Clinical and genetic risk factors for the development of multi-drug resistant tuberculosis in non-HIV infected patients at a tertiary care center in India: a case-control study
Introduction
Global tuberculosis (TB) control efforts are seriously threatened by increasing rates of drug resistance (WHO, 1997; Pablos-Mendez et al., 1998, Espinal et al., 2001). The treatment of patients with drug resistant strains of tuberculosis is exceedingly costly, difficult, and less effective (WHO, 1999). In this context, the determination of host susceptibility factors for MDR-TB is of vital importance for control of this disease. Identification of risk factors will not only help to understand the genetic susceptibility of the host to MDR-TB but also potentially help to identify causal associations, which could be further investigated. Various predictors of MDR-TB that have been reported in the literature include past history of TB, poor compliance to treatment, severity of disease and inadequate treatment (Weltman and Rose, 1994, Mendoza et al., 1997, Harrow et al., 1998, Telzak et al., 1999, Garcia-Garcia et al., 2000). Convincing evidence has been put forward for the involvement of immune response genes in the major histocompatibility complex (MHC) in governing susceptibility to tuberculosis. An association of HLA-DR2 and its molecular subtypes (DRB1∗1501/02) with pulmonary TB (Singh et al., 1983, Mehra et al., 1986, Brahmajothi et al., 1991, Rajalingam et al., 1996, Teran-Escandon et al., 1999) and of NRAMP1 gene variants with susceptibility to TB (Bellamy et al., 1998) has been demonstrated. Similarly in a Polish population, an association of HLA-DRB1∗16 allele, another subtype of DR2 with susceptibility to TB and HLA-DRB1∗13 with resistance to the disease has been reported (Dubaniewicz et al., 2000). However, in most of these studies, genetic host susceptibility to MDR-TB is not clearly defined. Recently, Park et al. (2002) reported an association of HLA-DRB1∗08032 and DQB1∗0601 with MDR-TB in Korean patients. We present here the results of our case-control study conducted at a tertiary care center to evaluate the clinical and immunogenetic predictors of MDR disease in Indian patients with TB. Identification of patients with these predictors will facilitate careful monitoring and control of drug resistance.
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Materials and methods
The study comprised of 260 patients, recruited prospectively from the medical outpatient department, inpatient wards and the chest clinic of the All India Institute of Medical Sciences (AIIMS) hospital during the period between January 1994 and October 1999. These patients belonged to the north Indian states of Punjab, Haryana, Uttar Pradesh and Delhi and represented both referred as well as fresh cases since AIIMS is a tertiary care hospital in India. All patients presented with symptoms of
Characteristics of study population
The MDR-TB and drug sensitive groups differed significantly in composition by age, sex and socio-economic status (Table 1). The patients in the former group were younger, predominantly male and belonged to the lower socio-economic class. All patients in the MDR-TB group presented with past history of tuberculosis (100%) as against 13% in the drug sensitive group (P<0.001), since most of these patients were fresh cases of TB. Compliance to treatment was significantly lower in the MDR-TB group
Discussion
Drug resistant or multi-drug resistant (MDR) TB is a growing problem worldwide. It also increases the mortality rate in certain African countries by co-infection with human immunodeficiency virus (HIV) infection. However, the magnitude of the problem of MDR-TB is still not known. A recent survey conducted by the world health organization/international union against tuberculosis and lung disease (WHO/IUATLD) from 1994 to 1997 in 35 different countries estimated the overall prevalence of 2.2%
Acknowledgements
Financial support for the study was provided through grants (No: BT/PRO 145/09/025/96 and BT/PRO585/MED/09/113/97) from the Department of Biotechnology, Ministry of Science and Technology, Government of India. Authors thank Ms. Yogita Dixit, laboratory technician and Mr. Mukesh Singh, laboratory attendant, Department of Medicine, AIIMS, New Delhi, for their help during the conduct of the study.
References (28)
- et al.
Association of pulmonary tuberculosis and HLA in South India
Tubercle
(1991) - et al.
Molecular subtypes of the HLA-DR antigens in pulmonary tuberculosis
Int. J. Infect. Dis.
(2000) - et al.
Epidemiology and clinical consequences of drug-resistant tuberculosis in a Guatemalan hospital
Chest
(1998) - et al.
Tuberculosis in patients with various HLA phenotypes
Tubercle
(1990) - et al.
HLA-DRB1 and DQB1 gene polymorphism is associated with multidrug-resistant tuberculosis in Korean patients
Hum. Immunol.
(2002) - et al.
Human leukocyte antigen associated susceptibility to pulmonary tuberculosis. Molecular analysis of class II alleles by DNA amplification and oligonucleotide hybridization in Mexican patients
Chest
(1999) - et al.
Transmission of tuberculosis in New York City: an analysis by DNA fingerprinting and conventional epidemiologic methods
N. Engl. J. Med.
(1994) - et al.
Variants in the NRAMP1 gene and susceptibility to tuberculosis in West Africans
N. Engl. J. Med.
(1998) - et al.
Association of tuberculosis and M. tuberculosis-specific antibody levels with HLA
J. Infect. Dis.
(1989) - et al.
Resurgent tuberculosis in New York City: human immunodeficiency virus, homelessness and the decline of tuberculosis control programs
Am. Rev. Respir. Dis.
(1991)