Abstract
Background Cerebral toxoplasmosis, a life-threatening opportunistic infection that can occur in patients with advanced human immunodeficiency virus (HIV) infection, is commonly treated with sulfonamide-based regimens such as trimethoprim-sulfamethoxazole (TMP-SMX) or a combination regimen of pyrimethamine, sulfadiazine, and leucovorin (P-S-L). Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare but potentially fatal hypersensitivity reaction that complicates treatment, particularly among immunocompromised individuals.
Case Report A 41-year-old male with untreated HIV presented with right-sided weakness and visual disturbances. Neuroimaging and serology confirmed cerebral toxoplasmosis. The patient was initially treated with TMP-SMX but developed acute kidney injury, necessitating a change to P-S-L. Following an 8-day course of P-S-L, the patient developed fevers, a morbilliform rash, eosinophilia, transaminitis, and worsening renal function, and his RegiSCAR (Registry of Severe Cutaneous Adverse Reactions) score progressed from 2 to 4, indicating probable DRESS syndrome. The sulfadiazine component of P-S-L and the patient's earlier exposure to TMP-SMX were identified as potential triggers of DRESS syndrome resulting from sulfonamide cross-reactivity. Sulfadiazine was discontinued, and the patient's condition steadily improved after initiation of high dose systemic corticosteroids with a gradual taper.
Conclusion Diagnosing DRESS syndrome in immunocompromised patients is challenging because the symptoms overlap with infection and may evolve slowly. Cross-reactivity among sulfonamide antibiotics complicates therapy for opportunistic infections such as toxoplasmosis. This case highlights the importance of maintaining a high index of suspicion for DRESS syndrome in patients with HIV who are treated with sulfonamides. Early recognition, drug withdrawal, and corticosteroid therapy are essential to prevent severe outcomes.
INTRODUCTION
Cerebral toxoplasmosis is an opportunistic infection that occurs in immunocompromised individuals, particularly patients with advanced human immunodeficiency virus (HIV) infection, and typically results from reactivation of latent Toxoplasma gondii infection; the risk substantially increases when the patient's CD4 count falls below 100 cells/μL.1-3 Clinical manifestations include focal neurologic deficits, cognitive disturbances, seizures, and signs of increased intracranial pressure. Diagnosis relies on a combination of clinical presentation, serologic testing, and neuroimaging that typically shows ring-enhancing lesions, with molecular and immunologic assays providing additional support in complex or atypical cases.1-3 If left untreated, the infection can progress rapidly and is often fatal. Standard treatment involves the prompt initiation of anti-Toxoplasma therapy, either a combination of pyrimethamine, sulfadiazine, and leucovorin (P-S-L) or monotherapy with trimethoprim-sulfamethoxazole (TMP-SMX) or atovaquone.1,4
The management of cerebral toxoplasmosis in HIV-infected individuals can be complicated by severe cutaneous adverse drug reactions such as drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome.5 DRESS syndrome is a T cell–mediated hypersensitivity reaction characterized by a constellation of symptoms including morbilliform rash, fever, hematologic abnormalities, and internal organ involvement (most commonly the liver) occurring several weeks after exposure to certain medications.6 The estimated prevalence is 2 cases per 100,000 population.7 Many medication classes have been associated with DRESS syndrome, but exposure to antibiotics, especially TMP-SMX, has been linked in approximately 25% of cases.6,8 DRESS syndrome is a clinical diagnosis that is made using the widely accepted European RegiSCAR (Registry of Severe Cutaneous Adverse Reactions) criteria: fever ≥38.5 °C (101.3 °F), lymphadenopathy in more than 2 sites, eosinophilia, atypical lymphocytosis, rash (covering >50% of the body surface, characteristic morphologic features, or histologic features consistent with drug hypersensitivity on biopsy), internal organ involvement, and time to resolution >15 days.6,8,9 RegiSCAR scores range from –4 to 9, with scores <2, scores of 2-3, scores of 4-5, and scores >5 indicating no disease, possible disease, probable disease, and definite disease, respectively. Management of DRESS syndrome involves discontinuation of the offending agent and initiation of a high dose systemic corticosteroid such as prednisone with a gradual steroid taper over a course of 6 to 12 weeks.6,9
We present a case of DRESS syndrome in an HIV-infected patient with cerebral toxoplasmosis who was initially treated with TMP-SMX followed by P-S-L.
CASE REPORT
A 41-year-old male with untreated HIV presented to the emergency department as a transfer from an outside hospital for neurosurgical evaluation of intracranial masses, progressive right-sided upper and lower extremity weakness and numbness, intermittent left-sided diplopia, and blurry vision. Magnetic resonance imaging (MRI) of the brain demonstrated a 1.6-cm ring-enhancing lesion in the posterosuperior parasagittal left frontal lobe with extensive vasogenic edema and a left orbital mass. Computed tomography of the head without contrast showed a 1.6-cm hyperdense lesion with associated vasogenic edema in the left frontal lobe and a left orbital mass. The differential diagnosis at this time included cerebral toxoplasmosis, malignancy, tuberculoma, gummatous neurosyphilis, and fungal abscess. The patient had no known drug allergies, had no noteworthy medical history other than untreated HIV, and was not taking any home medications at the time of hospital admission. A medication reconciliation was performed at the time of hospital admission.
Initial investigations revealed leukopenia (white blood cell count of 3.79 K/μL [reference range, 4-11 K/μL]), an HIV supplemental assay positive for HIV-1, an absolute CD4 count of 13 cells/mm3 (reference range, ≥500 cells/mm3), and a reactive rapid plasma reagin with a titer of 1:32. Further testing revealed the presence of Toxoplasma gondii with immunoglobulin (Ig) G seropositivity, Treponema pallidum IgG and IgM seropositivity, adenovirus, and human herpesvirus 8. Tests for other infectious causes of the patient's presentation included the following, all of which were negative: Mycobacterium tuberculosis, Epstein-Barr virus, cytomegalovirus, John Cunningham virus, cryptococcal antigen, hepatitis B virus, and Histoplasma capsulatum/Blastomyces dermatitidis.
During his hospitalization, the patient completed a 3-week course of intramuscular penicillin G benzathine (2.4 million U weekly) for the treatment of syphilis evidenced by the reactive rapid plasma reagin titer and the presence of T pallidum antibodies.
The patient reported ongoing right-sided lower extremity weakness for which Neurosurgery recommended lumbar puncture to test for meningoencephalitis. Lumbar puncture was completed on day 2 of hospitalization, and results were a negative meningoencephalitis panel, negative cerebrospinal fluid (CSF) culture and Gram stain, and negative CSF cytology. Repeat MRI of the brain revealed a 9-mm intra-axial lesion in the left precentral gyrus at the left frontal vertex suspicious for toxoplasmosis because of the target sign appearance of the lesion. After consultation with Infectious Disease, the patient was started on empiric therapy with oral TMP-SMX 5 mg/kg every 12 hours because of the high clinical suspicion for toxoplasmosis.
On day 11 of hospitalization, after being treated with TMP-SMX for 9 days, the patient reported right leg spasms and developed asymptomatic acute kidney injury as evidenced by an increase in serum creatinine level from the patient's baseline of 0.9 mg/dL to 1.5 mg/dL (reference range, 0.5-1.4 mg/dL) (Table 1). Urinalysis performed at this time demonstrated no evidence of sterile pyuria and was negative for nitrites, leukocytes, and leukocyte esterase. After consultation with Infectious Disease, TMP-SMX was discontinued because of the patient's acute kidney injury, and the patient was transitioned to a P-S-L regimen of oral pyrimethamine 200 mg daily, oral sulfadiazine 1,500 mg every 6 hours, and oral leucovorin 25 mg daily.
Patient's Laboratory Values
On day 19 of hospitalization, after being treated for toxoplasmosis with oral P-S-L for 8 days, the patient developed unexplained fevers (Figure 1), prompting a sepsis workup that included blood cultures, lactic acid levels, procalcitonin levels, creatinine kinase levels, and a bilateral lower extremity venous ultrasound. All tests were negative. Laboratory evaluation revealed elevated liver enzymes with an aspartate aminotransferase (AST) of 43 U/L (reference range, 11-45 U/L) and an alanine transaminase (ALT) of 76 U/L (reference range, 10-44 U/L). Given the concern for infection and possible sepsis of unknown origin in the setting of unexplained fevers in an immunocompromised individual, the patient was started on intravenous piperacillin-tazobactam 4.5 g every 6 hours.
The patient's temperature graph for the duration of his hospital stay shows that he experienced a temperature spike on days 19 to 22, coinciding with the development of drug reaction with eosinophilia and systemic symptoms syndrome. A fever spike is also shown on days 11 and 12, but nursing staff confirmed that patient was afebrile on those days, and the values were inaccurate entries in the electronic medical record.
On day 21 of hospitalization, the patient developed a morbilliform rash involving the posterior torso (Figure 2). His elevated ferritin level of 2,298 ng/mL (reference range, 20-300 ng/mL) prompted an abdominal ultrasound that was normal. MRI of the brain showed a reduction in the size of the left frontal intra-axial lesion and reduced vasogenic edema. Dermatology was consulted, and the differential diagnosis included viral exanthem, exanthematous drug eruption, and DRESS syndrome. The patient's initial RegiSCAR score was 2, suggesting a possible case of DRESS syndrome. Sulfadiazine was discontinued per Infectious Disease recommendation because of the possibility of DRESS syndrome. Pyrimethamine and leucovorin were continued, and the patient was started on oral clindamycin 600 mg every 6 hours for continued toxoplasmosis treatment.
On day 21 of hospitalization, the patient developed a morbilliform eruption on the posterior torso characteristic of drug reaction with eosinophilia and systemic symptoms syndrome. The erythematous maculopapular rash was a critical early indicator of the patient's severe drug hypersensitivity reaction.
On day 22 of hospitalization, the rash had progressed to involve the patient's face, and he developed cervical and submandibular lymphadenopathy (Figure 3). These symptoms were accompanied by rising peripheral eosinophilia (13% eosinophils), transaminitis (AST and ALT of 163 U/L and 171 U/L, respectively), and worsening renal function (creatinine of 2.3 mg/dL). Dermatology reassessed the patient and calculated the RegiSCAR score as 4, consistent with a probable case of DRESS syndrome and likely secondary to the TMP-SMX treatment and the sulfadiazine component of the P-S-L regimen. Punch biopsy of the rash revealed mild spongiosis with focal basal vacuolar changes and a superficial to middermal lymphohistiocytic infiltrate with scattered eosinophils, consistent with a drug reaction. Given the patient's evolving clinical picture and the histopathology report, a diagnosis of sulfonamide-induced DRESS syndrome was confirmed. Intravenous piperacillin-tazobactam was discontinued, and the patient was started on systemic high dose oral prednisone 1 mg/kg/day with a planned steroid taper over 6 weeks.
On day 22 of hospitalization, the patient developed marked periorbital edema and facial erythema. Facial swelling is a characteristic early sign of drug reaction with eosinophilia and systemic symptoms syndrome and often precedes systemic involvement in this severe drug hypersensitivity reaction.
Fevers resolved on day 23 of hospitalization, but the patient reported dizziness, nausea, and vomiting. Oral clindamycin was discontinued, and the patient was started on oral atovaquone 1,500 mg twice daily and oral pyrimethamine 75 mg daily to treat toxoplasmosis. The patient was monitored closely with serial complete blood counts, comprehensive metabolic panels, and inflammatory markers.
By day 32 of hospitalization, the patient showed substantial clinical and biochemical improvement as evidenced by improving transaminitis (AST and ALT of 21 U/L and 87 U/L, respectively), improving renal function (creatinine of 1.6 mg/dL), and resolved peripheral eosinophilia.
The patient was deemed ready for hospital discharge because he was asymptomatic, the rash and lymphadenopathy were completely resolved, and renal function and liver function were trending toward normal. A medication reconciliation was performed at the time of discharge, and the patient was discharged on oral atovaquone 1,500 mg twice daily, oral pyrimethamine 75 mg daily, oral leucovorin 25 mg daily, oral prednisone taper, and the oral triple antiretroviral therapeutic agent BIKTARVY for management of HIV. The patient was scheduled for Infectious Disease hospital follow-up and for primary care follow-up in his home state of Mississippi. No follow-up information following hospital discharge is available. A summary of the patient's case is provided in Table 2.
Patient's Hospital Course
DISCUSSION
DRESS syndrome in immunocompromised patients is a challenging diagnosis that requires a high degree of clinical suspicion. The primary challenge is that DRESS syndrome is a clinical diagnosis that relies on a constellation of clinical features that may appear in a delayed fashion and evolve over time, especially in immunocompromised individuals.10 Additionally, although skin biopsy is a component of the RegiSCAR criteria, DRESS syndrome has no unique histopathologic finding, although spongiosis, interface dermatitis, and perivascular infiltration are common.11 Furthermore, the symptoms of DRESS syndrome typically appear within a 2- to 6-week window or a 3- to 8-week window following drug exposure, further complicating the diagnostic process.6,11
Antibiotic selection in treating opportunistic infections such as toxoplasmosis may play a role in the pathogenesis of DRESS syndrome in immunocompromised patients. Many medication classes have been implicated in cases of DRESS syndrome, but the sulfonamide antibiotics, especially TMP-SMX, have been linked to DRESS syndrome in the general population.6,8 Although sulfadiazine is not a widely recognized cause of DRESS syndrome, Monge-Ortega et al reported the case of an immunocompromised patient who developed DRESS syndrome after treatment with TMP-SMX and sulfadiazine.12 Additionally, studies have shown cross-reactivity between sulfamethoxazole and sulfadiazine.13,14 Sulfonamide antibiotics such as TMP-SMX and sulfadiazine are among the first-line or alternative treatments for opportunistic infections such as toxoplasmosis and pneumonia secondary to Pneumocystis jirovecii. In immunocompromised patients, however, special attention must be paid to antibiotic selection because of the increased risk of life-threatening adverse drug reactions such as DRESS syndrome secondary to cross-reactivity between antibiotics. The diagnosis of DRESS syndrome becomes more challenging when immunocompromised patients have comorbidities such as seizure disorders or gout, as DRESS syndrome has also been linked to the use of anticonvulsants and xanthine oxidase inhibitors.6
Consequently, when treating opportunistic infections in immunocompromised patients, choosing a treatment regimen that reduces the risk of adverse drug reactions should be prioritized by performing a thorough medication reconciliation. Medication reconciliations are typically performed at transition points during a patient's hospitalization, but immunocompromised patients presenting with opportunistic infections are a vulnerable patient population who tend to receive numerous medications and medication changes during their hospitalizations. Performing medication reconciliations at the time of administering new antibiotics, anti-Toxoplasma regimens, or additional medications can identify drug-drug interactions, help prevent the development of adverse drug reactions such as DRESS syndrome, and potentially avoid the necessity of treatment with high dose corticosteroids that are associated with a risk of immunosuppression and reactivation of opportunistic infections in immunocompromised patients. Although high dose corticosteroids were administered to our patient, avoiding the initiation of corticosteroids in immunocompromised patients is preferable because of the risk of immunosuppression.
In our patient, making the diagnosis of DRESS syndrome was a challenge as our patient was asymptomatic during TMP-SMX treatment for cerebral toxoplasmosis. The only abnormality was acute kidney injury; the patient did not have an allergic reaction such as anaphylaxis or a cutaneous drug eruption. Acute kidney injury, a well-documented adverse effect of TMP-SMX, prompted the transition to P-S-L. Urinalysis showed no evidence of sterile pyuria, lowering our clinical suspicion for acute interstitial nephritis. Furthermore, the patient had no documented history of sulfonamide allergy, which lowered clinical suspicion for cross-reactive hypersensitivity to sulfadiazine at the time of the transition. P-S-L is a guideline-directed, first-line regimen for cerebral toxoplasmosis, and the absence of an allergic reaction to TMP-SMX did not suggest an elevated risk of sulfonamide cross-reactivity. In retrospect, however, the acute kidney injury observed during TMP-SMX treatment may have represented an early manifestation of DRESS syndrome rather than isolated drug nephrotoxicity, as acute kidney injury has been reported as one of the first observed findings in DRESS syndrome.15
Although gummatous neurosyphilis was included in the initial differential diagnosis given the patient's reactive rapid plasma reagin and confirmed T pallidum seropositivity, this diagnosis was excluded because of the target sign morphology of the left frontal intra-axial lesion, a finding that is highly associated with toxoplasmosis. Furthermore, improvement in the lesion size and vasogenic edema was observed on repeat MRI following initiation of anti-Toxoplasma therapy. The diagnosis of DRESS syndrome in this case was only considered when the patient developed symptoms of unexplained fevers followed by a morbilliform rash and lymphadenopathy approximately 3 weeks after initial treatment with TMP-SMX, a timeline that is consistent with the evolving nature of symptoms in this disease process.
CONCLUSION
DRESS syndrome is a rare, life-threatening condition that can develop after exposure to medications, especially sulfonamide antibiotics. This case uniquely demonstrates that DRESS syndrome can develop following sequential sulfonamide exposure even in the absence of classic allergic features in response to the initial agent, underscoring the diagnostic challenge in immunocompromised patients. Clinicians should maintain a high index of suspicion and a low diagnostic threshold when treating opportunistic infections in immunocompromised patients because of the increased risk of iatrogenic DRESS syndrome associated with widely accepted treatment regimens. Medical practices such as patient-centered antibiotic selection may help mitigate the risk.
This article meets the Accreditation Council for Graduate Medical Education and the American Board of Medical Specialties Maintenance of Certification competencies for Patient Care and Medical Knowledge.
ACKNOWLEDGMENTS
The authors have no financial or proprietary interest in the subject matter of this article.
- ©2026 by the author(s); Creative Commons Attribution License (CC BY)
©2026 by the author(s); licensee Ochsner Journal, Ochsner Clinic Foundation, New Orleans, LA. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (creativecommons.org/licenses/by/4.0/legalcode) that permits unrestricted use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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