Brief Report: Performance of Tuberculosis Symptom Screening Among Hospitalized ART-Naive Children With HIV in Kenya.

BACKGROUND: The World Health Organization (WHO) recommends tuberculosis (TB) diagnostic evaluation for children with HIV (CHIV) who have history of TB contact, poor weight gain, cough, or fever. These screening criteria were developed based on studies of symptomatic CHIV with incomplete microbiologic confirmation. We performed routine TB microbiologic evaluation of hospitalized CHIV with and without symptoms to develop a data-driven TB symptom screen. METHODS: Among hospitalized antiretroviral therapy-naive Kenyan CHIV enrolled in the Pediatric Urgent Start of Highly Active Antiretroviral Therapy (PUSH) trial, we performed Xpert MTB/RIF and mycobacterial culture of respiratory and stool specimens independent of TB symptoms. We evaluated performance of WHO and other published pediatric TB screening criteria and derived optimized criteria using a combination of symptoms. RESULTS: Of 168 CHIV who underwent TB microbiologic evaluation, 13 (8%) had confirmed TB. WHO TB symptom screening had 100% sensitivity and 4% specificity to detect confirmed TB. Published TB screening criteria that relied on prolonged symptoms missed cases of confirmed TB (sensitivity 85%-92%). An optimized symptom screen including weight loss, cough, anorexia, or TB contact had 100% sensitivity and improved specificity (31%) compared with the WHO pediatric TB symptom screen. CONCLUSIONS: The WHO TB symptom screen was highly sensitive but resulted in a high proportion of hospitalized CHIV who would require TB diagnostic evaluation. Other published TB screening criteria missed CHIV with confirmed TB. Our optimized screening tool increased specificity while preserving sensitivity. Future multicenter studies are needed to improve TB screening tools for CHIV in both inpatient and outpatient settings.

Cumulative Mycobacterium tuberculosis Infection Incidence (Measured Primarily by Tuberculin Skin Test) Among Infants With Human Immunodeficiency Virus Exposure: Observational Follow-up of an Isoniazid Prophylaxis Trial.

Cumulative 24-month Mycobacterium tuberculosis infection incidence (measured primarily by tuberculin skin test [TST]) was high among human immunodeficiency virus exposed but uninfected infants (8.7 [95% confidence interval, 6.3-11.9] per 100 person-years). Trend for decreased TST positivity among infants at trial end (12 months postenrollment) randomized to isoniazid at 6 weeks of age was not sustained through observational follow-up to 24 months of age. CLINICAL TRIALS REGISTRATION: NCT02613169.

A CD4+ TNF+ monofunctional memory T-cell response to BCG vaccination is associated with Mycobacterium tuberculosis infection in infants exposed to HIV.

BACKGROUND: The immunologic correlates of risk of Mycobacterium tuberculosis (Mtb) infection after BCG vaccination are unknown. The mechanism by which BCG influences the tuberculin skin test (TST) remains poorly understood. We evaluated CD4+ T-cell responses in infants exposed to HIV and uninfected (HEU) who received BCG at birth and examined their role in susceptibility to Mtb infection and influence on TST induration. METHODS: HEU infants were enrolled in a randomised clinical trial of isoniazid (INH) to prevent Mtb infection in Kenya. We measured mycobacterial antigen-specific Th1 and Th17 cytokine responses at 6-10 weeks of age prior to INH randomisation and compared responses between Mtb infected and uninfected infants. Outcomes at 14 months of age included TST, QuantiFERON-Plus (QFT-Plus), and ESAT-6/CFP-10-specific non-IFN-γ cytokines measured in QFT-Plus supernatants. FINDINGS: A monofunctional mycobacterial antigen-specific TNF+ CD4+ effector memory (CCR7-CD45RA-) T-cell response at 6-10 weeks of age was associated with Mtb infection at 14 months of age as measured by ESAT-6/CFP-10-specific IFN-γ and non-IFN-γ responses (Odds Ratio 2.26; Confidence Interval 1.27-4.15; P = 0.006). Mycobacterial antigen-specific polyfunctional effector memory Th1 responses at 6-10 weeks positively correlated with TST induration in infants without evidence of Mtb infection at 14 months, an association which was diminished by INH therapy. INTERPRETATION: Induction of monofunctional TNF+ CD4+ effector memory T-cell responses may be detrimental in TB vaccine development. This study also provides mechanistic insight into the association of BCG-induced immune responses with TST induration and further evidence that TST-based diagnoses of Mtb infection in infants are imprecise. FUNDING: Thrasher Research Fund.

A Randomized Controlled Trial of Isoniazid to Prevent Mycobacterium tuberculosis Infection in Kenyan Human Immunodeficiency Virus-Exposed Uninfected Infants.

BACKGROUND: Human immunodeficiency virus (HIV)-exposed uninfected (HEU) infants in endemic settings are at high risk of tuberculosis (TB). For infants, progression from primary Mycobacterium tuberculosis (Mtb) infection to TB disease can be rapid. We assessed whether isoniazid (INH) prevents primary Mtb infection. METHODS: We conducted a randomized nonblinded controlled trial enrolling HEU infants 6 weeks of age without known TB exposure in Kenya. Participants were randomized (1:1) to 12 months of daily INH (10 mg/kg) vs no INH. Primary endpoint was Mtb infection at end of 12 months, assessed by interferon-γ release assay (QuantiFERON-TB Gold Plus) and/or tuberculin skin test (TST, added 6 months after first participant exit). RESULTS: Between 15 August 2016 and 6 June 2018, 416 infants were screened, with 300 (72%) randomized to INH or no INH (150 per arm); 2 were excluded due to HIV infection. Among 298 randomized HEU infants, 12-month retention was 96.3% (287/298), and 88.9% (265/298) had primary outcome data. Mtb infection prevalence at 12-month follow-up was 10.6% (28/265); 7.6% (10/132) in the INH arm and 13.5% (18/133) in the no INH arm (7.0 vs 13.4 per 100 person-years; hazard ratio, 0.53 [95% confidence interval {CI}, .24-1.14]; P = .11]), and driven primarily by TST positivity (8.6% [8/93] in INH and 18.1% [17/94] in no INH; relative risk, 0.48 [95% CI, .22-1.05]; P = .07). Frequency of severe adverse events was similar between arms (INH, 14.0% [21/150] vs no INH, 10.7% [16/150]; P = .38), with no INH-related adverse events. CONCLUSIONS: Further studies evaluating TB preventive therapy to prevent or delay primary Mtb infection in HEU and other high-risk infants are warranted. CLINICAL TRIALS REGISTRATION: NCT02613169.

Infant TB Infection Prevention Study (iTIPS): a randomised trial protocol evaluating isoniazid to prevent M. tuberculosis infection in HIV-exposed uninfected children.

INTRODUCTION: HIV-exposed uninfected (HEU) infants in tuberculosis (TB) endemic settings are at high risk of Mycobacterium tuberculosis (Mtb) infection and TB disease, even in the absence of known Mtb exposure. Because infancy is a time of rapid progression from primary infection to active TB disease, it is important to define when and how TB preventive interventions exert their effect in order to develop effective prevention strategies in this high-risk population. METHODS AND ANALYSIS: We designed a non-blinded randomised controlled trial to determine efficacy of isoniazid (INH) to prevent primary Mtb infection among HEU children. Target sample size is 300 (150 infants in each arm). Children are enrolled at 6 weeks of age from maternal and child health clinics in Kenya and are randomised to receive 12 months of daily INH ~10 mg/kg plus pyridoxine or no INH. The primary endpoint is Mtb infection, assessed by interferon-gamma release assay QuantiFERON-TB Gold Plus (QFT-Plus) or tuberculin skin test after 12 months post-enrolment. Secondary outcomes include severe adverse events, expanded Mtb infection definition using additional QFT-Plus supernatant markers and determining correlates of Mtb infection. Exploratory analyses include a combined outcome of TB infection, disease and mortality, and sensitivity analyses excluding infants with baseline TB-specific responses on flow cytometry. ETHICS AND DISSEMINATION: An external and independent Data and Safety Monitoring Board monitors adverse events. Results will be disseminated through peer-reviewed journals, presentations at local and international conferences to national and global policy-makers, the local community and participants. TRIAL REGISTRATION NUMBER: NCT02613169; Pre-results.

Hospitalized Children Reveal Health Systems Gaps in the Mother-Child HIV Care Cascade in Kenya.

To identify missed opportunities in HIV prevention, diagnosis, and linkage to care, we enrolled 183 hospitalized, HIV-infected, ART-naïve Kenyan children 0-12 years from four hospitals in Nairobi and Kisumu, and reviewed prevention of mother-to-child transmission of HIV (PMTCT), hospitalization, and HIV testing history. Median age was 1.8 years (IQR = 0.8, 4.5). Most mothers received HIV testing during pregnancy (77%). Among mothers tested, 60% and 40% reported HIV-negative and positive results, respectively; 33% of HIV-diagnosed mothers did not receive PMTCT antiretrovirals. First missed opportunities for pediatric diagnosis and linkage were due to failure to test mothers (23.1%), maternal HIV acquisition following initial negative test (45.7%), no early infant diagnosis (EID) or provider-initiated testing (PITC) (12.7%), late breastfeeding transmission (8.7%), failure to collect child HIV test results (1.2%), and no linkage to care following HIV diagnosis (8.7%). Among previously hospitalized children, 38% never received an HIV test. Strengthening initial and repeat maternal HIV testing and PITC are key interventions to prevent, detect, and treat pediatric HIV infections.

Tuberculosis Case Finding in HIV-Infected Pregnant Women in Kenya Reveals Poor Performance of Symptom Screening and Rapid Diagnostic Tests.

BACKGROUND: Tuberculosis (TB) during pregnancy in HIV-infected women is associated with poor maternal and infant outcomes. There are limited data on TB prevalence, optimal TB screening, and performance of rapid diagnostics in pregnant HIV-infected women. METHODS: We conducted a cross-sectional study among HIV-infected pregnant women seeking antenatal care in western Kenya. After a standardized questionnaire, sputum smear microscopy for acid-fast bacilli, mycobacterial liquid culture, GeneXpert MTB/RIF (Xpert), urine lipoarabinomannan, and tuberculin skin testing were performed. We determined prevalence and correlates of culture-confirmed pulmonary TB, and compared diagnostic performance of World Health Organization (WHO) symptom screening and rapid diagnostic tests to sputum culture. RESULTS: Between July 2013 and July 2014, we enrolled 306 women. Among 288 women with a valid sputum culture result, 54% were on antiretroviral treatment, median CD4 cell count was 437 cell per cubic millimeter (IQR 342-565), and prevalence of culture-confirmed pulmonary TB was 2.4% (confidence interval: 1.0% to 4.9%). Cough >2 weeks (P = 0.04) and positive tuberculin skin testing (≥ 5 mm, P = 0.03) were associated with pulmonary TB. Women with TB were 23-fold (95% confidence interval: 4.4 to 116.6) more likely to report a household member with TB symptoms (P = 0.002). WHO symptom screen (43%), acid-fast bacilli smear (0%), Xpert (43%), and lipoarabinomannan (0%) had low sensitivity but high specificity (81%, 99%, 99%, and 95%, respectively) for pulmonary TB. CONCLUSIONS: HIV-infected pregnant women had appreciable prevalence of pulmonary TB despite modest immunosuppression. Current TB screening and diagnostic tools perform poorly in pregnant HIV-infected women. Adapted TB screening tools that include household member TB symptoms may be useful in this population.