Characterization of the study population
A total of 525 household contacts (HHCs) were recruited from 176 index cases in the study area accounting for 94.3 % of all eligible households. Index cases reported a median of 20 days (IQR: [15, 30] days) from onset of symptoms to first doctor visit, and median of 6 days (IQR: [3, 20] days) from doctor visit to diagnosis. At inclusion, 93 index cases (57%) had started treatment. In these subjects, the median time from diagnosis to initiation of treatment was 2 days (IQR: [2, 4] days), and a median 2 days of treatment was given at the time of CI (IQR: [1, 2] days). Baseline investigations were completed in 490 (93%) HHCs, in a median of 4 days (IQR: [3, 5] days) in the 436 (83%) HHCs with only one TST needed and a median of 17.5 days (IQR: [15.0, 19.25]) in the 54 (10%) HHC with repeated TST. Adequate specimen for Mtb culture were harvested in 493 (93.9%) HHCs. Of these, 488 (99%) (and all 38 children <5 years) had two samples harvested on two consecutive days.
Males accounted for 40.5% of the study cohort, and 63% of the study cohort were aged >14 years. BCG scar was recorded in 221 (51.5%). All the 312 (60.4%) HHCs that agreed to HIV-testing were HIV negative. Houses were small with a mean of 4.25 (St.dev 2.04) subjects per room. Indoor pollution can be assumed high as 75% used wood and agricultural residue for fuel. In addition, 118 (24.8%) were/had been smokers for ≥6 months. The distribution of gender, age, TB risk factors and clinical parameters within the Mtb-infection categories given in Table 2.
Table 2. Distribution of age, gender and risk factors for tuberculosis (TB) in 525 household contacts of 176 adults with confirmed pulmonary TB according to infection categories at baseline Contact Investigation.
Among the 29 subclinical TB cases, one (5.5%) had symptoms, one had a positive smear and “abnormal TB” chest X-rays, one had “abnormal TB” and one “abnormal, not TB” chest X-ray.
Association between TB exposure scores and Mtb-infection in HHCs.
Although the association between TCS and TST/QFT is established in other cohorts (24-27), we first investigated the strength of this association in the present Indian cohort corrected for established risk factors for TB. The TCS and the Infectivity Score was associated with positive TST and QFT both in univariate and in multivariate analysis (Table 3).
Table 3. See at the end of the manuscript.
In the multivariate models, the likelihood for a positive TST increased by 16% (95%CI: 1-33%) per unit increase in the TCS and by 39% (95%CI: 10-76%) per unit increase in the Infectivity Score, whereas the likelihood for a positive QFT increased 33% (95%CI: 16-51%) per unit TCS and 41% (95%CI: 16-71%) per unit increase of the Infectivity Score. Surprisingly, LPG fuel, indicative of higher SES and less indoor pollution, was significantly associated with a positive TST in multivariate analysis (TCS model: OR 2.05, 95%CI: 1.07, 3.93. Infectivity Score model: OR 1.96, 95%CI: 1.02, 3.76). Notably, the association was not present when analyses were limited to HHCs ≥15 years regardless of BMI being included in analyses. No other known TB risk factors associated with TST or QFT result.
Association between TB exposure scores and subclinical TB in HHCs.
There was no association between the TCS or the Infectivity Score for subclinical TB (Table 4).
Table 4. Associations between Tuberculosis Contact Score, the Infectivity Score and other risk factors for tuberculosis (TB) and the dependant variables TST¹ and QFT¹ in 525 household contacts of 161 adults with pulmonary TB
Of TB risk factors, only crowding was associated with subclinical TB (TCS multivariate model: OR 0.72, 95%CI: 0.54, 0.95. Infectivity Score multivariate model: OR 0.71, 95%CI: 0.53, 0.95). This negative association was unexpected as crowding normally increases TB risk (36). Notably, crowding was not significant in the BMI model, suggesting interaction between BMI and crowding. To explore this, the interaction BMI/crowding was entered in the model resulting in no significant association for crowding alone.
The capacity of TB exposure scores to identify subclinical TB.
Finally, we assessed the capability of the TB exposure scores to identify individual contacts and/or families with ≥1 contact with subclinical TB. For comparison, the same analyses were performed for TST and QFT at baseline CI. As our aim was to evaluate the potential of the TB exposure scores as robust screening tools, no adjustments were made. The TCS and the established immunological tools, TST and QFT all had AUC values close to 0.5, indicating no capability to identify individual HHCs and/or families with ≥1 HHC with Mtb-positive cultures (data not shown). Interestingly, the simpler Infectivity Score showed moderate capability to identify individual contacts (AUC of 0.61, 95%CI: 0.52, 0.70) but marginal capability to identify families with ≥1 contact with growth of Mtb-positive sputum cultures (AUC of 0.58, 95%CI: 0.48, 0.68) (Figure 1).