When Tuberculosis Comes Back: Who Develops Recurrent Tuberculosis in California?

Background

Recurrent tuberculosis suggests potentially modifiable gaps in tuberculosis treatment and control activities. The frequency of late recurrences following treatment completion has not been well-studied. We determined the frequency of, and risk factors associated with, tuberculosis that recurs at least one year after completion of anti-tuberculosis therapy in California.

Methods

The study population included culture-positive, pulmonary tuberculosis patients reported to the California tuberculosis case registry from 1993 to 2007 who completed anti-tuberculosis therapy. A person with late recurrent tuberculosis was defined as an individual that appeared in the registry more than once, determined by match on name and date-of-birth, with at least one year between treatment completion of the first episode and treatment initiation of the second episode.

Results

Among 23,517 tuberculosis patients, 148 (0.63%) had a late recurrence. Independent risk factors for recurrence included: infection with a pyrazinamide mono-resistant isolate (adjusted hazard ratio, 2.93; p = 0.019); initiation of an isoniazid- and rifampin-only treatment regimen (adjusted hazard ratio, 2.55; p = 0.0412); sputum smear-positive disease (adjusted hazard ratio, 1.96; p = 0.0003); human immunodeficiency virus infection (adjusted hazard ratio, 1.81; p = 0.0149); and birth in the United States (adjusted hazard ratio, 1.88; p = 0.0002). Infection with an isoniazid mono-resistant isolate was protective (adjusted hazard ratio, 0.25; p = 0.0171).

Conclusions

The low frequency of late recurrent tuberculosis in California suggests that local TB control programs are largely successful at preventing this adverse outcome. Nonetheless, we identified subpopulations at increased risk of late tuberculosis recurrence that may benefit from additional medical or public health interventions.     

Tuberculosis Screening by Tuberculosis Skin Test or QuantiFERON?-TB Gold In-Tube Assay among an Immigrant Population with a High Prevalence of Tuberculosis and BCG Vaccination

Rationale

Each year 1 million persons acquire permanent U.S. residency visas after tuberculosis (TB) screening. Most applicants undergo a 2-stage screening with tuberculin skin test (TST) followed by CXR only if TST-positive at > 5 mm. Due to cross reaction with bacillus Calmette-Guérin (BCG), TST may yield false positive results in BCG-vaccinated persons. Interferon gamma release assays exclude antigens found in BCG. In Vietnam, like most high TB-prevalence countries, there is universal BCG vaccination at birth.

Objectives

1. Compare the sensitivity of QuantiFERON ®-TB Gold In-Tube Assay (QFT) and TST for culture-positive pulmonary TB. 2. Compare the age-specific and overall prevalence of positive TST and QFT among applicants with normal and abnormal CXR.

Methods

We obtained TST and QFT results on 996 applicants with abnormal CXR, of whom 132 had TB, and 479 with normal CXR.

Results

The sensitivity for tuberculosis was 86.4% for QFT; 89.4%, 81.1%, and 52.3% for TST at 5, 10, and 15 mm. The estimated prevalence of positive results at age 15–19 years was 22% and 42% for QFT and TST at 10 mm, respectively. The prevalence increased thereafter by 0.7% year of age for TST and 2.1% for QFT, the latter being more consistent with the increase in TB among applicants.

Conclusions

During 2-stage screening, QFT is as sensitive as TST in detecting TB with fewer requiring CXR and being diagnosed with LTBI. These data support the use of QFT over TST in this population.      

Association of Pulmonary Tuberculosis and Diabetes in Mexico: Analysis of the National Tuberculosis Registry 2000–2012

Background

Tuberculosis (TB) remains a public health problem in Mexico while the incidence of diabetes mellitus type 2 (DM) has increased rapidly in recent years.

Objective

To describe the trends of incidence rates of pulmonary TB associated with DM and not associated with DM and to compare the results of treatment outcomes in patients with and without DM.

Materials and Methods

We analysed the National Tuberculosis Registry from 2000 to 2012 including patients with pulmonary TB among individuals older than 20 years of age. The association between DM and treatment failure was analysed using logistic regression, accounting for clustering due to regional distribution.

Results

In Mexico from 2000 to 2012, the incidence rates of pulmonary TB associated to DM increased by 82.64%, (p <0.001) in contrast to rates of pulmonary TB rate without DM, which decreased by 26.77%, (p <0.001). Patients with a prior diagnosis of DM had a greater likelihood of failing treatment (adjusted odds ratio, 1.34 (1.11–1.61) p <0.002) compared with patients who did not have DM. There was statistical evidence of interaction between DM and sex. The odds of treatment failure were increased in both sexes.

Conclusion

Our data suggest that the growing DM epidemic has an impact on the rates of pulmonary TB. In addition, patients who suffer from both diseases have a greater probability of treatment failure.     

Multi Drug and Other Forms of Drug Resistant Tuberculosis Are Uncommon among Treatment Na?ve Tuberculosis Patients in Tanzania

Background

Surveillance and effective management of drug resistance is important to sustaining tuberculosis (TB) control efforts. We aimed to determine resistance rates to first line anti tuberculosis drugs and to describe factors associated with the resistance to any of the first line anti tuberculosis drugs in Dar es Salaam Tanzania.

Materials

Newly diagnosed, TB patients with neither history of tuberculosis treatment nor isoniazid prophylaxis were included into the study. Sputum specimens were cultured on either mycobacteria growth indicator tube 960 (MGIT 960) or Lowenstein Jenstein (LJ) medium supplemented with either glycerol (GLJ) or pyruvate (PLJ). Drug susceptibility for isoniazid, rifampicin, streptomycin and ethambutol was determined by either Lowenstein–Jensen (LJ) medium or mycobacteria growth indicator tube 960 (MGIT 960).

Results

A total of 933 newly diagnosed TB patients, were included into the study. Multi drug resistance (MDR) tuberculosis was detected among 2 (0.2%) patients. Resistance to any of the four tested drugs was detected among 54 (5.8%) patients. Mono-resistance to isoniazid, rifampicin, streptomycin and ethambutol were 21(2.3%), 3 (0.3%), 13 (1.4%), 9 (1.0%) respectively.

Conclusion

Primary resistance to first line anti tuberculosis drugs is still low in this setting. Continued vigilance including periodic national surveillance of anti-tuberculosis resistance is recommended.     

A Field Evaluation of the Hardy TB MODS Kit? for the Rapid Phenotypic Diagnosis of Tuberculosis and Multi-Drug Resistant Tuberculosis

Background

Even though the WHO-endorsed, non-commercial MODS assay offers rapid, reliable TB liquid culture and phenotypic drug susceptibility testing (DST) at lower cost than any other diagnostic, uptake has been patchy. In part this reflects misperceptions about in-house assay quality assurance, but user convenience of one-stop procurement is also important. A commercial MODS kit was developed by Hardy Diagnostics (Santa Maria, CA, USA) with PATH (Seattle, WA, USA) to facilitate procurement, simplify procedures through readymade media, and enhance safety with a sealing silicone plate lid. Here we report the results from a large-scale field evaluation of the MODS kit in a government service laboratory.

Methods & Findings

2446 sputum samples were cultured in parallel in Lowenstein-Jensen (LJ), conventional MODS and in the MODS kit. MODS kit DST was compared with conventional MODS (direct) DST and proportion method (indirect) DST. 778 samples (31.8%) were Mycobacterium tuberculosis culture-positive. Compared to conventional MODS the sensitivity, specificity, positive, and negative predictive values (95% confidence intervals) of the MODS Kit were 99.3% (98.3–99.8%), 98.3% (97.5–98.8%), 95.8% (94.0–97.1%), and 99.7% (99.3–99.9%). Median (interquartile ranges) time to culture-positivity (and rifampicin and isoniazid DST) was 10 (9–13) days for conventional MODS and 8.5 (7–11) for MODS Kit (p<0.01). Direct rifampicin and isoniazid DST in MODS kit was almost universally concordant with conventional MODS (97.9% agreement, 665/679 evaluable samples) and reference indirect DST (97.9% agreement, 687/702 evaluable samples).

Conclusions

MODS kit delivers performance indistinguishable from conventional MODS and offers a convenient, affordable alternative with enhanced safety from the sealing silicone lid. The availability in the marketplace of this platform, which conforms to European standards (CE-marked), readily repurposed for second-line DST in the near future, provides a fresh opportunity for improving equity of access to TB diagnosis and first and second-line DST in settings where the need is greatest.     

Negotiating “The Social” and Managing Tuberculosis in Georgia

In this paper I utilize anthropological insights to illuminate how health professionals and patients navigate and negotiate what for them is social about tuberculosis in order to improve treatment outcomes and support patients as human beings. I draw on ethnographic research about the implementation of the DOTS (Directly Observed Therapy, Short Course) approach in Georgia’s National Tuberculosis Program in the wake of the Soviet healthcare system. Georgia is a particularly unique context for exploring these issues given the country’s rich history of medical professionalism and the insistence that the practice of medicine is a moral commitment to society. I argue for critical attention to the ways in which treatment recipients and providers navigate what, for them, is “social” about therapeutic practices and their significance for avoiding biological and social reductionism.     

Immunomodulation with Recombinant Interferon-γ1b in Pulmonary Tuberculosis

Background

Current treatment regimens for pulmonary tuberculosis require at least 6 months of therapy. Immune adjuvant therapy with recombinant interferon-γ1b (rIFN-γb) may reduce pulmonary inflammation and reduce the period of infectivity by promoting earlier sputum clearance.

Methodology/Principal Findings

We performed a randomized, controlled clinical trial of directly observed therapy (DOTS) versus DOTS supplemented with nebulized or subcutaneously administered rIFN-γ1b over 4 months to 89 patients with cavitary pulmonary tuberculosis. Bronchoalveolar lavage (BAL) and blood were sampled at 0 and 4 months. There was a significant decline in levels of inflammatory cytokines IL-1β, IL-6, IL-8, and IL-10 in 24-hour BAL supernatants only in the nebulized rIFN-γ1b group from baseline to week 16. Both rIFN-γ1b groups showed significant 3-fold increases in CD4+ lymphocyte response to PPD at 4 weeks. There was a significant (p = 0.03) difference in the rate of clearance of Mtb from the sputum smear at 4 weeks for the nebulized rIFN-γ1b adjuvant group compared to DOTS or DOTS with subcutaneous rIFN-γ1b. In addition, there was significant reduction in the prevalence of fever, wheeze, and night sweats at 4 weeks among patients receiving rFN-γ1b versus DOTS alone.

Conclusion

Recombinant interferon-γ1b adjuvant therapy plus DOTS in cavitary pulmonary tuberculosis can reduce inflammatory cytokines at the site of disease, improve clearance of Mtb from the sputum, and improve constitutional symptoms.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00201123","term_id":"NCT00201123"}}NCT00201123     

HIV Seroprevalence among Tuberculosis Patients in India, 2006–2007

Background

Little information exists regarding the burden of HIV among tuberculosis patients in India, and no population-based surveys have been previously reported. A community-based HIV prevalence survey was conducted among tuberculosis patients treated by the national tuberculosis control programme to evaluate the HIV prevalence among tuberculosis patients in India.

Methodology/Principal Findings

Fifteen districts (total population: 40.2 million) across 8 states were stratified by HIV prevalence in antenatal clinic HIV surveillance sites and randomly selected. From December 2006 to May 2007, remnant serum was collected from patients'' clinical specimens taken after 2 months of anti-tuberculosis treatment and subjected to anonymous, unlinked HIV testing. Specimens were obtained and successfully tested for 5,995 (73%) of 8,217 tuberculosis patients eligible for the survey. HIV prevalence ranged widely among the 15 surveyed districts, from 1% in Koch Bihar, West Bengal, to 13.8% in Guntur, Andhra Pradesh. HIV infection was 1.3 times more likely among male TB patients than among female patients. Relative to smear-positive tuberculosis, HIV infection was 1.4 times more likely among smear-negative patients and 1.3 times more likely among extrapulmonary patients. In 4 higher-HIV prevalence districts, which had been previously surveyed in 2005–2006, no significant change in HIV prevalence was detected.

Conclusions

The burden of HIV among tuberculosis patients varies widely in India. Programme efforts to implement comprehensive TB-HIV services should be targeted to areas with the highest HIV burden. Surveillance through routine reporting or special surveys is necessary to detect areas requiring intensification of TB-HIV collaborative activities.     

Host-Directed Therapeutics for Tuberculosis: Can We Harness the Host?

SUMMARY

Treatment of tuberculosis (TB) remains challenging, with lengthy treatment durations and complex drug regimens that are toxic and difficult to administer. Similar to the vast majority of antibiotics, drugs for Mycobacterium tuberculosis are directed against microbial targets. Although more effective drugs that target the bacterium may lead to faster cure of patients, it is possible that a biological limit will be reached that can be overcome only by adopting a fundamentally new treatment approach. TB regimens might be improved by including agents that target host pathways. Recent work on host-pathogen interactions, host immunity, and host-directed interventions suggests that supplementing anti-TB therapy with host modulators may lead to shorter treatment times, a reduction in lung damage caused by the disease, and a lower risk of relapse or reinfection. We undertook this review to identify molecular pathways of the host that may be amenable to modulation by small molecules for the treatment of TB. Although several approaches to augmenting standard TB treatment have been proposed, only a few have been explored in detail or advanced to preclinical and clinical studies. Our review focuses on molecular targets and inhibitory small molecules that function within the macrophage or other myeloid cells, on host inflammatory pathways, or at the level of TB-induced lung pathology.     

Enhanced Tuberculosis Infection Treatment Outcomes after Implementation of QuantiFERON?-Gold Testing

Background

Use of the tuberculin skin test (TST) for diagnosis of latent tuberculosis infection (LTBI) among individuals who received the Bacille Calmette-Guérin (BCG) vaccine is complicated by its potential cross-reaction with TST antigens which may cause false-positive results and lead to patient and physician reluctance to initiate LTBI treatment. QuantiFERON®-TB Gold (QFT-G) lacks this cross-reaction. We sought to study the impact of implementing QFT-G testing in 2006 on LTBI treatment initiation and completion at NYC chest clinics.

Methods

QFT-G results from 10/2006–12/2008 in NYC Department of Health and Mental Hygiene chest clinics were obtained from the electronic medical record system. The proportions of patients who initiated and completed treatment among patients tested with QFT-G were compared to those tested with TST from 10/2004–9/2006.

Results

Among 36,167 patients tested with QFT-G, 2,300 (6%) tested positive, 33,327 (93%) tested negative, and 540 (1%) had an indeterminate result. Among those who had a positive QFT-G test and deemed eligible, 985 (80%) initiated LTBI treatment and 490 (40%) completed treatment. Historically, among patients tested with TST, 7,073 (19%) tested positive (p<0.0001 compared to QFT-G); 3,182 (79%) of those eligible initiated LTBI treatment and 1,210 (30%) completed treatment (p<0.0001 compared to QFT-G).

Conclusions

QFT-G implementation increased the proportion of patients completing LTBI treatment. Additional studies are needed in more settings to determine whether using QFT-G leads to a sustained increase in treatment completion.     

HIV Infection Disrupts the Sympatric Host–Pathogen Relationship in Human Tuberculosis

The phylogeographic population structure of Mycobacterium tuberculosis suggests local adaptation to sympatric human populations. We hypothesized that HIV infection, which induces immunodeficiency, will alter the sympatric relationship between M. tuberculosis and its human host. To test this hypothesis, we performed a nine-year nation-wide molecular-epidemiological study of HIV–infected and HIV–negative patients with tuberculosis (TB) between 2000 and 2008 in Switzerland. We analyzed 518 TB patients of whom 112 (21.6%) were HIV–infected and 233 (45.0%) were born in Europe. We found that among European-born TB patients, recent transmission was more likely to occur in sympatric compared to allopatric host–pathogen combinations (adjusted odds ratio [OR] 7.5, 95% confidence interval [95% CI] 1.21–infinity, p = 0.03). HIV infection was significantly associated with TB caused by an allopatric (as opposed to sympatric) M. tuberculosis lineage (OR 7.0, 95% CI 2.5–19.1, p<0.0001). This association remained when adjusting for frequent travelling, contact with foreigners, age, sex, and country of birth (adjusted OR 5.6, 95% CI 1.5–20.8, p = 0.01). Moreover, it became stronger with greater immunosuppression as defined by CD4 T-cell depletion and was not the result of increased social mixing in HIV–infected patients. Our observation was replicated in a second independent panel of 440 M. tuberculosis strains collected during a population-based study in the Canton of Bern between 1991 and 2011. In summary, these findings support a model for TB in which the stable relationship between the human host and its locally adapted M. tuberculosis is disrupted by HIV infection.     

Which Urban Migrants Default from Tuberculosis Treatment in Shanghai,China?

Background

Migration is a major challenge to tuberculosis (TB) control worldwide. TB treatment requires multiple drugs for at least six months. Some TB patients default before completing their treatment regimen, which can lead to ongoing infectiousness and drug resistance.

Methods

We conducted a retrospective analysis of 29,943 active TB cases among urban migrants that were reported between 2000 to 2008 in Shanghai, China. We used logistic regression models to identify factors independently associated with treatment defaults in TB patients among urban migrants during 2005-2008.

Results

Fifty-two percent of the total TB patients reported in Shanghai during the study period were among urban migrants. Three factors increased the odds of a treatment default: case management using self-administered therapy (OR, 5.84, 95% CI, 3.14-10.86, p<0.0005), being a retreatment case (OR, 1.47, 95% CI, 1.25-1.71, p<0.0005), and age >60 years old (OR, 1.33, 95% CI, 1.05-1.67, p=0.017). The presence of a cavity in the initial chest radiograph decreased the odds for a treatment default (OR, 0.87, 95% CI, 0.77-0.97, p=0.015), as did migration from central China (OR, 0.85, 95% CI, 0.73-0.99, p=0.042), case management by family members (OR, 0.73, 95% CI 0.66-0.81, p<0.0005), and the combination of case detection by a required physical exam and case management by health care staff (OR, 0.64, 95% CI, 0.45-0.93, p=0.019).

Conclusion

Among TB patients who were urban migrants in Shanghai, case management using self-administered therapy was the strongest modifiable risk factor that was independently associated with treatment defaults. Interventions that target retreated TB cases could also reduce treatment defaults among urban migrants. Health departments should develop effective measures to prevent treatment defaults among urban migrants, to ensure completion of therapy among urban migrants who move between cities and provinces, and to improve reporting of treatment outcomes.