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.

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.

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.

Risk Factors for Ventilator-Associated Events in a PICU.

OBJECTIVE: The term ventilator-associated events includes ventilator-associated condition, infection-related ventilator-associated complication, and ventilator-associated pneumonia. We sought to identify potential new risk factors for ventilator-associated condition and infection-related ventilator-associated complication in the PICU population. DESIGN: Matched case control study. SETTING: Children's hospital at a tertiary care academic medical center. PATIENTS: During the study period, 606 patients were admitted to PICU and ventilated more than 48 hours; 70 children met ventilator-associated condition criteria. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied the definition for ventilator-associated condition (i.e., a sustained increase in ventilator settings after a period of stable or decreasing support) to our database. Within ventilator-associated condition cases, 40 cases were infection-related ventilator-associated complication and 30 cases were noninfectious-related ventilator-associated condition. We identified 140 controls and matched to ventilator-associated condition cases with regard to age, immunocompromised status, and ventilator days to event. Patients with ventilator-associated condition had longer ICU stay versus controls; 24 days median (12-43 interquartile range) versus 7 days (4-14); (p < 0.01), respectively, and longer duration of ventilatory support 17 days (10-32) versus 6 days (3-10); p < 0.01, respectively. Mortality was 22.8% in the ventilator-associated condition versus 9% in the control group (p < 0.01). A multivariate regression analysis adjusted for Pediatric Index of Mortality 2 identified mean peak inspiratory pressure and acute kidney injury to be associated with ventilator-associated condition (odds ratio, 1.12 [95% CI, 1.02-1.22] and odds ratio, 2.85 [1.43-5.66], respectively). Acute kidney injury and neuromuscular blockade in a multivariate regression analysis adjusted for Pediatric Index of Mortality 2 were associated with infection-related ventilator-associated complication (odds ratio, 2.36 [1.03-5.40] and 3.19 [1.17-8.68], respectively). CONCLUSIONS: There is an association between ventilator-associated condition and infection-related ventilator-associated complication in critically ill children with acute kidney injury, ventilatory support, and neuromuscular blockade. Attention should be given by clinical practitioners to recognize these modifiable risk factors and to implement strategies to decrease the prevalence of ventilator-associated events.

Baseline Predictors of Treatment Outcomes in Children With Multidrug-Resistant Tuberculosis: A Retrospective Cohort Study.

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.

Angiostrongylus cantonensis Infection: A Cause of Fever of Unknown Origin in Pediatric Patients.

Fever of unknown origin (FUO) in children is frequently caused by infectious diseases. Angiostrongylus cantonensis, while a primary cause of eosinophilic meningitis, is rarely a cause of FUO. We present 2 pediatric cases of FUO caused by Angiostrongylus cantonensis acquired in Houston, Texas, outside its usual geographic distribution.

Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Executive Summary: Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis.

The American Thoracic Society, Centers for Disease Control and Prevention, and Infectious Diseases Society of America jointly sponsored the development of this guideline for the treatment of drug-susceptible tuberculosis, which is also endorsed by the European Respiratory Society and the US National Tuberculosis Controllers Association. Representatives from the American Academy of Pediatrics, the Canadian Thoracic Society, the International Union Against Tuberculosis and Lung Disease, and the World Health Organization also participated in the development of the guideline. This guideline provides recommendations on the clinical and public health management of tuberculosis in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. For all recommendations, literature reviews were performed, followed by discussion by an expert committee according to the Grading of Recommendations, Assessment, Development and Evaluation methodology. Given the public health implications of prompt diagnosis and effective management of tuberculosis, empiric multidrug treatment is initiated in almost all situations in which active tuberculosis is suspected. Additional characteristics such as presence of comorbidities, severity of disease, and response to treatment influence management decisions. Specific recommendations on the use of case management strategies (including directly observed therapy), regimen and dosing selection in adults and children (daily vs intermittent), treatment of tuberculosis in the presence of HIV infection (duration of tuberculosis treatment and timing of initiation of antiretroviral therapy), as well as treatment of extrapulmonary disease (central nervous system, pericardial among other sites) are provided. The development of more potent and better-tolerated drug regimens, optimization of drug exposure for the component drugs, optimal management of tuberculosis in special populations, identification of accurate biomarkers of treatment effect, and the assessment of new strategies for implementing regimens in the field remain key priority areas for research. See the full-text online version of the document for detailed discussion of the management of tuberculosis and recommendations for practice.

Laboratory Diagnosis of Mycobacterium tuberculosis Infection and Disease in Children.

Diagnosis of tuberculosis in children is challenging; even with advanced technologies, the diagnosis is often difficult to confirm microbiologically in part due to the paucibacillary nature of the disease. Clinical diagnosis lacks standardization, and traditional and molecular microbiologic methods lack sensitivity, particularly in children. Immunodiagnostic tests may improve sensitivity, but these tests cannot distinguish tuberculosis disease from latent infection and some lack specificity. While molecular tools like Xpert MTB/RIF have advanced our ability to detect Mycobacterium tuberculosis and to determine antimicrobial resistance, decades old technologies remain the standard in most locales. Today, the battle against this ancient disease still poses one of the primary diagnostic challenges in pediatric laboratory medicine.

Clinical Case Definitions for Classification of Intrathoracic Tuberculosis in Children: An Update.

Consensus case definitions for childhood tuberculosis have been proposed by an international expert panel, aiming to standardize the reporting of cases in research focusing on the diagnosis of intrathoracic tuberculosis in children. These definitions are intended for tuberculosis diagnostic evaluation studies of symptomatic children with clinical suspicion of intrathoracic tuberculosis, and were not intended to predefine inclusion criteria into such studies. Feedback from researchers suggested that further clarification was required and that these case definitions could be further improved. Particular concerns were the perceived complexity and overlap of some case definitions, as well as the potential exclusion of children with acute onset of symptoms or less severe disease. The updated case definitions proposed here incorporate a number of key changes that aim to reduce complexity and improve research performance, while maintaining the original focus on symptomatic children suspected of having intrathoracic tuberculosis. The changes proposed should enhance harmonized classification for intrathoracic tuberculosis disease in children across studies, resulting in greater comparability and the much-needed ability to pool study results.

The Centers for Disease Control and Prevention's New Definitions for Complications of Mechanical Ventilation Shift the Focus of Quality Surveillance and Predict Clinical Outcomes in a PICU.

OBJECTIVES: The Centers for Disease Control and Prevention shifted the focus of surveillance paradigm for adult patients receiving mechanical ventilation, moving from the current standard of ventilator-associated pneumonia to broader complications. The surveillance definitions were designed to enable objective measures and efficient processes, so as to facilitate quality improvement initiatives and enhance standardized benchmark comparisons. We evaluated the surveillance definitions in term of their ability to predict clinical outcomes and ease of surveillance in a PICU. DESIGN: Retrospective cohort study. SETTING: A PICU at a university-affiliated children's hospital. PATIENTS: Eight hundred thirty-six patients receiving mechanical ventilation over 1-year period. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We applied the definition for ventilator-associated condition (i.e., a sustained increase in ventilator setting after a period of stable or decreasing support) to our database. Of total 606 patients, 14.5% had ventilator-associated condition (20.9/1,000 ventilator days) and 8.1% had an infection-related ventilator-associated condition (12.9/1,000 ventilator days). The patients with infection-related ventilator-associated condition were classified into probable pneumonia (55%), possible pneumonia (28.6%), and undetermined infection (16.3%). A large portion of patients with ventilator-associated condition (44%) had other noninfectious etiologies (e.g., atelectasis, pulmonary edema, and shock). Patients who developed ventilator-associated condition had significantly longer ventilatory, ICU, and hospital days compared with those who did not. The ventilator-associated condition group had increased hospital mortality compared with the non-ventilator-associated condition group (19.3% vs 6.9%; p=0.0007). Multivariate regression analysis identified ventilator-associated condition as one of the predictors of hospital mortality with an adjusted odds ratio of 2.14 (95% CI, 1.03-4.42). Risk factors for developing a ventilator-associated condition included immunocompromised status (odds ratio, 2.90; 95% CI, 1.57-5.33), tracheostomy dependence (odds ratio, 2.78; 95% CI, 1.40-5.51), and chronic respiratory disease (odds ratio, 1.85; 95% CI, 1.03-3.3). CONCLUSIONS: The definitions for the various ventilator-associated conditions are good predictors of outcomes in children and adults and are amenable to automated surveillance. Based on the study findings, we suggest consideration for shifting the focus of surveillance for ventilator-associated events from only pneumonia to a broader range of complications.

Old and new approaches to diagnosing and treating latent tuberculosis in children in low-incidence countries.

PURPOSE OF REVIEW: The primary purpose is to review guidance on the testing and treatment of latent tuberculosis infection (LTBI) in children. Most children and adults with LTBI have positive tuberculin skin test (TST) or interferon gamma release assay (IGRA) results, normal examinations, and normal chest radiographs. Diagnosis of and treatment completion for LTBI are critical to diminish future cases of tuberculosis (TB) disease. RECENT FINDINGS: Children should be screened for TB risk factors, and only children with risk factors should be tested with either a TST or an IGRA. IGRAs measure interferon gamma production by lymphocytes after they are stimulated ex vivo by antigens that are primarily Mycobacterium tuberculosis-specific. The foundation of LTBI therapy in the United States has been 9 months of daily isoniazid, but shorter treatment regimens now exist, including a 12-dose regimen of weekly isoniazid and rifapentine. These shorter regimens are associated with higher completion rates. SUMMARY: There are two distinct modalities for LTBI diagnosis and several treatment regimens that can prevent TB disease in infected children. The selection of treatment regimen should take several factors into consideration, including adherence, drug susceptibility results of the presumed source case (if known), safety, cost, and patient preference.

Tuberculosis in pediatric oncology and bone marrow transplantation patients.

Five children with malignancies (3 hematologic, 1 medulloblastoma, 1 hepatoblastoma) and one bone marrow transplant patient were treated for tuberculosis over a 30-year period. Three had pulmonary disease, 3 disseminated tuberculosis, and 1 had scrofula. Four of five had positive tuberculin skin tests, cultures were positive in 5/6 children. One child died of disseminated TB after engraftment, and one child had hepatotoxicity likely related to tuberculosis therapy. All cases were potentially preventable had they been screened due to established risk factors of foreign birth (4/6) or parental foreign birth (2/6). All children should be screened for latent tuberculosis before chemotherapy.

LOCALIZED MYOSITIS AND TRANSIENT ENCEPHALOPATHY AS PRESENTING SYMPTOMS IN MURINE TYPHUS.

Murine typhus in the pediatric population has increased substantially in recent years. The most common clinical presentation of murine typhus includes fever, rash, headaches and myalgias. Murine typhus presenting with predominant myositis and/or encephalopathy is rare. It is important to recognize unusual clinical manifestations of murine typhus in children for early diagnosis and treatment.

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.

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.

Molecular epidemiological surveillance of multidrug-resistant Pseudomonas aeruginosa isolates in a pediatric population of patients with cystic fibrosis and determination of risk factors for infection with the Houston-1 strain.

Multiyear molecular epidemiological surveillance of multidrug-resistant Pseudomonas aeruginosa (MRPA) in a pediatric cystic fibrosis care center identified an endemic MRPA strain (Houston-1). Recent hospitalization was found to be a statistically significant risk factor for acquisition of the endemic strain. Multiple infection control improvements led to the reduced incidence of the Houston-1 strain in the CF population.

Cost-effectiveness of latent tuberculosis screening before steroid therapy for idiopathic nephrotic syndrome in children.

BACKGROUND: Guidelines differ on screening recommendations for latent tuberculosis infection (LTBI) prior to immunosuppressive therapy. We aimed to determine the most cost-effective LTBI screening strategy before long-term steroid therapy in a child with new-onset idiopathic nephrotic syndrome. STUDY DESIGN: Markov state-transition model. SETTING & POPULATION: 5-year-old boy with new-onset idiopathic nephrotic syndrome. MODEL, PERSPECTIVE, & TIMEFRAME: The Markov model took a societal perspective over a lifetime horizon. INTERVENTION: 3 strategies were compared: universal tuberculin skin testing (TST), targeted screening using a risk-factor questionnaire, and no screening. A secondary model included the newer interferon γ release assays (IGRAs), requiring only one visit and having greater specificity than TST. OUTCOMES: Marginal cost-effectiveness ratios (2010 US dollars) with effectiveness measured as quality-adjusted life-years (QALYs). RESULTS: At an LTBI prevalence of 1.1% (the average US childhood prevalence in our base case), a no-screening strategy dominated ($2,201; 29.3356 QALYs) targeted screening ($2,218; 29.3356 QALYs) and universal TST ($2,481; 29.3347 QALYs). At a prevalence >10.3%, targeted screening with a risk-factor questionnaire was the most cost-effective option. Higher than a prevalence of 58.5%, universal TST was preferred. In the secondary model, targeted screening with a questionnaire followed by IGRA testing was cost-effective compared with no screening in the base case when the LTBI prevalence was >4.9%. LIMITATIONS: There is no established gold standard for the diagnosis of LTBI. Results of any modeling task are limited by the accuracy of available data. CONCLUSIONS: Prior to starting steroid therapy, only patients in areas with a high prevalence of LTBI will benefit from universal TST. As more evidence becomes available about the use of IGRA testing in children, the assay may become a component of cost-effective screening protocols in populations with a higher burden of LTBI.