A total of 3114 cases of tuberculous meningitis were reported to the Centers for Disease Control between 1 January 1993 and 31 December 2005, and 3023 (97%) occurred in people without a previous diagnosis of tuberculosis. After exclusion of 967 patients lacking positive cultures from any site, 131 patients without isoniazid susceptibility results, and 29 patients with multi-drug resistant disease, 1896 patients remained for analysis (figure).
Selection of cases for primary analysis
Of these 1896 patients, 1614 (85%) had a positive culture from cerebrospinal fluid and 282 (15%) had positive cultures only from other sites. Five hundred and forty-one (29%) patients died during treatment. Of the remaining 1355 patients, 1177 (87%) completed treatment and 178 (13%) were lost to follow-up. Among patients who completed treatment, the median duration of treatment was 366 days for isoniazid susceptible disease and 438 days for isoniazid resistant disease. For patients who died, the median duration of treatment was 37 days for isoniazid susceptible disease and 52 days for isoniazid resistant disease. For patients who were lost to follow-up, the median duration of treatment was 146 days for isoniazid susceptible disease and 190 days for isoniazid resistant disease.
One hundred and twenty-three (6%) patients had isoniazid resistance on initial drug susceptibility testing. Overall, 43 (35%) of 123 patients with initial isoniazid resistance died during treatment, compared with 498 (28%) of 1773 patients without isoniazid resistance (odds ratio 1.38, 95% confidence interval 0.94 to 2.02).
Among all patients, 989 (52%) had known HIV status (404 HIV positive, 585 HIV negative) and 907 (48%) had unknown HIV status. HIV was not associated with initial isoniazid resistance (P=0.6) among patients with known HIV status, although it was strongly associated with death (odds ratio 4.20, 3.16 to 5.59).
When restricted to patients with known HIV status, the unadjusted association between isoniazid resistance and death was not significant among HIV positive or HIV negative patients. Specifically, among known HIV positive patients, 16 deaths occurred among 29 patients with isoniazid resistant disease and 181 deaths among 375 patients with isoniazid susceptible disease (odds ratio 1.32, 0.63 to 2.78). Among known HIV negative patients, six deaths occurred among 37 patients with isoniazid resistant disease and 102 deaths among 548 patients with isoniazid susceptible disease (odds ratio 0.85, 0.35 to 2.03). As both stratum specific associations (odds ratios) included the null value of 1, known HIV infection was not a significant effect modifier of the relation between initial isoniazid resistance and subsequent death.
In unadjusted analysis stratified by the presence or absence of a positive cerebrospinal fluid culture, the increased risk of death in patients with initial isoniazid resistance was limited to patients with a positive cerebrospinal fluid culture. Among 1614 patients with a positive cerebrospinal fluid culture, 43 (39%) of 109 with initial isoniazid resistance died during treatment, compared to 433 (29%) of 1505 patients without initial isoniazid resistance (odds ratio 1.61, 1.08 to 2.40). Among the 282 patients with a positive culture from a non-cerebrospinal fluid site, none of the 14 patients with initial isoniazid resistance died (odds ratio 0, 0 to 0.87).
Table 1 shows the characteristics screened for inclusion in the multivariate logistic regression model, the number of non-missing observations for each characteristic, the proportion of patients with each characteristic according to treatment outcome, and the unadjusted odds ratios for the outcome of death during treatment. In the adjusted analysis, advancing age and race were the only significant confounders of the association between initial isoniazid resistance and death. We found no interaction between HIV status and initial isoniazid resistance (P=0.7). In contrast, a significant interaction existed between isoniazid resistance and positive cerebrospinal fluid cultures (P<0.001). Among the 1614 patients with positive cerebrospinal fluid cultures, the odds ratio for initial isoniazid resistance and death was 2.07 (1.30 to 3.29). Table 2 shows the individual odds ratios for the other variables among patients with positive cerebrospinal fluid cultures.
Table 1 Unadjusted analysis of characteristics associated with death (n=1896). Values are numbers (percentages) unless stated otherwise
Table 2 Multivariate logistic regression model for death among 1614 patients with positive cerebrospinal fluid cultures
As the biological rationale of this investigation rested on the pharmacological properties of the first line agents, we did a secondary analysis of 1050 adults (older than 14 years) with positive cerebrospinal fluid cultures treated initially with isoniazid, rifampicin (or rifabutin), ethambutol, and pyrazinamide (odds ratio for initial isoniazid resistance and subsequent death 2.14, 1.25 to 3.64).
Multiple imputation assumes that whether an observation is missing does not depend on unobserved variables. The reporting of HIV status for residents of California occurs only for patients listed in the AIDS registry, and not for patients who tested negative for HIV, which violates this assumption. To test the sensitivity of our results to this mechanism, we repeated the analysis after imputing HIV status for all California residents, without matching to the AIDS registry (odds ratio for initial isoniazid resistance and subsequent death among patients with positive cerebrospinal fluid cultures 2.12, 1.34 to 3.36).
Intravenous drug use, non-intravenous drug use, and alcohol use were all associated with subsequent death in unadjusted analysis, yet these characteristics were not associated with isoniazid resistant disease among patients with known status. In a sensitivity analysis, we found that the potential for unmeasured confounding due to missing observations for these three characteristics was minimal.
Finally, we investigated the extent to which loss to follow-up could have influenced the observed association. Firstly, we excluded 178 patients with an outcome other than completion or death and repeated the steps of the primary analysis (odds ratio 2.22, 1.37 to 3.60). Secondly, we introduced non-differential misclassification of outcome among patients lost to follow-up, randomly assigning 50% of those patients to the outcome of death, regardless of exposure status (odds ratio 1.90, 1.24 to 2.92). Thirdly, we introduced differential misclassification of outcome, by randomly re-assigning 25% of patients lost to follow-up to death in the isoniazid susceptible category but none in the isoniazid resistant category (odds ratio 1.74, 1.10 to 2.76). None of these modifications changed the conclusion that initial isoniazid resistance was associated with subsequent death among cases of tuberculous meningitis with positive cerebrospinal fluid cultures.