Fatal rhabdomyolysis and fulminant myocarditis with malignant arrhythmias after one dose of ipilimumab and nivolumab

ABSTRACT

Immune checkpoint inhibitors (ICIs) related myocarditis is a rare complication of modern immunotherapy. It can present as an asymptomatic subclinical condition or full-blown fulminant myocarditis with malignant arrythmias and cardiogenic shock. Myositis/rhabdomyolysis and/or myasthenic symptoms can be present concomitantly. We present a case of fatal fulminant myocarditis presenting with cardiac arrythmias and severe systolic dysfunction, with accompanying rhabdomyolysis after the first dose of ipilimumab and nivolumab immunotherapy. First working diagnosis of subacute late presenting acute myocardial infarction (ACS) was incorrect and the correct diagnosis was established only after additional testing and consultation. Treatment consisted of high-dose corticosteroids, intravenous immunoglobulins, sedation with mechanical ventilation, antibiotic coverage, hemodialysis, and sustained low-efficiency daily diafiltration (SLEDD) with CytoSorb or TheraNova membranes, and intra-aortic balloon pump mechanical cardiac support. No tangible improvement in the condition was observed during the whole treatment period and the patient died on the sixth day of intensive care treatment.

Plain Language Summary

This case report describes a 77-year-old man who experienced a life-threatening autoimmune inflammation and diminished function of cardiac muscle (myocarditis) and breakdown of muscle cells (rhabdomyolysis), after receiving immunotherapy for pleural (membrane that surrounds the lungs) cancer (mesothelioma). He was initially thought of having a heart attack (cardiac infarction), and only further testing proved aforementioned autoimmune disease. Despite intensive treatment his condition worsened progressively. The disease was ultimately fatal.

1. Introduction

In recent years, advancements in immunotherapy have significantly improved the outlook for certain cancers. One of the most notable treatments is the use of immune checkpoint inhibitors (ICIs), which have shown the greatest effectiveness in skin, lung and renal cell carcinomas, though they are also applied in other types of cancer [1,2]. With the emergence of novel treatment options targeting specific immune pathways, there has been a corresponding rise in previously unrecognized immune-related adverse events (irAEs). One recognized but rare irAE is myocarditis, a condition marked by conduction system and functional cardiac impairment [3,4]. Diagnosis of immune-related myocarditis is still difficult without any specific markers. Clinical picture and history must be the main focus of workup as myocardial infarction, septic cardiomyopathy, pneumonias or other irAE can present similarly [5,6]. The presentation can vary from asymptomatic, stage 1, myocarditis (elevated troponin and/or electrocardiogram (ECG) changes without clinical symptoms) to fulminant, stage 4, myocarditis (elevated troponin, ECG changes, systolic disfunction with signs of cardiogenic shock) that is a life-threatening event [7]. Although myocarditis is a rare complication of immunotherapy, incidence is reported between 0.1% and 2.5%, mortality is very high at around 50% [4,8–10]. Monotherapy is seldom a cause of myocarditis, with combination therapy having higher incidences [9], can occur in any time during the treatment, and even after completion; but mostly in the first month after immunotherapy initiation [8]. High-dose corticosteroid pulse therapy is the first-line treatment with agents like infliximab (TNF-α inhibitor), intravenous immunoglobulins (IVIg), mycophenolate mofetil, abatacept (CTL4-A agonist) or alemtuzumab as rescue therapies for resistant cases. Mechanical cardiac support with extracorporeal membrane oxygenation (ECMO), intra-aortic balloon pump (IABP) or Impella must also be considered in acute phase.

We are presenting a case of fatal fulminant myocarditis manifesting with conduction system abnormalities (changing cardiac rhythm of wide/narrow QRS complex normo/tachycardia and new onset atrial fibrillation) and severe systolic dysfunction and dilatation of both ventricles, 3 weeks after the first dose of ipilimumab with nivolumab immunotherapy for mesothelioma. The first working diagnosis was subacute ST-elevated myocardial infarction (STEMI) and diagnosis of immune-related myocarditis was made only toward the end of first 48 hours of hospital treatment. The patient required intensive care unit (ICU) level treatment with two-tire vasopressor support, inotropic support, and mechanical ventilation. Concomitant was the diagnosis of rhabdomyolysis with elevated mioglobin and creatinine kinase (CK) values. High doses of corticosteroids and IVIg were administered. In addition, mechanical support with IABP was instituted. Despite aggressive treatment, the patient died on the sixth day of ICU treatment as a result of septic and cardiogenic shock.

2. Case presentation

A 77-year-old male patient with a history of arterial hypertension and type 2 diabetes mellitus with neurologic pain in lower extremities was admitted to clinic of respiratory diseases in March 2024 with chief complaint of 2-month history of nonproductive cough accompanying general weakness and weight loss of 14 kg during the last 6 months. X-ray showed right-side pleural effusion that was not present one year before. Electrocardiogram was normal, as was basic laboratory testing. Computed tomography (CT) scan of thorax showed thickened pleura with enlarged lymph nodes suspicious for mesothelioma with possible metastasis in the twelfth vertebra and tenth right rib. Abdominal CT scan was normal with exception of enlarged prostate which was already known. Cranial CT scan was normal. CT guided biopsy was performed. Diagnosis of malignant mesothelioma (epithelioid type, high grade) of parietal pleura was confirmed a month later by surgical biopsy, positron emission tomography (PET)/CT scan revealed smaller metastatic lesions on the right apical side and in mediastinum with main 47-mm-thick lesion spanning whole-right costomediastinal recess. After surgical and oncology consultation, plan of systemic treatment was established, as his age and nutritional status prohibited comprehensive surgical intervention, even though stress testing showed satisfactory performance status. In early July 2024 first cycle of ipilimumab and nivolumab immunotherapy was conducted without any complications. On the scheduled follow-up visit he was feeling better with improved energy levels and physical capacity. Clinical examination, on the other hand, showed diffuse maculopapular rash over most of skin surface (back, both lower and upper extremities with spared cranial and torso-abdominal skin). Laboratory values were also abnormal with normocytic anemia, elevated lactate dehydrogenase (LDH) and elevated liver transaminases; thyroid function was normal and cardiac enzymes or myoglobin were not measured routinely. The diagnosis of cutaneous irAE grade 2 and hepatotoxic irAE grade 1 was made, and second cycle of immunotherapy postponed for ten days with instructions of sufficient hydration, daily antihistaminic and visit to urgent care center if necessary. Systemic corticosteroid therapy was not initiated at that point.

Eight days later he presented in our emergency department with chief complaint of dyspnea for the last 3 days that was worsening. He also experienced palpitations, increasing general weakness and loss of appetite, but did not report any chest pain. His blood pressure was normal, heart rate elevated (120/min), he was tachypneic 25/breaths/min, peripheral saturation with added oxygen 6 L/min through binasal cannula was 91%. ECG showed arrhythmic tachycardia with widened QRS complexes and Q waves in inferior and anterior leads (Figure 1). Chest X-ray showed mild signs of cardiac decompensation. Laboratory (Table 1) showed markedly elevated cardiac troponin, LDH, CK, elevated transaminases, mildly impaired kidney function and positive serum lactate. Myoglobin was not measured. Given clinical presentation (absence of chest pain was attributed to diabetes mellitus), high troponin values and ECG readings, the diagnosis of subacute ST-elevation myocardial infarction (STEMI) was made, dual antiplatelet therapy (DAPT) promptly started and he was admitted to cardiology ward for further treatment.

Figure 1.

Electrocardiogram (ECG) taken in emergency ward that warranted the diagnosis of subacute (late presenting) ST-segment elevation myocardial infarction (STEMI). Note extensive Q-waves in inferior and anterior leads, irregular QRS complex rhythm and absence of P-waves.

Table 1.

Timeline of the main laboratory findings.

Time	Day 0	Day 1	Day 2			Day 3		Day 4		Day 5	Day 6	Day 7
Test$	17:00#	6:00*	6:00*	11:00+	17:00	5:00	17:00	5:00	17:00	5:00	5:00	5:00
AST [µkat/L; <0.52]	4.22			3.31		1.88		1.80		6.96	22.56	12.08
ALT [µkat/L; 0.56]	3.37			3.28		2.74		2.36		8.19	28.95	28.61
LDH [µkat/L; 4.13]	11.82							9.83
CK [µkat/L; <2.85]	61.65			41.21		21.67
CK-MB [µkat/L; <0.40]	2.21			1.63
AF [µkat/L; 0.67-2.15]	1.12			1.44		1.38		1.43		2.29	3.04	2.93
GGT [µkat/L; <0.92]	0.53			1.05		0.99		1.27		3.59	3.88	3.91
Urea [mmol/L; 1.7-8.3]	12.6	12.9	18.1	19.1	20.8	27.2	30.6	33.1	14.4	21.3	18.0	17.5
Creatinine [µmol/L; 44-80]	114	105	133	130	143	191	237	253	149	266	237	227
Potassium [mmol/L; 3.80-5.50]	4.22	3.91	4.29	4.27	4.35	4.77	4.44	4.12	4.72	6.42	4.88	5.53
Sodium [mmol/L; 135-145]	138.4	138.1	142.1	142.1	141.4	141.6	139.7	141.1	136.7	133.5	133.0	129.3
Chloride [mmol/L; 95-105]	99.7	100.7	103.3	104.3	103.5	104.4	102.5	103.4	101.7	97.4	99.2	95.6
C-reactive protein [mg/L; <5]	16.8	17.1	25.6	28.4		48.2		34.3		22.8	46.1	160.3
Procalcitonin [mcg/L; <0.5]				0.2		0.6		0.4		0.4	1.1	2.5
Interleukin-6 [ng/L; ≤7]				27		12		7		19	206	95
Albumin [g/L; 38-50]	35							33		32	31
Lactate [mmol/L]	4.1	2.4		1.9	2.3	2.1		1.4		2.9	2.6	2.4
Myoglobin (serum) [µg/L; <58]				5251		6319		5552	2947	10,051	5474	4385
Troponin T hs [ng/L; ≤14]	3256	4006	4725	4849	5203	5383		5068		7660	8267	8084
Hemoglobin [g/L; 120-150]	118	127	128	119		111		102		108	108	105
Leukocyte count [10^9/L; 4-10]	9.77	9.12	14.14	11.57		13.18		11.91		10.54	23.59	26.10
Thrombocyte count [10^9/L; 150-450]	315	238	353	336		367		306		300	201	149
INR [0.90-1.27]	0.95			1.06		1.02		1.14		1.30	1.35	1.92
pH [7.35-7.45]		7.47		7.44	7.38	7.39	7.39	7.41	7.37	7.25	7.39	7.27
pCO2 [kPa; 4.3-6.4]		4.3		4.6	5.3	5.2	5.0	5.0	4.8	6.3	4.8	6.4
pO2 [kPa; 11.1-14.4]		11.0		10.6	13.7	11.3	14.2	14.7	13.6	11.4	15.4	14.7
ST-HCO3- [mmol/L; 22-26]		25.1		24.0	22.9	23.1	22.7	23.7	21.4	18.7	21.9	19.9
Base excess [mmol/L; −2 ± 3]		0.9		−0.4	−1.8	−1.5	−2.0	−0.9	−3.6	−6.9	−3.0	−5.5
ScvO2 [%; 65-80]				47.9	69.1	57.0	79.5	70.5	59.5	64.5	70.4	61.2
FiO2 [%]		21		31	40	35	35	35	28	28	35	40

Presenting timeline of important laboratory findings. ^#Emergency room. *Cardiology ward. ⁺Intensive care unit admission. ^$Test name [unit, normal value]. Abbreviations: ALT (alanine transaminase), AST (aspartate aminotransferase), CK (creatine kinase), CK-MB (creatine kinase MB cardiac isoenzyme), FEU (fibrinogen equivalent units), INR (international normalized ratio), LDH (lactate dehydrogenase), pCO₂ (partial pressure of carbon oxide), pO₂ (partial pressure of oxygen), ST-HCO₃ (standard bicarbonate), ScvO₂ (central venous oxygen saturation), FiO₂ (fraction of inspired oxygen). Additional laboratory values: Triglycerides measured on admission were 2.1 mmol/L (normal range: ≤2.3 mmol/L).

During 36 hours treatment on cardiology floor, DAPT was continued and also low-molecular heparin was added. Lactate values dropped, but did not normalize. Tachycardia persisted and digoxin was added without tangible effect. ECG changes evolved, there was interchangeable narrow and wide QRS complex irregular tachycardia, troponin values were slowly rising and transthoracic echocardiogram (TTE) showed normal ventricle diameters, normal right ventricle (RV) function and very diminished left ventricle (LV) function. Because of evolving hemodynamics instability with respiratory decompensation in supine position, he was transferred to our ICU with a plan of electrical cardioversion of suspected atrial fibrillation following transesophageal echocardiogram (TEE) to exclude thrombogenic conditions. Percutaneous coronary angiography was deliberately postponed per subacute STEMI diagnosis.

On ICU admission, he was tachycardic, blood pressure was still normal, tachypneic with need for oxygen supplementation via 40% venturi mask and unable to lie in supine position. ECG tracing showed interchanging narrow/wide complex tachycardia with changing morphology between even same-width QRS complexes. Invasive monitoring was established (EV1000/FloTrac, Edwards, Irvine, California, USA), first measured cardiac index (CI) was 1.4 L/min/m². Additionally, peripheral vasoconstriction was prominent in accordance with clinical picture of cardiogenic shock and multiorgan dysfunction. Sedation, endotracheal intubation and mechanical intubation was commenced before performing TEE. After intubation, hemodynamic status deteriorated with hypotension and additional drop in CI. Inotropic support with dobutamine and vasopressor support with noradrenaline was started. TEE confirmed normal dimensions of both ventricles with normal RV function and globally diminished LV function, ejection fraction (EF) of LV was 20% (Figure 2 and Supplementary video material: Video 1–3). Cardioversion with synchronized biphasic energy of 200 joules (J) was attempted twice – the second time was after administering a 300 mg dose of amiodarone over 20 minutes – but both attempts were unsuccessful. Serum troponin levels continued to rise, accompanied by worsening renal and liver function. Cardiac index (CI) improved and stabilized at approximately 2.5 L/min/m² after 2 hours of vasopressor and inotropic support.

Figure 2.

Transthoracic subcostal projections represent cardiac ventricle dimensions in systole. The snapshot on the left is from admission to intensive care unit (ICU). The snapshot on the right is from fourth day of ICU treatment. Dilatation of right ventricle is apparent. Additionally, please refer to videos in supplementary materials.

The observed global suppression of systolic cardiac function, without regional wall motion abnormalities, was inconsistent with a diagnosis of subacute STEMI. After consultation with the attending oncologist, our suspicion of a rare case of fulminant myocarditis, characterized by both systolic dysfunction and impairment of the cardiac conduction system, was confirmed. Percutaneous coronary angiography was performed and revealed no obstructions in the coronary arteries. Diagnosis of myocarditis was confirmed, DAPT was discontinued, and, following the oncologist’s suggestion, first corticosteroid bolus dose of methylprednisolone 250 mg administered. Additionally, myoglobin and CK were measured and were both highly elevated confirming concomitant diagnosis of rhabdomyolysis. Due to pathological urinalysis, empiric antibiotic treatment with ciprofloxacin was started due to the patient’s immunocompromised status. He became oligo-anuric, so he was started on continuous diuretic therapy with furosemide 1 g/day. Lactate values normalized to reference range. Hemodynamic and respiratory status remained stable during the second day, corticosteroid was continued as was inotropic and vasopressor support in stable dose of 5 mcg/kg/min dobutamine and 0.10 mcg/kg/min noradrenaline. Mechanical ventilation was uncomplicated with low need of added oxygen (35%). Bedside TTE showed stable cardiac function slight improvement in systolic cardiac function, EF LV increasing to 25–30%.

During the third day, the condition began to deteriorate. Renal impairment worsened with anuria. First four-hour hemodialysis with TheraNova adsorber for myoglobin removal was performed. Bedside TTE also showed worsening of cardiac function and morphology in accordance to drop in CI. Left and right ventricle began to dilate, RV was of the same diameter as LV, LV EF was 20% and tricuspid annular plane systolic excursion (TAPSE) was 14 mm (21 mm on admission) indication diminishing systolic function of RV (Figure 2 and Supplementary video material: Video 4). Methylprednisolone dose was increased to 1000 mg daily bolus and intravenous immunoglobulins (IVIg) were added in dose of 400 mg per kilogram of bodyweight. Till the fourth day, lactate values were once again positive with troponin and myoglobin values both in high rise despite treatment. CI values were once again below 2 L/min/m² and the decision to insert intra-aortic balloon pump (IABP) was made (Figure 3). Additionally, continuous infusion of amiodarone was started (48 mg per hour) in an attempt to lower heart rate as values were reaching 150/min; heart rate dropped to around 110/min in a few hours and CI improved with drop in serum lactate. Hemodialysis with TheraNova membrane was repeated due to high myoglobin rise (Table 1) and testing for cardiotropic viruses performed, that came back negative the same day (Table 2). On the fifth day, procalcitonin values were positive with positive lactate values and increasing need of vasopressor support. Diagnosis of septic shock was made and antibiotic treatment switched to piperacillin/tazobactam. Due to hemodynamic instability vasopressin was added on the same day. We initiated 10-hour sustained low-efficiency daily diafiltration (SLEDD) with CytoSorb hemadsorption membrane that was also performed on the sixth day. Despite all our therapeutic efforts, the condition was deteriorating with impaired cardiac function, high levels of myoglobin and troponin, acute anuric renal failure, worsening septic shock, and steep increase of liver transaminases. Cardiac arrythmia was present during the entire ICU stay with interchanging ventricular and supraventricular rhythm. Because of known diagnosis of terminal malignant disease and age of 77 years, the decision against extracorporeal membrane oxygenation (ECMO) therapy was made. The patient died on the sixth day of ICU treatment as a result of irreversible septic and cardiogenic shock.

Figure 3.

Chest X-ray taken after positioning intra-aortic balloon pump (additional correction was made after examining this X-ray). Also note the presence of central venous line in right subclavian vein, nasogastric tube, electrocardiogram leads and endotracheal tube. There are also signs of pleural effusion (blunting of the costophrenic angle), but were not present on pleural ultrasound. The X-ray was taken in supine position with 45° angle elevation.

Table 2.

Microbiology testing.

Sample	Test performed	Date taken	Final result
Blood$, 2 pairs	Culture, aerobic and anaerobic bacteria	ICU Admission	All negative.
Urine	Semiquantitative urine culture	ICU Admission	All negative.
Blood, serum	Cardiotropic viruses%	ICU Day 4	Positive IgG for enteroviruses+
Blood$, 2 pairs	Culture, aerobic and anaerobic bacteria	ICU Day 5	All negative&.
Urine	Semiquantitative urine culture	ICU Day 5	All negative&.

^$Peripheral blood was taken with fresh puncture every time with 30 minutes between pairs. ^%Testing for: enteroviruses, coxsackieviruses and echoviruses. ⁺Indicates an inactive or recovered infection. ^&Postmortem result.

Swabs for MRSA, ESBL+, CRE, CRAB and CRPA at admission and discharge were negative.

Abbreviations: MRSA (methicillin-resistant Staphylococcus aureus), ESBL (extended spectrum beta-lactamase), CRE (carbapenem-resistant Enterobacterales), CRAB (carbapenem-resistant Acinetobacter baumannii), CRPA (carbapenem-resistant Pseudomonas aeruginosa).

3. Discussion

Myocarditis is a rare but recognized complication of novel immune checkpoint inhibitors treatment. Presented case highlights three distinct points: diagnosis difficulties, fulminant clinical course with global cardiac dysfunction and concomitant rhabdomyolysis, and paucity of treatment options and treatment guidelines. Each will be discussed separately concluding with comprehensive comment about our treatment. The focus will be on acute presentation and treatment, long-term care will be omitted from the discussion.

The correct diagnosis of myocarditis was established only the second day of hospital treatment, the working diagnosis prior to that was subacute STEMI. In the emergency department, troponin levels were markedly elevated without any ST-segment elevations. Combined with a history of diabetes mellitus that could mask the chest pain, high incidence of coronary events in patients aged ≥75 years [11] and low incidence of immunotherapy-associated myocarditis, the diagnosis of myocardial infarction was in the foreground. As the symptoms were present for a few days, with already present Q-waves (Figure 1), acute coronary intervention was not recommended [12]. Clinical presentation also did not warrant checking for elevated CK or myoglobin as muscle pain was not present. The suspicion of myocarditis instead of coronary artery disease was made after performing TEE as TTE was not sensitive enough in showing complete absence of regional wall motion abnormalities, although they can be also seen in immunotherapy-related myocarditis [13]. Most cases present only with conduction system abnormalities with new-onset branch block, alternating branch block, complete atrio-ventricular block, atrial fibrillation, sinus tachycardia or malignant ventricular arrythmias [14]. All those ECG changes can be also observed in acute coronary syndrome cases [15]. Only after a thorough evaluation of the clinical, laboratory, and patient history data, and following consultation with the oncologist, the working diagnosis was revised to myocarditis, with a possible concurrent diagnosis of myositis/rhabdomyolysis and myasthenia [16,17]. Additional measurement of CK and myoglobin confirmed the diagnosis of myositis/rhabdomyolysis, but we did not observe any myasthenic symptoms. Percutaneous coronary angiography was performed revealing normal angiogram, definitively excluding ACS and confirming the diagnosis of myocarditis with previously established history of risk factor (namely, ipilimumab with nivolumab immunotherapy), positive troponin levels, diminished systolic function of left ventricle and consistent ECG changes [13]. In ambiguous cases, special magnetic resonance imaging and cardiac biopsy are definitive diagnostic approaches [4,18]. Possibility of delayed diagnosis due to heuristics also exists. Coronary syndrome is still much more prevalent then irAE. Large retrospective study [19] showed high probability of missed second diagnosis in Coronavirus disease 2019 (COVID-19) patients presenting with clinical presentation favoring pneumonia. In our case, the patient presented with high levels of troponin and clinical picture of cardiogenic shock, that by itself does not prove acute coronary event as, for example, pulmonary embolism [20] presents a common possible differential diagnosis; that was ruled out by bedside echocardiography in our case. The difference between our case and cited report is that positive test with consistent clinical picture, proves the primary diagnosis of COVID-19 pneumonia, with possibility of missed secondary diagnosis. In our case, the primary diagnosis was missed because of clinical, ultrasound and laboratory picture consistent with ACS and paucity awareness of irAE as we emphasize later in the discussion.

The fulminant clinical course as presented in our case in very rare. First two case reports of myocarditis associated with ipilimumab and nivolumab immunotherapy date to 2016 [21]. The main presentation of both cases was cardiac conduction system abnormality with complete heart block and ventricular tachycardia that were fatal in both cases. Similar case to ours was after pembrolizumab treatment of lung squamous cell carcinoma in 70-year-old patient, treated with high doses of methylprednisolone, IVIg, IABP, and ECMO, successfully weaned from all critical support, but succumbed to progression of malignant disease [18]. A review study of 244 reported cases showed mortality of 26.2%, one-third of the myocarditis cases developed after the first application of immunotherapy and confirmed high prevalence of ECG changes (81.1%) and lower prevalence (26.2%) of left ventricular systolic disfunction. Of all fatal cases, more than half had normal LV systolic function and the relationship between systolic dysfunction and mortality was not reported. A recent report found that all patients in the long-term survival group (>360 days) after myocarditis irAE presented with initial normal left ventricular ejection fraction and troponin elevation above 75-times over upper limit was strongly associated with short-term survival (<30 days) [22]. Low ventricular ejection fraction is one of the presenting features that differentiates ICIs myocarditis from myocarditis of other causes, as diminished systolic function is the defining feature of classic myocarditis [23].

As clinical presentation and prognostic factors, treatment strategy has also not reached a consensus. The cornerstone therapeutic approach is bolus corticosteroids in high doses for at least 3 days by tapering according to clinical response. The recommended initial daily dose is 500 mg to 1000 mg intravenous methylprednisolone. Clinical response is seen in drop of serum troponin, stabilization in cardiac rhythm or improvement in systolic function. If steroid treatment is unsuccessful, steroid-resistant ICI-associated myocarditis is confirmed and additional therapy should be considered. Intravenous immunoglobulins in low (200–400 mg/kg) or high (1–2 g/kg) dose, infliximab (5 mg/kg), mycophenolate mofetil, abatacept (CTL4-A agonist) or alemtuzumab (CD52 target monoclonal antibody) have all been tried [3,4,24,25]. Importance of prompt initiation of immunosuppressive therapy was also demonstrated as delayed treatment initiation resulted in worse outcomes [26]. In myocarditis with myositis and/or myasthenia gravis overlap syndrome (IM3OS), cyclophosphamide and plasmapheresis usages were reported [16]. All possible and necessary supportive care is mandatory as is immediate discontinuation of immunotherapy and diagnosis/treatment of other myocarditis causes.

Our patient presented to our emergency department with clinical picture of cardiogenic shock that was later confirmed on TTE/TEE and ECG changes that is by definition grade 4 fulminant myocarditis requiring immediate corticosteroid application. The diagnosis was missed for the first 48-hour treatment in the emergency room and cardiology ward, as was appropriate treatment. Even after the correct diagnosis, we have been treating our patient for the first 2 days with 250 mg of methylprednisolone daily according to oncologist recommendation, only the third day of ICU treatment did we administer the full corticosteroid dose of 1000 mg of methylprednisolone. Including preadmission history of 3 days of difficulty breathing the delay to full corticosteroid immunosuppression was at least 7 days, considering myocarditis progressing from asymptomatic to full blown. There were also no symptoms of chest or muscle pain to direct us to the alternate diagnosis earlier as high CK/myoglobin values would not fit the ACS diagnosis. After corticosteroid treatment failure, we were considering multiple therapeutic options. Tocilizumab was not used due to only mildly elevated interleukin-6 values. Infliximab was considered but decided against due to severe systolic cardiac failure [27]. Intravenous immunoglobulins were used ultimately without any lasting noticeable effect on clinical condition. Mycophenolate mofetil was not considered until late, however the decision against was made because of diagnosis of sepsis. Serum ferritin and fibrinogen were not measured during the hospital treatment. Nevertheless, secondary hemophagocytic lymphohistiocytosis/macrophage activation syndrome (sHLH/MAS) was not considered among differential diagnoses, the patient was not febrile till the last day (concomitant rise in inflammatory markers including PCT), he was not cytopenic and measured triglycerides on hospital admission were in reference range (Table 1). Lymphocyte activation markers were also not measured.

The case we are presenting is the second mayor complication of modern immunotherapy that was treated in our ICU; the first was a case of cytokine release syndrome, also after one application of ipilimumab with nivolumab immunotherapy, albeit for the treatment of lung carcinoma [5]. As our department is not a part of a specialized oncology center, we believe that the incidence of irAE could be higher than currently reported. This point is especially relevant in light of difficult establishment of the correct diagnosis that was present in this case and in our previously reported case. We would like to reserve the right for a few suggestions that would be very much appreciated from oncology community. First, we would like to recommend routine extended laboratory testing for all patients receiving ICIs, following guidelines from previously published recommendations [28]. In case of elevated troponin/myoglobin/proBNP values on first checkup after first immunotherapy application, the decision to start immediate corticosteroid treatment might not be postponed. Second, we could not find any studies regarding the epidemiology of irAEs coincidence. The possibility of drug rash with eosinophilia and systemic syndrome (DRESS) [29] is a recognized severe cutaneous complication that also involves other organs (hepatitis, pneumonitis, nephritis, colitis, myocarditis, pericarditis). Even though cutaneous involvement was only grade 2 in our case, we tested for eosinophilia, but eosinophils were not elevated in blood differential test. Regarding mentioned lack of clinical data, we believe that studies regarding irAE coincidence would be greatly appreciated. In the case off association between already different irAEs, the presence of one would incite active investigation of possible (subclinical) another. Co-occurrence of myocarditis and rhabdomyolysis/myositis was previously described among irAEs [17] and patients with proven COVID-19 [30]. This unique co-occurrence in hyperinflammatory states warrants further investigation as possible diagnostic criteria that favors myocarditis instead of ACS, especially in patients receiving ICIs. Third and last, clear and concise recommendations, based on prospective patient follow-up, are ever more necessary as immunotherapy is becoming a cornerstone of oncology treatment.

Funding Statement

This paper was not funded.

Article highlights

• Novel immunotherapies have improved cancer outcomes but can cause life-threatening immune-related myocarditis, presenting as arrhythmias or systolic dysfunction with a high mortality rate (up to 50%); main treatment involves corticosteroids, with rescue options like infliximab or IV immunoglobulins, though effectiveness is uncertain.

• A 77 old male with mesothelioma was treated with ipilimumab and nivolumab immunotherapy. He developed skin and hepatic adverse reactions and later presented with fulminant myocarditis and concomitant rhabdomyolysis. Initial diagnosis was late presenting acute coronary syndrome, because of signs of cardiogenic shock, high troponin values and electrocardiogram findings.

• The correct diagnosis was established after performing transesophageal echocardiography and coronary artery angiography, around 48 hours after hospital admission.

• He received bolus doses of methylprednisolone and intravenous immunoglobulins, was treated with multiple acute hemodialysis with TheraNova/CytoSorb membranes, and received mechanical cardiac support with intra-aortic balloon pump. Troponin and myoglobin values were in continues in spite of aggressive therapy. The patient died on the sixth day of intensive care unit treatment.

• This case highlights difficulties in irAEs diagnosis and possible fulminant fatal complications.

Contributor roles taxonomy (CRediT) author Statement

Marko Kurnik: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Visualization, Writing – original draft, Writing – review & editing.

Petra Kolar Kus: Resources, Validation, Writing – review & editing.

Mihela Krepek: Validation, Writing – review & editing.

Janko Vlaović: Validation, Writing – review & editing.

Matej Podbregar: Methodology, Project administration, Supervision, Writing – review & editing.

Disclosure statement

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Ethical statement

We have received verbal and written consent to publish this case report and patient’s name from the patient’s immediate family. The authors did not subject writing this report to ethics comity. In the writing of this report, we have adhered to the Declaration of Helsinki and have preserved the anonymity of the patient.

Supplemental data

Supplemental data for this article can be accessed online at https://doi.org/10.1080/1750743X.2024.2427563