Giant cell myocarditis with prolonged cardiac standstill after drug‐induced hypersensitivity syndrome: a case report

Abstract

Giant cell myocarditis (GCM) is a rare but fatal disease that can lead to cardiac failure. Survival with a cardiac standstill requires mechanical circulatory support or a biventricular assist device (BiVAD) and prolonged survival is extremely rare. Drug‐induced hypersensitivity syndrome (DIHS) is a severe cutaneous adverse reaction. Some cases of DIHS are reportedly associated with the onset of GCM. We present a case of a 28‐year‐old woman who developed GCM during steroid tapering after DIHS. She went into continuous cardiac standstill but survived for 74 days under BiVAD support. Our case is noteworthy because the histopathologic specimens obtained on three occasions contributed to the diagnosis of this particular condition over time. We also reviewed previous literature on concomitant cases of GCM and DIHS. We found that two are potentially associated and most cases of GCM occur within 3 months of DIHS during steroid tapering.

Introduction

Fulminant myocarditis is the most severe form of myocarditis with a high mortality rate, and is defined as myocarditis with new‐onset heart failure and cardiogenic shock requiring inotropic or mechanical circulatory support (MCS). ^{1 , 2} Among the pathologic types of myocarditis, giant cell myocarditis (GCM) is associated with the worst outcomes. ³ Myocarditis can lead to cardiac standstill; however, survival from cardiac arrest requires MCS or a ventricular assist device, and the survival rate is very low. ⁴

Drug‐induced hypersensitivity syndrome (DIHS), also known as drug reaction with eosinophilia and systemic symptoms, is a severe cutaneous adverse reaction characterized by an exanthema, fever, and hematologic and visceral involvement. Although the relationship between DIHS and GCM has not been elucidated, from a review of previous literature, we found that most of the GCM cases complicated by DIHS developed during steroid tapering after DIHS. ^{5 , 6 , 7 , 8 , 9 , 10 , 11 , 12}

Herein, we report a case of GCM requiring a biventricular assist device (BiVAD) due to prolonged cardiac standstill after DIHS, and review the literature on concomitant cases of GCM and DIHS.

Case Report

A 28‐year‐old woman with a history of DIHS presented with a 3‐day history of dyspnea and chest pain. She had been diagnosed with dermoid lesions in the left cerebello‐pontine nucleus 4 months previously and had been started on carbamazepine (200 mg/day) for numbness in her left cheek. Although it was effective in relieving the symptoms, a new rash developed 4 weeks after starting carbamazepine. Three months prior to admission, the patient presented with a prolonged rash, organ damage (liver dysfunction), and an abnormal blood count (increased eosinophils and atypical lymphocytes). She was diagnosed with atypical DIHS. Lymphadenopathy and human herpesvirus 6 reactivation were not evident, and skin biopsy of the rash suggested atypical DIHS with histopathologic features of interface dermatitis. Carbamazepine was discontinued and prednisolone (70 mg/day; 1 mg/kg) was started. This improved her rash, and the prednisolone dose was gradually tapered to 30 mg by decreasing 10 mg every 10–14 days, followed by 5 mg every 14 days. At her most recent visit, she was taking 10 mg of prednisolone and her rash had not recurred. She had no symptoms of a recent cold prior to the most recent visit.

Upon admission to a nearby hospital for dyspnea and chest pain, she went into ventricular fibrillation and was immediately placed on veno‐arterial extracorporeal membrane oxygenation (VA‐ECMO). Transthoracic echocardiography revealed myocardial edema and reduced contractility consistent with fulminant myocarditis. The coronary angiogram was normal. An endomyocardial biopsy (EMB) was performed and a percutaneous left ventricular assist device (Impella CP®; Abiomed, Inc., Danvers, MA, USA) was placed. An EMB from the right side of the interventricular septum revealed lymphocytic myocarditis (Figure 1 A ). Her peak creatine kinase level was 3661 U/L. The electrocardiographic changes are shown in Figure 2 . Initially, ventricular arrhythmias were observed, but the potential gradually decreased, resulting in cardiac arrest on day 4 of hospitalization. Temporary right ventricular pacing was attempted but was unsuccessful. The patient was transferred to our hospital on day 7 for further treatment.

Figure 1.

Histopathological findings of the myocardial biopsy specimens. (A) The initial biopsy specimen shows interstitial fibrosis and oedema with focal lymphocytic infiltration (white arrows). The variable sizes of myocardial fibres and myocyte vacuolar degeneration suggest myocardial damage. Giant cells or significant eosinophil infiltrates were not detected. Haematoxylin and eosin (HE) stain at 200× magnification. (B) The second biopsy specimen shows a diffuse inflammatory cell infiltration of abundant eosinophils (yellow arrows), lymphocytes, plasma cells, and scattered prominent giant cells (yellow arrowheads). The myocardial tissue is extensively injured. HE stain at 200× magnification. (C) Cardiac myocyte necrosis is widely observed (left side area), and granulation tissue has replaced myocardial tissue in the third biopsy specimen. Infiltration of lymphocytes, plasma cells, eosinophils, and neutrophils is observed. HE stain at 200× magnification.

Figure 2.

Electrocardiogram changes.

On arrival at our hospital, her mean arterial pressure was 62 mmHg with no pulse pressure, and she was receiving a total of 3.5 L/min of support with VA‐ECMO and Impella CP. Her blood tests revealed elevated levels of liver enzymes, creatinine, inflammatory markers, and cardiac enzymes (Table  1 ), and her chest radiograph showed severe pulmonary edema. On day 8, biventricular central ECMO was placed via sternotomy to treat this condition. The biventricular central ECMO circuit used a single centrifugal pump to remove blood from the right and left ventricle and deliver blood to the ascending aorta and pulmonary artery via an artificial lung. Histopathology of the myocardial specimen obtained at the time of surgery showed multinucleated giant cells and an inflammatory infiltrate consisting of eosinophils and lymphocytes, consistent with GCM (Figure 1 B ).

Table 1.

Laboratory findings on admission to our hospital (day 7)

Parameters	Result	Normal range	Unit
White blood cells	25 600	3300–8600	/μL
Neutrophil	81.2	45.0–55.0	%
Lymphocytes	8.9	25.0–45.0	%
Monocyte	4.9	4.0–7.0	%
Eosinophil	4.8	1.0–5.0	%
Basophil	0.2	0.0–1.0	%
Red blood cells	271	386–492	104/μL
Haemoglobin	8.3	11.6–14.8	g/dL
Mean cell volume	90.8	83.6–98.2	fL
Platelet counts	2.9	15.8–34.8	104/μL
PT‐INR	1.06	0.90–1.14
APTT	64.4	26.9–38.1	s
D dimer	5.8	<1.1	μg/mL
Total bilirubin	3.0	0.4–1.5	mg/dL
Aspartate aminotransferase	168	13–30	IU/L
Alanine aminotransferase	411	7–23	IU/L
Lactate dehydrogenase	1561	124–222	IU/L
Alkaline phosphatase	59	38–113	IU/L
γ‐glutamyl transpeptase	76	9–32	IU/L
Total protein	4.8	6.6–8.1	g/dL
Albumin	2.8	4.1–5.1	g/dL
Blood‐urea‐nitrogen	52	8–20	mg/dL
Creatinine	1.69	0.46–0.79	mg/dL
Creatine kinase	674	41–153	IU/L
Creatine kinase‐myocardial band	77	<3.1	ng/mL
Troponin I	10 407	<15.60	pg/mL
Glucose	191	73–109	mg/dL
Haemoglobin A1c	5.4	4.9–6.0	%
Na	137	138–145	mEq/L
K	5.7	3.6–4.8	mEq/L
Cl	106	101–108	mEq/L
Ca	8.3	8.8–10.1	mg/dL
C‐reactive protein	13.2	<0.14	mg/dL
N‐terminal pro‐brain natriuretic peptide	1740	<125	pg/mL
SARS‐CoV‐2 PCR	Negative
Influenza antigen	Negative
HHV‐6 (DNA)	Negative
EBV (IgM)	Negative
CMV (IgM)	Negative
Blood culture	Negative

APTT, activated partial thromboplastin time; CMV, cytomegalovirus; EBV, Epstein–Barr virus; DNA, deoxyribonucleic acid; HHV‐6, human herpesvirus 6; IgM, immunoglobulin M; PCR, polymerase chain reaction; PT‐INR, prothrombin time‐international normalized ratio; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.

The patient's clinical course is shown in Figure 3 . After the diagnosis of GCM, the patient received steroid pulse therapy (methylprednisolone, 1000 mg/day) for three consecutive days in addition to her maintenance dose of methylprednisolone. Isoproterenol administration was attempted to restore her heartbeat, but was unresponsive and the arrest persisted.

Figure 3.

Clinical course. Bleeding ① indicates lower gastrointestinal bleeding. Bleeding ② indicates femoral artery bleeding. Bleeding ③ indicates haemo‐pneumothorax. BiVAD, biventricular assist device; CHDF, continuous haemodialysis and filtration; ECMO, extracorporeal membrane oxygenation; EMB, endomyocardial biopsy; Ope, operation; VA‐ECMO, veno‐arterial extra‐corporeal membrane oxygenation; VV‐ECMO, venovenous extra‐corporeal membrane oxygenation.

ECMO blood flow was adjusted by varying pump speed and pulmonary artery route clamp intensity. Pulmonary blood flow was incrementally increased based on the patient's respiratory status and echocardiographic findings of the left and right ventricle by gradually releasing the clamp force. Repeat echocardiography showed no opening of the aortic valve. On day 16, enhanced computed tomography showed a large thrombus just below the aortic valve extending into the left ventricle, and thrombectomy was performed. Anticoagulation was intensified postoperatively. Subsequent histopathology of the left atrial and myocardial specimens revealed chronic active inflammation with replacement mainly by granulation tissue (Figure 1 C ). Additional immunosuppressive therapy, such as calcineurin inhibitors or antithymocyte globulin, was considered but not used due to irreversible myocardial degeneration and high risk of device infection as she had already undergone open heart surgery twice. On day 21, the patient regained consciousness, but her heart remained arrested. Meanwhile, her pulmonary congestion improved, and the single‐pump ECMO configuration was converted at the bedside to a more durable double‐pump BiVAD configuration using two Biofloat (Nipro, Osaka, Japan) centrifugal pumps. Later in the course, bleeding complications occurred, mainly in the lower gastrointestinal tract and at the femoral artery insertion site. The patient's clinical course was further complicated by sepsis due to pneumonia and refractory hemopneumothorax. Despite aggressive multidisciplinary treatment, she died of multiorgan failure on day 77.

Discussion

This case is noteworthy for three reasons. First, the patient was in a rare and prolonged state of cardiac arrest and was maintained on mechanical circulatory support for 74 days. Second, the histopathologic specimens obtained on three occasions contributed to the diagnosis of this particular condition over time. Finally, GCM developed after DIHS (during steroid tapering), a rare association that is not fully understood.

Regarding the first point, the patient's ventricle did not contract at all under the support of VA‐ECMO and Impella®, so we decided to switch to central ECMO to treat pulmonary congestion and then converted to BiVAD. Cardiac standstill essentially requires biventricular support; therefore, biventricular central ECMO and BiVAD management are recommended. In addition, the patient experienced bleeding and thromboembolism. Since cardiac standstill implies a failure of the aortic valve to open, it can easily lead to thromboembolism. However, when anticoagulation therapy is intensified, the risk of bleeding increases, as in our case.

Regarding the second point, the patient was initially diagnosed with lymphocytic myocarditis. However, the diagnosis of GCM was made after the second biopsy because it was performed intraoperatively and the amount of resected myocardial tissue was larger, which provided higher sensitivity than the first biopsy. The sensitivity of EMB for GCM has been reported to be 80–85% and repeat biopsy can increase this to 93%. ^{13 , 14} When there are no giant cells in the myocardium and only lymphocyte infiltration, it is clinically difficult to differentiate GCM from lymphocytic myocarditis. In addition, GCM and cardiac sarcoidosis are pathologically similar, and pathologic differentiation between the two is sometimes difficult. Although cardiovascular magnetic resonance imaging may be useful to raise the clinical suspicion of GCM and cardiac sarcoidosis, many patients, such as our case, are too unstable for cardiovascular magnetic resonance imaging. ¹⁵ The last cardiac specimen confirmed that most of the cardiac tissue had been replaced by granulation tissue, which appeared to be a chronic stage and ‘clinical cardiac death’.

Regarding the last point, the relationship between GCM and DIHS has not yet been established. Management of DIHS includes immediate discontinuation of the suspected drug and use of systemic corticosteroids as first‐line therapy. In contrast, the pathogenesis of GCM is commonly attributed to T‐lymphocyte–mediated inflammation. ¹⁶ Diagnosis of GCM is often challenging, with an annual detection rate of 0.13 cases per 100 000 persons. ¹⁶ Although myocarditis has been reported as a fatal and under‐recognized manifestation of DIHS, ¹⁷ the specific relationship between DIHS and GDM has not yet been fully elucidated. To date, only 11 concomitant cases of GCM and DIHS, including the present case, have been reported (Table  2 ). ^{5 , 6 , 7 , 8 , 9 , 10 , 11 , 12}

Table 2.

Literature review of cases of GCM with DIHS

Case [reference]	Age	Sex	Recent drug therapy	Time from drug initiation to DIHS	Treatment for DIHS	Time from DIHS to GCM diagnosis	Treatment for GCM	Prognosis
1 [5]	74	F	Loxoprofen	2 weeks	Steroid	3 weeks	‐	Dead
2 [6]	25	F	Minocycline	4 weeks	Steroid (taper)	3 months	‐	Dead
3 [6]	53	M	Cefadroxil monohydrate	12 weeks	Steroid (taper)	3 months	Steroid pulse	Dead
4 [6]	51	M	Primidone	12 weeks	Steroid (taper)	1 month	‐	Dead
5 [7]	19	F	Phenytoin/phenobarbital/mephobarbital	8 weeks	Steroid (taper)	2 months	‐	Dead
6 [8]	45	F	Lamotrigine	‐	Steroid (taper)	3 months	Steroid pulseMycophenolate mofetilCiclosporinMepolizumab (an anti‐interleukin‐5 inhibitor)	Alive at 1 year
7 [9]	18	F	Amoxicillin	1 week	Anti‐histamine	3 weeks	‐	Dead
8 [10]	25	F	Sulfasalazine	4 weeks	Steroid (taper)	15 months	Steroid pulseIVIGHeart transplantation	Alive (heart transplantation)
9 [11]	20	F	Minocycline	4 weeks	Steroid (taper)	1 month	SteroidMycophenolate mofetil	Dead
10 [12]	46	F	Minocycline	3 weeks	Steroid	6 months	‐	Dead
11 (Our case)	28	F	Carbamazepine	4 weeks	Steroid (taper)	3 months	Steroid pulseBiVAD	Dead

BiVAD, biventricular assist device; DIHS, drug‐induced hyper‐sensitivity syndrome; F, female sex; GCM, giant cell myocarditis; IVIG, intra‐venous immunoglobulin; M, male sex.

The characteristics of these cases showed that the mean age at presentation was 36.7 (range, 18–74) years, of which two were men and nine were women. The medications used were antibiotics (n = 6), anticonvulsants (n = 4), and loxoprofen (n = 1). The time from medication initiation to DIHS ranged from 1 to 12 weeks.

All but one patient was receiving steroid therapy, and of note, 8 out of 10 patients were on steroid tapering. The time from DIHS to GCM diagnosis ranged from 3 weeks to 15 months; however, most cases occurred within 3 months of tapering. Six of the 11 patients receive no treatment due to their rapid deterioration. The remaining patients were treated with steroids. Two patients survived: one underwent heart transplantation and the other was treated with multidrug immunosuppressive therapy, including mepolizumab. The overall mortality rate was 81.8% (n = 9).

In conclusion, we report a case of GCM requiring BiVAD due to prolonged cardiac standstill after DIHS. Prolonged cardiac standstill is rare and its management with single‐pump biventricular central ECMO or BiVAD is difficult. We also reviewed the literature on concomitant cases of GCM and DIHS. GCM can be associated with DIHS, and most cases occur within 3 months of DIHS during steroid tapering. Physicians should be aware of the association between GCM and DIHS; if GCM is suspected, multidrug immunosuppressive therapy or heart transplantation should be considered to salvage the patient.

Conflict of interest

The authors declare that there are no conflicts of interest.

Funding

This work was supported by JSPS KAKENHI Grant Number JP19K17514 (http://www.jsps.go.jp/english/).

Ono, R. , Kohno, H. , Kaminota, S. , Aoki, K. , Kato, H. , Iwahana, T. , Aihara, T. , Ota, M. , Matsumiya, G. , and Kobayashi, Y. (2024) Giant cell myocarditis with prolonged cardiac standstill after drug‐induced hypersensitivity syndrome: a case report. ESC Heart Failure, 11: 805–810. 10.1002/ehf2.14678.