Eleanor S. Click

Relationship Between Mycobacterium tuberculosis Phylogenetic Lineage and Clinical Site of Tuberculosis

BACKGROUND Genotyping of Mycobacterium tuberculosis has revealed 4 major phylogenetic lineages with differential distribution worldwide. It is not clear whether different lineages are associated with different sites of infection (eg, pulmonary tuberculosis versus extrapulmonary tuberculosis). We sought to determine whether M. tuberculosis lineage is associated with the site of tuberculosis disease. METHODS We conducted a cross-sectional analysis of all culture-confirmed cases of tuberculosis with routinely determined M. tuberculosis spoligotype-defined lineage reported to the US National Tuberculosis Surveillance System from 2004 through 2008. Odds ratios (ORs) were used to assess the relation between disease site and M. tuberculosis lineage, after adjustment for age, sex, human immunodeficiency virus infection status, region of birth, and race/ethnicity. RESULTS Of 53972 reported culture-positive tuberculosis cases, 32000 (59.3%) were cases of M. tuberculosis that included complete spoligotype-based data on lineage. Of these, 23844 (74.5%) were exclusively pulmonary, 5085 (15.9%) were exclusively extrapulmonary, and 3071 (9.6%) were combined pulmonary and extrapulmonary. The percentages of tuberculosis cases that were exclusively extrapulmonary differed by lineage: East Asian, 13.0%; Euro-American, 13.8%; Indo-Oceanic, 22.6%; and East-African Indian, 34.3%. Compared with East Asian lineage, the odds of exclusively extrapulmonary tuberculosis relative to exclusively pulmonary tuberculosis were greater for Euro-American (adjusted OR, 1.3; 95% confidence interval [CI], 1.1-1.4), Indo-Oceanic (adjusted OR, 1.7; 95% CI, 1.5-1.9), and East-African Indian (adjusted OR, 1.6; 95% CI, 1.4-1.9) lineages. CONCLUSIONS Phylogenetic lineage of M. tuberculosis is associated with the site of tuberculosis disease.

Epidemiology of Pyrazinamide-Resistant Tuberculosis in the United States, 1999–2009

BACKGROUND Pyrazinamide (PZA) is essential in tuberculosis treatment. We describe the prevalence, trends, and predictors of PZA resistance in Mycobacterium tuberculosis complex (MTBC) in the United States. METHODS We analyzed culture-positive MTBC cases with reported drug susceptibility tests for PZA in 38 jurisdictions routinely testing for PZA susceptibility from 1999 to 2009. National Tuberculosis Genotyping Service data for 2004-2009 were used to distinguish M. tuberculosis from Mycobacterium bovis and determine phylogenetic lineage. RESULTS Overall 2.7% (2167/79 321) of MTBC cases had PZA resistance, increasing annually from 2.0% to 3.3% during 1999-2009 (P < .001), largely because of an increase in PZA monoresistance. PZA-monoresistant MTBC (vs drug-susceptible) was associated with an age of 0-24 years (adjusted prevalence ratio [aPR],1.50; 95% confidence interval [CI], 1.31-1.71), Hispanic ethnicity (aPR, 3.52; 95% CI, 2.96-4.18), human immunodeficiency virus infection (aPR, 1.43; 95% CI, 1.15-1.77), extrapulmonary disease (aPR, 3.02; 95% CI, 2.60-3.52), and normal chest radiograph (aPR, 1.88; 95% CI, 1.63-2.16) and was inversely associated with Asian (aPR, 0.59; 95% CI, .47-.73) and black (aPR, 0.37; 95% CI, .29-.49) race. Among multidrug-resistant (MDR) cases, 38.0% were PZA-resistant; PZA resistance in MDR MTBC was associated with female sex (aPR, 1.25; 95% CI, 1.08-1.46) and previous tuberculosis diagnosis (aPR, 1.37; 95% CI, 1.16-1.62). Of 28 080 cases with genotyping data, 925 (3.3%) had PZA resistance; 465 of 925 (50.3%) were M. bovis. In non-MDR M. tuberculosis cases, PZA resistance was higher in the Indo-Oceanic than the East Asian lineage (2.2% vs 0.9%, respectively; aPR, 2.26; 95% CI, 1.53-3.36), but in MDR cases it was lower in the Indo-Oceanic lineage (22.0% vs 43.4%, respectively; aPR, 0.54; 95% CI, .32-.90). CONCLUSIONS Specific human and mycobacterial characteristics were associated with PZA-resistant MTBC, reflecting both specific subgroups of the population and phylogenetic lineages of the mycobacteria.

Tuberculosis Management Practices of Private Practitioners in Pune Municipal Corporation, India

Background Private Practitioners (PP) are the primary source of health care for patients in India. Limited representative information is available on TB management practices of Indian PP or on the efficacy of India’s Revised National Tuberculosis Control Programme (RNTCP) to improve the quality of TB management through training of PP. Methods We conducted a cross-sectional survey of a systematic random sample of PP in one urban area in Western India (Pune, Maharashtra). We presented sample clinical vignettes and determined the proportions of PPs who reported practices consistent with International Standards of TB Care (ISTC). We examined the association between RNTCP training and adherence to ISTC by calculating odds ratios and 95% confidence intervals. Results Of 3,391 PP practicing allopathic medicine, 249 were interviewed. Of these, 55% had been exposed to RNTCP. For new pulmonary TB patients, 63% (158/249) of provider responses were consistent with ISTC diagnostic practices, and 34% (84/249) of responses were consistent with ISTC treatment practices. However, 48% (120/249) PP also reported use of serological tests for TB diagnosis. In the new TB case vignette, 38% (94/249) PP reported use of at least one second line anti-TB drug in the treatment regimen. RNTCP training was not associated with diagnostic or treatment practices. Conclusion In Pune, India, despite a decade of training activities by the RNTCP, high proportions of providers resorted to TB serology for diagnosis and second-line anti-TB drug use in new TB patients. Efforts to achieve universal access to quality TB management must account for the low quality of care by PP and the lack of demonstrated effect of current training efforts.

A Blueprint to Address Research Gaps in the Development of Biomarkers for Pediatric Tuberculosis

Childhood tuberculosis contributes significantly to the global tuberculosis disease burden but remains challenging to diagnose due to inadequate methods of pathogen detection in paucibacillary pediatric samples and lack of a child-specific host biomarker to identify disease. Accurately diagnosing tuberculosis in children is required to improve case detection, surveillance, healthcare delivery, and effective advocacy. In May 2014, the National Institutes of Health convened a workshop including researchers in the field to delineate priorities to address this research gap. This blueprint describes the consensus from the workshop, identifies critical research steps to advance this field, and aims to catalyze efforts toward harmonization and collaboration in this area.

Tuberculosis Caused by Mycobacterium africanum, United States, 2004-2013.

Routine reporting of TB caused by this organism does not appear warranted at this time.

What are the reasons for poor uptake of HIV testing among patients with TB in an Eastern India District

Background National policy in India recommends HIV testing of all patients with TB. In West Bengal state, only 28% of patients with TB were tested for HIV between April-June, 2010. We conducted a cross-sectional survey to understand patient, provider and health system related factors associated with low uptake of HIV testing among patients with TB. Methods We reviewed TB and HIV program records to assess the HIV testing status of patients registered for anti-TB treatment from July-September 2010 in South-24-Parganas district, West Bengal, assessed availability of HIV testing kits and interviewed a random sample of patients with TB and providers. Results Among 1633 patients with TB with unknown HIV status at the time of diagnosis, 435 (26%) were tested for HIV within the intensive phase of TB treatment. Patients diagnosed with and treated for TB at facilities with co-located HIV testing services were more likely to get tested for HIV than at facilities without [RR = 1.27, (95% CI 1.20–3.35)]. Among 169 patients interviewed, 67 reported they were referred for HIV testing, among whom 47 were tested. During interviews, providers attributed the low proportion of patients with TB being referred and tested for HIV to inadequate knowledge among providers about the national policy, belief that patients will not test for HIV even if they are referred, shortage of HIV testing kits, and inadequate supervision by both programs. Discussion In West Bengal, poor uptake of HIV testing among patients with TB was associated with absence of HIV testing services at sites providing TB care services and to poor referral practices among providers. Comprehensive strategies to change providers’ beliefs and practices, decentralization of HIV testing to all TB care centers, and improved HIV test kit supply chain management may increase the proportion of patients with TB who are tested for HIV.

Association between Mycobacterium tuberculosis lineage and time to sputum culture conversion.

SETTING Mycobacterium tuberculosis comprises four principal genetic lineages: one evolutionarily ancestral (Indo-Oceanic) and three modern. Whether response to tuberculosis (TB) treatment differs among the lineages is unknown. OBJECTIVE To examine the association between M. tuberculosis lineage and time to sputum culture conversion in response to standard first-line drug therapy. DESIGN We conducted an exploratory retrospective cohort analysis of time to sputum culture conversion among pulmonary tuberculosis (PTB) cases reported in the United States from 2004 to 2007. RESULTS The analysis included 13,170 PTB cases with no documented resistance to first-line drugs who received a standard four-drug treatment regimen. Among cases with baseline positive sputum smear results, relative to cases with Euro-American lineage, cases with Indo-Oceanic lineage had higher adjusted hazards of sputum culture conversion (aHR 1.32, 95%CI 1.20-1.45), whereas cases with East-African-Indian or East-Asian lineage did not differ (aHR 1.05, 95%CI 0.88-1.25 and aHR 0.99, 95%CI 0.91-1.07, respectively). Among cases with baseline negative sputum smear results, time to sputum culture conversion did not differ by lineage. CONCLUSION Although these results are exploratory, they suggest that the eradication of viable bacteria may occur sooner among cases with Indo-Oceanic lineage than among those with one of the three modern lineages. Prospective studies of time to sputum culture conversion by lineage are required.

Association between Mycobacterium tuberculosis Complex Phylogenetic Lineage and Acquired Drug Resistance

Background Development of resistance to antituberculosis drugs during treatment (i.e., acquired resistance) can lead to emergence of resistant strains and consequent poor clinical outcomes. However, it is unknown whether Mycobacterium tuberculosis complex species and lineage affects the likelihood of acquired resistance. Methods We analyzed data from the U.S. National Tuberculosis Surveillance System and National Tuberculosis Genotyping Service for tuberculosis cases during 2004–2011 with assigned species and lineage and both initial and final drug susceptibility test results. We determined univariate associations between species and lineage of Mycobacterium tuberculosis complex bacteria and acquired resistance to isoniazid, rifamycins, fluoroquinolones, and second-line injectables. We used Poisson regression with backward elimination to generate multivariable models for acquired resistance to isoniazid and rifamycins. Results M. bovis was independently associated with acquired resistance to isoniazid (adjusted prevalence ratio = 8.46, 95% CI 2.96–24.14) adjusting for HIV status, and with acquired resistance to rifamycins (adjusted prevalence ratio = 4.53, 95% CI 1.29–15.90) adjusting for homelessness, HIV status, initial resistance to isoniazid, site of disease, and administration of therapy. East Asian lineage was associated with acquired resistance to fluoroquinolones (prevalence ratio = 6.10, 95% CI 1.56–23.83). Conclusions We found an association between mycobacterial species and lineage and acquired drug resistance using U.S. surveillance data. Prospective clinical studies are needed to determine the clinical significance of these findings, including whether rapid genotyping of isolates at the outset of treatment may benefit patient management.

Molecular, Spatial, and Field Epidemiology Suggesting TB Transmission in Community, Not Hospital, Gaborone, Botswana

During 2012–2015, 10 of 24 patients infected with matching genotypes of Mycobacterium tuberculosis received care at the same hospital in Gaborone, Botswana. Nosocomial transmission was initially suspected, but we discovered plausible sites of community transmission for 20 (95%) of 21 interviewed patients. Active case-finding at these sites could halt ongoing transmission.

Protocol for a population-based molecular epidemiology study of tuberculosis transmission in a high HIV-burden setting: the Botswana Kopanyo study

Introduction Mycobacterium tuberculosis (Mtb) is transmitted from person to person via airborne droplet nuclei. At the community level, Mtb transmission depends on the exposure venue, infectiousness of the tuberculosis (TB) index case and the susceptibility of the index cases social network. People living with HIV infection are at high risk of TB, yet the factors associated with TB transmission within communities with high rates of TB and HIV are largely undocumented. The primary aim of the Kopanyo study is to better understand the demographic, clinical, social and geospatial factors associated with TB and multidrug-resistant TB transmission in 2 communities in Botswana, a country where 60% of all patients with TB are also infected with HIV. This manuscript describes the methods used in the Kopanyo study. Methods and analysis The study will be conducted in greater Gaborone, which has high rates of HIV and a mobile population; and in Ghanzi, a rural community with lower prevalence of HIV infection and home to the native San population. Kopanyo aims to enrol all persons diagnosed with TB during a 4-year study period. From each participant, sputum will be cultured, and for all Mtb isolates, molecular genotyping (24-locus mycobacterial interspersed repetitive units-variable number of tandem repeats) will be performed. Patients with matching genotype results will be considered members of a genotype cluster, a proxy for recent transmission. Demographic, behavioural, clinical and social information will be collected by interview. Participant residence, work place, healthcare facilities visited and social gathering venues will be geocoded. We will assess relationships between these factors and cluster involvement to better plan interventions for reducing TB transmission. Ethics Ethical approval from the Independent Review Boards at the University of Pennsylvania, US Centers for Disease Control and Prevention, Botswana Ministry of Health and University of Botswana has been obtained.