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.
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.
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.
The traditional treatment of tuberculosis (TB) infection (9 months of daily isoniazid 9H) is safe but completion rates of <50% are reported. Shorter regimens (3 months of once-weekly isoniazid and ...rifapentine 3HP or 4 months of daily rifampin 4R) are associated with improved adherence in adults.
This was a retrospective cohort study (2014-2017) of children (0-18 years old) seen at a children's TB clinic in a low-incidence nation. We compared the frequency of completion and adverse events (AEs) in children receiving 3HP, 4R, and 9H; the latter 2 regimens could be administered by families (termed self-administered therapy SAT) or as directly observed preventive therapy (DOPT); 3HP was always administered under DOPT.
TB infection treatment was started in 667 children: 283 (42.4%) 3HP, 252 (37.8%) 9H, and 132 (19.8%) 4R. Only 52% of children receiving 9H via SAT completed therapy. Children receiving 3HP were more likely to complete therapy than the 9H (SAT) group (odds ratio OR 27.4, 95% confidence interval CI: 11.8-63.7). Multivariate analyses found receipt of medication under DOPT (OR: 5.72, 95% CI: 3.47-9.43), increasing age (OR: 1.09, 95% CI: 1.02-1.17), and the absence of any AE (OR: 1.70, 95% CI: 0.26-0.60) to be associated with completing therapy. AEs were more common in the 9H group (OR: 2.51, 95% CI: 1.48-4.32). Two (0.9%) children receiving 9H developed hepatotoxicity; no child receiving 3HP or 4R developed hepatotoxicity.
Shorter regimens are associated with increased completion rates and fewer AEs than 9H.
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.
Better diagnostic tests and a more effective vaccine are needed, but the number of childhood tuberculosis cases and deaths could be substantially and rapidly decreased with available and inexpensive ...tools and strategies that can be applied anywhere, such as screening for tuberculosis symptoms, reporting of clinically defined cases, provision of the new, child-friendly tuberculosis drugs, and provision of preventive therapy to household contacts.
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.
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.
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.
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