A case of drug‐induced hypersensitivity syndrome complicated with fulminant type 1 diabetes and type 2 myocardial infarction

Drug‐induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a type of drug eruption that causes multiorgan disorders after the administration of certain drugs such as anticonvulsants. Herein, we report the case of a 66‐year‐old man with DiHS/DRESS complicated by fulminant type 1 diabetes (FT1D), shock, and cardiac involvement who was treated conservatively without systemic corticosteroid administration. He had taken carbamazepine for trigeminal neuralgia for 7 weeks until he noticed eruptions on his trunk. Two days after admission, he developed diabetic ketoacidosis, resulting in hypovolemic shock. The patient was diagnosed with FT1D, and insulin was administered. Additionally, the patient had a fever over 38°C, elevated white blood cells (>20 000/μL), liver dysfunction, atypical lymphocytes, and lymphadenopathy, but no evidence of viral reactivation. The lymphocyte transformation test for carbamazepine was positive, and human leukocyte antigen typing revealed the A31:01 haplotype, a risk factor for carbamazepine‐induced cutaneous adverse drug reactions. Collectively, a diagnosis of atypical DiHS and a definitive case of DRESS was made. Moreover, myocardial dysfunction wall motion was observed. A close examination revealed mild coronary artery stenosis, leading to a diagnosis of type 2 myocardial infarction due to relative ischemia. The patient was carefully monitored without systemic corticosteroid administration because both clinical findings and laboratory data peaked on the same day. The patient's eruption and general condition improved, and he was discharged 4 weeks later. While most cases of DiHS/DRESS with cardiac involvement present with myocarditis, the possibility of ischemic heart disease should be considered in patients with cardiac involvement under shock.

FT1D, and insulin was administered.Additionally, the patient had a fever over 38°C, elevated white blood cells (>20 000/μL), liver dysfunction, atypical lymphocytes, and lymphadenopathy, but no evidence of viral reactivation.The lymphocyte transformation test for carbamazepine was positive, and human leukocyte antigen typing revealed the A31:01 haplotype, a risk factor for carbamazepine-induced cutaneous adverse drug reactions.Collectively, a diagnosis of atypical DiHS and a definitive case of DRESS was made.Moreover, myocardial dysfunction wall motion was observed.A close examination revealed mild coronary artery stenosis, leading to a diagnosis of type 2 myocardial infarction due to relative ischemia.The patient was carefully monitored without systemic corticosteroid administration because both clinical findings and laboratory data peaked on the same day.The patient's eruption and general condition improved, and he was discharged 4 weeks later.While most cases of DiHS/DRESS with cardiac involvement present with myocarditis, the possibility of ischemic heart disease should be considered in patients with cardiac involvement under shock.

K E Y W O R D S
diabetes mellitus, type 1, drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms, myocardial infarction, steroids

| INTRODUC TI ON
Drug-induced hypersensitivity syndrome (DiHS)/drug reaction with eosinophilia and systemic symptoms (DRESS) is a type of drug eruption that causes multiorgan disorders after administration of drugs such as anticonvulsants. 1 Cardiac involvement in DiHS/ DRESS has been sporadically reported; however, myocarditis and myocardial infarction (MI) have not been well differentiated in this context.Herein, we report a case of carbamazepine-induced DiHS/DRESS complicated early by fulminant type 1 diabetes (FT1D), shock, and type 2 MI due to relative ischemia, which was treated conservatively, without systemic corticosteroid administration.

| C A S E REP ORT
A 66-year-old man visited our emergency department after noticing eruptions on his trunk, 7 weeks after taking carbamazepine for trigeminal neuralgia.The eruption progressed even after drug discontinuation and, subsequently, sore throat and dysphonia developed.
No toxic epithelial changes suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis, erythema, multiforme-like drug reactions, or vasculitis were observed.The patient tested negative for herpesvirus (HHV)-6 DNA (whole blood, quantitative PCR, tested three times) (Figure 2) and HHV-7 (serum, qualitative PCR).The varicella-zoster virus IgG antibody titer was slightly elevated from 11.5 to 34.6 (3-fold increase), whereas no other antibodies against the herpesvirus family, including Epstein-Barr virus, cytomegalovirus, or herpes simplex virus, were altered.The clinical symptoms continued for 2 weeks even after discontinuation of the causative drug, and a diagnosis of atypical DiHS was made. 2 The scoring system for the diagnosis of DRESS was 8 (definite; positive: fever, enlarged lymph nodes, eosinophilia, atypical lymphocytes, skin involvement, organ involvement [liver, heart, and pancreas], and resolution after ≥15 days, negative: antinuclear antibody, serology for hepatitis viruses, and blood cultures). 3e lymphocyte transformation test for carbamazepine was first negative (Stimulation Index [SI] 87%, day 10) and then positive (SI 691%, day 108), confirming carbamazepine-induced DiHS/DRESS.Human leukocyte antigen typing revealed the HLA-A31:01 haplotype, a genetic risk factor for carbamazepine-induced cutaneous adverse drug reactions in the Japanese population. 4o days post-admission (10 days after onset), the patient developed nausea and listlessness, and a few hours later, hypotension (blood pressure, 80/46 mmHg), tachycardia (heart rate, 129 beats/ min), and tachypnea (respiratory rate, 32 breaths/min).FT1D was diagnosed based on the abrupt onset of diabetic ketoacidosis (DKA) 5 (glucose level 759 mg/dL, pH 6.935, urine ketone 2+, plasma Cpeptide ≤0.03 ng/mL).His hemoglobin A1c was 6.3% on admission.
Anti-islet, glutamic acid decarboxylase, and insulinoma-associated protein-2 antibodies tested negative.Fluid and insulin administration were promptly initiated.

| DISCUSS ION
Our patient developed concurrent DKA, shock, and cardiac involvement.Although FT1D associated with DiHS has been reported to develop with herpesvirus reactivation, the reactivation of HHV-6 was not always detected in these cases and other viruses such as cytomegalovirus or coxsackie virus B3 could be causative of FT1D. 5 In this case, we did not detect any viral reactivation or infection with other viruses.
Initially, cardiogenic was considered as the pathophysiology of shock (Figure S1).However, cardiac enzyme levels peaked over the course of the day and hemodynamics improved after insulin administration.This suggested that cardiac involvement was not the primary cause of this life-threatening condition.Hypovolemic shock due to DKA/hypertonic dehydration was considered the primary pathophysiology, resulting in acute type 2 MI due to relative ischemia.
We initially considered myocarditis as a differential diagnosis for cardiac involvement.Myocarditis is a fatal complication of DiHS/ DRESS due to viral reactivation 6 and is clinically challenging to differentiate from MI. 7 ST depression and high T-waves, which were considered associated with tachycardia and hyperkalemia in our case, could be seen both with myocarditis and with MI.Neither the elevation of cardiac enzymes nor the echocardiographic findings could differentiate myocarditis from other myocardial diseases.Using contrast medium for coronary angiography was not a priority, at least in the acute phase in our case, because of cross-reactivity with multiple drugs in DiHS/DRESS. 1 We decided against endomyocardial biopsy because of its invasiveness.Elective coronary MRA revealed stenosis in the LCX confirming the diagnosis of type 2 MI.While MI (type 1) is usually caused by coronary plaque rupture or erosion and superimposed thrombosis, type 2 MI is characterized by an imbalance between myocardial oxygen supply and demand.Extracardiac stressors, such as hypertension, tachycardia, or hypotension, precipitate this imbalance, 8 therefore the treatment is to correct those factors.In our case, insulin administration and fluid infusion for hypertonic dehydration caused by DKA were administered.
Only two reported cases of DiHS/DRESS complicated by MI have been reported. 9Both patients were young men (35 and 36 years old) with DiHS/DRESS triggered by allopurinol who were treated with corticosteroids and developed MI a few months after fully recovering from DiHS/DRESS symptoms; however, the evaluation of their coronary arteries was unavailable.A recent systematic review 10 identified 42 cases of myocarditis with probable or definite DRESS.A unique characteristic of DiHS/DRESS myocarditis is its delayed onset, which may occur long after the resolution of DiHS/ DRESS features (such as rash, fever, and eosinophilia), whereas cardiac involvement and DKA/shock occurred simultaneously in our case.Dyspnea, cardiogenic shock, chest pain, and tachycardia are the most common symptoms, and patients often have abnormal ECGs and decreased LVEF on echocardiography.In the review, 22 of the 42 patients underwent endomyocardial biopsy or postmortem autopsy.MI associated with DiHS/DRESS may be overlooked in patients without the use of diagnostic tools.
Administration of corticosteroids should be carefully considered regardless of the patient's complications associated with DiHS/ DRESS, since the discontinuation of the causative drug and systemic corticosteroid administration or abrupt dose reduction both pose a risk of immune reconstitution syndrome and viral reactivation, 1,11 causing systemic symptom flare-ups and secondary autoimmune diseases. 1 conclusion, we report a case of atypical DiHS/DRESS with concurrent FT1D and type 2 MI relatively early after onset.In this case, hypovolemic shock secondary to FT1D/DKA resulted in type 2 MI.
The possibility of ischemic heart disease should also be considered in patients with DiHS/DRESS and cardiac involvement under shock.

ACK N OWLED G M ENTS
3°C), leukocytosis (26 600/μL), atypical lymphocytes (10%), liver dysfunction (aspartate aminotransferase [AST], 660 U/L), and enlarged cervical lymph nodes were observed during F I G U R E 1 Clinical (a-d) and histopathological (e) features of the DiHS/DRESS patient on admission.(a,b) Morbilliform eruption was found on his trunk and extremities.(c) An erosion and redness were observed on posterior pharyngeal wall.(d) Periorbital pallor or perioral papules were not evident.(e) A skin biopsy was performed on an erythematous lesion on the lower leg on day 4. Pathologically, slight hyperkeratosis and mild perivascular lymphocytic infiltrate in the dermis are observed (hematoxylin-eosin; scale bar = 100 μm).
Furthermore, creatine kinase (CK; 6845 U/L) and troponin T (24 ng/mL) levels were elevated.Electrocardiography (ECG) showed ST depression and a high T-wave first, and ECG a few days later showed T-wave flattening to inversion in leads V5/V6.Severe hypokinesis of the cardiac apex and posterior wall was observed on transthoracic echocardiography, with a left ventricular ejection fraction (LVEF) of 43%.No thickened ventricular wall or pericardial effusion was observed.The patient did not experience any dyspnea or chest pain.Nonenhanced coronary magnetic resonance angiography (MRA) revealed mild coronary artery stenosis in segment 11, the proximal portion of the left circumflex artery (LCX), thus the patient was diagnosed with type 2 MI.We did not initiate systemic corticosteroids despite the severe condition and cardiac involvement because both clinical symptoms and enzyme levels, including AST and CK, peaked on the same day, thus administration of systemic corticosteroids was considered less significant for protecting the organs and the risk of immune reconstitution syndrome was judged to outweigh the benefit.The skin rash and general condition were relieved without systemic corticosteroid administration, and the patient was discharged from the F I G U R E 2 Clinical course with laboratory data.Blue line indicates WBC, light green line indicates CK, pink line indicates IgG, green line indicates TARC, red line indicates AST, each in serum.Carbamazepine was administered with 400 mg dose (day −51) and then increased to 900 mg (day −4), and eruption was observed on day 0. The patient was admitted on day 8. WBC, CK, and AST levels were elevated the next day.LTT to carbamazepine was negative first (day 10) but turned to positive (day 108).HHV6 was tested for three times during the time course but all tests were negative.HHV7 DNA PCR was also negative (day 10).VZV IgG antibody was slightly elevated through day 24 to day 38.Ag, antigen; AST, aspartate aminotransferase; CBZ, carbamazepine; CK, creatine kinase; CMV, cytomegalovirus; HHV, human herpes virus; LTT, lymphocyte transformation test; VZV, varicella zoster virus; WBC, white blood cell.hospital 4 weeks later with permanent insulin.The patient did not develop flare-ups or other autoimmune diseases within 15 months post-discharge.
This study was supported by the Scientific Research Fund of the Ministry of Health, Labour and Welfare, Japan (21FE2001).The ethics for a national epidemiological survey to create diagnostic criteria guidelines for DiHS were approved by the Institutional Review Board of the Tachikawa Hospital, Federation of National Public Service Personnel Mutual Aid Associations (approval number: 2020-35) and informed consent was obtained from our patient.