Management of the infant born to a mother with tuberculosis: a systematic review and consensus practice guideline.

Infants born to mothers with tuberculosis disease are at increased risk of developing tuberculosis disease themselves. We reviewed published studies and guidelines on the management of these infants to inform the development of a consensus practice guideline. We searched MEDLINE, CINAHL, and Cochrane Library from database inception to Dec 1, 2022, for original studies reporting the management and outcome of infants born to mothers with tuberculosis. Of the 521 published papers identified, only three met inclusion criteria and no evidence-based conclusions could be drawn from these studies, given their narrow scope, variable aims, descriptive nature, inconsistent data collection, and high attrition rates. We also assessed a collection of national and international guidelines to inform a consensus practice guideline developed by an international panel of experts from different epidemiological contexts. The 16 guidelines reviewed had consistent features to inform the expert consultation process. Two management algorithms were developed-one for infants born to mothers considered potentially infectious at the time of delivery and another for mothers not considered infectious at the time of delivery-with different guidance for high and low tuberculosis incidence settings. This systematic review and consensus practice guideline should facilitate more consistent clinical management, support the collection of better data, and encourage the development of more studies to improve evidence-based care.

Identifying adolescents at risk for suboptimal adherence to tuberculosis treatment: A prospective cohort study.

Adolescents account for an estimated 800,000 incident tuberculosis (TB) cases annually and are at risk for suboptimal adherence to TB treatment. Most studies of adolescent TB treatment adherence have used surveillance data with limited psychosocial information. This prospective cohort study aimed to identify risk factors for suboptimal adherence to rifampicin-susceptible TB treatment among adolescents (10-19 years old) in Lima, Peru. We collected psychosocial data using self-administered surveys and clinical data via medical record abstraction. Applying k-means cluster analysis, we grouped participants by psychosocial characteristics hypothesized to impact adherence. Then, we conducted mixed effects regression to compare suboptimal adherence-defined as <90% (missing >10% of doses)-between clusters. Treatment setting (facility vs. home) and drug formulation (single drug vs. fixed dose combination) were interaction terms. Of 249 participants, 90 (36.1%) were female. Median age was 17 (IQR: 15, 16.6) years. We identified three clusters-A, B, and C-of participants based on psychosocial characteristics. Cluster C had the lowest support from caregivers, other family members, and friends; had the weakest motivation to complete TB treatment; were least likely to live with their mothers; and had experienced the most childhood adversity. Among the 118 (47.4%) participants who received facility-based treatment with single drug formulations, adherence did not differ between Clusters A and B, but Cluster C had six-fold odds of suboptimal adherence compared to Cluster A. In Clusters B and C, adherence worsened over time, but only in Cluster C did mean adherence fall below 90% within six months. Our findings have implications for the care of adolescents with TB. When caring for adolescents with low social support and other risk factors, clinicians should take extra measures to reinforce adherence, such as identifying a community health worker or peer to provide treatment support. Implementing newly recommended shorter regimens also may facilitate adherence.

Use of Interferon-Gamma Release Assays in Children <2 Years Old.

While interferon-gamma release assays (IGRAs) are widely used for detecting tuberculosis (TB) infection, tuberculin skin tests (TSTs) remain preferred for children under the age of 2 years. The preference for TST stems from concern over IGRA sensitivity in young children. However, TSTs are susceptible to false-positive results following Bacille Calmette-Guérin (BCG) vaccination, which is common in infancy, and exposure to nontuberculous mycobacteria. We reviewed available data for IGRA performance in children under age 2 years. Across four cohorts of high-risk children under age 2 (mostly case contacts or those born in tuberculosis endemic regions), 0 of 575 untreated children with negative IGRA test results progressed to tuberculosis disease-including 0 of 70 who were TST positive but IGRA negative. While neither TSTs nor IGRAs are perfectly sensitive for the diagnosis of tuberculosis infection, IGRAs are an acceptable alternative to TST in children <2 years of age.

Clinical Worsening in an Adolescent With Pleural Tuberculosis.

A 17-year-old previously healthy female presented with unilateral chest pain and dyspnea. Chest radiographs demonstrated a unilateral pleural effusion and pneumonia. Pleural fluid bacterial cultures were negative; acid-fast cultures grew Mycobacterium tuberculosis. Two months after starting appropriate therapy, she had a recrudescence of symptoms and reaccumulation of the pleural fluid. Her tuberculosis antibiotic regimen was expanded, the effusion drained, and systemic corticosteroids initiated, resulting in rapid clinical improvement. Cultures of the second pleural fluid collection were negative. Her clinical deterioration was due to immune reconstitution inflammatory syndrome (IRIS). IRIS can be seen within the first several months of starting tuberculosis therapy and can result in paradoxical worsening of symptoms or radiographic findings in adolescents who are on the appropriate therapy. IRIS is a diagnosis of exclusion after drug resistance and medication malabsorption, intolerance, and nonadherence are excluded. Therapy includes nonsteroidal anti-inflammatory agents for milder reactions and systemic corticosteroids for more severe IRIS cases.

New Drugs and Regimens for Tuberculosis Disease Treatment in Children and Adolescents.

After almost 30 years of relative stagnation, research over the past decade has led to remarkable advances in the treatment of both drug-susceptible (DS) and drug-resistant (DR) tuberculosis (TB) disease in children and adolescents. Compared with the previous standard therapy of at least 6 months, 2 new regimens lasting for only 4 months for the treatment of DS-TB have been studied and are recommended by the World Health Organization (WHO), along with a shortened 6-month regimen for treatment of DS-TB meningitis. In addition, the 18- to 24-month regimens previously used for DR-TB that included painful injectable drugs with high rates of adverse effects have been replaced with shorter, safer all-oral regimens. Advances that have improved treatment include development of new TB drugs (bedaquiline, delamanid, pretomanid), reapplication of older TB drugs (rifampicin and rifapentine), and repurposing of other drugs (clofazimine and linezolid). The development of child-friendly formulations for many of these drugs has further enhanced the ability to safely and effectively treat DS- and DR-TB in children and adolescents. The characteristics and use of these drugs, regimens, and formulations are reviewed.

Tuberculous Meningitis in Children: A Forgotten Public Health Emergency.

Tuberculous meningitis (TBM) remains a major cause of morbidity and mortality in children with tuberculosis (TB), yet there are currently no estimates of the global burden of pediatric TBM. Due to frequent non-specific clinical presentation and limited and inadequate diagnostic tests, children with TBM are often diagnosed late or die undiagnosed. Even when diagnosed and treated, 20% of children with TBM die. Of survivors, the majority have substantial neurological disability with significant negative impact on children and their families. Surveillance data on this devastating form of TB can help to quantify the contribution of TBM to the overall burden, morbidity and mortality of TB in children and the epidemiology of TB more broadly. Pediatric TBM usually occurs shortly after primary infection with Mycobacterium tuberculosis and reflects ongoing TB transmission to children. In this article we explain the public health importance of pediatric TBM, discuss the epidemiology within the context of overall TB control and health system functioning and the limitations of current surveillance strategies. We provide a clear rationale for the benefit of improved surveillance of pediatric TBM using a TB care cascade framework to support monitoring and evaluation of pediatric TB, and TB control more broadly. Considering the public health implications of a diagnosis of TBM in children, we provide recommendations to strengthen pediatric TBM surveillance and outline how improved surveillance can help us identify opportunities for prevention, earlier diagnosis and improved care to minimize the impact of TBM on children globally.

Strengthening Tuberculosis Services for Children and Adolescents in Low Endemic Settings.

In low tuberculosis-burden countries, children and adolescents with the highest incidence of tuberculosis (TB) infection or disease are usually those who have immigrated from high-burden countries. It is, therefore, essential that low-burden countries provide healthcare services to immigrant and refugee families, to assure that their children can receive proper testing, evaluation, and treatment for TB. Active case-finding through contact tracing is a critical element of TB prevention in children and in finding TB disease at an early, easily treated stage. Passive case-finding by evaluating an ill child is often delayed, as other, more common infections and conditions are suspected initially. While high-quality laboratory services to detect Mycobacterium tuberculosis are generally available, they are often underutilized in the diagnosis of childhood TB, further delaying diagnosis in some cases. Performing research on TB disease is difficult because of the low number of cases that are spread over many locales, but critical research on the evaluation and treatment of TB infection has been an important legacy of low-burden countries. The continued education of medical providers and the involvement of educational, professional, and non-governmental organizations is a key element of maintaining awareness of the presence of TB. This article provides the perspective from North America and Western Europe but is relevant to many low-endemic settings. TB in children and adolescents will persist in low-burden countries as long as it persists throughout the rest of the world, and these wealthy countries must increase their financial commitment to end TB everywhere.

Tuberculosis Infection in Children and Adolescents: Testing and Treatment.

Tuberculosis (TB) remains an important problem among children in the United States and throughout the world. There is no diagnostic reference standard for latent tuberculosis infection (also referred to as tuberculosis infection [TBI]). The tuberculin skin test (TST) has many limitations, including difficulty in administration and interpretation, the need for a return visit by the patient, and false-positive results caused by cross-reaction with Mycobacterium bovis-bacille Calmette-Guerin vaccines and many nontuberculous mycobacteria. Interferon-gamma release assays (IGRAs) are blood tests that use antigens specific for M tuberculosis; as a result, IGRAs yield fewer false-positive results than the TST. Both IGRAs and the TST have reduced sensitivity in immunocompromised children, including children with severe TB disease. Both methods have high positive predictive value when applied to children with risk factors for TBI, especially recent contact with a person who has TB disease. The advantages of using IGRAs and diminished experience with the placement and interpretation of the TST favor expanded use of IGRAs in children in the United States. There are now several effective and safe regimens for the treatment of TBI in children. For improved adherence to therapy, the 3 rifamycin-based regimens are preferred because of their short duration. Daily isoniazid can be used if there is intolerance or drug interactions with rifamycins. A TB specialist should be involved when there are questions regarding testing interpretation, selection of an appropriate treatment regimen, or management of adverse effects.

Tuberculosis in Internationally Displaced Children Resettling in Harris County, Texas, USA, 2010-20151.

US guidelines have recommended testing children emigrating from high tuberculosis-incidence countries with interferon-gamma release assays (IGRAs) or tuberculin skin tests (TSTs). We describe the Harris County (Texas) Public Health Refugee Health Screening Program's testing results during 2010-2015 for children <18 years of age: 5,990 were evaluated, and 5,870 (98%) were tested. Overall, 364 (6.2%) children had >1 positive test: 143/1,842 (7.8%) were tested with TST alone, 129/3,730 (3.5%) with IGRA alone, and 92/298 (30.9%) with both TST and IGRA. Region of origin and younger age were associated with positive TST or IGRA results. All children were more likely to have positive results for TST than for IGRA (OR 2.92, 95% CI 2.37-3.59). Discordant test results were common (20%) and most often were TST+/IGRA- (95.0%), likely because of bacillus Calmette-Guérin vaccination. Finding fewer false positives supports the 2018 change in US immigration guidelines that recommends using IGRAs for recently immigrated children.

Advanced imaging tools for childhood tuberculosis: potential applications and research needs.

Tuberculosis is the leading cause of death globally that is due to a single pathogen, and up to a fifth of patients with tuberculosis in high-incidence countries are children younger than 16 years. Unfortunately, the diagnosis of childhood tuberculosis is challenging because the disease is often paucibacillary and it is difficult to obtain suitable specimens, causing poor sensitivity of currently available pathogen-based tests. Chest radiography is important for diagnostic evaluations because it detects abnormalities consistent with childhood tuberculosis, but several limitations exist in the interpretation of such results. Therefore, other imaging methods need to be systematically evaluated in children with tuberculosis, although current data suggest that when available, cross-sectional imaging, such as CT, should be considered in the diagnostic evaluation for tuberculosis in a symptomatic child. Additionally, much of the understanding of childhood tuberculosis stems from clinical specimens that might not accurately represent the lesional biology at infection sites. By providing non-invasive measures of lesional biology, advanced imaging tools could enhance the understanding of basic biology and improve on the poor sensitivity of current pathogen detection systems. Finally, there are key knowledge gaps regarding the use of imaging tools for childhood tuberculosis that we outlined in this Personal View, in conjunction with a proposed roadmap for future research.

Multiple Cranial Tuberculomas Without Meningitis in Two Infants With Miliary Tuberculosis.

Magnetic resonance imaging may detect central nervous system involvement even when cerebrospinal fluid is normal and tests to detect Mycobacterium tuberculosis are negative. We describe 2 cases of miliary tuberculosis in young children with clinically unexpected central nervous system involvement. Magnetic resonance imaging of the brain should be considered part of the initial diagnostic workup for miliary tuberculosis in very young children.

Treatment of Drug-Resistant Tuberculosis. An Official ATS/CDC/ERS/IDSA Clinical Practice Guideline.

Background: The American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America jointly sponsored this new practice guideline on the treatment of drug-resistant tuberculosis (DR-TB). The document includes recommendations on the treatment of multidrug-resistant TB (MDR-TB) as well as isoniazid-resistant but rifampin-susceptible TB.Methods: Published systematic reviews, meta-analyses, and a new individual patient data meta-analysis from 12,030 patients, in 50 studies, across 25 countries with confirmed pulmonary rifampin-resistant TB were used for this guideline. Meta-analytic approaches included propensity score matching to reduce confounding. Each recommendation was discussed by an expert committee, screened for conflicts of interest, according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology.Results: Twenty-one Population, Intervention, Comparator, and Outcomes questions were addressed, generating 25 GRADE-based recommendations. Certainty in the evidence was judged to be very low, because the data came from observational studies with significant loss to follow-up and imbalance in background regimens between comparator groups. Good practices in the management of MDR-TB are described. On the basis of the evidence review, a clinical strategy tool for building a treatment regimen for MDR-TB is also provided.Conclusions: New recommendations are made for the choice and number of drugs in a regimen, the duration of intensive and continuation phases, and the role of injectable drugs for MDR-TB. On the basis of these recommendations, an effective all-oral regimen for MDR-TB can be assembled. Recommendations are also provided on the role of surgery in treatment of MDR-TB and for treatment of contacts exposed to MDR-TB and treatment of isoniazid-resistant TB.

Fluid Overload and Kidney Injury Score as a Predictor for Ventilator-Associated Events.

Objective: The Pediatric and Neonatal Working group developed new ventilator associated events (VAE) definitions for children and neonates. VAE includes ventilator-associated condition (VAC), infection-related ventilator-associated complication (IVAC), and ventilator-associated pneumonia (VAP). Acute kidney injury (AKI) and fluid overload (FO) have been associated with worse clinical outcomes of ventilated children. Fluid Overload and Kidney Injury Score (FOKIS) is an automatically calculated score that combines AKI and FO in one numeric quantifiable metric. This study analyzed the association between FOKIS and VAE. Design: Retrospective matched case control study. Setting: A freestanding children's hospital. Patients: A total of 168 who were ventilated > 2 days. Interventions: None. Measurements and Main Results: We identified 42 VAC cases (18 IVAC and 24 non-infection-related VAC cases). Controls were matched to cases for age, immunocompromised status and ventilator days prior to VAC. VAC cases had longer ICU days, median (IQR), 28.5 (15, 47) vs. controls 11 (6, 16), p < 0.001; longer ventilation days, 19.5 (13, 32) vs. 9 (4,13), p < 0.001; and higher hospital mortality, 45.2 vs. 18%, p < 0.001. VACs had a higher incidence of AKI, 85.7 vs. 47.3%, p < 0.001; higher peak daily FO% within 3 days preceding VAC, mean (SD), 8.1(7.8) vs. 4.1 (3.4), p < 0.005; and higher peak FOKIS, 6.4(3.8) vs. 3.7(2.8), (p < 0.001). Multivariate regression model adjusted for severity of illness identified peak FOKIS (odds ratio [OR] 1.29, 95%CI: 1.14-1.48, p < 0.001) and peak inspiratory pressure (OR 1.08, 95%CI: 1.02-1.15, p = 0.007) as risk factors for VAC. Conclusions: The FOKIS and its clinical variables were associated risk factors for ventilator-associated events. Further studies will determine the utility of FOKIS as a predictor for VAEs.

Monitoring Treatment of Childhood Tuberculosis and the Role of Therapeutic Drug Monitoring.

Most children tolerate the first-line antibiotics used to treat Mycobacterium tuberculosis (TB) very well. The most common adverse effect is gastrointestinal distress unrelated to hepatotoxicity; the latter is seen in less than 1% of children. Despite the infrequency of hepatotoxicity, the potential long-term impact of hepatic insufficiency dictates that all children receiving antimycobacterial therapy should be evaluated periodically by symptom screening and physical examination. Routine measurement of transaminases in previously healthy, asymptomatic children is discouraged, as up to 40% of children will have transient, asymptomatic transaminase elevation that should not alter clinical management; measurement of serum liver enzymes is reserved for children who develop symptoms and those with existing liver disease or taking other potentially hepatotoxic drugs. Caregivers and personnel distributing directly-observed therapy need to be cognizant of potential drug toxicities and have a clear understanding of what to do if a child develops symptoms. There are substantial inter-patient variations in serum antibiotic concentrations when the same milligram per kilogram dose is given to different children of varying ages and sizes, reflecting differences in drug absorption and metabolism. While these variations may not impact the outcome of previously healthy children with mild disease, outcomes for children with human immunodeficiency virus infection or severe disease can be worse if sub-therapeutic drug concentrations are achieved. Therapeutic drug monitoring, wherein serum drug concentrations are used to optimize medication doses, should be considered for children with severe disease or if there is concern about alterations in drug absorption or metabolism.

Window Period Prophylaxis for Children Exposed to Tuberculosis, Houston, Texas, USA, 2007-2017.

In this retrospective study, we assessed the safety of window period prophylaxis and proportion of tuberculin skin test (TST) conversions in children <5 years of age who were exposed to an adult with tuberculosis disease during 2007-2017. Children included in this study had unremarkable examination and chest radiograph findings and negative test results for TB infection. In total, 752 children (41% cohabitating with the index patient) received prophylaxis during the window period, usually directly observed therapy with isoniazid. Hepatotoxicity and tuberculosis disease did not develop in any child. TST conversion occurred in 37 (4.9%) children and was associated with the index patient being the child's parent (odds ratio 3.2, 95% CI 1.2-8.2). TST conversion was not associated with sputum smear results, culture positivity, or cohabitation. Thresholds for initiation of window prophylaxis in exposed young children should be low given the safety of medication and difficulties with risk stratification.

Treatment of tuberculosis infection in children.

INTRODUCTION: Identifying and treating children with tuberculosis (TB) infection in both low and high-TB burden settings will decrease the incidence of TB disease worldwide. Areas covered: This review covers each of the available TB infection treatment options for children based on effectiveness, safety, tolerability and treatment completion rates. Six to 9 months of daily administered isoniazid is no longer the treatment of choice for many children with TB infection. Shorter, rifamycin based, TB infection treatment regimens are effective, safe and easier for children to complete. Fluroquinolone-based regimens are recommended for the treatment of children infected by a source case with drug-resistant TB. Directly observed therapy (DOT) programs improve childhood TB infection treatment completion rates. Expert commentary: As shorter, rifamycin-based, TB infection treatment regimens offer superior treatment success rate in both adults and children; the widespread use of these regimens has huge potential to decrease the burden of TB disease worldwide. The implementation of these programs will involve improving patient access to the medications, decreasing their cost to the patient, and the use of novel electronic methods to document patient treatment completion.