Adverse Cutaneous Drug Reactions Due to Antituberculosis Therapy

in Dr. Sardjito General Hospital Yogyakarta

Kusnindita Noria Rahmawati

, Danar Wicaksono

, Fajar Waskito

, Sri Awalia Febriana

Resident of Departement of Dermatovenereology, Universitas Gadjah Mada, Yogyakarta, Indonesia

Division of Allergy Immunology, Departement of Dermatovenereology, Universitas Gadjah Mada, Yogyakarta, Indonesia

Keywords: Tuberculosis, Antituberculosis, Adverse Cutaneous Drug Reaction, Rifampicin, Cutaneous Reaction.

Abstract: Tuberculosis (TB) is a major health problem worldwide. From 2014-2017, 577 cases of TB were recorded in

Dr. Sardjito Hospital Yogyakarta. Use of specific agents against Mycobacterium tuberculosis is mainstay of

TB treatment. First line anti-TB therapy used are rifampicin, isoniazid, pyrazinamide, and ethambutol. This

regimen can cause various adverse drug reaction affecting several organs, including skin. Presence of adverse

cutaneous drug reactions (ACDRs) to anti-TB therapy can reduce the effectiveness of therapy and increase

the morbidity and mortality of TB patients. This study aimed to understand the type of ACDRs that frequently

occur due to anti-TB therapy, the most common causative drugs, and to describe the clinical characteristics

including the patch test results. This is a retrospective cross-sectional study on TB patients receiving anti-TB

therapy in Dr. Sardjito General Hospital Yogyakarta from 2014-2017. Medical record investigation was

conducted to find cutaneous reactions appeared during the course of anti-TB therapy. There were 33 out of

577 patients recorded with ACDRs, maculopapular rash was the most common type (66.7%), followed with

Stevens Johnson-Syndrome (12%); Drug Reaction Eosinophilia & Systemic Symptoms (DRESS) (6%) and

acneiform eruption (6%); erythroderma(3%), exfoliative dermatitis(3%), and bullous drug eruption (3%).

Fifteen out of 33 patients had underwent patch tests examination. Rifampicin was found to be the most

causative agent, followed by pyrazinamide, ethambutol and isoniazide. As conclusion, maculopapular rash is

the most frequent anti-TB therapy-related ACDRs with rifampicin as the most frequent causative drug based

on patch test results in Dr. Sardjito General Hospital Yogyakarta.

1 INTRODUCTION

Tuberculosis (TB) is still a major health problem in all

over the world, including Indonesia. TB occurs almost

in all countries but more than 80% of TB cases

reported to occur in 22 countries worldwide. In 2013,

56 % of new cases of TB occurred in Southeast Asia

and Western Pacific (WHO, 2004). Ranked at number

3 as the biggest contributor of TB after India and

China, the prevalence of TB in Indonesia was

272/100,000 population in 2013, while the incidence

rate was 183/100,000 population (Departemen

Kesehatan RI, 2016). From 2014-2017, 577 cases of

TB were recorded in Dr. Sardjito General Hospital

Yogyakarta.

According to the National Guidelines of

Tuberculosis Diagnosis and Management, use of

specific agents against Mycobacterium tuberculosis is

the mainstay of TB treatment. For the first line, anti-

TB therapy used are rifampicin (RIF), isoniazid

(INH), pyrazinamide (PZA), and ethambutol (EMB).

To improve the compliance of TB patient, fixed dose

combination (FDC) were produced and available in 2

forms, which consist of 4 drugs (RIF 150 mg, INH 75

mg, PZA 400 mg, EMB 275 mg) and 3 drugs (RIF 150

mg, INH 75 mg, PZA 400 mg) in each tablet

(Departemen Kesehatan RI, 2016). This multidrug

therapy of TB could cause various adverse drug

effects, ranging from the mild to severe condition.

Adverse drug reactions related to anti-TB therapy

could happen in several organs, most common of them

are hepatotoxicity, gastrointestinal intolerance

peripheral neuropathy, optic neuritis and cutaneous

lesions (Ton, 2008).

World Health Organization (WHO) classifies

toxicity adverse drug reactions into 2 subtypes, type A

and type B reactions. Type A reaction is the most

common and related to pharmacological properties of

a drug. It can occur in everyone, usually predictable

and often dose-dependent. Symptoms may improve

186

Rahmawati, K., Wicaksono, D., Waskito, F. and Febriana, S.

Adverse Cutaneous Drug Reactions Due to Antituberculosis Therapy in Dr. Sardjito General Hospital Yogyakarta.

DOI: 10.5220/0008153601860189

In Proceedings of the 23rd Regional Conference of Dermatology (RCD 2018), pages 186-189

ISBN: 978-989-758-494-7

with drug dose reduction. Type A reactions may

include drug interactiotoxicity, and side effects. Type

B reaction occurs in 10-15% of patients. It has

unpredictable characteristics, tends to occur in people

who have predisposing factors. Type B reactions, both

non-immunologic and hypersensitivity-based, are

usually not dose-dependent and require drug

discontinuation for resolution. Type B reactions

include drug intolerance, hypersensitivity, or

idiosyncratic reactions to drugs (Kardaun et al., 2013).

Adverse cutaneous drug reactions (ACDRs) of

anti-TB therapy can present as a mild reactions such

as flushing and/or itching of the skin with or without

rashes, also can appear in conjunction with hot

flashes, palpitations, headache and/or increased blood

pressure. This can be considered as type A reactions.

Moderate/severe reactions to anti-TB therapy are

more related to type B reactions. Clinical

presentations vary from hives and rashes until the

severe conditions like exfoliative dermatitis and those

involving mucous membranes, such as Stevens-

Johnson Syndrome (SJS) (Lawrence Flick Memorial

Tuberculosis Clinic, 1993).

The presence of ACDRs to anti-TB therapy could

reduce the effectiveness of therapy; with regard of

patients’ reduced compliance or drugs cessation that

leads to treatment failure or relapses.

Moreover, ACDRs as well could increase the

morbidity and mortality of TB patients. This study

aimed to understand the type of ACDRs that

frequently occur due to anti-TB therapy, the causative

drugs, and to describe the clinical characteristics

including the patch test results to anti-TB therapy. We

hope that it can increase the awareness and assist

medical provider to perform the proper management.

2 METHODS

This is a retrospective cross-sectional study on TB

patients receiving anti-TB therapy in Dr. Sardjito

General Hospital Yogyakarta from 2014-2017. A

study on patient’s medical record was done to find

ACDRs appeared during the course of anti-TB

therapy. ACDRs due to anti-TB therapy was

diagnosed based on anamnesis, physical and

dermatological examination and laboratory

examinations. DRESS was diagnosed based on

RegiSCAR criteria.

3 RESULT

This study included 577 patients receiving anti-TB

therapy in Dr. Sardjito General Hospital, Yogyakarta.

Thirty-three patient were experiencing ACDRs due to

anti-TB therapy.Characteristics of patients with

cutaneous manifestations as an adverse effects of

anti-TB therapy are described in Table 1.

Table 1: Baseline characteristics of patient with ACDRs due to anti-TB therapy.

Variable

Number of patients

n (%)

Sex

Female

11 (33.3%)

Male

22 (66.7%)

Age

≤ 18 years

6 (18.2%)

19-35 years

14 (42.4%)

35-49 years

7 (21.2%)

≥50 years

6 (18.2%)

Types of ACDRs

Maculopapular rash

22 (66.7%)

Erythroderma

1 (3%)

Drug Reaction Eosinophilia & Systemic

Symptoms (DRESS)

2 (6%)

Stevens-Johnson Syndrome (SJS)

4(12%)

Exfoliative dermatitis

1 (3%)

Bullous drug eruption

1 (3%)

Acneiform eruption

2 (6%)

Adverse Cutaneous Drug Reactions Due to Antituberculosis Therapy in Dr. Sardjito General Hospital Yogyakarta

187

Table 2: Patch test results and culprit anti-TB drug.

Patch Test Results and Culprit

Drug

n (%)

Positive

Rifampicin

3 (20%)

Isoniazid

1 (6%)

Pyrazinamide

1 (6%)

Ethambutol

1 (6%)

4 FDC (RHZE)

3 (20%)

Doubtful

Rifampicin

2 (13%)

Isoniazid

Pyrazinamide

1 (6%)

Ethambutol

4 FDC (RHZE)*

1 (6%)

Negative

5 (27.7%)

Note: each patient can have more than one positive results to anti-TB therapy

RHZE : rifampicin, isoniazid, pyrazinamide, ethambutol

The age of patients ranged from 3 to 58 years

(mean = 31.09 years; median = 29 years). Most of the

patients were male (66.7%) and came from 19-35

years age group (42.4%). Maculopapular rash

(66.7%) was the most common type of ACDRs in

patients receiving anti-TB therapy, followed by SJS,

DRESS, and acneiform eruption. Erythroderma,

exfoliative dermatitis, and bullous drug eruption was

found in one patient each. Fifteen out of 33 patients

were underwent patch test examination with anti-TB

therapy to found the causative drugs. Patch test results

are described Table 2.

Based on the patch testing results, rifampicin was

found to be the most anti-TB therapy causing

ACDRs, followed by pyrazinamide. Positive patch

test results to isoniazid and ethambutol only found in

each one patient.

4 DISCUSSION

Side effects and hypersensitivity to anti-TB therapy

that manifests in many organs still remains a

difficulty in treating TB patients, so as those affecting

the skin. In severe ACDRs, it is recommended to

withdraw the suspected drug in order to improve

symptoms and outcomes (Dheda, 2012). Interruption

of TB therapy could carry consequences in worsening

the prognosis of patients, development of drug

resistance, and risk of transmission to others. Tan et

al. found that there is a significant association

between TB treatment interruption and risk of death

during the intensive phase of treatment (p = 0.001)

(Tan et al., 2007). Clinicians should be very careful

in determining the severity of ACDRs and to decide

whether to stop one or all type of anti-TB therapy also

when to re-introduce the therapy with thorough

consideration.

From the result of the study, ACDRs found in 33

patient out of 577 patients receiving anti-TB therapy

(5.7%). There were some other studies that also

reported the rates of ACDRs related to anti-TB

therapy were approximately 4.8%-6% (Farazi et al.,

2014).

Male gender counts higher than female.

Some studies showed no differences between the

two genders in developing ADR to anti-TB therapy

(Sharma et al., 2002).We also found that ACDRs

appeared mostly in productive age (19-35 years).

Among all types of ACDRs, maculopapular rash

was the most common presentation, about almost

95% of all cases (Bigby, 2001).

In this study,

maculopapular rash also found to be the most

common ACDRs (66.7%). All types of anti-TB

therapy can induce maculopapular rash, even though

some studies reported it is most likely related to

pyrazinamide as the most offending drug, followed

by ethambutol, then isoniazid and rifampicin of all the

4 first-line anti-TB therapy (Tan et al., 2007).

However, in our study, patch testing that conducted

in 15 patients showed that rifampicin was the most

causative agents. Any possible explanation of this is

ACDRs may be associated with both type A and B

reaction, wherein the patch test indicates a

hypersensitivity reaction to a drug which is included

in type B reaction. Maculopapular rash is one of the

most common forms of allergic manifestations of

rifampicin, as well as urticaria and anaphylactic

reactions.

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188

Stevens-Johnsons Syndrome (SJS) also found to

be a common manifestation of ACDRs in anti-TB

therapy recipients. Some studies reported cases of

SJS during the course of TB therapy, mostly caused

by rifampicin (Nyirenda & Gill, 1977). DRESS also

found in patients receiving anti-TB therapy according

to some reports. Anti-TB therapy that are known to

cause DRESS include isoniazid, rifampicin,

streptomycin, and pyrazinamide (Wang & Li, 2017).

Isoniazid was associated to occurrence of acneiform

eruption, as well as bullous drug reaction (Pantello &

Kondo, 2013). Exfoliative dermatitis and

erythroderma were least common manifestations to

anti-TB therapy, it was related to administration of

pyrazinamide and ethambutol (Jaisuresh, 2013).

Because of the limited type of effective anti-TB

therapy that can reach the favorable outcomes and

prevent TB relapse, correct assessment and

management of ACDRs to anti-TB therapy are

required. Rifampicin-based regimens are still

superior to non-rifampicin based until nowadays.

Rechallenge of anti-TB therapy by some steps of

desensitization should be considered in any condition

in which the advantages of TB therapy outweigh the

risk of possible reaction. Severe or life-threatening

history of ACDRs such as the bullous reactions,

erythroderma, DRESS, anaphylaxis, systemic

vasculitis and drug-induced autoimmune disease are

contraindicated to anti-TB therapy rechallenge and

therefore should be switched to alternative anti-TB

drug combination (Ton, 2008; Dheda, 2012).

5 CONCLUSION

Maculopapular rash is the most frequent type of

ACDRs induced by anti-TB therapy, while rifampicin

found to be the most frequent anti-TB therapy

inducing ACDRs according to patch test results in Dr.

Sardjito General Hospital Yogyakarta in 2014-2017.

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