Performance of a stool-based quantitative PCR assay for the diagnosis of tuberculosis in adolescents and adults: a multinational, prospective diagnostic accuracy study.

BACKGROUND: Despite increasing availability of rapid molecular tests for the diagnosis of tuberculosis in high-burden settings, many people with tuberculosis are undiagnosed. Reliance on sputum as the primary specimen for tuberculosis diagnostics contributes to this diagnostic gap. We evaluated the diagnostic accuracy and additive yield of a novel stool quantitative PCR (qPCR) assay for the diagnosis of tuberculosis in three countries in Africa with high tuberculosis burdens. METHODS: We undertook a prospective diagnostic accuracy study in Eswatini, Mozambique, and Tanzania from Sept 21, 2020, to Feb 2, 2023, to compare the diagnostic accuracy for tuberculosis of a novel stool qPCR test with the current diagnostic standard for Mycobacterium tuberculosis DNA detection from sputum and stool, Xpert-MTB/RIF Ultra (Xpert Ultra). Sputum, stool, and urine samples were provided by a cohort of participants, aged 10 years or older, diagnosed with tuberculosis. Participants with tuberculosis (cases) were enrolled within 72 h of treatment initiation for tuberculosis diagnosed clinically or following laboratory confirmation. Participants without tuberculosis (controls) consisted of household contacts of the cases who did not develop tuberculosis during a 6-month follow-up. The performance was compared with a robust composite microbiological reference standard (CMRS). FINDINGS: The cohort of adolescents and adults (n=408) included 268 participants with confirmed or clinical tuberculosis (cases), 147 (55%) of whom were living with HIV, and 140 participants (controls) without tuberculosis. The sensitivity of the novel stool qPCR was 93·7% (95% CI 87·4-97·4) compared with participants with detectable growth on M tuberculosis culture, and 88·1% (81·3-93·0) compared with sputum Xpert Ultra. The stool qPCR had an equivalent sensitivity as sputum Xpert Ultra (94·8%, 89·1-98·1) compared with culture. Compared with the CMRS, the sensitivity of the stool qPCR was higher than the current standard for tuberculosis diagnostics on stool, Xpert Ultra (80·4%, 73·4-86·2 vs 73·5%, 66·0-80·1; p=0·025 on paired comparison). The qPCR also identified 17-21% additional tuberculosis cases compared to sputum Xpert Ultra or sputum culture. In controls without tuberculosis, the specificity of the stool qPCR was 96·9% (92·2-99·1). INTERPRETATION: In this study, a novel qPCR for the diagnosis of tuberculosis from stool specimens had a higher accuracy in adolescents and adults than the current diagnostic PCR gold standard on stool, Xpert-MTB/RIF Ultra, and equivalent sensitivity to Xpert-MTB/RIF Ultra on sputum. FUNDING: National Institutes of Health (NIH) Allergy and Infectious Diseases, and NIH Fogarty International Center.

Pathogenesis of tuberculosis: the 1930 Lübeck disaster revisited.

During the 1930 Lübeck Mycobacterium bovis bacille Calmette-Guérin (BCG) disaster, 251 neonates received three oral BCG doses accidentally contaminated by virulent Mycobacterium tuberculosis; 67 (26.7%) infants died of tuberculosis. BCG reversion to pathogenicity did not occur. Detailed post mortem examinations clarified contested aspects of tuberculosis pathogenesis. Gastrointestinal infection was seldom "silent" and did not cause typical primary pulmonary lesions. In 15 infants, primary pulmonary foci were found but these resulted from vaccine ingestion and aspiration and were not caused by gastrointestinal infection spreading to the lungs without trace of its journey, as claimed by prominent researchers such as Calmette and von Behring. Further, among 60 infants in whom post mortem evaluation was completed, a "silent" gastrointestinal infection without an intestinal primary focus was found in only one. Lymphohaematogenous-disseminated tuberculosis caused death in 24/67 (35.8%) infants and tuberculous meningitis in a further 17/67 (25.4%). Gastrointestinal tuberculosis complications caused death in 26/67 (38.8%) infants. Half of the tuberculosis-attributed deaths had occurred by 3 months, 93% by 6 months and 100% by 12 months; remarkably no further deaths or tuberculosis recurrences occurred within 5 years post-vaccination/infection. These findings provide graphic confirmation that the early introduction of chemoprophylaxis in recently M. tuberculosis-infected young children is critical and urgent.

Quality matters: Redefining child TB care with an emphasis on quality.

Children have been neglected in the fight against tuberculosis (TB) for decades. Despite being the number one infectious disease killer, TB does not feature on the child survival agendas partly due to absent and inaccurate data. Quality is a missing ingredient in TB care in children, yet high rates of unfavorable TB outcomes highlight its importance in this age group. Quality care is particularly important for TB affected children in the absence of a point of care sensitive and specific diagnostic test. Using the current models of child TB care, it will take another 200 years to end TB. Without focusing on the quality of child TB care, the ambitious country specific United Nations High Level Meeting for TB targets will carry minimal impact. High TB burden countries must also adopt Universal Health Care (UHC) and ensure that quality TB care is made free and equitable for all children, adolescents and their affected families. We advocate for the importance of evaluating the quality of child TB care, and provide a basic framework for quality in child TB with special attention given to creating differentiated service delivery models for children and families affected by TB.

Management of drug-resistant tuberculosis.

Drug-resistant tuberculosis is a major public health concern in many countries. Over the past decade, the number of patients infected with Mycobacterium tuberculosis resistant to the most effective drugs against tuberculosis (ie, rifampicin and isoniazid), which is called multidrug-resistant tuberculosis, has continued to increase. Globally, 4·6% of patients with tuberculosis have multidrug-resistant tuberculosis, but in some areas, like Kazakhstan, Kyrgyzstan, Moldova, and Ukraine, this proportion exceeds 25%. Treatment for patients with multidrug-resistant tuberculosis is prolonged (ie, 9-24 months) and patients with multidrug-resistant tuberculosis have less favourable outcomes than those treated for drug-susceptible tuberculosis. Individualised multidrug-resistant tuberculosis treatment with novel (eg, bedaquiline) and repurposed (eg, linezolid, clofazimine, or meropenem) drugs and guided by genotypic and phenotypic drug susceptibility testing can improve treatment outcomes. Some clinical trials are evaluating 6-month regimens to simplify management and improve outcomes of patients with multidrug-resistant tuberculosis. Here we review optimal diagnostic and treatment strategies for patients with drug-resistant tuberculosis and their contacts.

HIV-associated pediatric tuberculosis: prevention, diagnosis and treatment.

PURPOSE OF REVIEW: The detrimental synergy of colliding HIV and tuberculosis (TB) epidemics is most devastating among children and adolescents living with HIV (CALWH) who shoulder a disproportionate burden of all child TB mortality. RECENT FINDINGS: CALWH benefit less from Bacille-Calmette Guerin vaccination than HIV-uninfected children and are not receiving TB preventive therapy despite global recommendations. Further, the predictive utility of most diagnostic tools is reduced in CALWH. Finally, antiretroviral and anti-TB drug interactions continue to complicate cotreatment for children. Despite these challenges, recent data fuel a new awareness of TB as a hidden cause of child mortality and a renewed commitment to TB prevention. New diagnostic approaches using existing tools with novel specimens, such as stool, may improve the diagnosis of TB in CALWH. Further, pharmacokinetic studies and the development of new drug formulations promise better treatment options for CALWH in the near future. SUMMARY: With the awareness that TB is the leading cause of mortality among CALWH, comes a responsibility to accelerate research to prevent, diagnose and treat TB in this vulnerable population. In the present, we must adopt evidence-based preventive and treatment strategies to enhance outcomes of CALWH and combating TB.

School and household tuberculosis contact investigations in Swaziland: Active TB case finding in a high HIV/TB burden setting.

BACKGROUND: Investigation of household contacts exposed to infectious tuberculosis (TB) is widely recommended by international guidelines to identify secondary cases of TB and limit spread. There is little data to guide the use of contact investigations outside of the household, despite strong evidence that most TB infections occur outside of the home in TB high burden settings. In older adolescents, the majority of infections are estimated to occur in school. Therefore, as part of a project to increase active case finding in Swaziland, we performed school contact investigations following the identification of a student with infectious TB. METHODS: The Butimba Project identified 7 adolescent TB index cases (age 10-20) with microbiologically confirmed disease attending 6 different schools between June 2014 and March 2015. In addition to household contact investigations, Butimba Project staff worked with the Swaziland School Health Programme (SHP) to perform school contact investigations. At 6 school TB screening events, between May and October 2015, selected students underwent voluntary TB screening and those with positive symptom screens provided sputum for TB testing. RESULTS: Among 2015 student contacts tested, 177 (9%) screened positive for TB symptoms, 132 (75%) produced a sputum sample, of which zero tested positive for TB. Household contact investigations of the same index cases yielded 40 contacts; 24 (60%) screened positive for symptoms; 19 produced a sputum sample, of which one case was confirmed positive for TB. The odds ratio of developing TB following household vs. school contact exposure was significantly lower (OR 0.0, 95% CI 0.0 to 0.18, P = 0.02) after exposure in school. CONCLUSION: School-based contact investigations require further research to establish best practices in TB high burden settings. In this case, a symptom-based screening approach did not identify additional cases of tuberculosis. In comparison, household contact investigations yielded a higher percentage of contacts with positive TB screens and an additional tuberculosis case.

BUTIMBA: Intensifying the Hunt for Child TB in Swaziland through Household Contact Tracing.

BACKGROUND: Limited data exists to inform contact tracing guidelines in children and HIV-affected populations. We evaluated the yield and additionality of household contact and source case investigations in Swaziland, a TB/HIV high-burden setting, while prioritizing identification of childhood TB. METHODS: In partnership with 7 local TB clinics, we implemented standardized contact tracing of index cases (IC) receiving TB treatment. Prioritizing child contacts and HIV-affected households, screening officers screened contacts for TB symptoms and to identify risk factors associated with TB. We ascertained factors moderating the yield of contact tracing and measured the impact of our program by additional notifications. RESULTS: From March 2013 to November 2015, 3,258 ICs (54% bacteriologically confirmed; 70% HIV-infected; 85% adults) were enrolled leading to evaluation of 12,175 contacts (median age 18 years, IQR 24-42; 45% children; 9% HIV-infected). Among contacts, 196 TB cases (56% bacteriologically confirmed) were diagnosed resulting in a program yield of 1.6% for all forms of TB. The number needed to screen (NNS) to identify a bacteriologically confirmed TB case or all forms TB case traced from a child IC <5 years was respectively 62% and 40% greater than the NNS for tracing from an adult IC. In year one, we demonstrated a 32% increase in detection of bacteriologically confirmed child TB. Contacts were more likely to have TB if <5 years (OR = 2.0), HIV-infected (OR = 4.9), reporting ≥1 TB symptoms (OR = 7.7), and sharing a bed (OR = 1.7) or home (OR = 1.4) with the IC. There was a 1.4 fold increased chance of detecting a TB case in households known to be HIV-affected. CONCLUSION: Contact tracing prioritizing children is not only feasible in a TB/HIV high-burden setting but contributes to overall case detection. Our findings support WHO guidelines prioritizing contact tracing among children and HIV-infected populations while highlighting potential to integrate TB and HIV case finding.

Predictive value of immunization records and risk factors for immunization failure in internationally adopted children.

OBJECTIVES: To measure the predictive value of immunization records for protective immunity and identify risk factors for immunization failure. DESIGN: Prospective cross-sectional study, 2001-2006. SETTING: International Adoption Clinic, Rainbow Babies and Children's Hospital, Cleveland, Ohio. PARTICIPANTS: A total of 465 international adoptees presenting within 180 days of arrival. Main Exposure Immunization records of vaccines given. OUTCOME MEASURES: Protective immunity to polio, hepatitis B, tetanus, diphtheria, and measles. RESULTS: Vaccination records were available for 397 (85.4%) adoptees (mean age, 19.4 months; 65.2% girls). Most children came from Russia (41.7%), China (20.9%), and Guatemala (15.7%). Acute or chronic malnutrition was present in 5.5% and 15.4% of adoptees, respectively. Preadoptive settings were institutional (52%), community-based (14%), or both (34%). Of adoptees with 3 or more tetanus (n = 203) or 3 or more diphtheria (n = 205) vaccinations, 87.2% and 94.6% had protective immunity, respectively. Of adoptees with 3 or more polio vaccinations (n = 216), protective immunity was present in 58.3%, 82.4%, and 51.9% for polio types 1, 2, and 3, respectively. Of adoptees with 2 or more hepatitis B vaccinations (n = 170), 94.1% had protective immunity. A total of 80.8% of adoptees with measles vaccination (n = 99) had protective immunity. Children from China were less likely to have protective immunity than children from Russia (odds ratio, 0.34; 95% confidence interval, 0.17-0.66). Nutritional status had no predictive effect. CONCLUSIONS: The predictive value of immunization records in international adoptees is limited and varies between birth countries. Immunization records should not be accepted as evidence of protective immunity. Parents should be well informed and supported to choose between revaccination or vaccination, based on serologic testing.