Drug reaction with eosinophilia and systemic symptoms (DRESS) is a life-threatening drug adverse effect [1]. It can be caused by a specific spectrum of drugs (most commonly carbamazepine, phenobarbital, allopurinol) and usually occurs with left and fever, multi-organ involvement, and lymphadenopathy [2]. Severe cutaneous adverse reactions (SCARs) are a collection of syndromes, among which is included the DRESS syndrome [3]. The syndrome has distinct characteristics that include hematologic abnormalities, involvement of internal organs, characteristic cutaneous features, and potential long-term autoimmune sequelae [4].

The epidemiology of DRESS syndrome has a global incidence ranging from 2.18–9.63 per 100,000 patients [5]. In hospitalized patients, the range is between 3–40 per 100,000, with higher prevalence in women and African patients. The higher incidence in hospitalized patients is probably due to pronounced antibiotic exposure in hospitals [6]. With continued utilization of anticancer and immunotherapy medications, incidences could rise over the next several years [7]. Very few drugs can cause DRESS syndrome, which is typified by delayed onset and long-standing clinical manifestations despite withdrawal of the causative drug [8].

Sequential reactivation of herpesviruses, notably human herpesvirus 6 (HHV-6) [9,10], is one of the typical features that differentiate DRESS from other drug eruptions. The recent case report by Saleem et al. documents a DRESS syndrome induced by piperacillin-tazobactam in a patient with CKD and comorbidities [11]. The case describes the diagnostic difficulties and stresses the importance of clinical suspicion in those patients who are receiving multiple drugs simultaneously.

The case here by Saleem et al. (2025) is noteworthy in that the offending agent is rare—piperacillin-tazobactam, a broad-spectrum beta-lactam antibiotic not classically associated with DRESS syndrome [11]. While aromatic anticonvulsants and sulfonamides remain the most common offending drugs, more recent evidence indicates that antibiotics may be the cause in approximately 30% of cases of DRESS in children and adults [12]. Piperacillin-tazobactam is a rising but underappreciated perpetrator [13]. A 2023 review of pharmacovigilance by Chen et al. enumerated several more recent antibiotic agents resulting in SCARs, including DRESS syndrome, thus validating the importance of clinician vigilance beyond the "classical" agents [14]. Shen et al. particularly implicated piperacillin-tazobactam as a culprit of DRESS syndrome, adding further credence to the findings in Saleem's case report [15]. The patient's complex previous medical history—including chronic kidney disease, high blood pressure, and childhood asthma—likely contributed to the prolonged diagnostic process [11]. Initial presentations such as fever, elevated inflammatory markers, and hepatic dysfunction are likely to be attributed to sepsis, a common condition among CKD patients who are on broad-spectrum antibiotics [16]. This case illustrates a bigger diagnostic dilemma: DRESS syndrome usually presents as infectious or autoimmune illnesses at the early stage, particularly in the inpatient or immunocompromised patient [17]. It has been shown in recent studies that it is conceivable that 50% of DRESS cases can be initially misdiagnosed, and the delay in withdrawing the causative drug may lead to a poor outcome [18].

Kardaun et al. developed and tested the RegiSCAR scoring system as a move towards standardizing the diagnosis of DRESS in ambiguous clinical presentations, emphasizing systematic evaluation even if classic signs are not present [19]. This case highlights the importance of maintaining high suspicion in patients on high-risk drugs who present with delayed fever and eosinophilia, even in non-classically implicated drugs in DRESS syndrome [20].

A critical diagnostic challenge in the case presented was cutaneous late manifestation, and systemic manifestations occurring before dermatological features [11]. In the classical presentations, DRESS syndrome is characterized by a morbilliform or erythema usually within 2-8 weeks of initiating the offending drug [21]. However, atypical or partial cutaneous presentations are increasingly being noted, particularly in elderly, immunocompromised, or chronically ill patients [22]. Cacoub et al. documented variable clinical manifestations of DRESS across different patient populations, pointing to the heterogeneity of the condition [20]. In a 2023 multicenter study, Mizukawa and Shiohara emphasized that systemic abnormalities—such as hematologic eosinophilia, hepatic insufficiency, and lymphadenopathy—may arise before the cutaneous manifestations in approximately 15% of cases of DRESS, leading to delayed diagnosis and awareness [22,23].

Failure or delayed appearance of skin characteristics, as in the case presented by Saleem et al., supports the application of non-cutaneous parameters—peripheral eosinophilia, organ involvement, and lymphadenopathy—in the initial assessment protocols [11]. Application of well-validated scoring instruments like RegiSCAR or J-SCAR facilitates early diagnosis and risk stratification of suspected cases even without the presence of characteristic skin features [4]. This trend facilitates the generation of diagnostic uncertainty and reinforces the importance of recognizing systemic warning signs—such as eosinophilia, elevated liver enzymes, and lymphadenopathy—even when there is no early rash [24]. Mizukawa and Shiohara outlined in their review that such "incomplete" or unclassical manifestations are still diagnosable if systematically assessed, justifying the use of scoring systems when faced with clinical uncertainties [23].

The treatment regimen followed in the patient in Saleem's report complied with evidence-based practice recommendations for moderate to severe DRESS syndrome, based on the severity of internal organ involvement [11]. Systemic corticosteroids are still the mainstay of treatment, with a typical initial dose of prednisone 1 mg/kg/day, tapered over 6-8 weeks to avoid the risk of relapse [25]. Administration of corticosteroids in this patient, with CKD and comorbidities, proceeded uneventfully, testifying to prudent patient selection and monitoring [11]. Similar efficacy was reported by Funck-Brentano et al. with corticosteroid therapy in renal impairment patients, confirming this treatment mode [26].

Recent consensus recommendations of the JAMA Dermatology Delphi panel recommend corticosteroid treatment as first-line therapy in cases of hepatic, renal, or pulmonary involvement [27]. Rationale for this recommendation arises from evidence showing reductions in mortality, severity of organ dysfunction, and hospital stay duration [28]. Descamps et al. also proposed an algorithm-based treatment strategy based on DRESS syndrome severity and organ involvement, once again supporting an organized management pathway [29]. The danger of relapse with tapering is a clinical concern, with recurrence at a rate of 10-20% cited in the literature [30]. Relapse could have been avoided in the case reported by Saleem et al. with gradual and individualized corticosteroid tapering, according to the patient's comorbidities and renal status [11].

Other forms of therapy, such as intravenous immunoglobulin (IVIG), cyclosporine, mycophenolate mofetil, and biologically targeted drugs such as mepolizumab (anti-IL-5 monoclonal antibody), have been investigated in steroid-resistant or fulminant disease [30,31]. As the patient recovered clinically quite rapidly with conventional therapy, adjunct therapies were not required in this patient [11].

A significant omission from the case as described was viral reactivation testing—in this case, specifically HHV-6, CMV, or EBV—which increasingly has been implicated in DRESS pathogenesis and course [11]. Successive herpesvirus reactivation is now recognized as a characteristic of DRESS syndrome and can itself play a direct role in severity and chronicity [9]. Ramirez et al. also recently investigated the role of viruses in the pathophysiology and diagnosis of DRESS syndrome, highlighting the utility of viral testing in suspected DRESS [32]. Shiohara et al. went further and described DRESS as a drug-induced response caused by intricate interactions between herpesviruses and antiviral/antidrug immune response [33].

Current recommendations advise adding HHV-6 PCR evaluation to patients in cases where the diagnosis seems to be delayed or in cases of flare recurrences [34]. Although viral monitoring was not conducted in the case reported by Saleem et al., future cases of DRESS would greatly benefit from structured virological evaluation to illustrate whether such correlations exist in terms of disease severity and treatment response [11]. This would also establish if these patients could be considered for targeted antiviral therapy, as new evidence keeps emerging [35].

The outcomes of this case have implications beyond the individual patient, offering more general insight into the detection, diagnosis, and treatment of DRESS syndrome in medically complex, high-risk patients [11]. Firstly, the case reiterates that piperacillin-tazobactam, although historically underrecognized as a DRESS incitant, is a consideration when systemic hypersensitivity manifestations occur during antimicrobial therapy [36]. These suggest that DRESS can mimic routine nosocomial complications like sepsis in CKD patients and immunocompromised conditions, which can result in delayed diagnosis and preventable morbidity [37]. Early diagnosis mandates caution for subtle hematologic and liver abnormalities without cutaneous manifestations [38]. Third, the case suggests favor for systematic application of validated diagnostic scoring systems (e.g., RegiSCAR), immediate drug causative withdrawal, and early corticosteroid therapy to maximize outcomes [4]. Various studies have reported improved outcomes with early intervention and proper management steps [39].

The case also highlights some key gaps in current clinical practice, namely viral reactivation monitoring and long-term follow-up for autoimmune sequelae [40]. Wolfson et al. demonstrated the worth of thorough documentation and follow-up of DRESS cases to enable improved future management strategies [41]. Lastly, this case yields a significant hypothesis to investigate: does CKD and related immune dysregulation render patients more susceptible or to atypical presentations of DRESS syndrome, either by perturbed drug metabolism, accumulation of reactive intermediates, or chronic low-grade inflammation [42].

Considering this patient's renal insufficiency, an interesting point arises: Do decreased renal clearance of drug metabolites or uremic immune changes enhance DRESS susceptibility in patients with CKD[11]? Various investigators have suggested possible mechanisms, including chronic inflammation and dysregulated detoxification pathways in renal disease as etiopathogenic contributors to severe cutaneous adverse reactions [43]. Lasting conclusions are still lacking. This case argues in favor of exploring further whether CKD patients are at higher risk of developing DRESS syndrome if treated with certain antibiotics, and if there needs to be dosage tailoring or heightened monitoring protocols [44]. Prospective studies could elucidate the role that renal function plays in vulnerability to DRESS syndrome, leading the way to improved risk assessment and prevention.

Saleem et al., case report discusses piperacillin-tazobactam-induced DRESS syndrome in a patient with end-stage renal disease, highlighting the diagnostic and therapeutic challenges. The atypical antibiotic culprit, absence of initial skin symptoms, and early sepsis-like presentation make DRESS underdiagnosed in polypharmacy patients. Early drug withdrawal and corticosteroid treatment led to a favorable outcome, emphasizing the need for vigilant monitoring, viral reactivation checks, and long-term follow-up. Further research is needed to explore the elevated risk of DRESS in CKD patients and those with comorbidities.