrictive physiology, but the speed of onset varies enormously. In the fulminant form, hypotension may progress to oliguria, elevated lactate and multiorgan failure within hours; a mildly dilated cavity with walls apparently thickened by edema does not represent chronic hypertrophy and may accompany severe contractile impairment.

Chest pain with elevated troponin may mimic an acute coronary syndrome, while pericardial effusion produces a myopericarditis phenotype. Coronary angiography or CT angiography excludes obstruction when indicated, but normal coronary arteries do not establish the etiology; the clinical pattern must be rapidly reinterpreted if eosinophilia, rash, fever or a recent medication change appears.

Palpitations, syncope and cardiac arrest result from ventricular tachycardia, ventricular fibrillation or conduction disturbances; arrhythmias may be driven by acute inflammation, microvascular ischemia and, in later phases, fibrosis. The absence of severe reduction in ejection fraction does not eliminate electrical risk when CMR shows extensive injury or telemetry documents instability.

Extracardiac manifestations guide etiologic assessment and should be actively sought; skin rash, facial edema, lymphadenopathy and hepatocellular injury suggest DRESS; asthma, sinusitis, neuropathy and purpura suggest EGPA; splenomegaly, cytopenias or peripheral smear abnormalities make a myeloid neoplasm plausible; however, no combination is pathognomonic, and multiple causes may coexist.

Eosinophilia is expressed as an absolute count, not only as a percentage, and interpreted serially; an initially normal value may increase over the following days, while stress, infection and corticosteroids may reduce it. Persistence beyond the cardiac phase requires an independent systemic investigation, because ventricular recovery does not eliminate the risk of new organ damage.

During the thrombotic phase, cerebral or peripheral emboli may be the first manifestation, and apical thrombi may form even without extreme dilation. The fibrotic phase produces signs of right-sided congestion, ascites, hepatomegaly and exercise intolerance with apparently preserved systolic function; mitral or tricuspid regurgitation may result from entrapment of the subvalvular apparatus.

In patients exposed to immune checkpoint inhibitors, cardiac injury may be accompanied by myositis and myasthenia and may present with disproportionately severe conduction disturbances. This setting requires a specific oncologic and immunologic pathway, because risk and treatment doses differ from those of ordinary hypersensitivity; biopsy may show a mixed infiltrate, making integration with exposure history and phenotype necessary.

The medication timeline records the date of initiation, interruptions, previous exposures and the onset of each organ manifestation, because latency ranges from a few days to several weeks. Drugs taken for years are less plausible but not impossible causes after dose changes or interactions. Attributing the cause to the most recent prescription simply because it is easier to remember risks leaving the true culprit in place or depriving the patient of essential therapy.

Investigations and Diagnosis

Initial evaluation includes serial ECGs, telemetry, troponin, natriuretic peptides, a complete blood count with a manually verified differential, renal and liver function, electrolytes and inflammatory markers. Peripheral blood smear and the trend in eosinophil count distinguish a transient abnormality from a persistent process, while IgE and other biomarkers may support an allergic phenotype without confirming cardiac involvement. In unstable presentations, perfusion and lactate are assessed and an advanced center is involved early.

Echocardiography describes biventricular function, wall thickness, effusion, pressures and valves, with contrast-enhanced images specifically obtained to look for thrombi when the apex is not well visualized. Strain may reveal dysfunction more extensive than suggested by ejection fraction; in restrictive phases, filling velocities, atrial dimensions and right ventricular function contribute to hemodynamic characterization.

CMR identifies edema, necrosis and fibrosis through mapping, T2 edema imaging and late gadolinium enhancement, often with a subendocardial or multifocal distribution that may differ from the more common patterns of lymphocytic myocarditis. Subendocardial LGE with normal coronary arteries should raise consideration of eosinophilic and vasculitic injury, but is not specific; CMR also searches for thrombi and guides the biopsy site, without replacing tissue when the histologic subtype changes therapy.

Endomyocardial biopsy is indicated particularly in shock, threatening arrhythmias or conduction block, suspected eosinophilic myocarditis and failure to respond; multiple samples reduce sampling error in a focal disease and should be allocated among histology, immunohistochemistry and molecular microbiology. Corticosteroids administered before sampling may reduce the infiltrate, but an unstable patient should not be left without life-saving therapy solely to preserve diagnostic yield.

Histology distinguishes an interstitial infiltrate with little necrosis, more typical of hypersensitivity, from necrotizing eosinophilic myocarditis with extensive destruction and a more severe prognosis. Vasculitis, granulomas and giant cells point toward EGPA, sarcoidosis or alternative diagnoses; the number of eosinophils must be interpreted together with degranulation and myocyte injury, because rare cells may be nonspecific.

Etiologic investigation begins with a complete timeline of prescriptions, self-medication, supplements, substances and oncologic infusions, including products discontinued in the preceding weeks. This is followed by exposure-guided testing for parasites, selected serologic tests, ANCA and rheumatologic assessment, as well as hematologic studies for clonality when eosinophilia is marked or persistent. Indiscriminate testing increases false positives and does not replace a good clinical history.

The differential diagnosis includes acute coronary syndrome, sepsis with myocardial dysfunction, endocarditis, lymphocytic myocarditis, giant-cell myocarditis, sarcoidosis and genetic cardiomyopathies. Reactive eosinophilia may accompany one of these conditions without causing it, while drugs started for the acute presentation may confound the timeline. A multidisciplinary review must therefore separate causal findings, consequences and coincidences.

When hypereosinophilic syndrome is suspected, the diagnostic work-up does not end with exclusion of parasites and allergy; molecular rearrangements and fusions, tryptase, bone marrow morphology and aberrant T-cell populations may identify myeloid or lymphocytic forms requiring profoundly different treatments. Classification remains necessary even after a response to corticosteroids, because it determines maintenance therapy, prognosis and hematologic surveillance.

Treatment and Prognosis

The first etiologic measure is immediate withdrawal of the suspected drug, documenting its name and preventing inadvertent re-exposure. If several candidates exist, safety takes priority without definitively assigning causality before review; in infectious forms the causative agent is treated, while EGPA, DRESS and clonal syndromes follow specific protocols coordinated with rheumatology, allergy, hematology and infectious diseases.

Systemic corticosteroids are widely used in symptomatic acute forms, particularly when biopsy demonstrates an eosinophilic infiltrate and uncontrolled infection has been reasonably excluded. In shock or necrotizing myocarditis, high intravenous doses are frequently used, followed by an oral regimen and tapering guided by cause and response. Evidence derives mainly from case series and individual cases, so an identical regimen for all patients would be scientifically unjustified.

Additional therapy depends on the mechanism: conventional immunosuppressants or biologic agents may be necessary in refractory or relapsing EGPA, whereas a neoplasm with a molecular target requires targeted hematologic treatment. Interleukin 5 antagonists reduce eosinophilia in specific diseases, but do not automatically replace urgent control of severe myocarditis; every choice must distinguish induction of remission from maintenance.

Shock and heart failure are treated according to physiology, with diuretics for congestion, vasopressors and inotropes for perfusion, and early mechanical circulatory support when the trajectory worsens. Venoarterial ECMO or other forms of support may serve as a bridge to recovery in a potentially reversible disease; escalation should not wait for irreversible multiorgan injury while immunologic investigations are being completed.

Neurohormonal heart-failure therapy is introduced after stabilization and maintained when dysfunction persists, adapting it to blood pressure, renal function and recovery. Arrhythmias and conduction block receive specific treatment, but permanent device therapy is assessed in light of reversibility and residual scar; restriction from intense physical activity continues until inflammation, function and rhythm have been stably reassessed.

Anticoagulation is indicated in the presence of an intracardiac thrombus, embolism or another recognized indication, not solely because eosinophilia is present. Echocardiography and CMR monitor thrombus size and organization and guide duration together with persistence of endocardial disease; in advanced fibrosis with severe valvular involvement, selected surgical procedures may be required after eosinophilic activity has been controlled.

Prognosis ranges from complete recovery to rapid death or restrictive cardiomyopathy. Shock, a necrotizing form, delayed diagnosis, uncontrolled systemic disease, thrombosis and extensive scar identify greater risk, but even patients who are initially stable require surveillance. The prognostic value of published data is limited by the rarity of the disease and the strong selection bias of case series.

Follow-up combines symptoms, ECG, Holter monitoring, echocardiography, troponin, eosinophil count and markers of the causative disease. CMR documents resolution of edema and scar burden when the result changes management, while repeat biopsy is reserved for recurrence or therapeutic uncertainty. Reduction of immunosuppression requires concordance between cardiac and systemic control, because one may precede the other.

In DRESS, the half-life of some drugs and persistence of the immune response may explain worsening after withdrawal, making a supervised corticosteroid taper necessary. In EGPA, cardiac involvement represents organ damage that guides induction therapy beyond asthma control, while in clonal forms molecular therapy may radically alter the source of eosinophils; therefore, the apparent similarity of the cardiac presentation should not lead to uniform treatment regimens.

Complications

The most feared acute complication is refractory cardiogenic shock, in which edema, necrosis, arrhythmias and biventricular dysfunction amplify one another. Renal and hepatic failure narrow immunosuppressive options and increase procedural risk; timely mechanical support can preserve organ function while removal of the cause and corticosteroids reduce disease activity.

Ventricular tachycardia, fibrillation and advanced conduction block may cause sudden death even before severe dilation develops; residual risk depends more on scar than on eosinophilia alone and must be reassessed after the acute phase. Prolonged monitoring, CMR and arrhythmic history guide decisions regarding a defibrillator better than a single ejection-fraction value.

Endomyocardial thrombosis exposes the patient to stroke, systemic embolism and intracavitary obstruction; laminated thrombi may be missed by echocardiography without contrast, whereas CMR improves their characterization. Risk persists while the endocardium, stasis and eosinophilic activity remain abnormal and does not necessarily disappear when systolic function normalizes.

Endomyocardial fibrosis and entrapment of the valvular apparatus produce restrictive physiology, right-sided congestion and mitral or tricuspid regurgitation. At this stage, suppression of eosinophils prevents further injury but does not remove a mature scar; diuretics, rhythm control, anticoagulation when indicated and selected surgery address consequences that require dedicated expertise.

Eosinophilic disease may relapse during corticosteroid tapering, after new exposure or when control of the systemic condition is lost. An increase in the eosinophil count may precede cardiac injury, but not always, and monitoring should not rely on a single parameter; recurrence of symptoms, troponin elevation or electrical abnormalities requires rapid reassessment of the cause and adherence.

Infections, osteoporosis, diabetes, myopathy and adrenal suppression result from prolonged therapy and should be prevented according to dose and duration. In latent parasitic infections, immunosuppression may transform a paucisymptomatic infection into a disseminated complication; epidemiologic screening, prophylaxis and a rational taper are therefore components of treatment, not ancillary activities.

Multiorgan injury from DRESS, EGPA or hypereosinophilic syndrome may dominate prognosis even after cardiac recovery. Neuropathy, kidney, lung, skin and the hematologic system require specific markers and a shared plan; fragmented management risks considering the patient recovered when only one of the manifestations is temporarily silent.

The drug-reaction record should distinguish the probable culprit from classes not implicated, documenting severity, biopsy findings and temporal interval, because a generic warning against many drugs can unnecessarily restrict future treatment. When causality is uncertain, allergy specialists and pharmacovigilance assess alternatives without resorting to dangerous re-exposure; the patient receives comprehensible documentation to present in an emergency, together with a plan for monitoring eosinophils and the heart after new prescriptions.

At centers that collect rare cases, inclusion in prospective registries makes it possible to link cause, histology, treatment and outcome more reliably than individual reports. Informed consent must distinguish care from research, but standardized documentation already improves daily practice because it makes eosinophil counts, imaging, doses and recurrences comparable and reduces information loss during transitions between specialists.