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Global efforts to eliminate tuberculosis (TB) must address the unique barriers that children (ages 0 through 9 years) and adolescents/young adults (AYA; ages 10 through 24 years) face in adhering to treatment for TB infection and disease. We conducted a narrative review to summarize current knowledge on the social determinants of treatment adherence among these age groups to guide efforts and policy to address their unique needs. Our findings revealed that research on TB treatment adherence among children and AYA is still in its nascent stage. The current literature revealed structural/community-, health system-, household-, and individual-level factors that influence treatment adherence and varied with developmental stage. There is a need to develop multilevel interventions to address the unique challenges that children and AYA face in adhering to TB treatment.

BACKGROUND: Despite being a preventable and treatable disease, tuberculosis (TB) is a leading cause of death among young people globally. Each year, an estimated 1.8 million adolescents and young adults (AYAs; 10–24 years old) develop TB. In 2019, an estimated 161,000 AYAs died of the disease. AYAs have unique developmental, psychosocial, and healthcare needs, but these needs have been neglected in both TB care and research agendas. In order to improve outcomes in this age group, the specific needs of AYAs must be considered and addressed. METHODS: Through a consensus process, an international panel of 34 clinicians, researchers, TB survivors, and advocates with expertise in child/adolescent TB and/or adolescent health proposed interventions for optimizing AYA engagement in TB care. The process consisted of reviewing the literature on TB in AYAs; identifying and discussing priority areas; and drafting and revising proposed interventions until consensus, defined a priori, was reached. RESULTS: The panel acknowledged the dearth of evidence on best practices for identifying and managing AYAs with TB. The final consensus statement, based on expert opinion, proposes nine interventions to reform current practices that may harm AYA health and well-being, and nine interventions to establish high-quality AYA-centered TB services. CONCLUSION: AYA-specific interventions for TB care and research are critical for improving outcomes in this age group. In the absence of evidence on best practices, this consensus statement from an international group of experts can help address the needs of AYA with TB or at risk for TB.

We reviewed autopsy data from general hospitals in Lviv, Ukraine to understand pediatric mortality due to tuberculosis (TB). We identified 14 (0.6%) of 2345 autopsied children with unrecognized or untreated TB. More sensitive TB diagnostics for children and improved strategies for identifying which children require TB evaluation are urgently needed.

ObjectivesPatients with tuberculosis (TB) generally are instructed to isolate at the beginning of treatment in order to prevent disease transmission. The duration of isolation varies and may be prolonged (ie, lasting 1 month or more). Few studies have examined the impact of isolation during TB treatment on adolescents, who may be more vulnerable to its negative effects.MethodsThis study took place from 2018 through 2019 in Lima, Peru, where the Ministry of Health mandates the exclusion of patients with TB from educational institutions for at least 2 months. Using semi-structured guides, we conducted individual in-depth interviews with adolescents who received treatment for drug-susceptible TB, their primary caregivers and health providers. We performed thematic analysis of the transcribed interviews.ResultsWe interviewed 85 participants: 34 adolescents, 36 caregivers and 15 healthcare workers. At the time of their TB diagnoses, 28 adolescents were in secondary, postsecondary, vocational or military school. Adolescents with drug-susceptible TB were prescribed home isolation usually for 2 (and occasionally for 1) months. Consequently, they could neither attend school nor socialise with family members or friends. Two primary themes emerged from the interviews. First, as a result of their exclusion from school, most adolescents fell behind academically and had to repeat a semester or academic year. Second, absence from school, separation from friends and loved ones, and reinforcement of TB-related stigma (arising from fear of TB transmission) harmed adolescents’ mental health.ConclusionProlonged isolation led to educational setbacks and emotional trauma among adolescents with TB. Prolonged isolation is not supported by current evidence on TB transmission and is problematic from a human rights perspective, as it violates adolescents’ rights to education and freedom of movement. Isolation recommendations should be re-evaluated to align with data on TB transmission and the principles of patient-centred care.

BACKGROUND: Timely diagnosis and treatment of pediatric tuberculosis (TB) is critical to reducing mortality but remains challenging in the absence of adequate diagnostic tools. Even once a TB diagnosis is made, delays in treatment initiation are common, but for reasons that are not well understood.METHODS: To examine reasons for delay post-diagnosis, we conducted semi-structured interviews with Ministry of Health (MoH) physicians and field workers affiliated with a pediatric TB diagnostic study, and caregivers of children aged 0–14 years who were diagnosed with pulmonary TB in Lima, Peru. Interviews were analyzed using systematic comparative and descriptive content analysis.RESULTS: We interviewed five physicians, five field workers and 26 caregivers with children who initiated TB treatment < 7 days after diagnosis (n = 15) or who experienced a delay of ≥7 days (n = 11). Median time in delay from diagnosis to treatment initiation was 26 days (range 7–117). Reasons for delay included: health systems challenges (administrative hurdles, medication stock, clinic hours), burden of care on families and caregiver perceptions of disease severity.CONCLUSION: Reasons for delay in treatment initiation are complex. Interventions to streamline administrative processes and tools to identify and support families at risk for delays in treatment initiation are urgently needed.

Background During adolescence, childhood and adult forms of tuberculosis (TB) overlap, resulting in diverse disease manifestations. Knowing which patient characteristics are associated with which manifestations may facilitate diagnosis and enhance understanding of TB pathophysiology. Methods In this cross-sectional study, we included 10–19-year-olds in Ukraine's national TB registry who started TB treatment between 2015 and 2018. Using multivariable regression, we estimated associations between patient characteristics and four presentations of TB: pleural, extrathoracic, cavitary and rifampicin-resistant (RR). We also described the epidemiology of adolescent TB in Ukraine. Results Among 2491 adolescent TB cases, 88.4% were microbiologically confirmed. RR-TB was confirmed in 16.9% of new and 29.7% of recurrent cases. Of 88 HIV-infected adolescents, 59.1% were not on antiretroviral therapy at TB diagnosis. Among 10–14-year-olds, boys had more pleural disease (adjusted OR (aOR) 2.12, 95% CI: 1.08–4.37). Extrathoracic TB was associated with age 15–19 years (aOR 0.26, 95% CI: 0.18–0.37) and HIV (aOR 3.25, 95% CI: 1.55–6.61 in 10–14-year-olds; aOR 8.18, 95% CI: 3.58–17.31 in 15–19-year-olds). Cavitary TB was more common in migrants (aOR 3.53, 95% CI: 1.66–7.61) and 15–19-year-olds (aOR 4.10, 95% CI: 3.00–5.73); among 15–19-year-olds, it was inversely associated with HIV (aOR 0.32, 95% CI: 0.13–0.70). RR-TB was associated with recurrent disease (aOR 1.87, 95% CI: 1.08–3.13), urban residence (aOR 1.27, 95% CI: 1.01–1.62) and cavitation (aOR 2.98, 95% CI: 2.35–3.78). Conclusions Age, sex, HIV and social factors impact the presentation of adolescent TB. Preventive, diagnostic and treatment activities should take these factors into consideration., Analysing 2491 cases of adolescent tuberculosis in Ukraine, associations were observed between four clinical presentations – cavitary, pleural, extrathoracic and rifampicin-resistant TB – and age, sex, HIV status, prior treatment and social factors. https://bit.ly/2XplZFt

Background Household contacts of patients with drug-resistant tuberculosis (TB) are at high risk for being infected with Mycobacterium tuberculosis and for developing TB disease. To guide regimen composition for the empirical treatment of TB infection and disease in these household contacts, we estimated drug-resistance profile concordance between index patients with drug-resistant TB and their household contacts. Methods We performed a systematic review and meta-analysis of studies published through 24 July 2018 that reported resistance profiles of drug-resistant TB index cases and secondary cases within their households. Using a random-effects meta-analysis, we estimated resistance profile concordance, defined as the percentage of secondary cases whose M. tuberculosis strains were resistant to the same drugs as strains from their index cases. We also estimated isoniazid/rifampin concordance, defined as whether index and secondary cases had identical susceptibilities for isoniazid and rifampin only. Results We identified 33 eligible studies that evaluated resistance profile concordance between 484 secondary cases and their household index cases. Pooled resistance profile concordance was 54.3% (95% confidence interval [CI], 40.7–67.6%; I2 = 85%). Pooled isoniazid/rifampin concordance was 82.6% (95% CI, 72.3–90.9%; I2 = 73%). Concordance estimates were similar in a subanalysis of 16 studies from high-TB-burden countries. There were insufficient data to perform a subanalysis among pediatric secondary cases. Conclusions Household contacts of patients with drug-resistant TB should receive treatment for TB infection and disease that assumes that they, too, are infected with a drug-resistant M. tuberculosis strain. Whenever possible, drug susceptibility testing should be performed for secondary cases to optimize regimen composition.

The multisystem inflammatory syndrome in children (MIS-C) is a known complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the pediatric population. Recent studies have demonstrated high efficacy of a two-dose vaccine series in preventing MIS-C among adolescents. To date, such studies have only included children exposed to SARS-CoV-2 prior to the emergence of the Omicron variant (B.1.1.529). We report a case of an adolescent who received three doses of a vaccine yet developed MIS-C following known exposure to SARS-CoV-2. Given the uncertainty in whether current vaccines offer as much protection against MIS-C due to the Omicron variant or any potential new variants as they have for older variants, pediatric providers should maintain a high index of suspicion for MIS-C regardless of vaccination status.

Background Improved understanding of the epidemiology and mortality risk factors of extrapulmonary tuberculosis (EPTB) may facilitate successful diagnosis and management. Methods We analyzed national surveillance data from Ukraine to characterize EPTB subtypes (ie, localized in different anatomic sites). We calculated annual reported incidence, stratified by age, sex, and human immunodeficiency virus (HIV) status. Using Cox regression, we estimated mortality risk factors. Results Between January 2015 and November 2018, 14 062 adults/adolescents (≥15 years) and 417 children ( Conclusions We identified the most common EPTB subtypes by age and sex, patterns of EPTB disease by HIV status, and mortality risk factors. These findings can inform diagnosis and care for people with EPTB.

Background Before August 2021, the only regimen recommended by the World Health Organization (WHO) to treat pediatric drug-susceptible tuberculous meningitis was a 12-month regimen consisting of isoniazid, rifampicin, ethambutol, and pyrazinamide (2HRZE/10HR). The comparative effectiveness of shorter regimens is unknown. Methods To inform a WHO guideline update, we undertook a systematic review and meta-analysis to evaluate outcomes from regimens of 6- to less than 12-months’ duration that included, at a minimum, isoniazid, rifampicin, and pyrazinamide. We included studies that applied rigorous diagnostic criteria and reported outcomes for ≥10 children or adolescents. Using generalized linear mixed models, we estimated the random effects pooled proportions of patients with key outcomes. Results Of 7 included studies, none compared regimens head-to-head. Three studies (724 patients) used a 6-month intensive regimen, which includes isoniazid and rifampicin at higher doses, pyrazinamide, and ethionamide instead of ethambutol (6HRZEto). Outcomes for this versus the 12-month regimen (282 patients, 3 studies) were, respectively, as follows: death, 5.5% (95% confidence interval [CI], 2.1%–13.4%) vs 23.9% (95% CI, 17.5%–31.7%); treatment success (survival with or without sequelae), 94.6% (95% CI, 73.9%–99.1%) vs 75.4% (95% CI, 68.7%–81.1%); and neurological sequelae among survivors, 66.0% (95% CI, 55.3%–75.3%) vs 36.3% (95% CI, 30.1%–43.0%). Relapse did not occur among 148 patients followed-up for 2 years after completing the 6-month intensive regimen. Conclusions Our findings are limited by the small number of studies and substantial potential for confounding. Nonetheless, the 6HRZEto regimen was associated with high treatment success and is now recommended by WHO as an alternative to the 12-month regimen.

The health needs of adolescents and young adults (AYAs) have been neglected in tuberculosis (TB) care, control, and research. AYAs, who are distinct from younger children and older adults, undergo dynamic physical, psychological, emotional, cognitive, and social development. Five domains of adolescent well-being are crucial to a successful transition between childhood and adulthood: (1) Good health; (2) connectedness and contribution to society; (3) safety and a supportive environment; (4) learning, competence, education, skills, and employability; and (5) agency and resilience. This review summarizes the evidence of the impact of TB disease and treatment on these five domains of AYA well-being.

PurposeTo evaluate the diagnostic value of symptoms used in the screening approaches by daycares and schools for identifying children and adolescents with possible SARS-CoV-2 infection, we designed a large observational study utilizing the data from primary care settings.MethodsThis cohort study included children and adolescents evaluated in a network of clinics in Rhode Island. Participants were age-stratified: 0-4, 5-11, and 12-17 years. We estimated the sensitivity, specificity, and area under the receiver operating curve (AUC) of individual symptoms and three symptom combinations: a probable case definition published by the Rhode Island Department of Health (RIDOH), and two novel combinations generated by different statistical approaches to maximize sensitivity and AUC. We evaluated the test characteristics of symptom combinations both with and without consideration of COVID-19 exposure.ResultsTwo-hundred seventeen (39.1%) of 555 participants were SARS-CoV-2-infected. Fever was more common among 0-4 years-olds (p=0.002); older children more frequently reported fatigue (p=0.02) and anosmia or ageusia (p=0.047). In children >5 years old, anosmia or ageusia had 94-98% specificity. In all age groups, exposure history most accurately predicted infection. In combination with COVID-19 exposure history, various symptom combinations had sensitivity >95% but specificity ConclusionsAnosmia or ageusia in children ≥5 years old and dyspnea in children 5-11 years old should raise providers’ index of suspicion for COVID-19. However, our overall findings underscore the limited diagnostic value of symptoms and the critical need for widely available, efficient testing.

Background In order for healthcare systems to prepare for future waves of COVID-19, an in-depth understanding of clinical predictors is essential for efficient triage of hospitalized patients. Methods We performed a retrospective cohort study of 259 patients admitted to our hospitals in Rhode Island to examine differences in baseline characteristics (demographics and comorbidities) as well as presenting symptoms, signs, labs, and imaging findings that predicted disease progression and in-hospital mortality. Results Patients with severe COVID-19 were more likely to be older (p = 0.02), Black (47.2% vs. 32.0%, p = 0.04), admitted from a nursing facility (33.0% vs. 17.9%, p = 0.006), have diabetes (53.9% vs. 30.4%, p Conclusions Certain patient characteristics and clinical features can help clinicians with early identification and triage of high-risk patients during subsequent waves of COVID-19.

We followed 35 children meeting a research definition for unconfirmed tuberculosis (TB) but in whom a pediatric pulmonologist did not diagnose or treat TB. After a median follow-up of 16.4 months, most children were not diagnosed with TB following a comprehensive evaluation. However, 2 were diagnosed with TB, demonstrating high TB risk (6%; exact 95% CI, 1%–19%). In some contexts, researchers may wish to supplement these research definitions with clinical decision data and longitudinal follow-up in order to improve specificity.

Background International guidelines recommend monitoring weight as an indicator of therapeutic response in childhood tuberculosis (TB) disease. This recommendation is based on observations in adults. In the current study, we evaluated the association between weight change and treatment outcome, the accuracy of using weight change to predict regimen efficacy, and whether successfully treated children achieve catch-up weight gain. Methods We enrolled children treated for drug-susceptible TB disease (group 1) and multidrug-resistant TB disease (group 2) in Peru. We calculated the change in weight-for-age z score (ΔWAZ) between baseline and the end of treatment months 2–5 for group 1, and between baseline and months 2–8 for group 2. We used logistic regression and generalized estimating equation models to evaluate the relationship between ΔWAZ and outcome. We plotted receiver operating characteristic curves to determine the accuracy of ΔWAZ for predicting treatment failure or death. Results Groups 1 and 2 included 100 and 94 children, respectively. In logistic regression, lower ΔWAZ in months 3–5 and month 7 was associated with treatment failure or death in groups 1 and 2, respectively. In generalized estimating equation models, children in both groups who experienced treatment failure or death had lower ΔWAZ than successfully treated children. The ΔWAZ predicted treatment failure or death with 60%–90% sensitivity and 60%–86% specificity in months 2–5 for group 1 and months 7–8 for group 2. All successfully treated children—except group 2 participants with unknown microbiologic confirmation status—achieved catch-up weight gain. Conclusions Weight change early in therapy can predict the outcome of childhood TB treatment.

The coronavirus disease 2019 (COVID-19) pandemic is a rapidly evolving global emergency that continues to strain healthcare systems. Emerging research describes a plethora of patient factors-including demographic, clinical, immunologic, hematological, biochemical, and radiographic findings-that may be of utility to clinicians to predict COVID-19 severity and mortality. We present a synthesis of the current literature pertaining to factors predictive of COVID-19 clinical course and outcomes. Findings associated with increased disease severity and/or mortality include age > 55 years, multiple pre-existing comorbidities, hypoxia, specific computed tomography findings indicative of extensive lung involvement, diverse laboratory test abnormalities, and biomarkers of end-organ dysfunction. Hypothesis-driven research is critical to identify the key evidence-based prognostic factors that will inform the design of intervention studies to improve the outcomes of patients with COVID-19 and to appropriately allocate scarce resources.

BackgroundTuberculosis (TB) stigma remains a barrier to early diagnosis and treatment completion. Increased understanding of stigma is necessary for improved interventions to minimise TB stigma and its effects. The purpose of this study is to quantitatively measure TB stigma and to explore qualitatively its manifestation among TB patients in a rural Kenyan community.MethodsThis hospital based study using explanatory sequential mixed methods approach was conducted in 2016. In the quantitative part of the study, a questionnaire containing socio-demographic characteristics and scales measuring perceived TB stigma and experienced TB stigma, was administered to 208 adult pulmonary TB patients receiving treatment in West Pokot County. Respondents with high stigma were purposively selected to take part in in-depth interviews and focus group discussions. The qualitative data were collected through 15 in-depth interviews and 6 focus group discussions with TB patients. Descriptive and bivariate analysis was done for the quantitative data while the thematic analysis was done for qualitative data.ResultsThe internal consistency reliability coefficients were satisfactory with Cronbach alphas of 0.87 and 0.86 for the 11-item and 12-item stigma measurement scale. The investigation revealed that TB stigma was high. The key drivers of TB stigma were the association of TB with HIV/AIDS and the fear of TB transmission. TB stigma was exemplified through patients being isolated by others, self-isolation, fear to disclose TB diagnosis, association of TB with human immunodeficiency virus (HIV) and lack of social support. Being a woman was significantly associated with high levels of both experienced stigma (p = 0.007) and perceived stigma (p = 0.005) while age, marital status, occupation and the patient's religion were not.ConclusionThere is a need to implement stigma reduction interventions in order to improve TB program outcomes.

Background The enteric string test can be used to obtain a specimen for microbiological confirmation of tuberculosis in children, but it is not widely used for this. The aim of this analysis to evaluate this approach in children with tuberculosis symptoms. Methods We conducted a cross-sectional study to assess children’s ability to complete the test (feasibility), and self-reported pain (tolerability). We examined caregivers’ and children’s willingness to repeat the procedure (acceptability) and described the diagnostic yield of cultures for diagnostic tools. We stratified estimates by age and compared metrics to those derived for gastric aspirate (GA). Results Among 148 children who attempted the string test, 34% successfully swallowed the capsule. Feasibility was higher among children aged 11–14 than in children 4–10 years (83% vs 22% respectively, p

Although tens of thousands of children and adolescents become sick with multidrug-resistant tuberculosis (MDR-TB) each year, fewer than 1,500 cases documenting treatment have been reported in the literature. Children treated for MDR-TB tend to have excellent clinical outcomes, but they suffer from the adverse events associated with current management strategies. This article will review the recommendations, evidence base, and future directions for MDR-TB therapy in children and adolescents.

Background To better understand patient factors that impact clinical outcomes in COVID-19, we performed a retrospective cohort study of patients hospitalized with COVID-19 in Rhode Island to identify patient and clinical characteristics associated with severe disease. Methods We analyzed 259 patients admitted to our academic medical center during a three month period with confirmed COVID-19. Clinical data was extracted via chart review and lab results within the first 24 hours of admission were extracted directly from electronic medical records. Patients were divided in two groups based upon the highest level of supplemental oxygen (O2) required during hospitalization: severe COVID-19 (high flow O2, non-invasive, or invasive mechanical ventilation) and non-severe COVID-19 (low flow O2 or no supplemental O2). SAS 9.4 (Cary, NC) was used for statistical analyses. Chi-square or Fisher’s exact tests for categorical variables and the Student’s t-test for continuous variables were used to compare demographics, baseline comorbidities, and clinical data between the severe and non-severe groups. Table 1: Demographics Results Of 259 patients, 166 (64%) had non-severe disease, and 93 (36%) severe disease; median age [IQR] was 62 [51,73]. There were 138(53%) males and 75 (29%) Hispanics. Among non-Hispanics,124(48%) were White, 48(19%) African Americans, and 12(5%) other races. Sixty (23%) were admitted from a nursing facility and the in-hospital mortality rate was 15% (38/259). Severe COVID-19 was associated with older age (p=0.02), admission from nursing facility (p=0.009), increased BMI (p=0.03), diabetes mellitus (p=0.0002), and COPD (p=0.03). At the time of presentation, severe COVID-19 was associated with tachypnea, hypoxia, hypotension (all p< 0.0001), elevated BUN (p=0.002) and AST (p=0.001), and acute or chronic kidney injury (p=0.01). Median hospital stay [IQR] was 11 days [7,18] in the severe vs. 6 days [3,11] in the non-severe group. In the severe group, 72% required ICU admission and 39% died. Table 2: Medical comorbidities Table 3: Presenting symptoms and signs in the first 48 hours of admission Table 4: Basic labs in the first 24 hours Conclusion In this cohort of patients with COVID-19, specific comorbidities, and vital signs at presentation were associated with severe COVID-19. These findings help clinicians with early identification and triage of high risk patients. Disclosures All Authors: No reported disclosures

Adolescence is characterised by a dramatic increase in the incidence of tuberculosis, a fact that has been appreciated since the early 20(th) century. The majority of the world’s adolescents live in low and middle-income countries where tuberculosis remains common, and where they comprise one quarter of the population. Despite this, adolescents have not yet been addressed as a distinct population in tuberculosis policy or within tuberculosis treatment services, and emerging evidence suggests that current models of care do not meet their needs. This article reviews current knowledge about tuberculosis in adolescence with a focus on the management of infection and disease, including HIV co-infection and rifampicin-resistant tuberculosis. Recent progress in vaccine development is outlined and important directions for future research are highlighted.

OBJECTIVE: To evaluate the performance of a survey that quantifies the intensity of household tuberculosis (TB) exposure among children.METHODS: Children aged 0–14 years in Lima, Peru, with ≥1 signs and/or symptoms of TB and a history of contact with an adult TB patient were included. The 10-question survey was administered to caregivers and addressed sleep proximity, frequency of exposure, and infectiousness of the contact. Infection status was determined using tuberculin skin tests (TSTs). The exposure scale was evaluated for association with TST positivity using mixed-effects regression analyses.RESULTS: The exposure score was significantly associated with TST positivity (age-adjusted odds ratio [aOR] 1.14, 95%CI 1.02–1.28). We observed a stronger association with TST positivity in children aged ≤5 years; (aOR 1.23, 95%CI 1.07–1.41) and no association in children 6–14 years of age (aOR 0.99, 95%CI 0.82–1.20).CONCLUSION: This survey was easy to use and modestly successful in predicting TST positivity in children aged ≤5 years. It may be a useful resource for clinicians for diagnosing TB in children, and for national TB programs aiming to scale up preventive therapy initiatives.

Tuberculosis (TB) is the leading single-agent infectious disease killer worldwide. The World Health Organization (WHO)'s End TB Strategy aims to achieve tuberculosis (TB) elimination by 2030, and in September 2018, the United Nations General Assembly held a High-Level Meeting on TB to address the urgency of the TB epidemic and the health inequalities that continue to propel it. The meeting endorsed an ambitious, comprehensive approach to the TB epidemic that incorporates universal health coverage and tackles the social determinants of this disease. In this article, we provide an overview of the key strategies promoted in this meeting and introduce work by five Rhode Island-based physicians that align with these goals.

* Abbreviation: IGRA — : interferon γ release assay Globally, an estimated 239 000 children younger than 15 years, including 39 000 with HIV infection, die of tuberculosis each year. More than 95% of these deaths occur in children who did not receive tuberculosis treatment.1 Children treated for tuberculosis have low mortality rates.2 Therefore, it is likely that the number of childhood tuberculosis deaths would decline dramatically if the case-detection ratio were improved from its current proportion of ∼1 in 3. Multiple factors contribute to this dismal case-detection rate, including the health care barriers faced by the poor and marginalized populations most affected by tuberculosis, the inability of most children to expectorate sputum for sample collection, and the paucibacillary nature of childhood tuberculosis, which leads to infrequent microbiologic confirmation. The most sensitive microbiologic test (culture) identifies Mycobacterium tuberculosis in just 25% of cases.3 Health officials in countries with high tuberculosis burden have prioritized contagious adult cases as the drivers of the tuberculosis epidemic. Consequently, front-line providers often lack adequate training to evaluate children for tuberculosis.4 Because their clinical training emphasizes tuberculosis … Address correspondence to Andrea T. Cruz, MD, MPH, Department of Pediatrics, Baylor College of Medicine, 6621 Fannin St, Suite A2210, Houston, TX 77030. E-mail: acruz{at}bcm.edu

Few reports have described pediatric Multidrug-resistant Tuberculosis (MDR-TB) in the former Soviet republics, despite the fact that these countries have the highest proportion of TB cases that are MDR. We aimed to examine pediatric MDR-TB in Ukraine. This retrospective cohort study included all children

SETTING In 2012, Peru's National TB Program (NTP) reported approximately 2400 incident cases of tuberculosis (TB) disease in children aged

Background Few studies have evaluated the association between preexisting vitamin D deficiency and incident tuberculosis (TB). We assessed the impact of baseline vitamins D levels on TB disease risk. Methods and findings We assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6,751 HIV-negative household contacts of TB patients enrolled between September 1, 2009, and August 29, 2012, in Lima, Peru. We screened for TB disease at 2, 6, and 12 months after enrollment. We defined cases as household contacts who developed TB disease at least 15 days after enrollment of the index patient. For each case, we randomly selected four controls from among contacts who did not develop TB disease, matching on gender and year of age. We also conducted a one-stage individual-participant data (IPD) meta-analysis searching PubMed and Embase to identify prospective studies of vitamin D and TB disease until June 8, 2019. We included studies that assessed vitamin D before TB diagnosis. In the primary analysis, we defined vitamin D deficiency as 25–(OH)D < 50 nmol/L, insufficiency as 50–75 nmol/L, and sufficiency as >75nmol/L. We estimated the association between baseline vitamin D status and incident TB using conditional logistic regression in the Lima cohort and generalized linear mixed models in the meta-analysis. We further defined severe vitamin D deficiency as 25–(OH)D < 25 nmol/L and performed stratified analyses by HIV status in the IPD meta-analysis. In the Lima cohort, we analyzed 180 cases and 709 matched controls. The adjusted odds ratio (aOR) for TB risk among participants with baseline vitamin D deficiency compared to sufficient vitamin D was 1.63 (95% CI 0.75–3.52; p = 0.22). We included seven published studies in the meta-analysis and analyzed 3,544 participants. In the pooled analysis, the aOR was 1.48 (95% CI 1.04–2.10; p = 0.03). The aOR for severe vitamin D deficiency was 2.05 (95% CI 0.87–4.87; p trend for decreasing 25–(OH)D levels from sufficient vitamin D to severe deficiency = 0.02). Among 1,576 HIV-positive patients, vitamin D deficiency conferred a 2-fold (aOR 2.18, 95% CI 1.22–3.90; p = 0.01) increased risk of TB, and the aOR for severe vitamin D deficiency compared to sufficient vitamin D was 4.28 (95% CI 0.85–21.45; p = 0.08). Our Lima cohort study is limited by the short duration of follow-up, and the IPD meta-analysis is limited by the number of possible confounding covariates available across all studies. Conclusion Our findings suggest vitamin D predicts TB disease risk in a dose-dependent manner and that the risk of TB disease is highest among HIV-positive individuals with severe vitamin D deficiency. Randomized control trials are needed to evaluate the possible role of vitamin D supplementation on reducing TB disease risk., Megan B. Murray and colleagues combine data from a case-control study in Lima, Peru, with previously published prospective studies to investigate whether low vitamin D is associated with risk of developing tuberculosis disease., Author summary Why was this study done? Although multiple lines of evidence suggest that vitamin D may play a role in host susceptibility to tuberculosis (TB) disease, the impact of low vitamin D on the risk of developing TB disease has not yet been firmly established. What did the researchers do and find? We conducted a study in Lima, Peru, in which we measured serum 25–(OH)D levels in individuals at high risk for TB disease and followed them for development of TB over 1 year. We pooled individual-level data from seven previously published prospective studies conducted worldwide and from our Lima cohort. We found that individuals with low levels of vitamin D were at higher risk of future progression to TB disease. What do these findings mean? These findings suggest that vitamin D deficiency is a risk factor for developing TB disease. Randomized control trials are needed to determine whether vitamin D supplementation reduces risk of TB disease.

In high burden settings, the risk of infection with Mycobacterium tuberculosis increases throughout childhood due to cumulative exposure. However, the risk of progressing from tuberculosis (TB) infection to disease varies by age. Young children (

BackgroundFew studies have evaluated the association between pre-existing vitamin D deficiency (VDD) and incident TB. We assessed the impact of baseline vitamin D on TB risk.MethodsWe assessed the association between baseline vitamin D and incident TB in a prospective cohort of 6751 household contacts of TB patients in Peru. We also conducted a one-stage individual participant data meta-analysis searching PubMed and Embase for studies of vitamin D and TB until December 31, 2017. We included studies that assessed vitamin D before TB diagnosis. We defined VDD as 25–(OH)D 75nmol/L. We estimated the association between vitamin D and incident TB using conditional logistic regression in the Peru cohort and generalized linear mixed models in the meta-analysis.FindingsIn Peru, baseline VDD was associated with a statistically insignificant increase in incident TB (aOR 1·70, 95% CI 0·84–3·46; p=0·14). We identified seven studies for the meta-analysis and analyzed 3544 participants. Individuals with VDD and very low vitamin D (p=0· 03 and aOR 2 08, 95% CI 0·88–4·92; p trend=002 respectively). Among HIV-positive patients, VDD and very low vitamin D conferred a 2-fold (aOR 2.18, 95% CI 1· 22–3·90; p=0· 01) and 4-fold (aOR 4·28, 95% CI 0·85–21·44; p trend=0·01) increased risk of TB respectively.InterpretationOur findings suggest vitamin D predicts TB risk in a dose-dependent manner and vitamin D supplementation may play a role in TB prevention.FundingNational Institute of Health (NIH), National Institute of Allergy and Infectious Diseases (NIAID), National Institute on Drug Abuse (NIDA), National Institute of Mental Health (NIMH), International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institute of Dental and Craniofacial Research (NIDCR), Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Foundation, Ujala Foundation, Wyncote Foundation, NIH - Fogarty International Center Program of International Training Grants in Epidemiology Related to AIDS, NIAID Byramjee Jeejeebhoy Medical College HIV Clinical Trials Unit, NIAID’s Baltimore-Washington-India Clinical Trials Unit, National Commission on Biotechnology, the Higher Education Commission, International Research Support Initiative Program of the Higher Education Commission Government of Pakistan, the Bill and Melinda Gates Foundation, and the NIH Fogarty International Center.Research in ContextEvidence before this studyNumerous studies have found lower serum vitamin D levels among patients with active TB disease compared to healthy controls. However, research has not clarified whether low vitamin D increases TB risk or whether TB disease leads to decreased vitamin D levels. We conducted PubMed and Medline searches for all studies available through December 31, 2017 on the association between vitamin D status and TB disease. We included the following keywords: “vitamin D,” “vitamin D deficiency,” “hypovitaminosis D,” “25-hydroxyvitamin D,” “1,25-dihydroxyvitamin D,” “vitamin D2,” “vitamin D3,” “ergocalciferol,” “cholecalciferol,” and “tuberculosis.” We found only seven studies had prospectively evaluated the impact of baseline vitamin D levels on risk of progression to TB disease.We report here the results of a case control study nested within a large prospective longitudinal cohort study of household contacts of TB cases and the results of an individual participant data (IPD) metaanalysis of available evidence on the association between vitamin D levels and incident TB disease.Added value of this studyWe demonstrated that low vitamin D levels predicts risk of future progression to TB disease in a dose-dependent manner.Implications of all the available evidenceThese findings suggest the possibility that vitamin D supplementation among individuals at high risk for developing TB disease might play a role in TB prevention efforts.

INTRODUCTION The teste rápido molecular para tuberculose (TRM-TB) was introduced in 2014 in Brazil for tuberculosis screening. However, its role in adolescents in Brazil has not been studied. METHODS A descriptive study of adolescents with suspected tuberculosis using National Laboratory software. RESULTS Of 852 (15.4%) suspected cases, 131 were positive by TRM-TB and 2% were resistant to rifampicin. Among TRM-TB-positive cases, 105 (91.4%) were culture-positive. Sixty-four of 96 samples were sensitive to rifampicin by TRM-TB; 11 were resistant to other drugs by drug sensitivity test (DST). CONCLUSIONS Among suspected cases, 16% were diagnosed by TRM-TB, of which 17% were drug-resistant by DST.

Setting In 2012, Peru's National Tuberculosis Program (NTP) reported that children aged 0-14 years accounted for 7.9% of the country's tuberculosis (TB) incidence. This figure is likely an underestimate due to suboptimal diagnosis of childhood TB. Objective To identify barriers to childhood TB diagnosis in Lima, Peru. Design Using semi-structured guides, moderators conducted in-depth interviews with four NTP administrators and five pulmonologists specializing in TB and 10 focus groups with 53 primary care providers, community health workers (CHWs), and parents and/or guardians of pediatric TB patients. Two authors independently performed inductive thematic analysis and identified emerging themes. Results Participants identified five barriers to childhood TB diagnosis: ignorance and stigma among the community, insufficient contact investigation, limited access to diagnostic tests, inadequately trained health center staff, and provider shortages. Conclusion Recent efforts to increase childhood TB detection have centered on the development of new technologies. However, our findings demonstrate that many diagnostic barriers are rooted in socio-economic and health system problems. Potential solutions include implementing multimedia campaigns and community education to reduce ignorance and stigma, prioritizing contact investigation for high-risk households, and training primary care providers and CHWs to recognize and evaluate childhood TB.

The challenge of diagnosing childhood tuberculosis (TB) results from its paucibacillary nature and the difficulties of sputum collection in children. Mycobacterial culture, the diagnostic gold standard, provides microbiological confirmation in only 30% to 40% of childhood pulmonary TB cases and takes up to 6 weeks to result. Conventional drug susceptibility testing requires an additional 2 to 4 weeks after culture confirmation. In response to the low sensitivity and long wait time of the traditional diagnostic approach, many new assays have been developed. These new tools have shortened time to result; however, none of them offer greater sensitivity than culture.

Summary Background Tuberculous meningitis disproportionately affects young children. We aimed to characterise treatment outcomes for this deadliest and most debilitating form of tuberculosis. Methods We did a systematic review and meta-analysis of childhood tuberculous meningitis studies published up to Oct 12, 2012. We included study reports that applied predefined diagnostic criteria and described treatment regimens and outcomes. We pooled risks of death during treatment and neurological sequelae among survivors. As secondary objectives, we assessed study-level characteristics as sources of heterogeneity, and we pooled frequencies of presenting symptoms and diagnostic findings. For all meta-analyses we used random-effects models with the exact binomial likelihood method. Findings 19 studies met our inclusion criteria, with reported treatment outcomes for 1636 children. Risk of death was 19·3% (95% CI 14·0–26·1) and probability of survival without neurological sequelae was 36·7% (27·9–46·4). Among survivors, risk of neurological sequelae was 53·9% (95% CI 42·6–64·9). Diagnosis in the most advanced disease stage (3) occurred in 307 (47%) of 657 patients and was associated with worse outcomes than was earlier diagnosis. The most common findings at presentation were cerebrospinal fluid (CSF) leucocytosis (frequency 99·9%, 95% CI 68·5–100·0), CSF lymphocytosis (97·9%, 51·9–100·0), fever (89·8%, 79·8–95·2), and hydrocephalus (86·1%, 68·6–94·6). Frequency of CSF acid-fast-bacilli smear positivity was 8·9% (95% CI 5·0–15·4), and frequency of CSF culture positivity for Mycobacterium tuberculosis was 35·1% (16·8–59·2). Interpretation Despite treatment, childhood tuberculous meningitis has very poor outcomes. Poor prognosis and difficult early diagnosis emphasise the importance of preventive therapy for child contacts of patients with tuberculosis and low threshold for empirical treatment of tuberculous meningitis suspects. Implementation of consensus definitions, standardised reporting of data, and high-quality clinical trials are needed to clarify optimum therapy. Funding None.

Background: As most national tuberculosis programmes (NTPs) focus on adult tuberculosis (TB), NTP providers may not appreciate differences in the pathophysiology and presentation of childhood TB. Objectives: This study aimed to identify strengths and weaknesses in knowledge of childhood TB among the 326 NTP providers in Lima Ciudad and Lima Este—two of the Peruvian capital’s four health districts. Methods: 310 providers—103 physicians, 106 nurses, 101 nursing technicians—accepted personal invitations to complete self-administered surveys, which included 14 childhood TB questions grouped into five sections: transmission, symptoms, diagnosis, prevention and treatment. Physicians were asked ten additional questions targeting their NTP diagnostic and management responsibilities. Results: All three groups scored 97–99% on the transmission section and 83–85% on the treatment section; however, no group scored above 66% on any other section. Fewer than 50% of nurses and technicians recognised young children’s high risk of extrapulmonary TB, extrapulmonary TB symptoms or the causes of false negative tuberculin skin tests. Twenty-three per cent of physicians correctly identified gastric aspirate culture sensitivity, and 42% the radiographical findings of pulmonary TB. Less than two-thirds of providers recognised the definition of latent TB infection (LTBI), young children’s high risk of progression from LTBI to disease or indications for isoniazid preventive therapy. Conclusions: Providers at the frontline of Peru’s TB control efforts demonstrated weaknesses in the areas of extrapulmonary disease, diagnosis and prevention. These knowledge gaps are likely to have resulted in delayed or missed diagnoses and lost opportunities for prevention. Educational interventions targeting NTP personnel may improve childhood TB care and outcomes.

BACKGROUND Globally, >30 000 children fall sick with multidrug-resistant (MDR) tuberculosis every year. Without robust pediatric data, clinical management follows international guidelines that are based on studies in adults and expert opinion. We aimed to identify baseline predictors of death, treatment failure, and loss to follow-up among children with MDR tuberculosis disease treated with regimens tailored to their drug susceptibility test (DST) result or to the DST result of a source case. METHODS This retrospective cohort study included all children ≤15 years old with confirmed and probable MDR tuberculosis disease who began tailored regimens in Lima, Peru, between 2005 and 2009. Using logistic regression, we examined associations between baseline patient and treatment characteristics and (1) death or treatment failure and (2) loss to follow-up. RESULTS Two hundred eleven of 232 (90.9%) children had known treatment outcomes, of whom 163 (77.2%) achieved cure or probable cure, 29 (13.7%) were lost to follow-up, 10 (4.7%) experienced treatment failure, and 9 (4.3%) died. Independent baseline predictors of death or treatment failure were the presence of severe disease (adjusted odds ratio [aOR], 4.96; 95% confidence interval [CI], 1.61-15.26) and z score ≤-1 (aOR, 3.39; 95% CI, 1.20-9.54). We did not identify any independent predictors of loss to follow-up. CONCLUSIONS High cure rates can be achieved in children with MDR tuberculosis using tailored regimens containing second-line drugs. However, children faced significantly higher risk of death or treatment failure if they had severe disease or were underweight. These findings highlight the need for early interventions that can improve treatment outcomes for children with MDR tuberculosis.

PurposeUnderstanding how specific genetic variants modify drug action pathways may provide informative blueprints for individualized chemotherapy.MethodsWe applied a pathway-based approach to examine the impact of a comprehensive panel of genetic polymorphisms on clinical outcomes in 210 esophageal cancer patients.ResultsIn the Cox proportional hazards model, MTHFR Glu429Ala variant genotypes were associated with significantly improved survival (hazard ratio [HR] = 0.56; 95% CI, 0.35 to 0.89) in patients treated with fluorouracil (FU). The 3-year survival rates for patients with the variant genotypes and the wild genotypes were 65.26% and 46.43%, respectively. Joint analysis of five polymorphisms in three FU pathway genes showed a significant trend for reduced recurrence risk and longer recurrence-free survival as the number of adverse alleles decreased (P = .004). For patients receiving platinum drugs, the MDR1 C3435T variant allele was associated with significantly reduced recurrence risk (HR = 0.25; 95% CI, 0.10 to 0.64) and improved survival (HR = 0.44; 95% CI, 0.23 to 0.85). In nucleotide excision repair genes, there was a significant trend for a decreasing risk of death with a decreasing number of high-risk alleles (P for trend = .0008). In base excision repair genes, the variant alleles of XRCC1 Arg399Gln were significantly associated with the absence of pathologic complete response (odds ratio = 2.75; 95% CI, 1.14 to 6.12) and poor survival (HR = 1.92; 95% CI, 1.00 to 3.72).ConclusionSeveral biologically plausible associations between individual single nucleotide polymorphisms and clinical outcomes were found. Our data also strongly suggest that combined pathway-based analysis may provide valuable prognostic markers of clinical outcomes.

Background: In Western countries, the overall incidence of gastric cancer is declining, while the incidence of proximal gastric cancer is rising. We evaluated the effect of sex, racial/ethnic group, and age on the localization of gastric cancer. Methods: The records of all gastric cancer patients who registered at The University of Texas M. D. Anderson Cancer Center from January 1, 1985, to May 31, 1998, were reviewed. Tissue diagnosis and established tumor location were required. Results: The case records of 1242 eligible patients, consisting of 821 non-Hispanic white, 230 Hispanic, 125 African American, 63 Asian, and 3 Native American patients, were analyzed. Among the 459 women, racial/ethnic group did not have a significant impact on gastric cancer localization ( P = 0.57). However, among the 783 men, proximal cancers were significantly more frequent in the non-Hispanic white patients (57% vs 38% Hispanic, 41% African American, 17% Asian; P < 0.0001). Symptoms at diagnosis significantly varied for proximal vs non-proximal cancers. Conclusion: Proximal gastric cancer localization was more frequent among non-Hispanic white men, while non-Hispanic white women had a localization pattern similar to those of other racial/ethnic groups. Proximal gastric cancer represents a distinct subtype of gastric cancer that may have different biology, risk factors, and clinical behavior.