INTRODUCTION

Drug-induced reaction with hypereosinophilia and systemic signs (DRESS) syndrome is a severe idiosyncratic T-cell mediated drug reaction characterized by fever, skin rashes, hematological abnormalities, and organ failure. Since it was first described in cases of an adverse drug reaction to sulfonamides and hydantoin (anticonvulsant) in the 1940s, the appellation of this disease entity has significantly evolved. It lies within a large group of disorders known as drug hypersensitivity reactions (DHRs) [1–3]. DRESS syndrome is a rare hypersensitivity reaction, accounting for about 2.18/100 000 admissions and about 12.6% of severe drug reactions [4,5]. DRESS syndrome affects every organ system, invariably leading to failure and death. Rare gastrointestinal manifestations of DRESS syndrome have been reported, principally affecting the pancreas, colon, esophagus, small bowel, and stomach [6]. However, cholecystitis is an extremely rare manifestation of the disease.

CASE REPORT

Herein, we present the case of a 49-year-old black female admitted to the emergency unit for severe abdominal pain.

The patient was initiated on carbamazepine approx. three weeks prior to admission for abnormal twitching of the head. Four days after the initiation of carbamazepine, she developed an erythematous morbilliform rash on her face and trunk, associated with intermittent pruritus. By the 7^th to 8^th day, the patient noted the gradual onset of fever described as being predominantly constant, for which she self-medicated with paracetamol 1 g one to three times a day. At this time, the rash progressed by coalescing in various areas. Around the 17^th day following carbamazepine initiation, she noticed the slow onset of pain in the right hypochondrium followed shortly by the onset of watery diarrhea (6 to 8 bowel movements daily) associated with nausea, retching, and spontaneous vomiting. She was seen at a local health center where ceftriaxone 2 g daily, metronidazole 500 mg every 8 hours, and paracetamol 1 g every 8 hours were administered. Her progress, then, was marked by a rapid extension of the rash to the limbs prompting referral to our emergency unit. Figure 1 shows the chronology of the event.

On admission (21^st day), the Glasgow coma score was 14/15, arterial blood pressure was 106/64 mmHg, respiratory rate was 28 breaths per minute, and pulse was 126 beats per minute. The quick sequential organ failure assessment score (qSOFA) score was 2/3, peripheral oxygen saturation was 98% on room air, and the temperature was 38.2^°C. There was anuria lasting more than 18 hours. On the skin, there was facial edema (Fig. 2) and a generalized erythematous maculopapular rash, discrete on the upper and lower limbs and confluent on the trunk (Figs. 3a – 3b) involving up to 64.5% of the total body surface area. On abdominal examination, we noted splenomegaly and a tender hepatomegaly with a positive Murphy’s sign. There was no guarding. Bowel sounds were decreased.

Abdominal ultrasound revealed an enlarged gall bladder with a thickened wall measuring 14–16 mm with intramural and peri-cystic fluid collection (Figs. 4a – 4c). The liver was homogenously enlarged with regular contours, measuring 185 mm. The celiac and mesenteric lymph nodes were enlarged (> 1 cm), and there was moderate diffused ascites. There was no evidence of bladder lithiasis or sludge.

Blood workup revealed leukocytosis, mild thrombocytopenia, elevated CRP and PCT, moderate hyponatremia, mild hypokalemia, elevated BUN and creatinine, elevated transaminases (>10 times above the normal), an abnormal clotting profile, and elevated serum lactate (Table 1). Hemoglobin and blood sugar levels were normal. Blood culture and hepatitis B, hepatitis C, and HIV viral serologies were negative. Urine output was 1.42 mL/kg/hr with an estimated renal clearance of 27.96 mL/min.

The European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) scale, which classifies suspected cases of DRESS syndrome as definite (score 6 and above), probable (score 4 and 5), possible (score 2 and 3), and no DRESS syndrome (score < 2) was used in our patient, and yielded a score of 5, suggesting probable DRESS syndrome [7–9]. The criteria in our patient were the presence of skin rash suggesting DRESS syndrome (1), skin rash extending beyond 50% of the body surface area (1), fever < 38.5°C (-1), eosinophilia ≥ 0.7×109/L (1), enlarged lymph nodes > 1cm and ≥ 2 different areas; celiac and mesenteric nodes (1), and organ involvement, i.e., the gall bladder, liver, kidney (2).

A diagnosis of acute acalculous cholecystitis from probable DRESS syndrome secondary to carbamazepine complicated by septic shock and multiple organ failures was made.

She received fluid resuscitation, methylprednisolone 120 mg/24 hrs, levofloxacin 500 mg starting dose, gentamycin 280 mg starting dose, and metronidazole 500 mg/8 hours. Carbamazepine was stopped. She was planned for emergent cholecystectomy by open laparotomy.

Despite receiving treatment, the patient did not show any improvement and her condition rapidly deteriorated. Her neurological condition worsened, and she developed severe refractory hypoglycemia, shock, and spontaneous bleeding from various body orifices. Furthermore, her skin lesions spread and became erythrodermic, affecting more than 84% of her total body surface. Unfortunately, the patient passed away twenty hours after being admitted to the hospital.

DISCUSSION

There is a huge dearth of data on DRESS syndrome in sub-Saharan Africa, probably from its rare occurrence coupled with under-diagnosis, given its strong similarity to other disease conditions. Culprit drugs most often reported include aromatic anticonvulsants (phenytoin, phenobarbital, carbamazepine), antibiotics (trimethoprim-sulfamethoxazole, minocycline, dapsone), anti-rheumatic drugs (sulfasalazine, gold salt), lamotrigine, abacavir and allopurinol [8,10,11]. According to the 2011 version of the French method of drug side effect causality assessment, our patient had an intrinsic validity score of 5 (I5) out of 6 (C2S3, for the chronological and semiological criteria, respectively) and an extrinsic (bibliographical) validity score of 3 (B3) stemming from published scientific evidence of the implication of carbamazepine in DRESS syndrome [12,13].

DRESS typically occurs at least 3 weeks (2–8 weeks) after exposure to culprit drugs. However, some authors have reported that it may occur within two weeks of exposure, depending on the medications involved [14]. Ciprofloxacin has been reported to have a two-day delay of occurrence [15]. Other medications like abacavir, lamotrigine, and nevirapine induce DRESS syndrome in shorter intervals compared to carbamazepine and allopurinol, which generally have unusually long delays of occurrence of more than 3 months [16]. However, DRESS syndrome occurring after three days of carbamazepine in a forty-year-old man was reported in a case report from Tunisia in 2021 [17]. Therefore, the rapid onset of symptoms should not exclude the diagnosis of DRESS syndrome.

DRESS syndrome is a T cell-mediated delayed-type drug hypersensitivity reaction. There has been evidence of genetic predispositions to DRESS syndrome with specific HLA alleles associated with the condition [18]. Viral infections have also been implicated in the disease pathogenesis, including human herpesvirus-6 (HHV6), as well as HHV7, Epstein–Barr virus (EBV), and cytomegalovirus (CMV) [8,19]. In our patient, aside from hepatitis B and C and HIV viral serologies, no other viral serologies were investigated. Pro-inflammatory cytokines such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) have been implicated in the pathogenesis as well as the pro-eosinophilic cytokine, interleukin-5 (IL-5) [8,20,21]. The mechanism of acute cholecystitis in DRESS syndrome is thought to be due to pro-inflammatory cytokines, endothelial injury, bladder ischemia, leading to bladder wall edema and necrosis, cystic duct occlusion, bile stasis followed by secondary bacterial invasion that may get disseminated compounding the clinical picture with sepsis and eventually septic shock [22,23]. The diagnosis of septic shock in our patient was based on qSOFA score of 2 as recommended by the Third International Consensus Definitions for Sepsis and Septic Shock [24,25]. This diagnosis was further supported by exceptionally high levels of procalcitonin (PCT) > 200 ng/mL and the presence of leukocytosis at 14200 (Table 1). The clinical course of the symptoms in our patient indicated that the cause of septic shock, i.e., acute cholecystitis, only appeared around the last three days. However, blood cultures were negative, and this could be explained by previous intake of antibiotics. The International Society on Thrombosis and Hemostasis (ISTH) have recognized that no single laboratory test has sufficient accuracy for the diagnosis of disseminated intravascular coagulation (DIC) and have suggested a simple scoring system that uses four routine laboratory values: platelet count, prothrombin time/INR, a fibrin-related marker such as D-dimer, and fibrinogen, to improve diagnostic accuracy for DIC [26]. Although fibrinogen and D-dimer tests were not available to establish a definitive diagnosis, DIC was nonetheless suspected due to the presence of an abnormal clotting profile (INR > 1.5) associated with spontaneous bleeding from orifices. Despite the fact that patients with visceral involvement such as our patient (hepatitis, nephritis, etc.) are at higher risk of mortality [27], death is generally not this abrupt. We postulate that the combination of sepsis with suspected DIC is the most plausible explanation for the rapid mortality in this case.

The European Registry of Severe Cutaneous Adverse Reaction (RegiSCAR) is the most famous scale used in the diagnosis of DRESS syndrome. The criteria in our patient were the presence of skin rash suggesting DRESS syndrome, skin rash extending beyond 50% of the body surface area, fever < 38.5°C, eosinophilia ≥ 0.7×109/L, enlarged lymph nodes, and organ involvement [8,20]. Our patient was a probable case of DRESS syndrome based on the RegiSCAR score of 5, limited by the fact that the patient died before the drug withdrawal effect could be observed and before additional investigations, such as a skin biopsy, antinuclear antibody (ANA), and viral serologies, could be obtained. Lymphadenopathy, although commonly associated with NSAIDS (60%), is a rare finding in carbamazepine-induced DRESS syndrome (4%) [11]. A lymph node biopsy helps exclude other causes of prolonged fever and splenomegaly such as lymphomas [28–30]. However, a biopsy of celiac and mesenteric lymph nodes was contraindicated in our patient because of suspected DIC and hemodynamic instability. Although the clinical course of diarrhea in our patient may have been related to sepsis or the use of antibiotics, the associated moderate electrolyte imbalance on admission prompted us to consider DRESS syndrome colitis a potential etiology as it tends to occur much later after the onset of the rash [6,31,32]. Other non-hepatic gastrointestinal manifestations of DRESS syndrome, which include vomiting, abdominal pain, nausea, epigastric pain, and dysphagia, also occur significantly late in the course of the disease [6].

There are no specific treatment guidelines for DRESS syndrome. However, the main treatment involves the withdrawal of the culprit drug and the administration of corticosteroids [33]. The efficacy of corticosteroids is thought to be variable. The dose and duration of corticosteroid treatment depends on the severity of the symptoms and the patient’s response to treatment. In severe cases, intravenous immunoglobulin or plasmapheresis has been suggested [34]. Ideally, all other drugs are withdrawn due to the possibility of worsening disease conditions. Thus, the concomitant occurrence of DRESS syndrome with different disease conditions, such as sepsis, renders an already uncertain treatment more complex, given the primordial need for antibiotics in this case. Acalculous cholecystitis accounts for ten percent of all cases of acute cholecystitis [35]. Few cases of acalculous cholecystitis in patients with DRESS syndrome have been reported in the literature [36–38] The treatment approach to acute cholecystitis in DRESS syndrome has the peculiarity of the underlying immune-mediated condition. In general, the successful treatment of acute cholecystitis depends on the severity of the disease. The initial treatment often includes supportive care, pain relief, and intravenous fluids. Antibiotics may be prescribed if there is evidence of infection [39]. In some cases, percutaneous cholecystostomy may be considered a treatment option, particularly in critically ill patients unfit for surgery, followed by delayed cholecystectomy or as a definitive treatment option in patients deemed unfit for surgery [39]. These treatment modalities have been used variably in reported cases of acute acalculous cholecystitis in DRESS syndrome (Table 2). Unfortunately, our patient did not survive long enough to benefit from any surgical interventions.

Owing to the atypical clinical presentation, the absence of full diagnostic modalities, and the rapid fatal outcome, a definitive diagnosis of DRESS syndrome in our patient could not be achieved. Nonetheless, this case report contributed to the existing body of literature describing the rare occurrence of acalculous cholecystitis as a complication of probable DRESS syndrome.

CONCLUSION

DRESS syndrome should be suspected in any patient with a history of potentially causative drug exposure and suggestive symptoms. Acalculous cholecystitis, although uncommon, represents a life-threatening clinical scenario with significant diagnostic and therapeutic challenges when associated with DRESS syndrome. Clinicians are encouraged to maintain a high level of suspicion to ensure timely investigation and the potential aversion of a fatal outcome.

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