European Journal of Cardiovascular Medicine

Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is a severe, idiosyncratic drug-induced hypersensitivity reaction characterized by extensive skin rash, fever, hematologic abnormalities (eosinophilia or atypical lymphocytosis), and internal organ involvement, including liver, kidney, and lungs ¹. DRESS syndrome is indeed a severe condition with a mortality rate reaching up to 10% in cases, highlighting its potential life-threatening nature ². Rifampicin, a first-line anti-tubercular agent, is indeed implicated in the development of DRESS syndrome, alongside other drugs like aromatic anticonvulsants and certain antibiotics ³. Rifampicin is a rifamycin antibiotic that works by inhibiting bacterial DNA-dependent RNA polymerase ⁴. It is considered the cornerstone of tuberculosis treatment due to its broad-spectrum activity against Mycobacterium tuberculosis. However, like many antimicrobial agents, rifampicin can cause adverse drug reactions (ADRs), ranging from mild dermatologic reactions to more severe manifestations like DRESS syndrome ⁵.

The occurrence of DRESS syndrome due to rifampicin is considered rare, but when it does occur, it poses a significant challenge in clinical practice due to the need for discontinuation of an essential anti-tubercular drug ⁶. The epidemiologic data on disease incidence and the aetiologic factors involved are lacking, making it difficult to predict true incidence of DRESS. However, it has been estimated that the overall population risk is between 1 in 1000 and 1 in 10,000 drug exposures ²⁴.However, in clinical practice, a diagnosis of DRESS syndrome is frequently overlooked because of unfamiliarity with the syndrome and its criteria. This happens especially when skin findings are minimal, making the diagnosis difficult. The risk for developing hypersensitivity within 60 days of the first or second prescription in new users of phenytoin and carbamazepine was estimated to be 2.3–4.5/10,000 and 1–4.1/10,000, respectively ²⁵. Studies have shown 80% cross-reactivity between the anticonvulsants ²⁶.

The pathophysiology of DRESS syndrome is complex and remains incompletely understood. The current hypothesis suggests a multifactorial process involving genetic predisposition, immune dysregulation, and abnormal drug metabolism ⁷. In individuals with a genetic susceptibility, such as those carrying specific HLA alleles (e.g., HLA-B57:01, HLA-A31:01), exposure to the offending drug leads to the formation of reactive drug metabolites that cannot be adequately detoxified ⁸. The activation of T-cells in response to hapten-protein complexes is a critical mechanism in the development of drug-induced hypersensitivity reactions, such as DRESS syndrome. This immune response is characterized by the release of pro-inflammatory cytokines, including IL-5, which facilitates eosinophil recruitment. Additionally, the reactivation of herpesviruses like HHV-6 and EBV is frequently observed in DRESS patients, suggesting a complex interplay between drug metabolites and viral factors ^9,10. 

Rifampicin-induced DRESS syndrome is a severe hypersensitivity reaction that typically manifests two to eight weeks after treatment initiation. Initial symptoms are often nonspecific, evolving into a widespread cutaneous eruption and significant internal organ involvement, particularly affecting the liver. Patients commonly present with fever, malaise, and flu-like symptoms ^11,12. A maculopapular rash or exfoliative dermatitis is prevalent, with facial edema noted in many cases ¹³. Hepatic dysfunction is frequent, with elevated transaminase levels indicating liver injury, alongside potential renal, pulmonary, and cardiac complications ^14,15. 

A significant increase in eosinophil count is often observed, with some cases showing profound levels ^11,13. Laboratory tests may reveal atypical lymphocytes, contributing to the diagnosis ¹⁵. Despite the serious nature of DRESS syndrome, early recognition and prompt withdrawal of rifampicin can lead to recovery, underscoring the importance of vigilance in monitoring patients on antitubercular therapy. However, the potential for recurrence upon re-exposure remains a critical concern ¹⁴. The diagnosis of DRESS syndrome is indeed complex due to its overlapping symptoms with other drug-induced hypersensitivity reactions and infections. A high index of suspicion is essential, particularly in patients on known offending medications. The RegiSCAR scoring system is a valuable tool in this diagnostic process, assessing clinical features such as fever, rash, lymphadenopathy, and organ involvement to categorize the likelihood of DRESS. The RegiSCAR system evaluates symptoms like fever, rash, and lymphadenopathy, assigning scores that help determine the probability of DRESS ¹⁶. Skin biopsies often reveal interface dermatitis with lymphocytic and eosinophilic infiltration, aiding in diagnosis. PCR testing for herpesvirus reactivation can further support the diagnosis ^17,18.

The management of rifampicin-induced DRESS syndrome is complex due to the critical role of rifampicin in tuberculosis treatment. Immediate discontinuation of the drug is essential, followed by alternative therapies and supportive care. Here are the key aspects of managing this condition: The first step in managing DRESS syndrome is the prompt cessation of rifampicin, which is often the primary offending agent ^19,20. In cases where rifampicin is essential, sequential reintroduction of non-offending anti-tubercular drugs may be considered under medical supervision ²¹. Systemic corticosteroids, such as prednisone, are crucial for severe cases, particularly those with multi-organ involvement, and treatment duration typically spans several weeks ^21,22. For mild to moderate cases, supportive care including antihistamines and topical steroids may suffice ²³. Regular monitoring of liver and renal function, along with hematological parameters, is vital during recovery to prevent complications ^20,22. While the immediate focus is on drug withdrawal and corticosteroid therapy, the potential for recurrence of DRESS syndrome upon re-exposure to rifampicin poses a significant challenge, necessitating careful management and monitoring strategies ²³.

A 47-year-old female patient presented with the recent onset of widespread skin lesions, accompanied by fever, body aches, and generalized itching. She also reported a loss of appetite and persistent fever over the past seven days.

Physical Examination:

On physical examination, the patient presented with a low-grade fever (99.4°F) and a diffuse erythematous maculopapular rash affecting the face, trunk, and limbs. Notably, there was significant facial edema, though no mucosal involvement was observed. The patient’s vital signs were as follows: heart rate of 76 bpm, blood pressure of 102/70 mmHg, respiratory rate of 16 breaths per minute, and oxygen saturation of 97% on room air.

Past History:

The patient had no prior history of allergies or documented drug reactions, and there was no family history of hypersensitivity. The patient has been diagnosed with extrapulmonary tuberculosis (involving lymph nodes) and has been on antitubercular therapy (ATT) for the past three months due to a minor swelling in the neck. Based on the pulmonologist's recommendation, the antitubercular therapy was discontinued, and antibiotic treatment was initiated.

Laboratory Findings:

[gm/dL: grams per decilitre, fL: femtoliters, pg/cell: picograms per cell, mEq/L: milliequivalents per liter, IU/L: international units per  liter, mg/dL: milligrams per decilitre, cmm: cubic millimetres]

Diagnostic Tests:

Absolute Eosinophil Count: 4640/μL (elevated)

HCV (Hepatitis C Virus): Negative

HBSAg (Hepatitis B Surface Antigen): Negative

FNAC (Fine Needle Aspiration Cytology): Revealed a granulomatous lesion with cystic changes

RegiSCAR Criteria: patient presented with generalized itching, skin lesions covering the entire body, occasional fever (38°C), cold, body aches, and loss of appetite for seven days. According to the RegiSCAR criteria, she exhibited acute skin involvement, fever, and lymphadenopathy at two sites. There was evidence of internal organ involvement with mild liver enzyme abnormalities. Blood tests revealed a significantly elevated eosinophil count (4640/μL), while other blood parameters such as lymphocytes were either above or below normal limits, and platelet count was reduced. With these findings, the total score strongly suggests a diagnosis of DRESS syndrome.

Final Diagnosis: 

Rifampicin-induced Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) presenting as dermatitis, ongoing for one week.

Treatment Given:

Discharge Medication:

Rifampicin-induced DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) syndrome is a rare, but severe hypersensitivity reaction that poses a significant clinical challenge, particularly in the treatment of tuberculosis (TB). Rifampicin, a cornerstone of TB management, can trigger this life-threatening condition, making it difficult to balance the effective treatment of TB with the need to manage such serious adverse drug reactions.

In this case, the patient, a 47-year-old female, developed widespread skin lesions, fever, and systemic involvement after being on antitubercular therapy (ATT) for three months. The clinical presentation, which included elevated eosinophil count, liver enzyme abnormalities, and significant skin and systemic involvement, aligned with the diagnostic criteria of DRESS syndrome, confirmed by the RegiSCAR scoring system. DRESS syndrome's pathophysiology involves an intricate interplay of genetic factors, immune dysregulation, and abnormal drug metabolism. In genetically predisposed individuals, reactive metabolites from drugs like rifampicin can trigger an immune response, characterized by eosinophilia and multi-organ involvement, as seen in this patient. The activation of T-cells and cytokines, particularly IL-5, drives eosinophil recruitment and inflammation, which in turn leads to damage in organs such as the liver.

Management of DRESS syndrome necessitates the immediate cessation of the offending drug—in this case, rifampicin—to halt the progression of the hypersensitivity reaction. However, discontinuing rifampicin in a TB patient creates a dilemma, as it is a key drug in the treatment regimen. To resolve this, corticosteroids were administered to control the systemic inflammation and prevent further damage. The patient responded well to the corticosteroid therapy, which aligns with existing best practices that recommend systemic corticosteroids as the treatment of choice for severe cases of DRESS.

Literature shows that while rifampicin-induced DRESS is uncommon, similar cases have reported clinical manifestations like fever, skin rash, and multi-organ involvement, particularly affecting the liver. The therapeutic strategy, including discontinuation of the drug and corticosteroid treatment, remains consistent across most cases. However, this case underlines the importance of individualized treatment plans, especially in TB patients where continuing antitubercular therapy is critical. Careful monitoring and the introduction of alternative therapies were crucial in managing this patient without compromising the treatment of the underlying TB infection.

This case also highlights the challenges of diagnosing DRESS syndrome due to its nonspecific early symptoms, which can overlap with other hypersensitivity reactions or conditions like infections. The patient’s symptoms of fever and rash could have easily been mistaken for TB-related complications or a simple drug-induced rash. However, the application of the RegiSCAR criteria, alongside the markedly elevated eosinophil count, played a pivotal role in confirming the diagnosis and facilitating timely intervention.

This case report of rifampicin-induced DRESS syndrome emphasizes the need for prompt recognition and management to prevent potentially fatal complications. The successful recovery of the patient through the discontinuation of rifampicin and corticosteroid therapy underscores the importance of early intervention. Clinicians should maintain a high level of suspicion for DRESS syndrome in patients presenting with skin rashes, fever, and eosinophilia, especially when on long-term medications like rifampicin. The use of the RegiSCAR criteria can assist in making an accurate diagnosis, particularly in cases where symptoms overlap with other conditions.

Moreover, the case sheds light on the complex management of DRESS in TB patients, where rifampicin is essential for treatment. Careful monitoring, alternative drug regimens, and continuous research into safer therapeutic options are necessary to improve outcomes in such high-risk populations. This report underscores the need for ongoing vigilance in managing adverse drug reactions, especially in critical treatments like TB, where balancing efficacy and safety can be challenging

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