Non-Tuberculous Mycobacteria in TB-Endemic Countries: Are We Neglecting the Danger?

Abstract

There are more than 120 members of the genus Mycobacterium, which are diverse in pathogenicity, in vivo adaptation, virulence, response to drugs, and growth characteristics. Mycobacteria other than M. tuberculosis complex and M. leprosy are known as Non-Tuberculous Mycobacteria (NTM) and are known by various acronyms. They attracted abrupt attention only after the AIDS epidemic, but most of the reports were published from TB non-endemic countries [1] and only rarely from TB-endemic countries. This is probably because the chances of missing NTM species are higher in TB-endemic countries, which are poorly equipped and overburdened with other diseases (Box 1). The information regarding their true incidence and prevalence in these countries is scarce [2]. In the absence of such authentic information, the current dogma has been that the NTM are of the least consequence. However, we do not agree with this myth and wish to present our viewpoint on this important aspect and emphasize the need for a fresh look at this neglected aspect. Box 1. Possible Factors for Under-reporting of NTM from TB-Endemic Countries NTM infections are not reportable in any country. Awareness is lacking among treating physicians and microbiologists. Laboratory infrastructure is lacking for culture and identification of non-tuberculous mycobacteria. High burden of TB and HIV attracts the bulk of the attention of the health care system; governmental fiscal inputs toward the costs of these neglected infections continue to be neglected. Standardized or accepted criteria to define NTM respiratory disease are lacking. Prevalence of NTM Infections before and after the AIDS Epidemic We searched methodological search terms and phrases such as “non-tuberculous mycobacteria and AIDS” in Medline records and found that 3,020 articles were published between 1981 and 2009. Using the same phrase, only 59 articles were published between 1900 and 1981, indicating a clear upsurge of NTM disease in the post-AIDS era. However, most of these publications were from TB non-endemic countries [1]–[5], but not much significance could be adhered to these isolations [2]. The disseminated NTM infection is typically seen when the CD4+ T lymphocyte number falls below 50 µl. For this reason, it is argued that in TB-HIV co-endemic countries, AIDS patients usually die of tuberculosis or other infections before their CD4+ count falls low enough for NTM to cause a disease (Box 2). Nevertheless, we feel that besides this argument, in a majority of the patients, the diagnosis of NTM disease gets missed in these countries. Box 2. Facts about Non-tuberculous Mycobacterial Disease AIDS patients are significantly more vulnerable to NTM infections due to severe T cell immunodeficiency. Solid organ transplant patients, even though immunocompromised, are not at as high a risk as their HIV-positive counterparts. Although some genetic and anatomical factors predispose to NTM, no proven associations have been proven among geographical, occupational, or ethnic factors and NTM infections. Anatomical abnormalities and other co-morbidities such as chronic obstructive pulmonary disease (COPD), bronchiectasis, cystic fibrosis (CF), pneumoconiosis, past history of TB, pulmonary alveolar proteinosis, and esophageal motility disorders are well-established predisposing conditions. Disseminated NTM infections have been associated with specific genetic syndromes such as mutations in interferon (IFN)-γ, interleukin (IL)-12 synthesis, and in response pathways and the nuclear factor-κB essential modulator (NEMO). Conventional methods are not sufficiently sensitive to estimate prevalence and incidence of NTM infections. Monoplex TB-specific PCR needs to be replaced by multiplex PCR systems on relevant clinical samples along with blood and urine samples in tertiary-care settings. Multiplex PCR primers have been designed to amplify genus-specific regions, M. tuberculosis complex specific, M. avium complex specific, M fortuitum complex specific, and species-specific gene targets, that can be performed in a single tube. Geographical Distribution of NTM Some workers also consider that the low detection rate of NTM is due to diversity in the environmental and climatic conditions in the HIV-TB-endemic countries, but this argument is not supported by the literature [3]–[5]. In most of the surveys, the rate of human NTM infections is estimated by non-specific antibody assays or skin tests [6]. Hence, these findings may not be a reliable source of information. The International Union against Tuberculosis and Lung Diseases (IUATLD) reviewed data from 14 countries and found that the M. avium complex (MAC) was the most frequently isolated species in all these countries, which included China, India, and Korea. While M. fortuitum was the most frequently encountered species in Belgium (2.1%), the Czech Republic (17.5%), Denmark (5.3%), Finland (6.7%), France (6.5%), Germany (12.2%), Italy (2.5%), Portugal (16.5%), Spain (10.8%), Switzerland (17.5%), Turkey (33.9%), and the United Kingdom (6.0%), undoubtedly, environment is the main reservoir of NTM. There is no evidence of human-to-human or animal-to-human transmission [6]. Most infections are acquired either from the water (treated or untreated) or soil. MAC and M. fortuitum are frequently isolated from the drinking water distribution systems and swimming pools in both developing and developed countries.