Severe Cutaneous Adverse Reactions Caused by Anti-Tubercular Drugs.

Tuberculosis (TB) is still a major health problem worldwide. It is estimated that about a quarter of the world's population is infected with Mycobacterium tuberculosis. There are about 7 million new incident cases and about 1.6 million TB-related death annually.1 For successful treatment and control of TB, treatment adherence is very important. However, in the treatment of TB and latent TB infection, adverse reactions to antitubercular drugs (ATD) frequently occur, interfering with the scheduled drug treatment and treatment success.23 Certain types of adverse reactions to ATD may threaten life requiring discontinuation of medication and hospitalization for the management of illness. These severe adverse drug reactions to ATD include liver injury and immediate or delayed hypersensitivity reactions.4

Severe cutaneous adverse reactions (SCAR) refer to several serious conditions involving the skin.5 They include Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP), and drug reaction with eosinophilia and systemic symptoms (DRESS), also known as drug-induced hypersensitivity syndrome (DIHS). While ATD has not been considered a common causative drug of SCAR,67 an increasing number of reports have shown that ATD could induce DRESS (or DIHS),891011 SJS/TEN,1213 and AGEP.14 In this issue of the Allergy, Asthma & Immunology Research, Jin et al.15 reported demographic and clinical characteristics of 56 cases of ATD-related SCAR (42 cases of DRESS and 12 cases of SJS/TEN) selected from the Korean registry of SCAR. In the analysis of the causative drugs of SCAR cases enrolled in the Korean registry, isoniazid and rifampin were listed in the top 15 causative drugs.16 It is noteworthy that ATD-related SCAR more frequently present as DRESS rather than as SJS/TEN or AGEP compared with other causative drugs of SCAR. Compared with SJS/TEM, the clinical presentation of DRESS is more diverse and complex. Thus, the diagnosis of DRESS depends on collective features of clinical manifestations of adverse reactions and laboratory tests without the use of the confirmation tests.17 Major features of adverse reactions included in the diagnostic criteria for DRESS are fever, skin rash, eosinophilia, involvement of internal organs, such as liver injury. However, each of these adverse reactions to ATD frequently occurs solely or with other adverse reactions in the treatment with ATD. In addition, since 3 or more drugs are prescribed and taken at the same time for the treatment of TB, different adverse reactions to multiple drugs can occur simultaneously or overlap. In this case, the diagnosis of DRESS can be made mistakenly. Therefore, it is recommended that the diagnostic criteria for DRESS should be applied more strictly and objective tests for drug allergy should be used in the diagnosis of ATD-related DRESS.

Regarding the characteristics of ATD-related SCAR, the study by Go et al.18 showed that subjects with ATD-induced SCAR are older compared with those with other drugs-related SCAR. They also stated that since there are no data regarding risk factors of developing SCAR in patients taking ATD, it is not certain whether old age is a risk factor for ATD-induced SCAR. It is more likely that TB patients on treatment are relatively old, given that nearly half of the incident cases occurred in elderly population in Korea. For the same reason, worse clinical outcomes of ATD-related SCAR could be related to old age of TB patients. Furthermore, most mortality occurred in cases of SJS and TEN. ATD-induced DRESS was not different in severity from DRESS caused by other drugs.19

Isoniazid, rifampin, ethambutol, and pyrazinamide are recommended as the first-line ATD by the WHO and national guidelines. These drugs have frequently been implicated as the causative drugs of ATD-induced SCAR in the previous reports and a study by Jin et al.,15 while the frequency of the culprit drugs differed among studies. The inconsistency of the results on causative drugs reflects the absence of valid and effective tests for causality in ATD-induced SCAR. Even though patch test1120 and lymphocyte transformation test21 have been used to confirm the causative drugs of ATD-induced SCAR, they have not been validated and commercially available. Although rechallenge is usually discouraged in the management of SCAR due to the possible serious risks, previously prescribed ATD has been readministered in cases of ATD-related DRESS.1011 Since the treatment of TB requires long-term medication and the second-line drugs are less effective than the first-line ATD, rechallenge with ATD can be considered in finding the culprit drug and in administering the other ATDs to patients with adverse reactions including hepatotoxicity.22 In the study of Jin et al.,15 14 cases of ATD-induced SCAR had rechallenge of ATD. They argued that rifampin was the most common causative drug and that 42.9% of the cases of ATD-induced SCAR (6 of 14) were induced by 2 or more drugs. However, their argument can be misleading, since a positive response to the rechallenge test does not necessarily mean that the response to each rechallenge meets diagnostic criteria for DRESS. Instead, it is more likely that clinical manifestations of the suspected cases of ATD-induced DRESS might be a summation of various adverse reactions to multiple drugs. Considering that several drugs are administered simultaneously in the treatment of TB, the diagnosis of DRESS and the identification of causative drugs should be made more carefully.

Several genetic variants have been found to be related to ATD-induced liver injury and maculopapular eruption.232425 Also, the association between human leukocyte antigen and ATD-induced DRESS has been reported in the Korean population.9 This association and discovery of other genetic variations need to be validated in different populations and ethnic groups. To find strong genetic markers to predict SCAR in patients receiving ATD, pharmacogenetic studies would be required using confirmed cases of ATD-induced DRESS, SJS, or TEN, of which one single causative drug is detected by using immunological tests and rechallenge. In the treatment of TB, the prevention, diagnosis, and management of SCAR to ATD is crucial. A novel strategy is urgently needed to manage patients with suspected SCAR caused by ATD in the treatment of TB.