Treatment and management of hypersensitivity reactions developed against anti-tuberculosis drug.

Background: The World Health Organization Global Tuberculosis Report 2021 defines tuberculosis as the second infectious disease that causes sickness and death after COVID 19 and ranks it as the 13^th among the global causes of death. However, the prevalence of the patients developing a hypersensitivity reaction against antituberculosis treatment is yet unknown. This study aimed to investigate the prevalence of drug allergy against antituberculosis treatment and the management of such a problem. Methods: This is a case--control study. All patients hospitalized in the tuberculosis inpatient service between February 01, 2015 and May 01, 2021 due to hypersensitivity reaction or who developed hypersensitivity during hospitalization were included in the case group. Patients who received inpatient treatment between the same dates and did not develop any drug allergy were included in the control group. The demographic characteristics of the patients, the tuberculosis diagnostic indicator, the type of hypersensitivity reaction that developed, the duration of the manifestation of the reaction and its treatment were evaluated for the purpose of the study. Results: A total of 2677 patients were hospitalized in the tuberculosis inpatient service between the specified dates. Two hundred and ten patients were consulted for drug hypersensitivity reactions in the Allergy Clinic. The prevalence of drug allergy in inpatients was calculated as 7.8%. One hundred and forty-eight patients examined by the authors were included in the study. Seventy-nine of the 148 patients (53.4%) who developed a hypersensitivity reaction were male, the mean age of these patients was 47.20 ± 18.95 years, 89.2% (n = 132) were citizens of the Republic of Turkey, 7.4% (n = 11) of the patients had received tuberculosis treatment before, 16.9% (25) had developed antituberculosis drug resistance and the bacteriological diagnosis was present in 79.7% (118) of the patients. Chi-square test results applied in the allergy group revealed that the risk of developing a hypersensitivity reaction is statistically significantly higher in female patients (P < 0.001), Turkish citizen patients (P = 0.004), in new cases (P = 0.017), in the group not diagnosed bacteriologically (histopathologically, clinically, and radiologically) (P = 0.006). The results of the logistic regression analysis performed also revealed that the risk of developing a hypersensitivity reaction is statistically significantly higher in female patients (P = 0.006), Turkish citizen patients (P = 0.023), in new cases (P = 0.017) and in the group not diagnosed bacteriologically (histopathologically, clinically, and radiologically) (P = 0.006). The success of the treatment was higher in the group that developed a hypersensitivity reaction compared to the control group. About 63.5% (94) of the patients examined developed Type I hypersensitivity reactions, whereas 36.7% (53) of the patients examined developed Type IV hypersensitivity reactions. Type I and Type IV reactions were observed simultaneously in a single patient. Considering the prevalence of developing a hypersensitivity reaction, pyrazinamide was determined as the drug inducing the hypersensitivity reaction in 25 (48.1%) patients. This figure was 15 patients (28.2%) for rifampicin, nine patients (17.3%) for isoniazid, and five patients (9.6%) for ethambutol. As a result, even patients who developed Type I or Type IV reactions were able to complete their antituberculous drug regimens with successful desensitization. Conclusion: The risk of developing an allergic reaction in patients who are administered on antituberculosis treatment is common, particularly in the first 2 months of treatment. However, we believe that the compliance of the patients to the antituberculosis treatment has been improved at the end of appropriate management of hypersensitivity reactions and the treatment results in success.

Predictors for Pulmonary Tuberculosis Outcome and Adverse Events in an Italian Referral Hospital: A Nine-Year Retrospective Study (2013-2021).

Background: The COVID-19 pandemic has undone years of progress in providing essential TB services and controlling the TB burden. Italy, a low TB burden country, has an incidence of 7.1 cases per 100,000 people. To control the TB spreading in Italy is critical to investigate the characteristics of patients with the worst outcomes and the highest risk of adverse events related to antituberculosis therapy. Therefore, we conducted a large retrospective study in TB patients admitted to the Clinic of Infectious Diseases University of Bari, Italy, in order to describe the clinical presentation and the factors associated with adverse events and outcomes. Methods: We retrospectively evaluated the patients admitted to the Clinic of Infectious Diseases from January 2013 to 15 December 2021. We stratified our cohort into two groups: <65 years of age and ≥65 years in order to assess any differences between the two groups. Two logistic regression models were implemented considering the dependent variables as: (I) the adverse events; and (II) the unsuccessful treatments. Results: In total, 206 consecutive patients [60% (n = 124) M, median age 39 years, range 16-92] were diagnosed and admitted with TB at Clinic of Infectious Diseases. Of the whole sample, 151 (74%) were <65 years and 55 (26%) were ≥65. Statistically significant differences between the two groups were detected (p-value < 0.05) for nationality (p-value = 0.01), previous contact with TB patient (p-value = 0.00), type of TB (p-value = 0.00), unsuccessful treatment (p-value = 0.00), length of hospitalization (p-value = 0.02) and diagnostic delay (p-value = 0.01). Adverse events related to TB drug regimen were reported in 24% (n = 49). Age < 65 years (O.R. = 3.91; 95% CI 1.72-4.21), non-Italian nationality (O.R. = 4.45; 95% CI 2.22-4.98.), homeless (O.R. = 3.23; 95% CI 2.58-4.54), presence of respiratory symptoms (O.R. = 1.23; 95% CI 1.10-1.90), diagnostic delay (O.R = 2.55; 95% CI 1.98-3.77) resulted associated with unsuccessful treatment outcome (death, failure or lost to follow up). Finally, age < 65 years (O.R. = 1.73; 95% CI 1.31-2.49), presence of pulmonary TB (O.R. = 1.15; 95% CI 1.02-1.35), length of hospitalization (O.R. = 1.82; 95% CI 1.35-2.57) and TB culture positive (O.R. = 1.35; 95% CI 1.12-1.82) were associated with adverse events in our populations. Conclusions: The pharmacological approach alone seems insufficient to treat and cure a disease whose ethiopathogenesis is not only due to the Mycobacterium tuberculosis, but also to the poverty or the social fragility. Our data suggest that young foreigners, the homeless, and the people with low social and economic status are at higher risk of an unfavorable outcome in low incidence TB countries. Targeted actions to support this highly vulnerable population both in terms of outcome and occurrence of adverse events are needed.

Practical management of suspected hypersensitivity reactions to anti-tuberculosis drugs.

Tuberculosis (TB) is the commonest cause of death by a single infectious agent globally and ranks amongst the top ten causes of global mortality. The incidence of TB is highest in Low-Middle Income countries (LMICs). Prompt institution of, and compliance with, therapy are cornerstones for a favourable outcome in TB and to mitigate the risk of multiple drug resistant (MDR)-TB, which is challenging to treat. There is some evidence that adverse drug reactions (ADRs) and hypersensitivity reactions (HSRs) to anti-TB drugs occur in over 60% and 3%-4% of patients respectively. Both ADRs and HSRs represent significant barriers to treatment adherence and are recognised risk factors for MDR-TB. HSRs to anti-TB drugs are usually cutaneous and benign, occur within few weeks after commencement of therapy and are likely to be T-cell mediated. Severe and systemic T-cell mediated HSRs and IgE mediated anaphylaxis to anti-TB drugs are relatively rare, but important to recognise and treat promptly. T-cell-mediated HSRs are more frequent amongst patients with co-existing HIV infection. Some patients develop multiple sensitisation to anti-TB drugs. Whilst skin tests, patch tests and in vitro diagnostics have been used in the investigation of HSRs to anti-TB drugs, their predictive value is not established, they are onerous, require specialist input of an allergist and are resource-dependent. This is compounded by the global, unmet demand for allergy specialists, particularly in low-income countries (LICs)/LMICs and now the challenging circumstances of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. This narrative review provides a critical analysis of the limited published evidence on this topic and proposes a cautious and pragmatic approach to optimise and standardise the management of HSRs to anti-TB drugs. This includes clinical risk stratification and a dual strategy involving sequential re-challenge and rapid drug desensitisation. Furthermore, a concerted international effort is needed to generate real-time data on ADRs, HSRs, safety and clinical outcomes of these interventions.

Adverse drug reactions & drug interactions in MDR-TB patients.

Multiple drugs taken for long duration in tuberculosis (TB) treatment, especially drug resistant TB (DR-TB), may produce adverse drug reactions (ADRs). Although any anti-TB drug can cause ADRs, but these are more common with drugs used for treatment of DR-TB. However, most of ADRs with these drugs are mild or moderate and can be managed if adequate supervision and monitoring is done. However, few ADRs can be severe or potentially life-threatening and may require removal of the offending drug(s). TB patients having comorbidities and on treatment for them may experience drug interaction with anti TB drugs and may require dose modification or change of drug. For a good TB treatment outcome patient's compliance should be ensured, and adverse events and drug interactions should be appropriately addressed by the clinicians. This article outlines the majority of the possible ADRs to anti-TB drugs used for management of DR-TB and their common drug interactions with practical recommendations to identify the possible drug(s) responsible and the most adequate management in each situation.