CD4+ lymphocytes and tuberculin skin test as survival predictors in pulmonary tuberculosis HIV-infected patients

Background. We analyse whether the tuberculin skin test is a good survival marker in a cohort of pulmonary tuberculosis patients with HIV infection (PTB/HIV). In all, 494 PTB/HIV patients were enrolled in Barcelona (Spain) between January 1992 and December 1994 in the Tuberculosis Program of Barcelona. The main data problem was the large proportion of missing values in the covariates percentage of T CD4+ lymphocytes and the tuberculin test results: only 157 patients (31.8%) had both covariates recorded. Methods. Patients were dichotomized into two groups according to their level of immunosuppression (≤ 14 and > 14% T CD4+ cells). First, we carried out the semiparametric and parametric complete case analysis. After this, we analysed the data assuming a missing at random non-response pattern. We developed a bootstrap approach where missing data in the markers are imputed via a two-way linear model. Using Weibull regression estimation, we used a multiple imputation scheme to estimate the parameters of interest. Results. We found significative differences for the most immunosuppressed group when comparing positive tuberculin patients with those who were tuberculin negative. From a complete case approach and through a multivariate Cox analysis, we obtained a significant relative hazard of 0.3657 (95% CI: 0.13-1.02; P = 0.054). When a Weibull model was fitted, we estimated a constant relative percentile value of pR = 4.1329 (95% CI: 0.97-17.59). From a missing data approach, we obtain a higher constant relative percentile 5.48 (P = 0.079). Conclusions. The imputation method allows us to assess the protective character of positivity for the tuberculin test for the lowest CD4+ level. These findings strongly suggest the value of the tuberculin skin test as a qualitative measure of the immunological response and its interest for developing countries where specific laboratory tests are not affordable.