Cough-aerosol cultures of Mycobacterium tuberculosis in the prediction of outcomes after exposure. A household contact study in Brazil.

BACKGROUND:Mycobacterium tuberculosis cultures of cough-generated aerosols from patients with pulmonary tuberculosis (TB) are a quantitative method to measure infectiousness and to predict secondary outcomes in exposed contacts. However, their reproducibility has not been established. OBJECTIVE:To evaluate the predictive value of colony-forming units (CFU) of M. tuberculosis in cough aerosols on secondary infection and disease in household contacts in Brazil. METHODS:Adult sputum smear+ and culture+ pulmonary TB cases underwent a standard evaluation and were categorized according to aerosol CFU. We evaluated household contacts for infection at baseline and at 8 weeks with TST and IGRA, and secondary disease. RESULTS:We enrolled 48 index TB cases; 40% had negative aerosols, 27% low aerosols (<10 CFU) and 33% high aerosols (≥10 CFU). Of their 230 contacts, the proportion with a TST ≥10 mm at 8 weeks was 59%, 65% and 75%, respectively (p = 0.34). Contacts of high aerosol cases had greater IGRA readouts (median 4.6 IU/mL, IQR 0.02-10) when compared to those with low (0.8, 0.2-10) or no aerosol (0.1, 0-3.7; p = 0.08). IGRA readouts in TST converters of high aerosol cases (median 20 IU/mL, IQR 10-24) were larger than those from aerosol-negative (0.13, 0.04-3; p = o.o2). 8/9 (89%) culture+ secondary TB cases occurred in contacts of aerosol+ cases. CONCLUSION:Aerosol CFU predicts quantitatively IGRA readouts among household contacts of smear positive TB cases. Our results strengthen the argument of using cough aerosols to guide targeted preventive treatment strategies, a necessary component of current TB elimination projections

Importance of Cough and <i>M. tuberculosis</i> Strain Type as Risks for Increased Transmission within Households

<div><p>Rationale</p><p>The degree to which tuberculosis (TB) is transmitted between persons is variable. Identifying the factors that contribute to transmission could provide new opportunities for TB control. Transmission is influenced by host, bacterial and environmental factors. However, distinguishing their individual effects is problematic because measures of disease severity are tightly correlated, and assessing the virulence of <i>Mycobacterium tuberculosis</i> isolates is complicated by epidemiological and clinical confounders.</p><p>Objectives</p><p>To overcome these problems, we investigated factors potentially associated with TB transmission within households.</p><p>Methods</p><p>We evaluated patients with smear-positive (≥2+), pulmonary TB and classified <i>M. tuberculosis</i> strains into single nucleotide polymorphism genetic cluster groups (SCG). We recorded index case, household contact, and environmental characteristics and tested contacts with tuberculin skin test (TST) and interferon-gamma release assay. Households were classified as high (≥70% of contacts with TST≥10 mm) and low (≤40%) transmission. We used logistic regression to determine independent predictors.</p><p>Result</p><p>From March 2008 to June 2012, we screened 293 TB patients to enroll 124 index cases and their 731 contacts. There were 23 low and 73 high transmission households. Index case factors associated with high transmission were severity of cough as measured by a visual analog cough scale (VACS) and the Leicester Cough Questionnaire (LCQ), and cavitation on chest radiograph. SCG 3b strains tended to be more prevalent in low (27.3%) than in high (12.5%) transmission households (p = 0.11). In adjusted models, only VACS (p<0.001) remained significant. SCG was associated with bilateral disease on chest radiograph (p = 0.002) and marginally associated with LCQ sores (p = 0.058), with group 3b patients having weaker cough.</p><p>Conclusions</p><p>We found differential transmission among otherwise clinically similar patients with advanced TB disease. We propose that distinct strains may cause differing patterns of cough strength and cavitation in the host leading to diverging infectiousness. Larger studies are needed to verify this hypothesis.</p></div

Additional file 1: Table S1. of Incident Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis patients in Brazil

Additional characteristics of household contacts, index tuberculosis cases and study dwellings according to the tuberculin skin test (TST) outcome in contacts at study completion. (DOCX 20 kb

Additional file 2: Table S2. of Incident Mycobacterium tuberculosis infection in household contacts of infectious tuberculosis patients in Brazil

Qualitative and quantitative analysis of tuberculin skin test (TST) and interferon gamma release assay (IGRA) results in household contacts with TST conversion according to contact age and additional TST conversion criteria. (DOCX 17 kb

Distribution of households according to study <i>M. tuberculosis</i> transmission categories by study time point.

<p>NA = Not applicable.</p

Study profile.

<p>Study profile.</p

Unadjusted and Adjusted Odds Ratios of Index TB Case, Household Contact and Environmental Factors for Predicting High <i>Mycobacterium tuberculosis</i> Transmission Households.

1<p>Household level data, except chest radiograph (see footnote E below), are modeled using logistic regression. Contact level data are modeled by using generalized estimating equations (GEE) approach to estimation for logistic regression with an independent working correlation matrix with standard errors obtained from a sandwich estimate of the variance.</p>2<p>Fit using a GEE approach to estimation for logistic regression with an independent working correlation matrix adjusted for all other covariates listed. Standard errors are from a sandwich estimator of the variance.</p>3<p>One participant whose SCG could not be distinguished between 5 or 6a was excluded.</p><p>*Wald (pairwise vs. reference) P-value.</p>+<p>Global (omnibus) score P-value.</p><p>E = denotes exact Odds Ratios and P-values using an exact test of the parameters from exact logistic regression.</p><p>VACS = Visual analog cough scale; LCQ = Leicester cough questionnaire.</p><p>BCG = Bacille Calmette Guérin vaccine; TST = Tuberculin skin test; OR = Odds ratio; CI = Confidence Interval.</p

Household contacts with tuberculin skin test (TST) conversion from entry to week 8–12 by initial household transmission category and age of contact.

<p>n/N are number of converters divided by the number at risk as defined by the various criteria below.</p>1<p>TST conversion <u>Criterion 1 (Brazilian guidelines)</u>: 1^st TST<10 mm; 2^nd TST≥10 mm; difference ≥10 mm. Does not include contacts with 1^st TST≥10 mm (407, 56%), and those with missing 1^st (21, 3%) or 2^nd TST (31, 4%) because they are not considered “at risk” by this criterion.</p>2<p>TST conversion <u>Criterion 2</u>: 1^st TST<5 mm; 2^nd TST≥10 mm; difference ≥6 mm. Does not include contacts with 1^st TST≥5 mm (458, 65%), and those with missing 1^st TST (21, 3%) or 2^nd TST (31, 4%) because they are not considered “at risk” by this criterion.</p><p>*Score test from generalized estimating equation (GEE) estimation approach to logistic regression.</p><p>Only contacts “at risk” of TST conversion are included for each criterion.</p