Tuberculosis infection risk, preventive therapy care cascade and incidence of tuberculosis disease in healthcare workers at Maputo Central Hospital

This is a cross sectional screen for active TB and LTBI with 6 months of follow-up to assess TB incidence and IPT care cascade. MCH is the largest hospital in Mozambique, with 1400 beds and 3679 HCW in 2013. Conditions are crowded and the facility is poorly ventilated. By policy, masks are available to staff and coughing patients but use is neither mandated nor consistent. There is no facility for the isolation of admitted TB suspects. Radiology, pathology and sputum microscopy are available on-site.

In 2013, all 3679 workers at least 18 years old, working at MCH for at least two years were invited to participate. Participants were recruited through posted flyers and informational sessions. Exclusion criteria were as follows: immune-suppressive therapy with steroids for over four weeks, recent live vaccine, prior active TB, or history of ulceration with TST. Of the 777 healthcare workers who responded, 758 were eligible and provided informed consent. Additional informed consent was obtained for those agreeing to HIV testing.

Demographics and tuberculosis exposure history were collected via interviews in Portuguese by study physicians at enrollment. Age, sex, education level, length of hospital service, department, professional category, Bacillus Calmette-Guerin (BCG) vaccination status and exposure to close contacts with active TB were solicited from each participant.

Symptoms of cough greater than two weeks, productive cough, hemoptysis, chest pain, fever, sweats, weight loss or weakness were solicited. All participants, with the exclusion of pregnant women, underwent a chest X-ray which was interpreted by a study radiologist or pulmonologist who was blinded to the symptom questionnaire. Those with any symptoms or suspicious X-ray findings underwent further testing, including sputum collection. Sputum samples were analyzed with fluorescence microscopy using Auramine O staining procedure, and nucleic acid amplification testing (GeneXpert, Cepheid) followed by mycobacterial culture in liquid media (BBL™ MGIT™, Becton, Dickinson and Company) and solid Löwenstein-Jensen media slants (BBL™ Lowenstein-Jensen Medium, Becton, Dickinson and Company). Further workup of computed tomography, bronchoscopy, and/or fine-needle aspiration were performed as indicated by a study pulmonologist.

Active TB cases were defined as positive laboratory testing (smear, culture, or nucleic acid amplification test) in a patient with suggestive symptoms and/or imaging.

All workers agreeing to HIV testing underwent HIV 1/2 immunochromatographic lateral flow antibody testing (Determine™ HIV-1/2 test, Abbott Laboratories). Initially reactive samples underwent confirmatory testing with an immunochromatographic assay (UniGold™ HIV-1/2 test, Trinity Biotech) according to the Mozambican national HIV testing algorithm. Those with confirmed HIV underwent CD4 T-cell count.

LTBI classifications are outlined in Table 1. HIV seronegative participants with TST induration of 10–14 mm or quantitative IGRA 0.35–0.99 IU/mL were designated as LTBI “low reactors” along with HIV seropositive participants with TST of 1-4 mm. HIV seropositive participants with TST induration of at least 5 mm, and those with a negative HIV antibody test and a TST of at least 15 mm together with an IGRA result of at least 1.0 were designated LTBI “high reactors.” Those who declined HIV testing but had TST induration of ≥1 mm were classified as LTBI “undetermined reactor status.”

After excluding active TB disease, all participants newly diagnosed with HIV were prescribed isoniazid 300 mg daily for six months according to contemporary Mozambican infection control and HIV/TB treatment guidelines [9, 15]. Additionally, those designated as “high reactor” LTBI were offered IPT.

The agreement of IGRA positivity with positive TST results was reported for the baseline screening, stratified by quantitative TST response. Frequencies of participant characteristics were reported at baseline as well as follow up. LTBI at baseline (defined above) was compared for the following risk factors: sex, age category, education level, duration of hospital service (five-year increments), work type, department, exposure to close contacts with TB outside of work, and HIV status. For dichotomous variables, chi-squared analysis was used. For variables with more than two categories univariate logistic regression with Wald chi-squared test statistic to evaluate for overall significance was used. Unadjusted odds ratio (OR), 95% confidence interval (CI) and p-value were reported. To compare the adjusted odds of LTBI in various departments, a multivariable logistic regression model was generated using department as the main effect and adjusting for covariates that were found to have p < 0.2 in the univariate analysis: age category, education, duration of service, and exposure to TB contacts outside of work. Significant interactions between age category and duration of hospital service as well as age group and department were identified, so a model stratified by age group was also generated (See Additional file 1). ORs and 95% CIs for the main effect as well as two-tailed p-values were reported. Given that loss-to-follow-up at 6 months was nearly 50%, baseline characteristics of those who did and did not follow up were compared using a chi-squared test statistic. Active tuberculosis incidence was calculated using the denominator of all who followed up multiplied by the duration of follow-up (6 months). All testing for significance was done using two-tailed alpha-level 0.05. Hosmer-Lemeshow goodness-of-fit testing was performed and tolerances calculated for the model to assess for collinearity. Outliers identified by Pearson Residuals were investigated. Statistical analysis was performed using SAS® Studio statistical software, version 3.6.

Of 777 workers screened for participation, 758 met criteria for enrollment in the study, and 690 completed the screening process which included a symptom questionnaire, chest X-ray, and testing for tuberculosis and HIV (Fig. 1).

Baseline characteristics are summarized in Table 2. Women comprised 74.2% of participants. Represented professional categories included auxiliary personnel (49.0%), nurses (17.7%), administrative personnel (14.8%), doctors (6.8%), laboratory (4.1%) and other (7.7%) staff. Of the 645 participants who underwent HIV testing, 78 (12.1%) tested positive, representing 11.3% of the whole sample.

Diagnosis of tuberculosis and LTBI at baseline screening is summarized in Table 2. Three cases of active TB were diagnosed at screening (0.4%) as well as 426 (61.8%) individuals with LTBI, 285 of whom were high reactors (41.3% of total participants). The remaining 261 (37.8%) participants were classified as “no LTBI.” Three additional active TB cases were diagnosed during follow up. The six active TB cases, described in Table 3, were from five different departments.

The univariate analysis comparing odds of LTBI is shown in Table 4. Age was significantly associated with LTBI, with those 35 to 49 years of age more likely to be positive for LTBI compared with those less than 35 years, OR 1.66 (95% CI 1.16, 2.37). Secondary or higher education was associated with lower odds of LTBI compared with the reference group of primary education or less, ORs of 0.63 (95%CI 0.43, 0.93) and 0.57 (95%CI 0.35, 0.94) respectively. The odds of LTBI increased with service duration with OR 1.12 (95% CI 1.04, 1.21) for each additional 5 years of service. Odds of LTBI were higher in the surgery department with OR 2.43 (95% CI 1.31, 4.49) and were lower in the medicine department with OR 0.53 (95% CI 0.30, 0.92) compared with non-clinical departments. Odds of LTBI did not vary by sex, professional category, BCG vaccination status, outside TB contacts or HIV status.

Summary statistics for the multivariable logistic regression model adjusted for age, education level, TB contact outside of work, service duration and department are shown in Table 5. Longer duration of hospital service was associated with increased odds of LTBI with OR 1.17 (95%CI 1.04, 1.31) for 5-year intervals, as was work in the surgery department with OR 2.31 (95%CI 1.27, 4.44). Age over 50 years was associated with reduced odds of LTBI with OR 0.48 (95% CI 0.26, 0.89), as was work in the medicine department with OR 0.56 (95%CI 0.31, 0.98). A multivariable logistic regression model stratified by age group is described in the supplement [see Additional file 1].

Of the 687 participants without active TB disease who completed initial screening, 358 (52.1%) reported for repeat evaluation at the six-month follow up interval. Active TB incidence among those who reported for evaluation at six months was three in 179 person-years, or 1676/100,000 person-years (95% CI 350, 4820). A summary comparing baseline characteristics of those who followed up compared with those who did not is shown in Table 6. Participants who followed up did not differ from those who did not follow up with respect to education level, outside TB contacts, HIV status and professional category. However, males, younger participants, those who worked less than 20 years, and those without LTBI at baseline were less likely to report for follow up.

A flow diagram of the care cascade for the 333 participants offered IPT is shown in Fig. 2. Of 333 participants offered IPT, 234 initiated and 99 declined. Of initiators, 181 completed six months, five stopped due to gastrointestinal side effects, and 46 abandoned treatment. Two cases of drug-sensitive extrapulmonary TB developed during follow-up in participants receiving IPT. One case of active pulmonary TB developed in a participant who declined IPT.

The agreement of positive IGRA with positive TST, stratified by quantitative TST response, is shown in Table 7. For HIV seropositive individuals, the agreement of positive IGRAs with positive TST results was 50% among those with TST 5-10 mm, and 87.5% among those with TST ≥ 10 mm. For HIV seronegative individuals, the agreement of TST 10-14 mm with positive IGRA results was 63.6%, and for TST ≥ 15 mm it was 82.2%.