Roger Calderon

The Effect of HIV-Related Immunosuppression on the Risk of Tuberculosis Transmission to Household Contacts

BACKGROUND Coinfection with human immunodeficiency virus (HIV) may modify the risk of transmitting tuberculosis. Some previous investigations suggest that patients coinfected with HIV and tuberculosis are less likely to transmit infection, whereas others do not support this conclusion. Here, we estimated the relative risk of tuberculosis transmission from coinfected patients compared to HIV-negative patients with tuberculosis. METHODS Between September 2009 and August 2012, we identified and enrolled 4841 household contacts of 1608 patients with drug-sensitive tuberculosis in Lima, Peru. We assessed the HIV status and CD4 counts of index patients, as well as other risk factors for infection specific to the index patient, the household, and the exposed individuals. Contacts underwent tuberculin skin testing to determine tuberculosis infection status. RESULTS After adjusting for covariates, we found that household contacts of HIV-infected tuberculosis patients with a CD4 count ≤250 cells/µL were less likely to be infected with tuberculosis (risk ratio = 0.49 [95% confidence interval, .24-.96]) than the contacts of HIV-negative tuberculosis patients. No children younger than 15 years who were exposed to HIV-positive patients with a CD4 count ≤250 cells/µL were infected with tuberculosis, compared to 22% of those exposed to non-HIV-infected patients. There was no significant difference in the risk of infection between contacts of HIV-infected index patients with CD4 counts >250 cells/µL and contacts of index patients who were not HIV-infected. CONCLUSIONS We found a reduced risk of tuberculosis infection among the household contacts of patients with active tuberculosis who had advanced HIV-related immunosuppression, suggesting reduced transmission from these index patients.

Bacillus Calmette-Guérin and Isoniazid Preventive Therapy Protect Contacts of Patients with Tuberculosis

RATIONALE Individuals living with patients with tuberculosis (TB) are at elevated risk of infection and disease, with children at greatest risk. The World Health Organization recommends isoniazid preventive therapy (IPT) for HIV-positive contacts and those younger than 5 years. Despite these recommendations, household-level IPT programs are rarely implemented in high TB burden settings. Evidence is scarce about the age-specific efficacy of interventions, such as IPT and bacillus Calmette-Guérin (BCG) vaccination for preventing TB disease among exposed contacts. OBJECTIVES We estimate the age-specific efficacy of IPT and BCG for preventing TB disease using data from a large observational prospective cohort study of household contacts of patients with TB in Lima, Peru. METHODS We identified all adults (>15 yr) with incident pulmonary TB (index cases) diagnosed at 106 public health centers in Lima from September 2009 to August 2012. Among 14,041 household contacts (of 3,446 index cases) assessed for infection and disease during the year-long follow-up period, we identified 462 additional TB cases. We estimate risk ratios (RR) for pulmonary TB associated with BCG, IPT, and latent TB infection. MEASUREMENTS AND MAIN RESULTS BCG confers protection against coprevalent and incident TB among HIV-negative children younger than 10 years (RR, 0.35; 95% confidence interval, 0.19-0.66). IPT confers protection against incident TB among HIV-negative contacts younger than 30 years (RR, 0.33; 95% confidence interval, 0.20-0.54). Risk of incident TB associated with latent TB infection is greatest for children younger than 5 years and decreases with age. CONCLUSIONS These findings support the use of IPT in older children and young-adult household contacts, in addition to children younger than 5 years.

Cigarette smoking among tuberculosis patients increases risk of transmission to child contacts.

SETTING Observational cohort study in Lima, Peru. OBJECTIVE To determine the association between exposure to a smoking tuberculosis (TB) case and latent tuberculous infection (LTBI). METHOD Between September 2009 and August 2012, we identified 2132 patients with drug-susceptible TB and their 2054 child household contacts. Data were collected on active and secondhand smoking status and other risk factors for infection specific to the index case, the household and the exposed contacts. Contacts underwent a tuberculin skin test (TST) to determine their tuberculous infection status at baseline, 6-month and 12-month follow-up. We estimated the association between exposure to a smoking index case and LTBI using a modified Poisson regression model. RESULTS The 21 children (age ⩿15 years) exposed to smoking index TB patients were more likely to be TST-positive at baseline (RR 2.64, 95%CI 1.78-3.91), by 6 months (RR 1.91, 95%CI 1.40-2.60) and by 12 months (RR 1.48, 95%CI 1.07-2.06), than those who were not exposed. TST positivity among children at these time points did not vary with secondhand smoke exposure. CONCLUSIONS TB patients who smoke may be more likely to transmit infection to their contacts. Interventions designed to reduce smoking among TB patients may minimise further spread of the disease.

Impact of Vitamin A and Carotenoids on the Risk of Tuberculosis Progression

Key Points Vitamin A deficiency was associated with a 10-fold increase in risk of developing TB disease after household exposure. Vitamin A supplementation among high risk individuals might represent an effective means of preventing progression from TB infection to TB disease.

Age-Specific Risks of Tuberculosis Infection From Household and Community Exposures and Opportunities for Interventions in a High-Burden Setting

We analyzed data from a large population-based prospective cohort study of household contacts of tuberculosis patients in Lima, Peru, to estimate the importance of within-household transmission relative to community-based transmission. We identified all adults (older than 15 years of age) who had incident pulmonary tuberculosis diagnosed at any of 106 public health centers in Lima from September 2009 to August 2012. A total of 14,041 household contacts of 3,446 index patients were assessed for tuberculosis infection and disease. We compared the prevalence of latent tuberculosis infection (LTBI) among persons who had received the Bacillus Calmette-Guérin vaccine in households with and without a microbiologically confirmed index case to estimate the age-specific risk of infection and excess risk of LTBI from household and community exposures. We found that the risk of infection from household and community sources increased from birth until 20 years of age. However, a large proportion of infections among child and young-adult household contacts could have been the result of household exposure. Excess infection risk associated with household exposure accounted for 58% (95% confidence interval: 47, 66) of LTBI prevalence among exposed children younger than 1 year of age, 48% (95% confidence interval: 39, 57) among 10-year-old children, and 44% (95% confidence interval: 34, 51) among 15-year-old adolescents. These findings suggest that expanded access to preventive therapy for older children and young-adult household contacts of known tuberculosis cases may be beneficial.

Pharmacokinetic Evidence from the HIRIF Trial To Support Increased Doses of Rifampin for Tuberculosis

ABSTRACT Rifamycins exhibit concentration-dependent killing of Mycobacterium tuberculosis; higher exposures potentially induce better outcomes. We randomized 180 tuberculosis patients in Peru to receive rifampin at 10, 15, or 20 mg/kg/day. A total of 168 had noncompartmental pharmacokinetic analyses; 67% were sampled twice, and 33% were sampled six times. The doses administered were well tolerated. The median area under the concentration-time curve from 0 to 6 h (interquartile range) was 24.9 (17.6 to 32.1), 43.1 (30.3 to 57.5), or 55.5 (35.7 to 73.2) h · μg/ml. The median maximum drug concentration in serum in the experimental arms reached the target of 8 μg/ml. Continued investigation of higher rifampin doses is warranted. (This study has been registered at ClinicalTrials.gov under registration no. NCT01408914.)

Acquired and Transmitted Multidrug Resistant Tuberculosis: The Role of Social Determinants.

Although risk factors for multi-drug resistant tuberculosis are known, few studies have differentiated between acquired and transmitted resistance. It is important to identify factors associated with these different mechanisms to optimize control measures. We conducted a prospective cohort study of index TB patients and their household contacts in Lima, Peru to identify risk factors associated with acquired and transmitted resistance, respectively. Patients with higher socioeconomic status (SES) had a 3-fold increased risk of transmitted resistance compared to those with lower SES when acquired resistance served as the baseline. Quality of housing mediated most of the impact of SES.

T cell autoreactivity directed toward CD1c itself rather than toward carried self lipids

The hallmark function of αβ T cell antigen receptors (TCRs) involves the highly specific co-recognition of a major histocompatibility complex molecule and its carried peptide. However, the molecular basis of the interactions of TCRs with the lipid antigen–presenting molecule CD1c is unknown. We identified frequent staining of human T cells with CD1c tetramers across numerous subjects. Whereas TCRs typically show high specificity for antigen, both tetramer binding and autoreactivity occurred with CD1c in complex with numerous, chemically diverse self lipids. Such extreme polyspecificity was attributable to binding of the TCR over the closed surface of CD1c, with the TCR covering the portal where lipids normally protrude. The TCR essentially failed to contact lipids because they were fully seated within CD1c. These data demonstrate the sequestration of lipids within CD1c as a mechanism of autoreactivity and point to small lipid size as a determinant of autoreactive T cell responses.CD1 molecules present diverse lipid ligands to TCRs expressed by NKT cells. Rossjohn, Moody and colleagues show a unique form of autoreactivity with human CD1c molecules, whereby TCRs recognize a closed conformation of CD1c molecules, which are loaded with a diverse array of ‘headless’ glycolipids.

Pyrazinamide Resistance Assays and Two-Month Sputum Culture Status in Patients with Multidrug-Resistant Tuberculosis

ABSTRACT Phenotypic drug susceptibility testing is the current “gold standard” for detecting Mycobacterium tuberculosis susceptibility to antituberculous drugs. Pyrazinamide is one antituberculous drug for which the correlation between in vitro resistance and clinical outcomes remains unclear. Here we performed latent class analysis (LCA) to develop a consensus gold standard definition of pyrazinamide resistance using three paired standard pyrazinamide resistance assays. We then compared this consensus measure to the 2-month culture results for patients with multidrug-resistant tuberculosis (MDR-TB) who were treated for 2 months with first-line antituberculous drugs before their resistance results were known. Among 121 patients with MDR-TB, 60 (49.6%) were resistant to pyrazinamide by the Wayne method (L. G. Wayne, Am Rev Respir Dis 109:147–151, 1974), 71 (58.7%) were resistant by the Bactec MGIT 960 method, and 68 (56.2%) were resistant by pncA sequencing. LCA grouped isolates with positive results by at least two assays into a category which we considered the “consensus gold standard” for pyrazinamide resistance. The sensitivity and specificity for this consensus gold standard were 82.4% and 92.5%, respectively, for the Wayne method; 95.6% and 88.7%, respectively, for the Bactec MGIT 960 method; and 92.6% and 90.6%, respectively, for pncA sequencing. After we adjusted for other factors associated with poor outcomes, including age, sex, alcohol use, and baseline ethambutol resistance, patients whose isolates were resistant by the LCA-derived consensus gold standard were more likely to be culture positive at 2 months with an odds ratio of 1.95 (95% confidence interval, 0.74 to 5.11), but this result was not statistically significant. These findings underscore the need for improved diagnostics for routine use in programmatic settings.

Nutritional Status and Tuberculosis Risk in Adult and Pediatric Household Contacts

Background Studies show obesity decreases risk of tuberculosis (TB) disease. There is limited evidence on whether high body mass index also protects against TB infection; how very high body mass indices influence TB risk; or whether nutritional status predicts this risk in children. We assessed the impact of body mass index on incident TB infection and disease among adults and children. Methods and Findings We conducted a prospective cohort study among household contacts of pulmonary TB cases in Lima, Peru. We determined body mass index at baseline and followed participants for one year for TB infection and disease. We used Cox proportional regression analyses to estimate hazard ratios for incident TB infection and disease. We enrolled 14,044 household contacts, and among 6853 negative for TB infection and disease at baseline, 1787 (26.1%) became infected. A total of 406 contacts developed secondary TB disease during follow-up. Body mass index did not predict risk of TB infection but overweight household contacts had significantly decreased risk of TB disease (HR 0.48; 95% CI 0.37–0.64; p <0.001) compared to those with normal weight. Among adults, body mass index ≥ 35 kg/m2 continued to predict a lower risk of TB disease (HR 0.30; 95% CI 0.12–0.74; p 0.009). We found no association between high body mass index and TB infection or disease among children under 12 years of age. Conclusions High body mass index protects adults against TB disease even at levels ≥ 35 kg/m2. This protective effect does not extend to TB infection and is not seen in children.