Clinical standards for drug-susceptible TB in children and adolescents.

BACKGROUND: These clinical standards aim to provide guidance for diagnosis, treatment, and management of drug-susceptible TB in children and adolescents.METHODS: Fifty-two global experts in paediatric TB participated in a Delphi consensus process. After eight rounds of revisions, 51/52 (98%) participants endorsed the final document.RESULTS: Eight standards were identified: Standard 1, Age and developmental stage are critical considerations in the assessment and management of TB; Standard 2, Children and adolescents with symptoms and signs of TB disease should undergo prompt evaluation, and diagnosis and treatment initiation should not depend on microbiological confirmation; Standard 3, Treatment initiation is particularly urgent in children and adolescents with presumptive TB meningitis and disseminated (miliary) TB; Standard 4, Children and adolescents should be treated with an appropriate weight-based regimen; Standard 5, Treating TB infection (TBI) is important to prevent disease; Standard 6, Children and adolescents should receive home-based/community-based treatment support whenever possible; Standard 7, Children, adolescents, and their families should be provided age-appropriate support to optimise engagement in care and clinical outcomes; and Standard 8, Case reporting and contact tracing should be conducted for each child and adolescent.CONCLUSION: These consensus-based clinical standards, which should be adapted to local contexts, will improve the care of children and adolescents affected by TB.

Administration and monitoring of clofazimine for NTM infections in children with and without cystic fibrosis.

Few studies have evaluated clofazimine (CLOF) drug monitoring and safety in children. We treated 10 children, 8 with CF, for NTM infection with multiple antimicrobials, including CLOF. All had serial blood CLOF concentrations measured and were followed for adverse events. Despite CLOF dose escalation, most children with CF did not reach a target CLOF concentration. Our data suggest that children with CF may require earlier initiation of CLOF at higher doses than is currently recommended.

Epidemiology and clinical characteristics of childhood TB identified using active and passive case finding.

BACKGROUND: Childhood TB cases can be found using passive case finding (PCF), i.e., by diagnosing children presenting with symptoms, or using active case finding (ACF), i.e., by identifying children with TB through contact tracing. Our study determined epidemiologic, clinical, and radiographic differences between these groups.DESIGN/METHODS: Retrospective cohort study of children aged 0-19 years diagnosed with TB from January 1, 2012 to December 31, 2019 at a U.S. TB clinic, comparing clinical, radiographic, microbiologic, and epidemiological characteristics of children identified using PCF and ACF.RESULTS: Of 178 eligible patients, 99 (55.6%) were diagnosed using PCF. Children identified using PCF were older (mean 8.9 vs. 6.1 years, P = 0.003), more often non-US-born (OR 2.29, 95% CI 1.12-4.67), had more extrapulmonary disease (44.4% vs. 3.8%, OR 20.27, 95% CI 5.98-68.64) and severe intrathoracic findings (39.4% vs. 10.1%, OR 5.77, 95% CI 2.50-13.29). Children identified using ACF were often asymptomatic, had isolated hilar/mediastinal adenopathy, but had more availability of drug susceptibility data from a link to a source case.CONCLUSION: Children identified using PCF had more severe manifestations, while those identified using ACF had greater availability of drug susceptibility data. Clinicians should be aware that clinical and radiographic presentations in children identified using PCF and those identified using ACF differ, and that the latter may be eligible for shorter treatment regimens.

Controversies in tuberculous infection among pediatric infectious disease specialists in North America.

OBJECTIVE: To evaluate the extent to which advancements in the diagnosis and treatment of latent tuberculous infection (LTBI) have been integrated into practice by pediatric infectious disease (PID) specialists. DESIGN: We conducted an online survey of the Infectious Diseases Society of America's Emerging Infections Network (EIN) membership. RESULTS: Of the 323 members, 197 (61%) responded: 7% cared for ⩾5 children with TB disease and 34% for ⩾5 children with LTBI annually. We identified substantial variations in the use of interferon-gamma release assays (IGRAs) based upon age, immune status, and TB risk factors. In addition, tuberculin skin test (TST) use was three times more common in younger children. Variations existed in managing children with discordant TST and IGRA results. Less variation existed in LTBI treatment, with 86% preferring a 9-month course of isoniazid; few other, newer regimens were used routinely. CONCLUSION: Substantial variations exist in LTBI management; uptake of newer diagnostic tools and treatment regimens has been slow. Variations in practice and the lag time to integrating new data into practice may indicate the relative infrequency with which providers encounter LTBI. Our findings reflect the need for increased visibility of existing TB guidelines and resources for expert consultation for scenarios not covered by guidelines.

Safety and completion of a 4-month course of rifampicin for latent tuberculous infection in children.

SETTING: Children's Tuberculosis Clinic, Houston, Texas. OBJECTIVE: To describe adherence to and tolerability of 4 months of rifampicin (4RMP) compared to 9 months of isoniazid (9INH) in children with latent tuberculous infection (LTBI). DESIGN: Retrospective descriptive case series of children treated for LTBI from 2010 to 2013 by self-administered therapy or directly observed preventive therapy (DOPT) administered by the local health department. RESULTS: Four hundred and four children were treated, 324 (80%) with 9INH and 80 with 4RMP: the mean age was 7.3 years, and 47% were girls. Of these, 37% were identified during contact investigations. DOPT was used in 51% and self-administered therapy in 49%; 81% completed therapy. Completion of self-administered 4RMP therapy was not significantly different from completion rates for children receiving 9INH administered as DOPT (93% vs. 88%, OR 0.6, 95%CI 0.2-1.7), but was significantly higher than in the 9INH self-administration group (OR 7.9, 95%CI 2.7-23.2). Adverse events were rare: 20 (6%) in the 9INH group and 2 (3%) in the 4RMP group, and none was serious. CONCLUSION: Completion rates for 4RMP surpassed those of 9INH for all methods of delivery, except for DOPT, where completion rates were similar. 4RMP was well tolerated. The increased cost of 4RMP over 9INH may be offset by increased effectiveness, as gauged by completion rates.

Requirements for the clinical evaluation of new anti-tuberculosis agents in children.

The ultimate goal of evidence-based drug treatment is to produce a desired pharmacological response in a predictable manner and also to minimise adverse effects. This goal requires not only an increased awareness of the need to provide specific dosing recommendations aimed at specific patient groups, but also the implementation of a consistent integrative approach to recognise all factors contributing to the within- and between-subject variability in drug disposition and response. The assessment of new anti-tuberculosis agents and regimens in children requires a specific programme of investigation, and should be included early in human drug evaluation programmes. Appreciation of this principle is an important step forward towards the full integration of children into the tuberculosis research agenda and control programmes. The development of anti-tuberculosis drug formulations and regimens tailored to the requirements of children needs to consider physiological age-related differences for pharmacokinetics and toxicity between adults and children. Research based on these principles will create an evidence base that will inform the appropriate treatment of children with novel agents and regimens and will also inform future research, including the use of chemoprophylaxis and treatment-shortening strategies in children.

Twice-weekly therapy for children with tuberculosis infection or exposure.

SETTING: Children's tuberculosis clinic, Houston, TX, United States. OBJECTIVE: To determine the safety, adherence and efficacy of intermittent directly observed preventive therapy (DOPT). DESIGN: Retrospective cohort of children receiving intermittent DOPT for exposure to tuberculosis (TB) or latent TB infection (LTBI) seen from 1989 to 2011 at one clinic. RESULTS: A total of 1383 children were treated for either TB exposure for 2-3 months (n = 935, 68%) or LTBI for 9 months (n = 448, 32%) with isoniazid 20-30 mg/kg/dose or rifampin 10-15 mg/kg/dose biweekly. All children with exposure and 411 (92%) with LTBI were identified via contact investigations. Twelve (1.3%) children with exposure experienced adverse effects (5 abdominal pain, 4 vomiting, 3 rash); 8 had transaminases evaluated and only 1 had elevated levels. Thirty (6.7%) children with LTBI experienced adverse effects (16 abdominal pain, 6 rash, 3 vomiting, 3 headache and 2 abdominal pain/vomiting); 19 had transaminases obtained and 2 had elevated transaminases. All transaminases normalized after the discontinuation of medication. Over 99% of exposed and 95.8% of infected children completed treatment. One child, who had sickle cell anemia, was treated for LTBI and later developed TB disease. When compared to rates of disease progression by age, the efficacy of intermittent DOPT was 98%. CONCLUSION: Intermittent DOPT in childhood TB is safe, effective and offers high adherence rates.

Pharmacokinetics of ethambutol in children and adults with tuberculosis.

SETTING: Five hospitals in the United States. OBJECTIVE: To describe ethambutol pharmacokinetics in children and adults with active tuberculosis (TB). DESIGN: Prospective, open-labeled study in 56 adults and 14 children with active tuberculosis who received ethambutol as part of their multidrug TB regimens. RESULTS: Most serum samples were collected up to 10 h post dose and assayed using a validated gas chromatography assay with mass selective detection (GC/MS). Concentration data were analyzed using non-compartmental and population pharmacokinetic methods. Drug exposure increased with dose, but less than proportionally at doses >3000 mg. Lower than expected maximum serum concentrations (Cmax <2 microg/ml) were common in adults. Very low Cmax (<1 microg/ml) were common in children, as was delayed absorption (time to Cmax >3 h). Many Cmax were at or below typical TB minimal inhibitory concentrations. Cmax values for HIV-positive patients were 20% lower than HIV-negative patients with daily doses, but were similar with larger twice-weekly doses. CONCLUSIONS: Adult TB patients often had lower than expected ethambutol serum concentrations, and most pediatric TB patients had very low ethambutol serum concentrations. Higher doses and therapeutic drug monitoring may be indicated for many of these patients.

Population pharmacokinetics of ethionamide in patients with tuberculosis.

SETTING: Three US referral hospitals. OBJECTIVE: Determine the population pharmacokinetic (PK) parameters of ethionamide (ETA) following multiple oral doses. DESIGN: Fifty-five patients with tuberculosis (TB) participated. Patients received multiple oral doses of ETA as part of their treatment. They also received other anti-tuberculosis medications based upon in vitro susceptibility data. Serum samples were collected over 12 h post-dose, and concentrations were determined using a validated high-performance liquid chromatography (HPLC) assay. Concentration-time data were analyzed using population methods. RESULTS: ETA areas under the concentration-versus-time curve (AUCs) increased linearly with increasing oral doses from 250 to 1000 mg. Compared to the population pattern, delayed absorption was seen at least once in 15% of patients. ETA PK parameter estimates were independent of age, weight, height, gender, and creatinine clearance. TB patients appeared to have larger volumes of distribution (3.22 l/kg) and clearance values (1.88 l/h/kg) compared to previously studied healthy volunteers. This resulted in lower AUC values (3.95 mcg h/ml) in the TB patients. ETA displayed a short elimination half-life (1.94 h). The effect of different dosing strategies on calculated pharmacodynamic parameters was explored. Simulated doses of 250 mg BID to TID failed to achieve serum concentrations above the MIC. CONCLUSION: ETA PK parameters differed between TB patients and healthy volunteers, possibly due to differences in the completeness of absorption. Doses of at least 500 mg appear to be required to achieve serum concentrations above the typical ETA MIC. Additional research is needed to determine the optimal dosing of ETA.

A critical review of diagnostic approaches used in the diagnosis of childhood tuberculosis.

SETTING: The diagnosis of tuberculosis (TB) in children is seldom confirmed, and is based mainly on clinical signs, symptoms and special investigations. Various attempts in the form of diagnostic approaches have been made to rationalise this diagnostic process. AIMS: To review and describe published diagnostic approaches aimed at diagnosing mainly intrathoracic tuberculosis in children in developing countries; to compare diagnostic approaches with each other and with bacteriologically confirmed TB; and to describe modifications to the diagnosis of TB in HIV-infected or malnourished children. METHODS: Literature review classified into 1) diagnostic approaches, 2) characteristics used in diagnostic approaches, and 3) studies done to validate diagnostic approaches. RESULTS: Sixteen systems were analysed. Comparison of systems is difficult because characteristic definitions and the ranking of characteristics are not standardised, few studies have been performed to validate these diagnostic approaches, and the gold standard of diagnosis is not practicable in most settings. The minority of systems are adapted for HIV-infected and malnourished patients. RECOMMENDATIONS: Characteristic definitions and ranking of characteristics should be standardised. Any new diagnostic approaches developed should be relevant to developing countries with limited resources, a high burden of tuberculosis, malnutrition and HIV/AIDS and a young population. Studies done to validate diagnostic approaches should be conducted scientifically.

Congenital tuberculosis presenting as sepsis syndrome: case report and review of the literature.

We report an infant with congenital tuberculosis who presented with fulminant septic shock, disseminated intravascular coagulation and respiratory failure. Aggressive resuscitation and supportive care and prompt initiation of antituberculosis medications led to resolution of the shock state. We reviewed six other cases with a similar presentation. Congenital tuberculosis should be in the differential of the infant presenting acutely with sepsis syndrome.

Childhood tuberculosis: treatment strategies and recent advances.

Over the past 20 years, several major studies have shown that 6-month therapy, initially using isoniazid, rifampin and pyrazinamide, is highly effective and extremely safe for the treatment of most forms of childhood tuberculosis. The various drug schedules and frequency of administration will be reviewed. Directly observed therapy is an essential component of a paediatric tuberculosis treatment plan, though using it does not solve all problems with adherence to treatment. As the rates of drug-resistant tuberculosis increase around the world, special aspects of paediatric tuberculosis will have to be considered when designing treatment regimens for children. Finally, the next frontier of antituberculosis therapy may be the manipulation of the host immune system.

Directly observed therapy for tuberculosis in children.

DOT is an important part of the treatment strategies for tuberculosis in children. It is highly effective, relatively inexpensive, and is the only way to ensure that the child is adequately treated. Although the public health ramifications of inadequate treatment of tuberculosis in children are not as severe as those for inadequate treatment in adults, the personal health consequences of nonadherence in children can be disastrous. In countries with adequate resources, DOT should be considered the standard of care for children with tuberculosis disease. The goal for the world should be to treat every child with tuberculosis with DOT.

Tuberculosis of the central nervous system in children.

Tuberculosis remains one of the most common and important infectious diseases in the world. Between 1% and 2% of children with untreated tuberculosis infection will develop tuberculous meningitis. In 1997, 186 cases of tuberculous meningitis were reported in the United States. The initial clinical manifestations of tuberculous meningitis are protean, making early disease difficult to recognize. The clinical and radiographic manifestations of tuberculous meningitis result from the combination of basilar meningitis, infarction, and vasculitis. Early diagnosis can be problematic as Mycobacterium tuberculosis is difficult to detect by rapid tests. Although the response to antituberculosis chemotherapy is generally favorable, complications commonly occur, particularly if the diagnosis is delayed. With appropriate public health management of known tuberculosis cases, cases of CNS tuberculosis in children can be prevented.