Patrick K. Moonan

Characterization of a Mycobacterium tuberculosis peptide that is recognized by human CD4+ and CD8+ T cells in the context of multiple HLA alleles

The secreted Mycobacterium tuberculosis 10-kDa culture filtrate protein (CFP)10 is a potent T cell Ag that is recognized by a high percentage of persons infected with M. tuberculosis. We determined the molecular basis for this widespread recognition by identifying and characterizing a 15-mer peptide, CFP1071–85, that elicited IFN-γ production and CTL activity by both CD4+ and CD8+ T cells from persons expressing multiple MHC class II and class I molecules, respectively. CFP1071–85 contained at least two epitopes, one of 10 aa (peptide T1) and another of 9 aa (peptide T6). T1 was recognized by CD4+ cells in the context of DRB1*04, DR5*0101, and DQB1*03, and by CD8+ cells of A2+ donors. T6 elicited responses by CD4+ cells in the context of DRB1*04 and DQB1*03, and by CD8+ cells of B35+ donors. Deleting a single amino acid from the amino or carboxy terminus of either peptide markedly reduced IFN-γ production, suggesting that they are minimal epitopes for both CD4+ and CD8+ cells. As far as we are aware, these are the shortest microbial peptides that have been found to elicit responses by both T cell subpopulations. The capacity of CFP1071–85 to stimulate IFN-γ production and CTL activity by CD4+ and CD8+ cells from persons expressing a spectrum of MHC molecules suggests that this peptide is an excellent candidate for inclusion in a subunit antituberculosis vaccine.

Does Alcohol Consumption during Multidrug-resistant Tuberculosis Treatment Affect Outcome?. A Population-based Study in Kerala, India

RATIONALE India reports the largest number of multidrug-resistant tuberculosis cases in the world; yet, no longitudinal study has assessed factors related to treatment outcomes under programmatic conditions in the public sector. OBJECTIVES To describe demographic, clinical, and risk characteristics associated with treatment outcomes for all patients with multidrug-resistant tuberculosis registered in the Revised National Tuberculosis Control Programme, Kerala State, India from January 1, 2009 to June 30, 2010. METHODS Cox regression methods were used to calculate adjusted hazard ratios with 95% confidence intervals (CIs) to assess factors associated with an unsuccessful treatment outcome. MEASUREMENTS AND MAIN RESULTS Of 179 patients with multidrug-resistant tuberculosis registered, 112 (63%) had successful treatment outcomes (77 bacteriologically cured, 35 treatment completed) and 67 (37%) had unsuccessful treatment outcomes (30 died, 26 defaulted, 9 failed treatment, 1 stopped treatment because of drug-related adverse events, and 1 developed extensively drug-resistant tuberculosis). The hazard for unsuccessful outcome was significantly higher among patients who consumed alcohol during treatment (adjusted hazard ratio, 4.3; 95% CI, 1.1-17.6) than those who did not. Persons who consumed alcohol during treatment, on average, missed 18 more intensive-phase doses (95% CI, 13-22) than those who did not. Although many patients had diabetes (33%), were ever smokers (39%), or had low body mass index (47%), these factors were not associated with outcome. CONCLUSION Overall treatment success was greater than global and national averages; however, outcomes among patients consuming alcohol remained poor. Integration of care for multidrug-resistant tuberculosis and alcoholism should be considered to improve treatment adherence and outcomes.

Underuse of Effective Measures to Prevent and Manage Pediatric Tuberculosis in the United States

OBJECTIVE To characterize problems with prevention and management of pediatric tuberculosis (TB) and latent TB infection (LTBI). DESIGN A multisite, cross-sectional study using data from medical records and public health logs to categorize and define use of routine prevention practices in managing pediatric TB and LTBI. SETTING Four areas of the United States. PARTICIPANTS Children younger than 5 years diagnosed with TB from January 1, 2002, through December 31, 2004, and children with LTBI reported during a continuous 12-month period in 2003 to 2004. Main Exposure Mycobacterium tuberculosis. MAIN OUTCOME MEASURES Underuse or nonuse of standard medical and public health interventions. RESULTS Almost 40% of children had a TB risk factor related to their country of birth, parental origin, or travel to a country with a high incidence of TB. Children having LTBI were less likely than those having TB to complete treatment (53.7% vs 88.6%, respectively). Almost half (46.3%) of the children with TB came to medical attention late in their course when they already had symptoms. Among 63 adult source patients, 19 (30.2%) previously had LTBI but were not treated, and none of the 40 foreign-born source patients were known to have been evaluated for TB before entry into the United States. CONCLUSIONS Prevention efforts are unsatisfactory to prevent TB in children. Effective interventions such as treatment of LTBI and TB evaluation of adult immigrants remain less than optimal.

Impact of awareness drives and community-based active tuberculosis case finding in Odisha, India.

Indias Revised National Tuberculosis Control programme employs passive case detection. The new sputum smear-positive case detection rate is less than 70% in Odisha State. During April-June 2012, active case finding (ACF) was conducted through awareness drives and field-based tuberculosis (TB) screening in select communities with the lowest case detection rates. During the campaign, 240 sputum smear-positive TB cases were detected. The number of smear-positive cases detected increased by 11% relative to April-June 2011 in intervention communities compared to an 0.8% increase in non-intervention communities. ACF brought TB services closer to the community and increased TB case detection.

Tuberculosis and excess alcohol use in the United States, 1997-2012.

BACKGROUND Excess alcohol use among tuberculosis (TB) patients complicates TB control strategies. OBJECTIVES To characterize the role of excess alcohol use in TB control, we describe the epidemiology of excess alcohol use and TB in the United States among those aged ⩾15 years. DESIGN Using data reported to the National Tuberculosis Surveillance System, 1997-2012, we examined associations between excess alcohol use and TB treatment outcomes and markers for increased transmission (involvement in a local genotype cluster of cases) using multivariate logistic regression. We used Cox proportional hazards regression analysis to examine the relationship between excess alcohol use and the rate of conversion from positive to negative in sputum culture results. RESULTS Excess alcohol use was documented for 31 207 (15.1%) of 207 307 patients. Prevalence of excess alcohol use was greater among male patients (20.6%) and US-born patients (24.6%). Excess alcohol use was associated with a positive sputum smear result (aOR 1.23, 95%CI 1.18-1.28) and death during treatment (vs. completion of treatment) (aOR 1.16, 95%CI 1.10-1.22). The rate of culture conversion was higher among patients without excess alcohol use (adjusted hazard ratio 1.20, 95%CI 1.18-1.23). CONCLUSIONS Excess alcohol use was common among patients with TB, and was associated with TB transmission, lower rates of sputum culture conversion, and greater mortality.

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.

Two tuberculosis genotyping clusters, one preventable outbreak.

In 2006, eight community tuberculosis (TB) cases and a ninth incarceration-related case were identified during an outbreak investigation, which included genotyping of all Mycobacterium tuberculosis isolates. In 1996, the source patient had pulmonary TB but completed only two weeks of treatment. From February 2005 to May 2006, the source patient lived in four different locations while contagious. The outbreak cases had matching isolate spoligotypes; however, the mycobacterial interspersed repetitive unit (MIRU) patterns from isolates from two secondary cases differed by one tandem repeat at a single MIRU locus. The source patients isolates showed a mixed mycobacterial population with both MIRU patterns. Traditional and molecular epidemiologic methods linked eight secondary TB cases to a single source patient whose incomplete initial treatment, incarceration, delayed diagnosis, and housing instability resulted in extensive transmission. Adequate treatment of the source patients initial TB or early diagnosis of recurrent TB could have prevented this outbreak.

Decline in tuberculosis among Mexico-born persons in the United States, 2000-2010.

BACKGROUND In 2010, Mexico was the most common (22.9%) country of origin for foreign-born persons with tuberculosis in the United States, and overall trends in tuberculosis morbidity are substantially influenced by the Mexico-born population. OBJECTIVES To determine the risk of tuberculosis disease among Mexico-born persons living in the United States. METHODS Using data from the U.S. National Tuberculosis Surveillance System and the American Community Survey, we examined tuberculosis case counts and case rates stratified by years since entry into the United States and geographic proximity to the United States-Mexico border. We calculated trends in case rates over time measured by average annual percent change. RESULTS The total tuberculosis case count (-14.5%) and annual tuberculosis case rate (average annual percent change -5.1%) declined among Mexico-born persons. Among those diagnosed with tuberculosis less than 1 year since entry into the United States (newly arrived persons), there was a decrease in tuberculosis cases (-60.4%), no change in tuberculosis case rate (average annual percent change of 0.0%), and a decrease in population (-60.7%). Among those living in the United States for more than 5 years (non-recently arrived persons), there was an increase in tuberculosis cases (+3.4%), a decrease in tuberculosis case rate (average annual percent change of -4.9%), and an increase in population (+62.7%). In 2010, 66.7% of Mexico-born cases were among non-recently arrived persons, compared with 51.1% in 2000. Although border states reported the highest proportions (>15%) of tuberculosis cases that were Mexico-born, the highest Mexico-born-specific tuberculosis case rates (>20/100,000 population) were in states in the eastern and southeastern regions of the United States. CONCLUSIONS The decline in tuberculosis morbidity among Mexico-born persons may be attributed to fewer newly arrived persons from Mexico and lower tuberculosis case rates among non-recently arrived Mexico-born persons. The extent of the decline was dampened by an unchanged tuberculosis case rate among newly arrived persons from Mexico and a large increase in the non-recently arrived Mexico-born population. If current trends continue, tuberculosis morbidity among Mexico-born persons will be increasingly driven by those who have been living in the United States for more than 5 years.

Evaluation of TB Case Finding through Systematic Contact Investigation, Chhattisgarh, India

Rationale. Contact investigation is an established tool for early case detection of tuberculosis (TB). In India, contact investigation is not often conducted, despite national policy, and the yield of contact investigation is not well described. Objective. To determine the yield of evaluating household contacts of sputum smear-positive TB cases in Rajnandgaon district, Chhattisgarh, India. Methods. Among 14 public health care facilities with sputum smear microscopy services, home visits were conducted to identify household contacts of all registered sputum smear-positive TB cases. We used a standardized protocol to screen for clinical symptoms suggestive of active TB with additional referral for chest radiograph and sputa collection. Results. From December 2010 to May 2011, 1,556 household contacts of 312 sputum smear-positive TB cases were identified, of which 148 (9.5%) were symptomatic. Among these, 109 (73.6%) were evaluated by sputum examination resulting in 11 cases (10.1%) of sputum smear-positive TB and 4 cases (3.6%) of smear-negative TB. Household visits contributed additional 63% TB cases compared to passive case detection alone. Conclusion. A standard procedure for conducting household contact investigation identified additional TB cases in the community and offered an opportunity to initiate isoniazid chemoprophylaxis among children.

Use of tuberculosis genotyping for postoutbreak monitoring.

CONTEXT Review of routinely collected tuberculosis genotyping results following a known outbreak is a potential mechanism to examine the effectiveness of outbreak control measures. OBJECTIVE To assess differences in characteristics between outbreak and postoutbreak tuberculosis cases. DESIGN Retrospective. SETTING United States. PARTICIPANTS All tuberculosis cases identified as a result of >5-person outbreaks investigated by the Centers for Disease Control and Prevention during 2003 to 2007 (original outbreak cases), and subsequent culture-positive tuberculosis cases with matching Mycobacterium tuberculosis genotypes reported in the same county during 2004 to 2008 (postoutbreak cases). MAIN OUTCOME MEASURE Proportion of demographic, social, and clinical characteristics of tuberculosis outbreak cases compared to postoutbreak cases. SECONDARY: Proportion of demographic, social, and clinical characteristics of epidemiologically linked versus nonlinked cases. RESULTS Six outbreaks with 111 outbreak cases and 110 postoutbreak cases were identified. Differences between outbreak and postoutbreak cases were gender (69% vs 85% male; P < .01), birth origin (3% vs 11% foreign-born; P = .02), disease severity (48% vs 62% sputum smear-positive; P = .04), homelessness (38% vs 51%; P = .05), and injection drug use (4% vs 11%; P = .04). For 5 of the 6 outbreaks, the status of epidemiologic relationships among postoutbreak cases was available (n = 89). The postoutbreak cases with a known epidemiologic link to the original outbreak were in younger persons (aged 39 vs 47 years; P < .01), and a larger proportion reported injection drug use (18% vs 4%; P = .04) or noninjection drug use (44% vs 18%; P < .01) than those without a reported link. CONCLUSIONS Health jurisdictions can utilize genotyping data to monitor and define the characteristics of postoutbreak cases related to the original outbreak.