|Year : 2013 | Volume
| Issue : 2 | Page : 50-53
Adverse drug reactions in tuberculosis patients due to directly observed treatment strategy therapy: Experience at an outpatient clinic of a teaching hospital in the city of Imphal, Manipur, India
Kumarjit Sinha1, Izora Trudy R Marak2, W Asoka Singh3
1 Department of Respiratory Medicine, Agartala Government Medical College, Agartala, Tripura (West), India
2 Department of Biochemistry, Agartala Government Medical College, Agartala, Tripura (West), India
3 Department of Respiratory Medicine, Regional Institute of Medical Sciences, Imphal, Manipur, India
|Date of Web Publication||18-Dec-2013|
Department of Respiratory Medicine, Agartala Government Medical College, Agartala - 799 006, Tripura (West)
Source of Support: None, Conflict of Interest: None
Background: As to the profile of adverse drug reactions (ADRs) due to directly observed treatment, short course (DOTS), there is no report available in patients receiving antituberculosis (anti-TB) chemotherapy in Manipur, India. One of the main reasons for non-adherence to anti-TB therapy (ATT) is ADRs, even under DOTS. Aims: This study aimed to determine the incidence of ADRs due to DOTS therapy with a TB population of Manipur, India. Setting and Design: A prospective institution-based cohort study, and performed during July 2009-December 2010. Materials and Methods: The study included 102 diagnosed TB patients on anti-TB treatment under DOTS. Every patient was followed-up for the duration he/she received the treatment. Statistical Analysis: Frequency of different ADRs was assessed and p value was determined. Results: Incidence of TB was more among males than female (76.47% against 23.53%). Seventy-one patients (69.01%) showed one or more ADR. Incidence of ADRs based on affected organ was: Gastrointestinal (GI) disorders in 38 patients (53.52%), generalized weakness in 12 patients (16.9%), liver dysfunction in 11 patients (15.49%), allergic skin reactions in six patients (8.45%), neurological system disorders in two patients (2.82%), and fever in two patients (2.82%). However, 30.99% did not experience any ADRs. Conclusion: Incidence of ADRs due to DOTS therapy was 69.01%. Majority of cases suffered from GI symptoms. This highlighted the importance of developing strategies to ameliorate ADRs both to improve the quality of patient care and to control TB safely.
Keywords: Adverse drug reactions, anti-TB therapy, directly observed treatment short course, pyrazinamide, rifampicin, severity, tuberculosis
|How to cite this article:|
Sinha K, Marak IR, Singh W A. Adverse drug reactions in tuberculosis patients due to directly observed treatment strategy therapy: Experience at an outpatient clinic of a teaching hospital in the city of Imphal, Manipur, India. J Assoc Chest Physicians 2013;1:50-3
|How to cite this URL:|
Sinha K, Marak IR, Singh W A. Adverse drug reactions in tuberculosis patients due to directly observed treatment strategy therapy: Experience at an outpatient clinic of a teaching hospital in the city of Imphal, Manipur, India. J Assoc Chest Physicians [serial online] 2013 [cited 2019 Sep 22];1:50-3. Available from: http://www.jacpjournal.org/text.asp?2013/1/2/50/123213
| Introduction|| |
Tuberculosis (TB) is known to afflict mankind since ancient times. It continues to rank among the world's most serious health problems despite the remarkable biomedical achievements of discovering effective diagnostic and treatment measures.  Directly observed treatment, short course (DOTS) was introduced in India in 1993 as part of Revised National Tuberculosis Control Programme (RNTCP), following a review of India's NTP a year earlier.  The key component of DOTS therapy is the standard anti-TB short course chemotherapy regimen, which requires continually taking drug combinations of isoniazid (INH), rifampicin (RFP), pyrazinamide (PZA), ethambutol (EMB), and/or streptomycin (SM) every other day for 6-9 months. 
Despite the positive therapeutic effects, studies have shown that utilization of multidrug regimens can cause undesirable adverse drug reactions (ADRs) of varying degrees of severity, such as hepatotoxicity, gastrointestinal (GI) disorders, allergic reactions, arthralgia, neurological disorders, and so on. ,,,, Studies suggest that more than 5% of the patients on anti-tubercular drugs (ATD) develop ADRs. , None of the anti-TB drugs is without adverse reactions only rarely are the adverse reactions life-threatening. ADRs can be a potential factor leading to treatment non-adherence.  ADRs increase patient suffering and incur substantial additional costs because of added outpatient visits, tests, and in more serious instances hospitalizations. ,, In this study, we aimed to get an overview of ADRs due to DOTS therapy.
| Materials and Methods|| |
Study design and sample selection
This observational prospective study was carried out in the Department of Respiratory Medicine, Regional Institute of Medical Sciences (RIMS), Imphal, Manipur from July 2009 to December 2010. The study was done after obtaining the approval from Institutional Ethical Committee. The study included 122 consecutive diagnosed TB patients attending outdoor of our department. The patients were selected irrespective of age, sex, and race. Patients receiving other treatment regimens were excluded, as were those who were human immunodeficiency virus (HIV)-positive, those who were transferred, those who abandoned treatment, those whose diagnosis was changed during the course of the treatment, and died because of reasons other than ADRs during the monitoring. Patients were divided according to the category of treatment (I, II, or III) they were receiving under DOTS.
Investigation and following-up
Before anti-TB therapy (ATT), participants recruited completed the baseline questionnaire and received several laboratory examinations, including blood routine test (the number of red blood cells, white blood cells, and platelet; and the level of hemoglobin in full blood count), urine routine test (pH value, the level of uric acid and urine protein, cylindruria, and the number of red blood cells and white blood cells in urine), liver and renal function test, and hepatitis B surface antigen (HBsAg) test. During the follow-up period, blood and urine routine test as well as liver and renal function test were measured again within 2 months after anti-TB treatment initiation. The participants were instructed to use a diary to self-record any signs or symptoms of ADRs and to report to the medical college outpatient clinic if they had discomfort or adverse reactions. Once a suspected ADR was identified, the clinicians recorded and followed-up until resolution or end of TB therapy. ADR patients modified their DOTS therapy and/or received symptomatic therapy according to the seriousness of the ADR. Follow-up was provided on a monthly basis to all participants until the completion of DOTS therapy.
ADR was defined as an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product ADRs and the timing of their appearance during treatment, as well as subsequent modifications in the treatment regimen, were noted. 
Severity of the ADRs were classified according to Hartwig et al.,  as: (i) Mild reactions which were self-limiting and able to resolve over time without treatment and did not contribute to prolongation of length of stay, (ii) moderate ADRs were defined as those that required therapeutic intervention and hospitalization prolonged by 1 day but resolved in <24 h or change in drug therapy or specific treatment to prevent a further outcome, and (iii) severe ADRs were those that were life-threatening, producing disability and those that prolonged hospital stay or led to hospitalization, required intensive medical care, or led to the death of the patient.
| Results|| |
During the 18-month period a total of 122 patients were enrolled in the study. Among those 10 patients transferred out during monitoring, three patients died other than ADRs, five patients' diagnosis were changed, and two patients abandoned treatment. As a result, a total of 102 patients were included in the study. The males outnumbered the females (76.47 vs 23.53%) in the present study. Age of the patients ranged from 14 to 78 years with a mean 38.4 years and median 39.5 years. Majority of study cases (27.45%) were in the age group of 31-40 years.
Incidence of ADRs was maximum in ≤20 years age group and minimum in 51-60 years age group of patients. Difference in ADRs among different age groups was statistically significant (P < 0.001). Majority of female TB patients experienced ADRs when compared to male (91.67 vs 62.82%) and this difference was statistically significant (P < 0.001) [Table 1].
|Table 1: Incidence of adverse drug reaction among tuberculosis patients according to age and sex|
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Of the total 102 patients, 71 patients (69.01%) showed one or more ADR. Majority of the patients (53.52%) suffered from GI symptoms, of which anorexia was the most common (31.58%). Neurological symptoms and fever were the least common (2.82% each) ADRs. In the present study, 30.99% did not experience any ADRs [Table 2].
|Table 2: Distribution of adverse drug reactions due to directly observed treatment strategy therapy in tuberculosis patients|
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Most of the ADRs were mild (73.24%), of which GI symptoms (73.08%) tops the list. Liver dysfunction was the only severe ADRs (15.49%) noted [Table 3].
|Table 3: Distribution of adverse drug reactions by severity due to directly observed treatment strategy therapy in tuberculosis patients|
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| Discussion|| |
The present study was undertaken to find out the ADRs of anti-TB drugs due to DOTS therapy among the TB patients in hospital setting. The males constitute the major population of the study group, that is, 76.47 against 23.53% females. It may be due to the fact that the males are having higher risk factors like smoking, alcoholism, and drug addiction to get TB than females and men are socially more active and visit public places more often. These risks make them more vulnerable for TB infection.  It has been found that TB was more prevalent in the age group 31-40 years (27.45%). Edoh and Adjei, also found higher incidence of TB in the age group of 21-40 years with the highest peak of 29.7% in the group of 31-40 years.  This is probably because the people in this age group are involved in TB infectious activities like smoking, large alcohol intake, etc., which results in the weakening of immunity. 
The majority of TB cases (57.84%) were with the body weight ≤50 kg and 42.15% were >50 kg body weight. In the study done by Iyer et al., TB patients (80%), weighed below average for Indian reference adult man (60 kg) and woman (50 kg).  Patients with TB often suffer from severe weight loss, a symptom that is considered immunosuppressive and a major determinant of severity and disease outcome.  Malnutrition is an important risk factor for TB, because cell-mediated immunity (CMI) is the key host defence against TB.
In the present study, the majority of the cases belonged to category I (64.71%), 23.53% were in category III, and 11.76% were in category II. It may be due to the fact that majority of TB cases in our study were new sputum positive cases. Mittal and Gupta also found in their study that majority of the TB patients belonged to category I (42.8%), followed by category III (31.1%), while 26.1% patients were in category II. 
The most common ADRs were GI symptoms (53.52%). The drugs, which are responsible for these side effects, may be PZA and RFP. 15.49% patients developed hepatic dysfunction as ADRs. The drugs that are responsible for this side effect may be PZA, RFP, and INH.  Six patients (8.45%) experienced allergic skin manifestations as ADRs. The drugs, which are responsible for this side effect, may be PZA, RFP, and INH and 2.82% of the ADR was fever and the drug, which is responsible for this side effect, may be RFP. In the present study, 30.99% did not experience any ADRs. Most of the ADRs (73.24%) were mild, only 15.49% were severe reaction (hepatic dysfunction).
In the present study, incidence of ADRs were highest (100%) in ≤20 years age group, followed by 31-40 years age group. According to Pande et al., ATD induced hepatitis was more frequent in older patients.  Drug induced hepatotoxicity due to INH has been more commonly observed with advancing age.
Female cases are more commonly affected by ADRs when compared with their male counterparts and this difference was statistically significant (P < 0.001). In general, females are at higher risk of developing ADRs.  It might be because they pass through life stages like pregnancy, menarche, etc., which modify the drug response.  Studies from the UK and Canada also reported females to have a significantly higher incidence of ADRs due to ATT drugs.  This suggests the need for special precautions while prescribing ATT drugs to females.
| Conclusion|| |
The study shows that TB was more prevalent in the age group 31-40 years (27.45%) and among the males. Most common ADR was GI symptoms, but most were mild. ADRs was more prevalent among females with number of patients more in the 31-40 years age group, but incidence was most in ≤20 years age group.
| References|| |
|1.||Central TB Division and National AIDS Control Organisation, New Delhi. Programme objectives. Training module for medical officers on TB/HIV 2005;14-8. |
|2.||Balasubramanian VN, Oommen K, Samuel R. DOT or not? Direct observation of anti-tuberculosis treatment and patient outcomes, Kerala State, India. Int J Tuberc Lung Dis 2000;4:409-13. |
|3.||World Health Organization. An expanded DOTS framework for effective tuberculosis control. Stop TB Communicable Diseases. Geneva: WHO Press; 2002. p. 1-20. |
|4.||Yee D, Valiquette C, Pelletier M, Parisien I, Rocher I, Menzies D. Incidence of serious side effects from first-line antituberculosis drugs among patients treated for active tuberculosis. Am J Respir Crit Care Med 2003;167:1472-7. |
|5.||Vieira DE, Gomes M. Adverse effects of tuberculosis treatment: Experience at an outpatient clinic of a teaching hospital in the city of São Paulo, Brazil. J Bras Pneumol 2008;34:1049-55. |
|6.||Zaka-Ur-Rehman Z, Jamshaid M, Chaudhry A. Clinical evaluation and monitoring of adverse effects for fixed multidose combination against single drug therapy in pulmonary tuberculosis patients. Pak J Pharm Sci 2008;21:185-94. |
|7.||Marra F, Marra CA, Bruchet N, Richardson K, Moadebi S, Elwood RK, et al. Adverse drug reactions associated with first-line anti-tuberculosis drug regimens. Int J Tuberc Lung Dis 2007;11:868-75. |
|8.||Chhetri AK, Saha A, Verma SC, Palaian S, Mishra P, Shankar PR. Study of adverse drug reactions caused by first line anti-tubercular drugs used in directly observed treatment, short course (DOTS) therapy in Western Nepal, Pokhara. J Pak Med Assoc 2008;58:531-6. |
|9.||Dhingra VK, Rajpal S, Aggarwal N, Aggarwal JK, Shadab K, Jain SK. Adverse drug reactions observed during DOTS. J Commun Dis 2004;36:251-9. |
|10.||Chukanov VI, Kaminskaia GO, Livchane E. Frequency and pattern of adverse reactions due to treatment of patients with pulmonary tuberculosis with antitubercular reserve drugs. Probl Tuberk Bolezn Legk 2004;10:6-10. |
|11.||Awofeso N. Anti-tuberculosis medication side-effects constitute major factor for poor adherence to tuberculosis treatment. Bull World Health Organ 2008;86:B-D. |
|12.||Edwards IR, Aronson JK. Adverse drug reactions: Definitions, diagnosis, and management. Lancet 2000;356:1255-9. |
|13.||Hartwig SC, Siegel J, Schneider PJ. Preventability and severity assessment in reporting adverse drug reactions. Am J Hosp Pharm 1992;49:2229-32. |
|14.||Lönnroth K, Williams BG, Stadlin S, Jaramillo E, Dye C. Alcohol use as a risk factor for tuberculosis - a systematic review. BMC Public Health 2008;8:289. |
|15.||Edoh D, Adjei R. Rapid assessment of a National Tuberculosis (TB) Control Programme in Eastern Ghana. Afr J Health Sci 2002;9:159-64. |
|16.||Horne N. Tuberculosis and other mycobacterial disease. In: Cook G, editor. Manson′s tropical diseases. London: W.B. Saunders; 1996. p. 971-1015. |
|17.||Iyer SP, Umakumar K, Mahajan A. Impact of HIV Infection on utcome of abdominal tuberculosis. Bombay Hospital J 2008;50:553-9. |
|18.||van Crevel R, Karyadi E, Netea MG, Verhoef H, Nelwan RH, West CE, et al. Decreased plasma leptin concentrations in tuberculosis patients are associated with wasting and inflammation. J Clin Endocrinol Metab 2002;87:758-63. |
|19.||Mittal C, Gupta SC. Effect of disease related variables on treatment outcome under DOTS. JK Science 2011;13:15-8. Available from: www.jkscience.org/archievevolume131/Effect/Disease/Related/Variables/Treatment/Outcome/Under?DOTS. [Last accessed on 2010 Jul 10]. |
|20.||Steele MA, Burk RF, DesPrez RM. Toxic hepatitis with isoniazid and rifampin. A meta-analysis. Chest 1991;99:465-71. |
|21.||Pande JN, Singh SP, Khilnani GC, Khilnani S, Tandon RK. Risk factors for hepatotoxicity from antituberculosis drugs: A case control study. Thorax 1996;51:167-70. |
|22.||Puavilai S, Timpatanapong P. Prospective study of cutaneous drug reactions. J Med Assoc Thai 1989;72:167-71. |
|23.||Wilson K. Sex-related difference in drug disposition in man. Clin Pharmacokinet 1984;9:189-202. |
[Table 1], [Table 2], [Table 3]