Accelerated Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome in Response to TMP-SMX: A Case Report

Introduction

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a rare and severe hypersensitivity reaction that mainly involves the skin, but can have widespread multisystem organ involvement [1]. DRESS is also known as drug-induced hypersensitivity syndrome and was first observed in the 1920s with the use of Nirvanol (5-ethyl-5-phenylhydantoin), a derivative of phenytoin with anticonvulsant properties [2]. In the 1940s, a patient was reported to have fever, posterior cervical lymphadenopathy, and macular eruption 1 week after undergoing treatment with Epanutin (diphenylhydantoin), another phenytoin-derived medication [1]. These first reported and published cases in 1959 by Saltzstein et al spoke on the difficulties of distinguishing drug-induced lymphadenopathy from malignant lymphomas, as they mimicked lymphomas clinically and pathologically. This collection of case reports describes a “characteristic clinical syndrome” of fever, eosinophilia, lymphadenopathy, and rash, all components of what we now know to be DRESS syndrome [1].

In a majority of patients diagnosed with DRESS syndrome, there is a clear connection between pharmacologic therapy and onset of symptoms. The medications with the highest pharmacogenetic susceptibility are anticonvulsants (carbamazepine, phenytoin, lamotrigine, phenobarbital), allopurinol, sulfonamide-containing antibiotics, mexiletine, minocycline, and vancomycin [1]. Risk factors include certain HLA genotypes, polymorphisms in drug metabolizing enzymes, and taking medications known to cause a hypersensitivity reaction [2]. The exact pathogenesis in which these medications activate a host immune response is not known, but is believed to be through activation of T cells or reactivation of the Herpesviridae family (HHV, EBV, CMV) [2].

The timeline between the first dose of medication and onset of symptoms can vary depending on the nature of the medication, but has been reported to be most commonly between 2 and 8 weeks [2]. Many patients will have resolution of symptoms and a full recovery, but the resolution timeline can vary depending on the extent of organ involvement. Patients who are affected by DRESS syndrome can have a relapse of symptoms, typically with involvement of 1 or more internal organs, even after the offending medication has been stopped. While the exact pathogenesis of DRESS is not fully understood, it is thought to be related to a T-cell-mediated response, immune dysregulation, and potential drug antigen presentation [2].

The European Registry of Severe Cutaneous Adverse Reactions to Drugs and Collection of Biological Samples (RegiSCAR) consortium released distinct criteria for the diagnosis of DRESS syndrome in 2007, including definitive criteria for hepatic and renal dysfunction [3]. The most common involved organs are the liver and kidneys, which can be evaluated by measuring serum transaminases, bilirubin, gamma-glutamyl transpeptidase, alkaline phosphatase, serum creatinine, electrolyte levels, and estimated glomerular filtration rate (eGFR) [3].

Below is a case report of a patient with a diagnosis of DRESS syndrome, who presented with an atypical timeline and overlapping clinical features, which led to the initial misidentification with Stevens-Johnson syndrome (SJS) and fixed-drug eruption (FDE).

Case Report

A 25-year-old woman presented to the Emergency Department (ED) with fever, widespread rash, and facial edema for 4 days. Eight days prior to this initial presentation, this patient had presented to the ED with suprapubic cramping and light vaginal bleeding for 1 week. At the start of these symptoms, the patient had noted minimal cramping and intermittent vaginal spotting throughout the day. It wasn’t until she awoke in the middle of the night to find she had passed a large blood clot, along with the onset of nausea, that she decided to present to the ED.

At that time, a transvaginal ultrasound and computed tomography scan were performed and revealed a 3.5-cm simple right-sided ovarian cyst on ultrasound and bladder wall thickening on computed tomography. Laboratory values from this initial ED visit are displayed in Table 1. Her urinalysis showed positive leukocyte esterase and positive leukocytes, with few bacteria. At that time, testing also confirmed the presence of Chlamydia trachomatis. She was empirically treated for acute pyelonephritis secondary to sexually transmitted infection and discharged with trimethoprim/sulfamethoxazole (TMP-SMX) 800 mg/160 mg twice daily for 10 days, and doxycycline 100 mg twice daily for 7 days. She took her first dose of TMP/SMX that night and her first dose of doxycycline 2 days later without difficulties, continuing the treatment course as prescribed.

The patient subjectively reported improvement in vaginal bleeding but persistence of light spotting and mild suprapubic cramping. On day 6 of her TMP/SMX regimen, the patient developed intense fatigue, chills, myalgias, and fever. She continued to take both antibiotics as prescribed, believing her symptoms to be related to a flu-like illness, and as a result, had impaired ability to attend school. The next day, the patient awoke with a flat, non-pruritic, diffuse, erythematous maculopapular rash over her bilateral forearms (Figure 1) and bilateral anterior proximal thighs (Figure 2). The rash continued to worsen, and by the end of that day, it spread to her upper chest, neck, torso, back and buttocks, with sparing of the mucosal membranes. This was also accompanied by periorbital swelling and edema of the hands and face. At that time, the patient decided to start taking diphenhydramine every 4 h and made the choice to discontinue her doxycycline antibiotic, as she believed she was having an allergic reaction to this medication. She continued taking her TMP/SMX through the next day, now 7 days into the prescribed timeline and a total of 3 missed school days.

On the evening of day 8, she presented again to the ED, concerned that her symptoms were not improving with the continuation of antibiotics and use of diphenhydramine. On initial intake, the patient had a temperature of 38.5°C, tachycardia to 127 beats per min, a diffuse rash, and cervical lymphadenopathy. Her treatment team in the ED was equally concerned, and she was quickly brought back into a patient room.

Laboratory values from this second ED visit are displayed in Table 1. A complete blood count (CBC) pathology report displayed leukopenia with normocytic, normochromic anemia. Rapid COVID-19 and influenza A and B panels were negative. Urinalysis, blood cultures, and troponin levels were within normal limits. Peripheral blood smear and bone marrow biopsies were not performed.

The patient was admitted, and several differential diagnoses were considered, including systemic inflammatory response syndrome (SIRS), SJS, sepsis, and FDE; DRESS was not on the list of differentials. She remained febrile, with blood pressures continuing to decline overnight. Despite no resolution of rash overnight, her rash did not further progress to sloughing, bullae, or mucosal lesions. As a result, the decision to use the RegiSCAR scoring tool was made, and the patient had a score of 5, which made her a probable case of DRESS syndrome.

It was then decided to begin continuous methylprednisolone 125 mg i.v., oxycodone 5–10 mg every 4 h (q4h) i.v., and morphine 0.5–1 mg q4h i.v. She was also given acetaminophen 500 mg q4h and diphenhydramine 25 mg q4h. Body temperature did not normalize until 24 h after admission. Her rash remained unchanged until mostly resolving on day 3, with persistence on her chest and upper back.

The patient was discharged home on day 3 with stable vital signs and subjective reports that she was much improved from admission. Despite this, she noted persistent symptoms of fatigue, weakness, and chills but was comfortable with the plan to be discharged home and follow up with her previously established gynecologist. It is worth noting her AST and ALT at discharge were 80 units/L (range 15–37 units/L) and 138 units/L (range 13–56 units/L), respectively. Laboratory values at the time of discharge from this ED visit are displayed in Table 1. She was sent home with a tapering dose of prednisone 10 mg for 7 days. Resolution of rash was reported 2 days following discharge. On follow-up with her primary care physician 9 days after discharge, the patient had aspartate transaminase (AST) and alanine aminotransferase (ALT) values of 13 units/L (range 0–40 units/L) and 66 units/L (range 0–32 units/L), respectively. All other laboratory values from the primary care physician follow-up were within normal limits and are displayed in Table 2.

The normalization of ALT was not followed nor documented. The patient returned to normal activity, with no recurrence of symptoms or rash.

Discussion

DRESS is a complex hypersensitivity reaction that poses significant diagnostic challenges due to its variable presentation and overlap with other severe cutaneous adverse drug reactions, such as SJS and FDE. The diagnostic process is further complicated by the wide latency range between drug exposure and symptom onset, which can vary depending on the offending agent and patient-specific factors [3–6]. Differentiating between these entities is critical, as each carry distinct prognostic implications. Understanding the nuances in the clinical course, distribution and morphology of the rash, mucosal involvement, and laboratory findings can help distinguish among them.

Kapadia et al present a series of 4 confirmed cases of drug-induced SJS caused by non-steroidal anti-inflammatory drugs (NSAIDs) and the anticonvulsant phenytoin [7]. All 4 patients presented with a high fever, diffuse erythematous or bullous rashes, and, most notably, mucosal erosions affecting the oral cavity, eyes, and genitals. These symptoms occurred within a typical latency period of a few days to 2 weeks after drug initiation. Similarly, in a case report by Xu et al, a 51-year-old woman developed a fever (39.2°C) and facial rash that spread rapidly to her upper and lower limbs, palms, trunk, and soles of both feet [8]. This occurred within hours of the start of offending medication. Although this patient’s rash was described as diffusely erythematous macules without blistering or mucosal erosions, the rapid onset and systemic involvement initially raised suspicion for SJS. Similarities in rash characteristics and timing onset can be drawn from our patient and from the case presented by Xu et al, especially due to the lack of mucosal involvement.

While mucosal involvement is not a requirement for SJS, it is often a key feature that distinguishes it from other cutaneous reactions and is found in greater than 90% of cases [9,10]. Mucosal involvement presents as exquisitely painful erosions of the buccal and genital mucosa, and can have ocular manifestations in 50% to 78% of cases [9]. It can be seen how our patient’s rash was initially confused for SJS given the short latency period and initial lack of mucosal involvement. Additionally, the rash seen in SJS can present just like that in our patient, before eventually blistering and sloughing, and it is important to observe for these findings, as they can be delayed in many scenarios. Although our patient’s rash presented like that of the patient in the report of Xu et al, their patient’s rash eventually crusted and peeled by day 10 [8]. This finding was not seen in our patient, whose rash resolved completely without blistering, sloughing, or crusting within 5 days. Our patient’s rash was also non-bullous, non-hemorrhagic, and lacked mucosal involvement, placing her presentation in contrast with typical SJS presentations.

Paulmann et al describe a 42-year-old man who developed generalized blisters with a positive Nikolsky sign just 2 days after initiating moxifloxacin. This patient had >50% body surface area involvement and a history of a similar reaction 1 year prior involving mucosal ulcers, supporting a diagnosis of generalized bullous FDE [11]. Although biopsy findings could not definitively distinguish FDE from epidermal necrolysis, the evolution of the rash into clearly demarcated brownish patches confirmed the diagnosis. While our patient similarly had a widespread rash involving >50% body surface area, there was no blistering, mucosal involvement, or prior history of re-exposure, making FDE less likely. Additionally, liver injury in our patient was a new finding, likely attributable to the hypersensitivity reaction, unlike the case of Paulmann et al, in which liver involvement preceded the skin eruption [11].

In contrast to the above SJS and FDE cases, the report by Fatima et al describes 4 patients with a diagnosis of DRESS syndrome, all of whom demonstrated organ involvement, a longer latency period, and a rash described as erythematous and maculopapular [12]. Each patient exhibited facial edema, lymphadenopathy ≥1 cm at >2 sites, and elevated AST/ALT levels, often 2 to 3 times the upper limit of normal. Additionally, eosinophilia (>1400 cells/mm3) and atypical lymphocytosis were seen in many of these patients [12]. These findings align more closely with the presentation of our 25-year-old patient, who similarly exhibited facial swelling, diffuse maculopapular rash, transaminitis, and eosinophilia, although with a shorter than expected latency period (1 week into TMP-SMX course, as opposed to the typical 2- to 8-week latency period). Table 3 summarizes the differences between SJS, FDE, and DRESS in skin involvement, onset, symptoms, and mortality [3–6].

In our patient, sepsis was originally considered, as the patient’s presenting vitals showed she had tachycardia and fever, in addition to her initial laboratory results from the first ED visit showing leukocytosis (Table 1). Furthermore, the source of infection was believed to be from acute pyelonephritis secondary to sexually transmitted infection. Blood culture results were negative, and repeat CBC on this admission showed leukopenia, not leukocytosis, ruling out the possibility of sepsis and bacteremia. SJS was originally considered based on eosinophilia and thrombocytopenia that was present on the admission CBC, in addition to recent use of medications known to be affiliated with SJS and the presence of flu-like symptoms.

It can be speculated that failure to accurately delineate symptoms of SJS/FDE from those of DRESS led to the delay in consideration of DRESS syndrome in our patient. This was likely based on inadequate knowledge and the confusing clinical picture, with overlapping ovarian cyst complication and diagnosis of acute pyelonephritis. DRESS was not considered until persistence of eosinophilia, thrombocytopenia, and neutropenia were believed to be part of a different disease process, and the differential was expanded. At that time, the decision to use the RegiSCAR scoring tool was made.

The RegiSCAR scoring system, developed by the European Registry of Severe Cutaneous Adverse Reactions (RegiSCAR) study group, is a tool used to assess the likelihood of DRESS [3]. While the diagnosis of DRESS is a clinical one, use of RegiSCAR can serve as a guide in early detection and can be key in reducing mortality in these patients. However, this tool has potential pitfalls, namely that it was originally intended for research studies and thus was not developed or validated for the purpose of use in clinical practice [13]. Furthermore, drug exposure is not included as a required criterion for diagnosis, and the definitions for organ involvement are lacking or incomplete [13]. Despite this, one recent study demonstrated that the RegiSCAR tool was accurate in diagnosing severe reactions as either probable or definite DRESS syndrome in 98.3% of confirmed cases [6].

Our patient had lymph nodes that were >1 cm at ≥2 sites, atypical lymphocytes, and a skin rash extent of >50%, each earning 1 point on the calculated score. She also had edema and scaling of her rash, 2 of the 4 rash defining criteria needed for an additional point on the RegiSCAR score calculator (edema, infiltration, purpura, and scaling). Her temperature of 38.5°C earned 1 point, and <10% eosinophilia earned no points. The calculated score of 7 was reduced to 5 as the symptom resolution was <15 days, and the patient’s rise in eosinophils did not meet criteria (Table 1). A RegiSCAR score of <2 indicates no case, 2–3 indicates a possible case, 4–5 indicates a probable case, and >5 indicates a definite case [3]. With a calculated RegiSCAR score of 5, our patient likely had a definitive case of DRESS syndrome. A summary of RegiSCAR criteria and the results of our patient can be seen in Table 4.

While the diagnosis of DRESS is clinical, various tests can be performed to identify the culprit of the cutaneous reaction. These include patch testing, intradermal tests, and the lymphocyte transformation test, which is the test of choice and should be performed within 4 to 8 weeks of reaction and preferably in the first 6 months [14,15]. When used alone, the lymphocyte transformation test has a sensitivity and specificity of 73% and 85%, respectively [14]. Further testing was offered to the patient but unfortunately was not completed, based on her personal preferences and discharge from emergency services. As a result, this is a major limitation and leaves speculation as to whether the culprit of her DRESS syndrome was due to TMP-SMX or doxycycline. The decision to continue the TMP-SMX regimen and discontinue doxycycline was one made solely by the patient prior to her second admission, as she believed the doxycycline was the cause of her rash and other prodromal symptoms. TMP-SMX was not continued upon her second presentation and admission to the ED.

Descamps et al attempted to create a treatment algorithm for DRESS syndrome based on the absence or presence of signs of severity, which include the presence of any of the following: moderate to severe organ involvement, pulmonary or cardiac involvement, and hemophagocytosis [16]. In the absence of severity signs, treatment can be completed with topical corticosteroids, prompt cessation of the suspected drug(s), and addition of supportive care measures like antihistamines with the avoidance of NSAIDs and antibiotics. The presence of any signs of severity should result in systemic steroids at 0.8 to 1 mg/kg/per day dosing for 2 to 3 weeks, followed by a tapered course over 2 to 3 months, as it is not uncommon for relapse of rash to be seen 2 to 4 weeks after onset or with the weaning of corticosteroids [14,16–18]. While there are currently no randomized control trials establishing the efficacy of systemic corticosteroids in the treatment of DRESS syndrome, it has been widely used as a first-line agent [17]. Despite this, our patient had a relatively quick resolution of the rash without relapse, using only 2 days of methylprednisolone 125 mg i.v. and a 1-week prednisone taper.

This treatment course deviated from established clinical guidance, which suggests longer corticosteroid regiments in the presence of organ involvement or other signs of severity. In this case, the abbreviated course was not the result of an evidence-based protocol, but rather clinical judgement made in real time during hospitalization and influenced by the patient’s rapid clinical improvement and prompt withdrawal of the offending agent. Additionally, limitations in follow-up, patient preferences, and quick admission to discharge time contributed to the choice of a shorter taper. While this deviation from guidelines could be viewed as a limitation, it also presents a noteworthy observation: the patient did not experience any known rash relapse or systemic symptom recurrence, suggesting that certain presentations of DRESS syndrome can resolve with shorter or alternative corticosteroid exposure than traditionally recommended.

Natkunarajah et al documented 10 patients successfully treated with pulse i.v. methylprednisolone for 3 consecutive days, followed by a prednisolone taper over 30 days, with rapid resolution in symptoms [18]. Cyclosporine, a calcineurin inhibitor that acts by inhibiting T-cell proliferation, is also gaining traction as an alternative to the protracted corticosteroid course [17]. Nguyen et al report 5 adults with DRESS syndrome who were successfully treated with cyclosporine. These 5 adults were compared with 21 patients with DRESS syndrome who received corticosteroids. Overall, the group treated with cyclosporine saw a reduction in hospital stay length and treatment duration [4]. However, our patient’s outcome should be interpreted cautiously, and more research is needed to understand the nuances of corticosteroid tapering in DRESS syndrome management.

The pathogenesis of DRESS syndrome remains complex, but several mechanisms have been proposed that may explain the rapid onset and clinical presentation in our case [2,9,19–22]. One hypothesis centers on genetic deficiencies in drug-metabolizing enzymes, which can lead to the accumulation of toxic drug metabolites. These metabolites can covalently bind to cell proteins, triggering immune-mediated tissue damage. In our patient, the use of TMP-SMX may have contributed to such metabolite buildup, particularly in the setting of concurrent doxycycline use, which could have compounded the immune response or altered drug metabolism. Although rare, several DRESS syndrome cases have been reportedly linked to the use of doxycycline when prescribed long-term, such as for malarial prophylaxis or acne vulgaris [3,6]. This case presentation was complicated by the compounded use of TMP/SMX and doxycycline, in addition to the continuation of 1 potential offending agent for at least 2 days prior to the onset of flu-like illness and then eventual development and worsening of her diffuse rash.

Skin patch testing was not performed in this patient, and thus, the offending agent is not definitively known. As a result, it is worth exploring the role doxycycline can play in the trigger of hypersensitivity reactions in the future, especially when compounded with other known high-risk antibiotics, like sulfonamides. It can be theorized that the compounded use of doxycycline played a role in this shortened latency period, but without skin patch testing or further studies, there is little evidence to support this claim.

Another mechanism involves T-cell-mediated immune activation, which plays a role in multiple severe cutaneous adverse reactions, including DRESS, SJS, and FDE [2,9,19–22]. In DRESS, drug-specific CD4+ and CD8+ T cells become activated and release cytokines, such as interluekin-5, contributing to eosinophilia and multi-organ inflammation. Our patient’s elevated eosinophil count and liver injury support this model. Comparatively, in SJS/TEN, CD8+ T cells are also the primary mediators of epidermal necrolysis, but the clinical course is marked by mucosal involvement and rapid skin detachment, neither of which was present in our patient. Additionally, in FDE, CD8+ memory T cells residing in the basal epidermis become reactivated upon drug re-exposure and take on a cytotoxic natural killer-like phenotype, resulting in localized epidermal necrosis [11]. However, this condition typically recurs at the same site and presents with well-demarcated lesions and post-inflammatory hyperpigmentation. Our patient had no prior rash history, and her eruption was diffuse and non-recurrent, arguing against FDE.

A third hypothesized contributor in DRESS is the reactivation of latent herpesviruses – particularly HHV-6, HHV-7, and EBV – which has been documented to occur in parallel with symptom onset and can amplify T-cell responses [19]. It is worth considering that her active Chlamydia trachomatis infection may have contributed to systemic immune activation. Although not a viral infection, Chlamydia is known to induce pro-inflammatory cytokines and can disrupt mucosal immune homeostasis, potentially priming the immune system and enhancing the likelihood of a hypersensitivity reaction upon exposure to high-risk medications.

Conclusions

This case illustrates a unique and diagnostically challenging presentation of DRESS syndrome, particularly when distinguishing it from other severe drug reactions, like SJS and FDE. With an accelerated onset just 1 week into a TMP-SMX and doxycycline regimen, the patient’s diffuse rash, absence of mucosal involvement, and rapid resolution contrasted with classic features of SJS and FDE, prompting diagnostic uncertainty. Ultimately, the diagnosis of DRESS was supported by systemic findings, including eosinophilia, transaminitis, facial edema, and lymphadenopathy, and confirmed by a RegiSCAR score of 5, suggesting a probable case. Comparative analysis with documented cases of SJS, FDE, and DRESS helped highlight critical clinical distinctions in onset, rash morphology, and associated organ involvement. Although the exact offending agent could not be confirmed, due to lack of skin patch testing and lymphocyte transformation tests, this case raises important questions about the pathophysiology of rapid-onset DRESS and the potential compounding effects of concurrent antibiotic use. Theories involving drug-metabolizing enzyme deficiencies, T-cell-mediated immune activation, and viral or microbial co-infections (such as the patient’s concurrent Chlamydia trachomatis infection) offer possible explanations for this atypical timeline. Furthermore, the patient’s recovery with a shorter than standard corticosteroid regimen invites further investigation into tailored treatment durations based on disease severity and clinical course.