Year : 2010 | Volume
: 55 | Issue : 4 | Page : 384--386
Pyrazinamide-induced maculopapular rash
Khalid Umer Khayyam1, Faisal Imam2, Manju Sharma2, KK Pillai2, D Behera3,
1 Department of Epidemiology and Public Health, Lala Ram Sarup Institute of TB & RD, Sri Aurobindo Marg, New Delhi - 110 030, India
2 Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard University, New Delhi - 110 062, India
3 Department of Pharmacology, Lala Ram Sarup Institute of TB & RD, Sri Aurobindo Marg, New Delhi - 110 030, India
Department of Pharmacology, Faculty of Pharmacy, Jamia Hamdard, Hamdard University, New Delhi - 110 062
Pyrazinamide is a commonly used first-line antitubercular drug. Gastric-related adverse drug reactions are common with pyrazinamide. Dermatological manifestations due to pyrazinamide are rare. This study aimed find out the dermatological manifestations/adverse drug reaction (ADR) due to pyrazinamide. We reported a case of maculopapular rash caused by pyrazinamide in a patient on antituberculosis treatment using structured questionnaires. The patient developed maculopapular rashes on receiving combination antituberculosis treatment. The rashes disappeared after stopping the suspected drug. The patient was rechallenged with pyrazinamide, which led to reappearance of a similar type of rash. The causality, preventability, and severity were assessed using the Naranjo algorithm and Hartwig scale. Since pyrazinamide is a commonly used drug in tuberculosis and which is a common infectious disease in developing countries, with the similar reports, we can predict early case detection and can prevent the occurrence of similar reactions in future.
|How to cite this article:|
Khayyam KU, Imam F, Sharma M, Pillai K K, Behera D. Pyrazinamide-induced maculopapular rash.Indian J Dermatol 2010;55:384-386
|How to cite this URL:|
Khayyam KU, Imam F, Sharma M, Pillai K K, Behera D. Pyrazinamide-induced maculopapular rash. Indian J Dermatol [serial online] 2010 [cited 2023 Dec 10 ];55:384-386
Available from: https://www.e-ijd.org/text.asp?2010/55/4/384/74562
Maculopapular exanthema (MPE) is the most frequent clinical manifestation of nonimmediate allergic reactions due to drugs and T helper 1 (Th1) cytokines and CD4 (+) T cells have been shown to play an important role in its pathogenesis.  It can be caused by many medications.  Pyrazinamide is used in the management of tuberculosis (TB) in combination with other drugs. The common side effects due to pyrazinamide are hyperuricemia (gout), hepatotoxicity, nausea, vomiting, flushing, dysuria, arthralgia, and sideroblastic anemia. Rarely skin rashes and photosensitivity are reported during the treatment with pyrazinamide.  We hereby report a case of maculopapular rash due to pyrazinamide in a patient undergoing antitubercular treatment. We also established the causality, severity, and preventability of the suspected adverse drug reactions (ADRs).
A 19-year-old patient of Bersarai area, New Delhi, belonging to a lower middle class family, visited a microscopic center situated in Delhi Government Dispensary of Bersarai area with complaints of cough with expectoration and fever, loss of appetite, and weight for the past 1 month. The sputa were examined as per Revised National Tuberculosis Control Programme (RNTCP) by Zeihl-Neelson (ZN) staining for acid-fast bacillus (AFB) and were found to be negative. Chest radiograph showed bilateral upper zone infiltration. On the basis of the above clinical examination and observation, the patient was diagnosed as a case of sputum negative pulmonary tuberculosis. He was referred to the Directly Observed Treatment (DOT) center of his area for the initiation of category I antituberculosis therapy as per national RNTCP guidelines according to his weight (40 kg). Category I antituberculosis therapy includes isoniazid 600 mg (2 tablets), rifampicin 450 mg (1 capsule), pyrazinamide 1500 mg (2 tablets), and ethambutol 1200 mg (2 tablets).  He tolerated the first dose of antituberculosis therapy.
On the third dosing day (after the second day of therapy), the patient visited DOT center with generalized maculopapular rashes all over the body and more on both shoulders and upper and lower limbs. A diagnosis of antitubercular drug-induced maculopapular rash was made by the medical officer. Rashes were round in shape, raised from the body surface, appeared reddish in color, and hot on touch. Therefore, pyrazinamide was stopped on the advice of the medical officer and other antituberculosis medicines were continued with the addition of oral antihistaminic and the patient was kept under close observation for evaluation. After 3 days of stopping the pyrazinamide, rashes started subsiding. Suspected drug (pyrazinamide) was stopped as per the national RNTCP guidelines.  He tolerated isoniazid, rifampicin, and ethambutol but on inclusion of pyrazinamide, rashes reappeared in the same part of the body. Pyrazinamide was again withheld. There was no recurrence of rash anywhere in the body. He is on regular follow-up with disappearance of rashes and signs and symptoms of tuberculosis .
We carried out the causality assessments as per the Naranjo  algorithm and preventability and severity assessments as per the Hartwig  scale. The causality assessment revealed a "probable" association (Naranjo score 7) between the ADR and pyrazinamide. The severity was found to be moderate (Level 3). The preventability analysis revealed the ADR to be "not preventable."
Approximately 5.3% of hospital admissions were associated with ADRs. Higher rates were found in elderly patients who are likely to be receiving multiple medications for long-term illnesses. Maculopapular eruption is a fairly common adverse cutaneous drug reaction. Maculopapular rashes consist of macules (distinct flat areas) and papules (raised lesions). The rash is usually bright red in color and the skin may feel hot with burning sensation or itch. The whole of the skin surface may be involved, though the face is often spared.  Up to 5% of the patients receiving penicillin, sulfonamides, phenytoin, or gold will develop a maculopapular rash. 
Dermatological reactions due to pyrazinamide are rare. In a case report,  erythema multiforme has been reported in one patient following pyrazinamide administration for cutaneous tuberculosis related to a pleural fistula. Daily antituberculosis treatment (ATT) was initiated in this patient with isoniazid, rifampicin, ethambutol, and pyrazinamide. After 26 days of therapy, maculopapular erythematous lesions appeared, and biopsy results confirmed the diagnosis of erythema multiforme. The rash disappeared with the discontinuation of all drugs, but reappeared when rifampicin and pyrazinamide were reintroduced 5 days later. No further reactions were observed with other antituberculosis drugs. In our case, the patient developed the rash on the third day (after second dosing day of therapy) after initiating antituberculosis therapy and disappeared after few days when the drug (pyrazinamide) was stopped. The rash again reappeared when pyrazinamide was restarted. The causal relationship between the drug and the ADR was found to be "probable."  Manufacturer leaflet also reported maculopapular rashes due to pyrazinamide as a rare ADR.. Generalized maculopapular skin rash was a common ADR reported in an investigational trial of ofloxacin (800 mg a day) and pyrazinamide (1500 mg a day). Of the 16 ADRs, 3 subjects presented with generalized maculopapular skin rash. 
The management of such reactions needed withdrawal of the suspected drug and management of symptoms, if any.  In this study, the suspected drug was stopped immediately following the ADR and antihistamines were added to manage associated itching due to drug reaction, to which patient responded well. The severity assessment revealed the ADR to be moderate (Level 3), suggesting that the suspected drug should be withheld, discontinued, otherwise changed, and/or on antidote or other treatment is required. There was no increase in the length of stay. Since this patient did not have any past history of skin reaction due to pyrazinamide or any other drugs, therefore this reaction was unpreventable.
Since pyrazinamide is a common drug used in TB management, and TB is also a common problem in countries like India, the dermatological manifestations due to pyrazinamide gain attention. Upon occurrence of dermatological manifestations, the patients may become noncompliant, which is one of the common causes with other anti-TB drugs for treatment failure in TB therapy. Although skin reactions due to pyrazinamide are not well reported, one should be suspicious of maculopapular rashes due to pyrazinamide also. Upon occurrence, the suspected drug/(s) should be stopped immediately and the patient should be managed symptomatically. The patients undergoing treatment on an outpatient basis should be counseled for the early recognition of dermatological manifestations.
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