Abstract
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon but potentially fatal hypersensitivity response, commonly triggered by medications such as antiepileptics and antibiotics. It typically presents with rash, fever, hematologic abnormalities, lymphadenopathy, and internal organ involvement—most commonly affecting the liver. We report a case of a 79-year-old woman with hypertension and dyslipidemia who underwent laparoscopic cholecystectomy for acute cholecystitis with early pancreatitis. Postoperatively, she developed persistent cholestatic liver injury without biliary obstruction. Ten days later, she presented with fatigue, a diffuse maculopapular rash, and elevated cholestatic liver enzymes and lipase. Skin biopsy revealed features consistent with drug-induced hypersensitivity. Using the RegiSCAR scoring system, the case met criteria for probable DRESS syndrome (score = 5). Ceftriaxone and metronidazole, the only new drugs introduced perioperatively, were identified as likely triggers using the Naranjo causality scale. The patient was treated with oral prednisone (0.75 mg/kg), with full resolution of clinical and laboratory abnormalities following a 5-week course. This case highlights an atypical presentation of DRESS syndrome mimicking postoperative cholestasis. It underscores the importance of considering DRESS in the differential diagnosis of unexplained cholestatic injury, even in the absence of classical features like fever, eosinophilia, or lymphadenopathy. Early recognition and timely corticosteroid therapy are critical to improving outcomes.
Introduction
Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a severe drug-induced hypersensitivity reaction that manifests with a constellation of symptoms, typically occurring 2 to 8 weeks after exposure to the offending medication. Initial symptoms often include fever, malaise, and pruritus, which may progress to a morbilliform rash, lymphadenopathy, and multi-organ involvement. Laboratory findings commonly reveal eosinophilia, atypical lymphocytes, and signs of organ dysfunction, particularly in the liver and kidneys. The syndrome has a notable association with certain medications, including antiepileptics and antibiotics, yet its exact incidence is challenging to determine due to underreporting and diagnostic difficulties. Understanding DRESS is critical as it can lead to significant morbidity and mortality; thus, early recognition and prompt management are essential to mitigate the associated risks and complications. 1 We report a 79-year-old woman developed DRESS syndrome with cholestatic liver injury after cholecystectomy, likely triggered by ceftriaxone/metronidazole, and responded well to corticosteroids. The purpose of reporting this case is to highlight a rare and diagnostically challenging presentation of syndrome that manifested postoperatively as isolated cholestatic liver injury without initial dermatologic or hematologic clues. Unlike typical presentations, this patient’s clinical picture mimicked more common postoperative complications, delaying recognition.
Case Presentation
A 79-year-old female with no history of alcohol or tobacco use, and a past medical history of hypertension and dyslipidemia managed with perindopril, bisoprolol, hydrochlorothiazide, and rosuvastatin, presented to the emergency department with intense epigastric pain, accompanied by fever, nausea, and vomiting of 1 day duration. On presentation, vital signs were stable, and the patient was afebrile. Clinical evaluation revealed icteric sclera, while abdominal assessment demonstrated a soft abdomen with tenderness over the epigastric region and a positive Murphy sign. There was no evidence of organomegaly, lymphadenopathy, or rash. Initial laboratory findings indicated elevated transaminases, with aspartate aminotransferase (AST) at 700 U/L predominating over alanine aminotransferase (ALT) at 199 U/L, and an elevated direct bilirubin level of 3.35 mg/dL, alongside normal GGT at 98 U/L and alkaline phosphatase at 116 U/L (Table 1). A CT scan of the abdomen revealed a thickened gallbladder wall, pericholecystic fluid, microlithiasis, along with edematous enlargement of the pancreas. No evidence of intrahepatic, extrahepatic, or pancreatic duct dilation was noted. These findings suggested acute cholecystitis with early acute pancreatitis. The patient was admitted for the management of acute biliary cholecystitis and pancreatitis and was started on intravenous fluids and antibiotics (ceftriaxone with metronidazole). An MRCP was subsequently performed, showing similar results to the CT, with gallbladder distention, pericholecystic fluid, and multiple stones in the gallbladder fundus measuring up to 5 mm (Table 2). The common bile duct was not dilated, and the liver appeared to be of normal size. The patient underwent a laparoscopic cholecystectomy without complications on 2/12/2025, which revealed an inflamed gallbladder with normal intraoperative cholangiography. Postoperative liver function tests indicated a cholestatic pattern, with elevated GGT at 441 U/L and alkaline phosphatase at 287 U/L (Table 1). In contrast, transaminases and bilirubin levels improved, with AST decreasing to 92 U/L, ALT to 102 U/L, and bilirubin to 1.18 mg/dL (Table 1). The patient’s symptoms resolved after surgery; she resumed oral feeding and had normal bowel movements. Vital signs were stable, and the clinical exam showed a soft, non-tender abdomen, except for the area of surgical sutures. An endoscopic ultrasound performed 3 days postoperatively revealed a normal, homogeneous pancreas with a regular and unremarkable main pancreatic duct and no signs of malignancy. The common bile duct was well visualized from the ampulla to the hepatic hilum, measuring 4.5 mm with no stones. A few perihilar lymph nodes were noted with an inflammatory appearance. The patient was discharged, and follow-up labs on day 10 postoperatively showed persistent elevation in the cholestatic pattern, with GGT at 1218 U/L, alkaline phosphatase at 884 U/L, and lipase at 1150 U/L, alongside resolution of the transaminases and bilirubin (Table 1). On post-operative day 20, the patient complained only of fatigue, with complete resolution of abdominal pain. Physical examination revealed a diffuse erythematous maculopapular rash predominantly affecting the abdomen (Figure 1) and back necessitating her readmission. The rash consisted of non-blanching, small macules and papules with no vesicles. No lymphadenopathy was detected.
Serial Laboratory Findings from Admission to Follow-Up.
Chronological Timeline of Clinical Events, Treatments, and Laboratory Findings.
Day 0 before steroid initiation.
Viral serologies for hepatitis B and C, as well as an autoimmune workup including ANA, AMA, anti-smooth muscle antibodies, and IgG4, were all negative. A skin biopsy revealed atrophic epidermis with effacement of rete ridges, basal layer vacuolization, scattered apoptotic bodies, mild dermal edema, and perivascular lymphocytic infiltrate containing eosinophils and neutrophils, consistent with a drug reaction from antibiotics, particularly DRESS syndrome with a RegiSCAR score of 5 (Table 3) and Naranjo score of 7 (Table 4) for both ceftriaxone and metronidazole indicating probable causality. The patient was started on oral prednisone at a dose of 0.75 mg/kg and showed progressive improvement later on (Figures 2-3) and no antihistamines were used. Liver enzymes began trending down, and she was discharged after 5 days of her new admission on prednisone for 3 weeks, followed by a slow taper over approximately 2 additional weeks. At follow-up, the patient’s laboratory tests had normalized, and she remained asymptomatic (Table 2).
Summary of the Different Available Clinical and Laboratoty Findings Used to Calculate the RegiSCAR Score.
Summary of the Different Available Clinical and Laboratory Findings Used to Calculate the Naranjo Score.
Day 2 post steroid initiation.
Day 4 post steroid initiation.
Discussion
DRESS syndrome may lead to a swift and severe decline in liver function and multi-organ failure, especially if not started on a suitable dose of prednisone; a case report by Delgado et al went over 5 cases of DRESS syndrome, one of which rapidly deteriorated and led to death. That specific patient was started on 25 mg of prednisone, a dose that is significantly lower than the doses used in the other cases, which ranged between 40 and 60 mg. Compensation by switching to methylprednisolone 250 mg IV 12 days later was not enough to prevent organ failure, which sheds the light on the importance of starting steroid therapy, with an appropriate dose, as soon as possible. 2 A case of DRESS syndrome complicated by acute hepatic failure was described, highlighting the severity of liver involvement and emphasizing the need for early corticosteroid therapy to prevent fatal outcomes. 3 Similarly, Wright et al stressed the importance of early recognition, showing that delays in diagnosing DRESS can lead to serious complications such as hepatic failure, reinforcing the necessity for clinical vigilance. In their article, they stated that mild hepatic symptoms in DRESS can be easily mistaken for other conditions. Therefore, DRESS syndrome should be suspected when patients are exposed to a new drug in the previous 2 to 8 weeks and present with skin eruptions, fever (38°C-40°C), facial edema and/or lymphadenopathy. 4 Oliveira et al mentioned a consensus on the management of DRESS syndrome. Based on this consensus, topical corticosteroids, emollients, and H1-antihistamines are recommended in the absence of severe symptoms. They suggest corticosteroids equal to 1 mg/kg of prednisolone every day in the case of severe symptoms, such as hyperphagocytosis, pneumonia, renal impairment, transaminases more than 5 times normal, or cardiac involvement. In our case, management with systemic corticosteroids (0.75 mg/kg) resulted in full resolution of symptoms. In cases of severe hepatitis, encephalitis, hemophagocytosis with renal failure, respiratory failure, or bone marrow failure, they recommend steroids typically combined with intravenous immunoglobulin (IVIG) at a dose of 2 g/kg over 5 days. Lastly, they recommend combining steroids with an antiviral (ganciclovir) and/or IVIG if there are warning symptoms of severe viral reactivation and proof of it. 5 No IVIG or antihistamines were needed in our case.
Liver injury is very common in DRESS syndrome; Lin et al, in their clinical study of 72 patients, found that 86.1% had liver injuries, however, of several types. Cholestatic injuries were the most common, followed by mixed and hepatocellular injuries. The median age for hepatocellular injuries was 31.5, significantly lower than the other 2 groups, 59 and 52. In addition, of all culprit drugs reported in this study, allopurinol mostly caused cholestatic injuries (12 of 14 cases), compared to carbamazepine, which only caused hepatocellular and mixed injuries (3 cases of each). 6 In their literature review, Martinez-Cabriales et al went over 21 studies about DRESS syndrome; liver involvement ranged from 60% in one study, to 100% in others. In addition, mortality (11% vs 1%), lymphadenopathy (23% vs 6%), and renal dysfunction (39% vs 1%) were significantly higher in patients with liver dysfunction compared to those with no dysfunction. 7
Sanabria-Cabrera et al noted that viral infections and the development of DRESS are related. Multiple studies have linked the development of DRESS syndrome to the reactivation of human herpesvirus-6 (HHV-6), with reactivation observed in approximately 62% of patients presenting with drug rash and systemic symptoms had elevated anti-HHV-6 IgG titers 2 to 4 weeks after the beginning of symptoms, according to a Japanese study. There have also been reports of DRESS patients experiencing the reactivation of other herpes viruses, including HHV-7, Epstein-Barr virus, and CMV. With more severe organ involvement and a longer course, virus reactivation in DRESS appears to affect the disease’s progression. Following exposure to carbamazepine, allopurinol, or sulfamethoxazole, DRESS developed as a result of systemic and cutaneous signs of an immunological response mostly driven by CD8+ T cells against herpes viruses. 8
In some cases, frequent occurrence of cholestatic or mixed liver injury patterns can occur. A large retrospective study examined 72 patients with DRESS and found that 86.1% had liver involvement; 23 patients were cholestatic type (35.5%), 17 patients were mixed type (29.0%) and 12 patients were hepatocellular type (19.4%), similar to the hepatic features described by Droz et al, where severe cholestatic hepatitis was the initial manifestation of DRESS syndrome. 9 A prospective study by Medina-Cáliz et al analyzed 53 cases of DILI-DRESS from the Spanish DILI Registry and Latin American DILI Network, revealing that 13% developed severe liver damage and only 1 patient (1.9%) progressed to acute liver failure and died. Compared to 881 general DILI cases, DILI-DRESS patients were younger (47 years vs. 53 years) and more often had cholestatic or mixed liver injury (P = .018). The most common causative drugs were anti-tuberculosis agents (13%), carbamazepine (13%), amoxicillin-clavulanate (11%), and both allopurinol and lamotrigine (7.6% each). Notably, 67% of all allopurinol- and lamotrigine-related DILI cases presented with a DRESS phenotype. Higher total bilirubin and absence of eosinophilia at diagnosis were linked to worse outcomes. 10 In contrast, Khan et al focused on antibiotic-induced DRESS, noting that antibiotics like beta-lactams and glycopeptides are the predominant causative agents and that liver injury can be particularly severe when multiple hepatotoxic antibiotics are used concurrently. 11 Beta-lactam antibiotics including ceftriaxone have been reported to cause DRESS in multiple case reports and allergology series, and confirmatory immunologic testing (patch test, lymphocyte transformation test) has been used in some reports to support drug attribution.12,13 Metronidazole is a less frequently reported cause but recent case reports document metronidazole-associated DRESS as well, sometimes in association with viral reactivation. 14 Large reviews of antibiotic-induced DRESS place both beta-lactams and other antibacterial agents among the non-negligible contributors to DRESS, supporting the plausibility of perioperative ceftriaxone and/or metronidazole as causative agents in our patient.15,16 Finally, pharmacovigilance summaries and recent case collections continue to register ceftriaxone and metronidazole as reported suspects, reinforcing the need to include these agents in the differential when DRESS presents after antibiotic exposure.17,18 Overall, despite variations in study design and population, these reports consistently underscore that liver injury is a critical and common manifestation of DRESS syndrome, often requiring prompt recognition and management with corticosteroids to improve outcomes.
Our case of DRESS syndrome is particularly noteworthy due to its atypical presentation and the unique combination of complications observed. Unlike many reported cases that primarily exhibit common symptoms such as fever, rash, and eosinophilia, our patient demonstrated rare manifestations including severe hepatic and renal involvement, alongside significant eosinophilia and atypical lymphocyte proliferation. The onset of symptoms occurred approximately 10 days postoperatively, which falls within the typical 2 to 8-week window for DRESS syndrome. However, the patient’s clinical progression, and diagnostic complexity, distinguishes this case from more straightforward presentations. Additionally, while the patient exhibited multi-organ involvement and required escalation of care, the subsequent rapid improvement following corticosteroid therapy underscores the importance of early recognition and treatment initiation in managing DRESS syndrome. The purpose of reporting this case is to emphasize that DRESS syndrome can mimic common postoperative complications, such as cholestasis, and may initially present without hallmark features like eosinophilia or rash. Early suspicion and timely corticosteroid initiation are key to preventing progression to liver failure or multi-organ involvement.
Although hepatic injury is the prototypical visceral manifestation of DRESS, clinicians should be aware of less-well-recognized gastrointestinal presentations that can complicate or obscure the diagnosis. Case reports and reviews document acute pancreatitis, drug-associated eosinophilic colitis/enterocolitis, and even esophagitis as manifestations of DRESS; pancreatitis is uncommon (<5% in most series) but when present may occur simultaneously with severe hepatic injury and can greatly affect prognosis and management. 19 Drug-induced eosinophilic colitis and mixed inflammatory mucosal lesions have been described with histologic eosinophil-rich infiltrates on biopsy, and patients may present with abdominal pain, diarrhea, or GI bleeding rather than florid dermatologic findings early in the course. 20 In our patient the prominent cholestatic picture with elevated lipase and later rash underscores this heterogeneity; explicitly considering DRESS in the differential for unexplained pancreatitis, cholestasis, or new-onset colitis after recent drug exposure can therefore improve early recognition and outcomes. 21
Regarding alternative diagnoses, several other conditions were considered in the differential. Postoperative cholestasis secondary to biliary obstruction was excluded by intraoperative cholangiography and postoperative endoscopic ultrasound, both of which showed a normal common bile duct without stones. Viral hepatitis was ruled out through negative hepatitis B and C serologies. Autoimmune hepatitis and cholangitis were excluded with a negative autoimmune panel (ANA, AMA, anti-smooth muscle antibodies, and IgG4). Drug-induced liver injury without hypersensitivity features was considered, but the presence of a diffuse maculopapular rash, compatible histopathological findings on skin biopsy, and multi-organ involvement favored a diagnosis of DRESS. Other severe cutaneous adverse reactions, such as Stevens–Johnson syndrome/toxic epidermal necrolysis, were excluded based on the absence of mucosal involvement and the morphology of the skin lesions. The temporal relationship between antibiotic initiation and symptom onset, combined with the RegiSCAR and Naranjo scores, further supported DRESS as the most likely diagnosis.
This case report contributes significantly to the literature by documenting an atypical presentation of DRESS syndrome manifesting solely as postoperative cholestasis, a presentation not commonly reported. One major strength lies in the diagnostic clarity provided by biopsy-confirmed DRESS syndrome and the favorable response to corticosteroid therapy, reinforcing the accuracy of diagnosis and management approach. Additionally, the use of validated tools such as the RegiSCAR and Naranjo scores strengthens the clinical attribution to ceftriaxone/metronidazole. The detailed chronology of symptoms, investigations, and laboratory trends offers a comprehensive view that enhances the clinical relevance of this case.
However, this report is limited by the absence of eosinophil counts and atypical lymphocyte data, which would have provided further diagnostic confirmation and potentially increased the RegiSCAR score. Another limitation is the lack of confirmatory viral reactivation studies (e.g., HHV-6 serology), which could have enriched the understanding of the immunological mechanism involved. Additionally, no drug rechallenge or pharmacogenetic testing was conducted, leaving some uncertainty in pinpointing the exact causative agent. These limitations reflect the real-world constraints of acute clinical settings but also underscore the need for increased awareness and comprehensive diagnostic workups in suspected DRESS cases.
Conclusion
This case underscores the need for heightened awareness and early recognition of DRESS syndrome, particularly in patients presenting with unusual clinical features, as timely intervention is critical in reducing morbidity and improving outcomes. Our findings contribute valuable insights into the diverse manifestations of DRESS, emphasizing its potential to present in rare and life-threatening forms.
Footnotes
Consent for Publication
Written informed consent to publish the case report from the patient was obtained.
Author Contributions
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.