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.

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.

Tuberculosis in the pediatric population of Houston, Texas.

From September 1984 to December 1987, the children's tuberculosis clinic in Houston, TX, cared for 110 children with active tuberculosis. The median age was 24 months. Approximately one half of the cases were in Hispanic children, but one third were in black children. Only 11% were foreign-born. Diagnosis resulted from case contact investigation in 50% of cases, routine tuberculin screening in 6%, and evaluation of an ill child in 44%. Intrathoracic disease alone was present in 77% of cases, and extrathoracic disease in 23%, including involvement of the cervical and supraclavicular lymph nodes, meninges, brain, liver, and skin. Gastric aspirates yielded Mycobacterium tuberculosis from 39% of the children with pulmonary disease. Of six children infected with drug-resistant tuberculosis, two became critically ill before referral because the probability of resistance was not recognized by the referring physician. Presently, 94% of patients have successfully completed therapy, which has been shortened from 12 to 18 months to 6 to 9 months. However, 39% were noncompliant with treatment and required twice-weekly supervised therapy to complete treatment. Tuberculosis remains a serious cause of morbidity in children; specific expertise in obtaining cultures, selecting drugs, and assuring compliance is crucial for adequate results.

Clinical features, diagnosis, and treatment of tuberculosis in infants.

OBJECTIVE: Despite the recent resurgence of tuberculosis among children in the United States, no series of infants < 1 year of age with tuberculosis has been reported in the last 20 years. This study was undertaken to describe the epidemiology, clinical, and radiographic manifestations, and response to therapy in infants < 1 year of age with tuberculous disease. METHODS: The medical records were reviewed for all infants age 12 months or less with a diagnosis of tuberculosis and cared for at the Children's Tuberculosis Clinic at Ben Taub General Hospital in Houston, Texas between January 1, 1985 and June 30, 1992. RESULTS: Of the 47 infants identified, 51% were female. The median age at diagnosis was 8 months (range 3.5 to 12 months). Fifty-one percent of the infants were African-American and over one-third were Hispanic. All patients were born in the United States. Diagnosis resulted from the examination of an ill infant in 79% of cases, a case contact investigation of an adult suspected of having tuberculosis in 19%, and routine tuberculin skin testing in 2%. An adult with infectious tuberculosis who had contact with the infant was identified in 68% of cases. Intrathoracic disease alone was present in 70% of cases. Fourteen (30%) infants had extrapulmonary tuberculosis (11 central nervous system disease, 2 disseminated disease, and 1 cervical adenitis). Gastric aspirate cultures yielded Mycobacterium tuberculosis from 75% of the infants with isolated intrathoracic disease. Forty-five infants successfully completed therapy and only one death was directly related to tuberculosis. Forty-eight percent of the infants with pulmonary tuberculosis were treated with a 6-month regimen consisting of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide. Eighteen infants received some twice weekly directly observed therapy mainly due to documented or suspected nonadherence. Treatment was well-tolerated; one patient (2%) developed hepatotoxicity due to isoniazid. No infant had a relapse or recurrence of disease in 6 months to 7 years follow-up for a median of 3 years (range, 6 months to 7 years). CONCLUSION: Most infants with tuberculosis are symptomatic at the time of diagnosis, and bacteriologic confirmation was obtained in 70% of cases. A contact investigation of the household should be initiated immediately when an infant is suspected of having tuberculosis because valuable information needed to establish the diagnosis and guide therapy in the infant may be obtained. Intensive 6-month and twice weekly directly observed therapy appear to be well-tolerated and effective for the treatment of pulmonary tuberculosis in infants.

Detection of Mycobacterium tuberculosis in clinical specimens from children using a polymerase chain reaction.

OBJECTIVE: We evaluated the usefulness of the polymerase chain reaction (PCR) using the insertion sequence IS6110 as the target for DNA to detect Mycobacterium tuberculosis in clinical specimens from children. STUDY DESIGN: This was a prospective, controlled, blinded study comparing PCR on clinical specimens, mycobacterial culture, and clinical diagnosis. PATIENTS: Sixty-five hospitalized children were evaluated, 35 with tuberculosis disease and 30 controls. Cases were defined by culture and/or specific clinical criteria. Controls included patients with tuberculosis infection but no detectable disease as well as patients free of tuberculosis infection and disease. RESULTS: Polymerase chain reaction had a sensitivity of 40% and a specificity of 80% compared with clinical diagnosis. Mycobacterial culture had a sensitivity of 37%. The combination of culture and PCR identified 19 of 35 children (54%) with clinically diagnosed tuberculosis. There were six children with false-positive PCR results: One had tuberculosis infection without disease, two had Mycobacterium avium lymphadenitis, and three had diagnoses unrelated to tuberculosis. CONCLUSIONS: The sensitivity of PCR is comparable to that of culture for detecting M tuberculosis in children, and may strengthen and hasten the clinical diagnosis in culture-negative patients. However, because of the limitations in specificity, the results of PCR alone are insufficient to diagnose tuberculosis in children. Although ongoing refinements in PCR techniques should improve the specificity of this test, epidemiologic and clinical information continue to be the most important consideration in the diagnosis of tuberculosis in culture-negative children.

Routine tuberculin screening of children during hospitalization.

Harris County, TX, which includes Houston, has one of the highest childhood tuberculosis case rates in the United States. For an 11-week period in the spring of 1988 all children admitted to the medical service of the Ben Taub General Hospital in Houston, TX, received a Mantoux skin test consisting of tuberculin purified protein derivative. The purpose was to assess the impact of routine tuberculin screening during hospitalization for acute medical care and to determine whether tuberculin screening in this setting is an effective means of identifying children with asymptomatic tuberculous infection. Of the 432 patients skin tested, 50% were younger than 1 year of age and only 304 were evaluable at 48 hours. Two new positive skin tests were discovered for a positive tuberculin rate of 0.66%. We conclude that even in a high risk region, routine tuberculin screening of all children admitted to the hospital may not be effective.

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.

Current chemotherapy for tuberculosis in children.

Antituberculosis medications are extremely well tolerated by children and have proved to be very successful. The newer regimens of intensive short-course chemotherapy for tuberculosis have several advantages over traditional two-drug regimens, including faster sterilization and bactericidal action, shorter duration over which patient noncompliance can occur, less expenditure of resources for monitoring treatment, lower failure and relapse rates, and broader coverage for possible drug-resistant M. tuberculosis. The currently recommended regimen for pulmonary and most extrapulmonary forms of tuberculosis in children is 6 months of isoniazid and rifampin supplemented during the first 2 months by pyrazinamide. Treatment during the first 1 to 2 months should, if possible, be daily but the last 4 to 5 months of therapy can be either daily or twice weekly under direct observation of a health-care professional. For patients in whom social or other constraints prevent reliable self-administration of daily treatment in the initial phase, medications may be given twice weekly from the beginning under close observation. For these situations, a total duration of treatment of 6 to 9 months is reasonable. Non-life-threatening forms of extrapulmonary tuberculosis can be treated in the same manner as pulmonary tuberculosis. Although tuberculous meningitis probably will respond to these regimens, the relative lack of data at present leads most experts to recommend total durations of between 6 and 12 months for this form of tuberculosis. The major limitation to controlling tuberculosis in the United States is noncompliance or nonadherence to medications by patients. The physician and other health-care providers must devote a great deal of their time and energy to ensuring adherence with medications and take whatever steps are necessary to make sure that the child with tuberculosis is adequately treated.

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.

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.

Tuberculosis in children.

The dramatic resurgence and increase in the total number of cases of tuberculous infection and disease in children is alarming in the United States. With poverty, poor access to health care, overcrowding (predominantly in inner-city areas), and an increase in immigration from areas with high endemic rates of TB, the problem in children will continue to increase. If the impact of coinfection with HIV and M. tuberculosis becomes significant in children, as it has in adults in the United States, the increase in the total number of cases of tuberculous disease in children could be staggering. The impact of multidrug-resistant strains of M. tuberculosis and the current crises in availability of effective anti-TB drugs will need a similar resurgence.

Tuberculosis and pregnancy.

After decades of decline, tuberculosis case rates are again increasing in the United States. The increases have been most dramatic among minority young adults of childbearing age. The availability of adequate chemotherapy means that the outcome for both mother and child in pregnancy complicated by tuberculosis should be good. Complete case finding and screening of high-risk adults is essential to bring tuberculosis under control again.

Nontuberculous mycobacterial infections of the head and neck.

OBJECTIVE: To review the treatment and outcome of patients with nontuberculous mycobacterial infections of the head and neck. DESIGN: Retrospective examination of the medical records of patients treated by several surgeons during a 5-year period with a minimum 6-month follow-up. SETTING: Large teaching children's hospital. PATIENTS: Twenty-six children hospitalized for treatment of nontuberculous mycobacterial infections of the head and neck. MAIN OUTCOME MEASURES: Resolution of infection, recurrence, and need for additional surgical intervention for cure. RESULTS: Eleven patients initially were treated by incisional biopsy or incision and drainage procedures; eight patients developed recurrence or a draining sinus tract, necessitating a second surgical procedure. In contrast, 15 patients initially underwent complete excision; only one developed a recurrence (P < .01). Thus, eight (31%) of 26 patients required at least two surgical procedures owing to inadequate initial treatment. CONCLUSIONS: Excisional biopsy is both the diagnostic procedure and treatment of choice for nontuberculous mycobacterial adenitis.

Nontuberculous mycobacterial mastoiditis.

Although nontuberculous mycobacterial (NTM) infections are recognized as an important cause of cervicofacial lymphadenopathy in children, NTM mastoiditis is rare. Further, NTM mastoiditis may be difficult to distinguish clinically from tuberculous mastoiditis since both may present with chronic, painless otorrhea and exuberant middle ear granulation tissue. The treatment of tuberculous mastoiditis is antituberculosis chemotherapy; however, most NTM infections are resistant to antituberculous agents, and the preferred treatment of NTM mastoiditis is mastoidectomy. We report a recent case of mastoiditis caused by Mycobacterium avium complex in an infant who presented with a temporal bone mass.

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.

Neuropathology of two fatal cases of measles in the 1988-1989 Houston epidemic.

The clinical course and autopsy findings of 2 patients with measles encephalitis that occurred during the 1988-1989 Houston epidemic are reported. A previously healthy 25-month-old boy had serologically-proved measles, hemophagocytic syndrome, and acute disseminated demyelinating encephalitis. A 19-year-old male with acute lymphocytic leukemia had proved measles pneumonia and acute hemorrhagic leukoencephalitis. These patients represent a broad spectrum of measles-induced immunopathic complications of the central nervous system.

Modern approach to the diagnosis and treatment of tuberculosis in children.

Tuberculosis in children remains an important infectious disease in the United States, with 1261 cases reported in 1985. The percentage of extrapulmonary manifestations is increasing. Advances in the diagnosis and treatment of tuberculosis in children have lagged behind those in adults owing to diminished familiarity with the disease and difficulty in performing clinical studies in children. Tuberculosis in the United States now occurs mainly in clusters of high-risk people, such as the foreign born, Hispanics, blacks, Native Americans, and the impoverished. In general, the diagnosis of tuberculosis is epidemiologic, supported by the chest roentgenogram, skin test, and, most important, contact tracing. As the rate of drug-resistant tuberculosis increases, greater effort should be made to obtain cultures. New advances, such as DNA probes and serodiagnosis, may improve diagnostic accuracy, especially for extrapulmonary tuberculosis. Noncompliance is the major problem in treating tuberculosis, and greater effort should be directed toward novel treatment approaches in children, such as twice-weekly supervised therapy and shorter, more intense durations of therapy.