Allergic Reaction due to Anti-Tuberculosis Drugs, How to Manage?

Article history: Received 05 July 2020 Received in revised form 05 May 2021 Accepted 19 May 2021 Available online 31 May 2021 Tuberculosis (TB) still becomes a significant health problem in Indonesia. The first-line anti-tuberculosis drug (ATD) is still the most effective TB drug, but it can have some side effects. One of them is allergic skin reactions that can affect a patient's compliance. Allergic reactions due to ATD are found in 4-6% of TB cases and are the third most frequent side effect after gastrointestinal and liver function disorder. All first-line ATD can cause allergic reactions. Allergic reactions due to ATD can be mild, such as itching and reddish rashes, to severe and life-threatening rashes, such as anaphylactic shock, Steven Johnson Syndrome (SJS), and Toxic Epidermal Necrotic (TEN). The most important things in the management are identifying and stopping drugs. It includes drug challenge and desensitization of causing drug. Desensitization must be distinguished from drug challenge or provocation tests, which are diagnostic tools. The proper management of ATD allergic reactions can improve compliance and patient's outcomes.


INTRODUCTION
Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. It is still a significant health problem in the world. 1 Every year, it is estimated that there are 8 million new cases and 2 million deaths due to TB. 2 The recommended first-line antituberculosis drugs (ATD) is a combination of Isoniazid, Rifampicin, Ethambutol, and Pyrazinamide for six months. First-line ATD has been proven effective in killing TB germs, although it can cause side effects, including liver dysfunction (1.74-13.9%), gastrointestinal disorders (1.64-10%), and skin allergies (1.43-7.5%). 2,3,4 Allergic reactions due to ATD are found in 4-6% of TB cases, which is one of the most common side effects. 5,6,7 In the study of Aligazhar, et al. (2018), allergic reaction of ATD was the third most side effect after gastrointestinal disturbances and liver function. 4 The studies of Marra, et al. (2007) and Amit, et al.

Risk Factor
Risk factors for drug allergies can be related to patient factors or drug factors. Patient risk factors include women, accompanying diseases (HIV, kidney disease, liver disease), ethnicity, polypharmacy, alcoholics, and genetics. Drug risk factors include the nature of the drug as a hapten, pro hapten, or the drug's ability to bind to immune receptors. The mode of administration also affects risk; topical, intramuscular, and intravenous administration more often causes allergies than oral; this is due to the presence of antigen in the skin and high drug concentrations achieved quickly with intravenous administration compared with oral administration. 10,14 Epidemiology Allergic reactions or drug hypersensitivity account for 15% of adverse drug events and affect 7% of the general population. 13 Allergy to first-line ATD is one of the side effects in 5.7% of TB patients. It ranks the third most side effects of ATD after impaired liver function and gastrointestinal disorders. 2,3,4,15 All firstline ATDs can cause rashes. This side effect in TB treatment ranges from 4.7% to 23%. 8 The incidence of first-line ATD allergic reaction is 2.38% in pyrazinamide; 1.45% in streptomycin; 1.44% in ethambutol; 1.23% in rifampicin; and 0.98% in isoniazid. 15 The onset of rash usually appears in the first two months of TB treatment. 8 The rash ranges from mild, such as maculopapular rash, to life-threatening ones, such as Steven Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Rash with Eosinophilia and Systemic Symptoms (DRESS).
Maculopapular rashes or morbilliform are the most common in 95% of cases. 8

Pathophysiology
The pathophysiology of drug allergy is not fully understood. However, according to Abe, et al., there are three hypotheses of cell-mediated immunity reaction and T cell activation in drug allergies 15 , namely: • Hapten/pro-hapten hypothesis • Interactions with immune receptors hypothesis (p-i model) • Altered peptide hypothesis The first hypothesis refers to the hapten/prohapten hypothesis. The drug is not antigenic before it binds to protein. 15 Drug molecules that enter the body act as hapten (small covalent molecules that bind to amino acids and proteins). Pro-hapten is a molecule that can turn into hapten after metabolism. Hapten and prohapten can act as allergens, antigens, immunogens, or sensitogens. They can cause hypersensitivity reactions in humans ( Figure 1). 10 Drugs that act as hapten bind covalently to serum proteins, including the Major Histocompatibility Complex (MHC) molecule. Bonding with MHC will activate T cells to initiate an immune response that causes systemic to skin reactions, and side effects can occur immediately or delayed. 10 The second hypothesis, the p-i model introduced by Pichler, is the direct bonding of drugs with T cell receptors or Human Leukocyte Antigen (HLA). It can cause T cell activation and the occurrence of an immune response. 10 The drug can bind to T and HLA cells without forming hapten. The changes of the previous paradigm state that drug induction in immunological reactions depends on the reactivity of the drug to the protein. Drug molecules that do not bind to proteins can stimulate T cells by binding to MHC and T-cell receptors (TCR). 15 The third hypothesis is the modified peptide.
Peptides are protein fragments released by Major Histocompatibility Complex I (MHC I) in an immune response to activating T lymphocyte cells. In this hypothesis, it is stated that a drug molecule with a low weight can bind non-covalently to the HLA molecule through an antigen-binding gap, therefore changes occur in peptide repertoire. 10 Because the drug binds directly to HLA, the HLA receptor gap will change. Peptides that bind to HLA will occupy holes with new shapes. If the subject is intolerant of unique peptides, T cells will DDD be activated through interactions with MHC. 15 In this process, there is no need for sensitization because the stimulation is directed at memory T cells and effectors. 10 The most frequent ATD hypersensitivity reaction type is type 1 or immediate type. It occurs in 3.4% of TB patients who take ATD. The severity of ATD is usually grade 1, but it can occur to grade 3. 14 Type 1 hypersensitivity reactions in TB patients are related to IgE levels. 16 Total specific IgE levels in TB patients is known to be higher than in healthy people. It can be related to M. tuberculosis infection, which stimulates the work of T-helper 2 (Th2) to produce interleukin-4 (IL-4), which stimulates B cells to produce IgE. 17 Allergic desensitization is an essential treatment for type 1 hypersensitivity reactions. 18 Clinical symptoms of each type of hypersensitivity reaction can be seen in Table 1.

Clinical symptoms and severity
Clinically drug allergies are divided into immediate or delayed, depend on the onset after drug administration ( Figure 2). The immediate type appears 1-6 hours after the drug is given (most often in the first hour). The symptoms include local erythema, urticaria, angioedema, conjunctivitis, rhinitis, bronchospasm, gastrointestinal disorders, anaphylaxis, or anaphylactic shock. Immediate drug hypersensitivity reactions may be mediated by IgE (type 1 hypersensitivity reactions). 13 Non-immediate or delayed-type hypersensitivity reactions usually appear after the first 6 hours of drug administration.
Common symptoms include maculopapular exanthema and slow type urticaria; often associated with a slow-type T-cell dependent allergic mechanism (type IV hypersensitivity reaction). 13 ATD allergy symptoms include morbilliform rash, erythema multiforme, urticaria, lichenoid eruption, exfoliative dermatitis, and SJS. 19 In a study of 9,111 hospitalized patients, 25 patients (0.27%) experienced SJS with the leading cause of Thiacetazone.
Pyazinamide ATD is the most common cause of allergy (2.38%), followed by Streptomycin 1.45%, Ethambutol 1.44%, Rifampicin 1.23%, and Isoniazid 0.98%. 20 There is no grading on the severity of allergic skin reactions due to ATD in general. The degree of severity is usually assessed from several types of skin allergic reactions due to drugs. SJS, TEN, DHS, vasculitis, FDE are assessed as severe allergic reactions. The need for hospitalization assesses the severity of the allergic reaction. 19 Nowadays, the recommended grade of severity of ATD allergy is from the International Union of Tuberculosis Lung Disease (IUATLD) ( Table 1). The various types of ATD allergic reaction can be seen in Figure 3

ATD allergic reaction with rash
If a rash occurs, all ATD must be stopped and the patient must be referred immediately to the referral health facility. In the event of a severe skin reaction involving mucosa or hypotension, give intravenous fluids immediately. 21 Given the need to complete TB treatment, in referral health facilities efforts can be made to find the type of ATD that causes the allergic reactions by drug challenge: • After the reaction is under control, ATD is given back gradually one by one, starting with ATD, which is less likely to cause a reaction (H or R) at low doses, e.g., 50 mg Isoniazid.
• ATD dose increased gradually in 3 days. If no response arises, add one more type of ATD the next day.
• The reaction after giving certain ATD shows that ATD is the cause.
• If the ATD that causes the reaction is known, treatment can be continued without the drug. 22,23 ATD regimen for allergic reaction with rash ATD regimen for allergic reaction with rash is the same as a specific regimen in liver disorders due to ATD, which are: • If Rifampicin is the cause of allergy, a regimen without Rifampicin is recommended, i.e., two months Isoniazid, Pyrazinamide, and Ethambutol followed by a 10-month follow-up phase of Isoniazid and Ethambutol.
• If isoniazid cannot be used because of an allergy, the regimen is Rifampicin, Pyrazinamide, and Ethambutol for 6-9 months.
• If Pyrazinamide is stopped before the intensive phase is completed due to drug allergy, the total administration of Isoniazid and Rifampicin is extended to 9 months.
• If Isoniazid and Rifampicin cannot be given, streptomycin, ethambutol, and fluoroquinolone are used for 18-24 months. 22,23 The drugs which cause allergic reactions from the lowest to the highest risk are Isoniazid, Rifampicin, Pyrazinamide, Ethionamide, Cycloserine, Ethambutol, Para-aminosalicylic acid (PAS), and Streptomycin. The desensitization is based on the order of the drug list. 24 The current guidelines for ATD allergy management are World Health Organization (WHO) guidelines which are described in the Treatment of Tuberculosis Guidelines. If there is rash due to ATD, all drugs must be stopped and re-challenged ATD immediately. 23 American Thoracic Society/Infectious Disease Society of America (ATS/IDSA) recommends re-challenging ATD can be given 2-3 days after symptoms improve. 25 The drug challenge starts from the drug with the lowest allergic risk, isoniazid, to the most common one, streptomycin ( Table 2). The principle of drug challenging ATD is to find an ATD that causes allergies. 21,26 The first-line ATD combination is still the best and most effective. 27 The limited efficacy and many side effects of second-line ATD and the limited use of in vivo and in vitro diagnostics in detecting allergic ATD make desensitization of first-line ATD is the first choice. 19,27 Desensitization is the act of re-giving allergycausing drugs in small doses and gradually increasing until the initial therapeutic dose is reached. After that, the dose is given according to the standard at regular. 10 Patients who experience hypersensitivity reactions within 24 hours after drug administration can achieve drug tolerance with rapid oral desensitization between 4 to 20 hours. 28  Hypersensitivity reactions of the two most potent ATD, Rifampicin and isoniazid, are rarely concurrent; if hypersensitivity still continues after the re-challenging process, desensitization should be done. An indication of desensitization is if there are no alternative drugs available or the benefits of drug desensitization outweigh the allergy risks. After the desensitization process is finished, give the drug according to the standard dose. In the process of giving the required dose, it also needs the participation of the pharmaceuticals. 5 Consider close monitoring of patients with severe hypersensitivity reactions. Patients should receive at  21,26 There is no consensus on antihistamine or corticosteroid premedication use during the desensitization process, and it should be avoided. 5,30 In general, isoniazid and Rifampicin desensitization protocols can be seen in Table 4.
ATD desensitization protocol according to the Philadelphia Protocol described in the Guidelines for the Management of Adverse Drug Reaction of Antimycobacterial Agents in general include: • Start giving ATD according to the first-day dose of drug challenges in Table 3. • If a reaction occurs after the drug challenge, stop giving the drug and start desensitization from 1/100-1/1000 dose the first day after the reaction has subsided. • Give a doubled dose every hour and until the daily therapeutic dose is reached. • When the therapeutic dose is reached, continue administering in divided doses for three days, then change to a single dose (e.g., Isoniazid 2x150 mg for three days, then 300 mg for a single dose). • • If during the desensitization process there is an allergy, decrease to the previous dose without allergy and slowly increase it again. 24

SUMMARY
The first-line ATD is still the most effective TB