H. S. Schaaf

Bacille Calmette-Guérin Vaccine—Induced Disease in HIV-Infected and HIV-Uninfected Children

Bacille Calmette-Guerin (BCG)--a live attenuated vaccine--is routinely given to neonates in settings where tuberculosis is endemic irrespective of human immunodeficiency virus (HIV) exposure. HIV infected infants and other immunodeficient infants are at risk of BCG-related complications. We report the presentation treatment and mortality of children who develop BCG disease with emphasis on HIV-infected children. In addition we present a revised classification of BCG disease in children and propose standard diagnostic and management guidelines. This retrospective hospital-based study was conducted in the Western Cape Province South Africa. Mycobacterium tuberculosis complex isolates recovered from children aged < 13 years during the period of August 2002 through January 2005 were speciated by polymerase chain reaction to confirm Mycobacterium bovis BCG. Clinical data were collected through medical file review. BCG disease was classified according to standard and revised disease classifications. Mortality was assessed at the end of the study period. BCG disease was diagnosed in 25 children; 22 (88%) had local disease and 8 (32%) had distant or disseminated disease; 5 children (20%) had both local and distant or disseminated disease. Seventeen children were HIV infected; 2 children had other immunodeficiencies. All 8 children with distant or disseminated disease were immunodeficient; 6 were HIV infected. The mortality rate was 75% for children with distant or disseminated disease. BCG vaccination poses a risk to infants perinatally infected with HIV and to other primary immunodeficient children. The proposed pediatric BCG disease classification reflects clinically relevant disease categories in HIV-infected children. The suggested diagnostic and treatment guidelines should improve existing case management and surveillance. Prospective evaluation of management strategies for BCG disease in HIV infected and HIV-uninfected children is essential. (authors)

High Incidence of Tuberculosis among HIV-Infected Infants: Evidence from a South African Population-Based Study Highlights the Need for Improved Tuberculosis Control Strategies

BACKGROUND There are limited population-based estimates of tuberculosis incidence among human immunodeficiency virus (HIV)-infected and HIV-uninfected infants aged < or =12 months. We aimed to estimate the population-based incidence of culture-confirmed tuberculosis among HIV-infected and HIV-uninfected infants in the Western Cape Province, South Africa. METHODS The incidences of pulmonary, extrapulmonary, and disseminated tuberculosis were estimated over a 3-year period (2004-2006) with use of prospective representative hospital surveillance data of the annual number of culture-confirmed tuberculosis cases among infants. The total number of HIV-infected and HIV-uninfected infants was calculated using population-based estimates of the total number of live infants and the annual maternal HIV prevalence and vertical HIV transmission rates. RESULTS There were 245 infants with culture-confirmed tuberculosis. The overall incidences of tuberculosis were 1596 cases per 100,000 population among HIV-infected infants (95% confidence interval [CI], 1151-2132 cases per 100,000 population) and 65.9 cases per 100,000 population among HIV-uninfected infants (95% CI, 56-75 cases per 100,000 population). The relative risk of culture-confirmed tuberculosis among HIV-infected infants was 24.2 (95% CI, 17-34). The incidences of disseminated tuberculosis were 240.9 cases per 100,000 population (95% CI, 89-433 cases per 100,000 population) among HIV-infected infants and 14.1 cases per 100,000 population (95% CI, 10-18 cases per 100,000 population) among HIV-uninfected infants (relative risk, 17.1; 95% CI, 6-34). CONCLUSIONS This study indicates the magnitude of the tuberculosis disease burden among HIV-infected infants and provides population-based comparative incidence rates of tuberculosis among HIV-infected infants. This high risk of tuberculosis among HIV-infected infants is of great concern and may be attributable to an increased risk of tuberculosis exposure, increased immune-mediated tuberculosis susceptibility, and/or possible limited protective effect of bacille Calmette-Guérin vaccination. Improved tuberculosis control strategies, including maternal tuberculosis screening, contact tracing of tuberculosis-exposed infants coupled with preventive chemotherapy, and effective vaccine strategies, are needed for infants in settings where HIV infection and tuberculosis are highly endemic.

Isoniazid pharmacokinetics in children treated for respiratory tuberculosis.

Aims: To define the pharmacokinetics of isoniazid (INH) in children with tuberculosis in relation to the N-acetyltransferase 2 (NAT2) genotype. Methods: The first order elimination rate constant (k) and area under the concentration curve (AUC) were calculated in 64 children <13 years of age (median 3.8) with respiratory tuberculosis from INH concentrations determined 2–5 hours after a 10 mg/kg INH dose. The NAT2 genotype was determined; 25 children were classified as homozygous slow (SS), 24 as heterozygous fast (FS), and 15 as homozygous fast (FF) acetylators. Results: The mean (SD) k values of the genotypes differed significantly from one another: SS 0.254 (0.046), FS 0.513 (0.074), FF 0.653 (0.117). Within each genotype a median regression of k on age showed a significant decrease in k with age. The mean (SD) INH concentrations (mg/l) two hours after INH administration were SS 8.599 (1.974), FS 5.131 (1.864), and FF 3.938 (1.754). A within genotype regression of 2-hour INH concentrations on age showed a significant increase with age. A within genotype regression of 3-hour, 4-hour, and 5-hour concentrations on age also showed a significant increase with age in each instance. In ethnically similar adults, mean (SD) 2-hour INH concentrations (mg/l) for each genotype were significantly higher than the children’s: SS 10.942 (1.740), FS 8.702 (1.841), and FF 6.031 (1.431). Conclusions: Younger children eliminate INH faster than older children and, as a group, faster than adults, and require a higher mg/kg body weight INH dose to achieve serum concentrations comparable to adults.

Respiratory tuberculosis in childhood: the diagnostic value of clinical features and special investigations.

During a 16-month period children presenting to a pediatric outpatient facility from an area with a high tuberculosis incidence (> 400/100 000) and suspected of having respiratory tuberculosis (TB) were evaluated for close contact with adult pulmonary tuberculosis, weight loss, symptom duration, respiratory signs, lymphadenopathy and hepatosplenomegaly and by chest radiography and tuberculin testing (Mantoux or tine). Probable tuberculosis was diagnosed in 258 children and was confirmed in 109 (42%) patients with a mean age of 31 months by culture of Mycobacterium tuberculosis from gastric aspirate or another source. Eleven children with confirmed TB had a normal chest radiograph. After review of special investigations, clinical course and follow-up of the remaining 149 children, 86 children (58%) with a mean age of 32.4 months were considered to have probable TB and 63 (42%) with a mean age of 27 months not to have TB. Significantly fewer children in the “not TB” group than in the confirmed and probable TB groups had a close adult pulmonary tuberculosis contact (13 (21%) and 95 (49%), respectively; P < 0.01). There was no difference between the “not TB” group and the confirmed and probable TB groups in the proportion presenting with weight loss, cough or other respiratory symptoms, a symptom duration >2 weeks, the presence of bronchial breathing, wheeze, hepatomegaly or splenomegaly or peripheral lymphadenopathy. Final diagnoses in the “not TB” group included bacterial or viral pneumonia or bron-chopneumonia in 37, asthma often accompanied by segmental collapse in 9 and cavitating pneumonia in 3 children. On the one hand children in whom there were sufficient criteria to be considered probable cases of TB were subsequently thought not to have TB; on the other hand 11 (10%) of children with TB confirmed by culture of Mycobacterium tuberculosis from gastric aspirate had a normal chest radiograph.

Danish Bacille Calmette-Guérin Vaccine-Induced Disease in Human Immunodeficiency Virus-Infected Children

An analysis of isolates of Mycobacterium tuberculosis complex was performed to determine the prevalence of bacille Calmette-Guérin (BCG) disease among human immunodeficiency virus (HIV)-infected children. Speciation was done with polymerase chain reaction; 183 isolates from mycobacterial cultures for 49 HIV-infected patients were analyzed. The Danish Mycobacterium bovis BCG strain was isolated from 5 patients. No cases of Tokyo M. bovis BCG strain disease were detected. All patients were asymptomatic at birth, <12 months of age, and severely immunodeficient at presentation. Four patients had regional axillary adenitis ipsilateral to the vaccination site, and 2 had pulmonary BCG disease. Two patients with regional BCG disease had simultaneous pulmonary M. tuberculosis infection. Although chest radiographic features were similar to those seen in patients with tuberculosis, BCG disease should be considered in HIV-infected infants with right axillary adenitis ipsilateral to the vaccination site. Young, symptomatic, HIV-infected infants are at risk for BCG-related complications. Controlled, population-based studies are needed to assess the risk of BCG in HIV-infected children.

Culture confirmed multidrug resistant tuberculosis: diagnostic delay, clinical features, and outcome

Aims: To determine the delay in diagnosis of multidrug resistant (MDR) tuberculosis (TB), the correlation between drug susceptibility patterns of adult-child contact pairs, the effectiveness of treatment, and the outcome in these children. Methods: MDR M tuberculosis culture results of children were prospectively collected during a four year period in the Western Cape Province of South Africa, an area with a TB incidence of 589/100 000 population, and a new MDR TB rate of 0.94%. Folder reviews were done to retrieve clinical information. Children not already on treatment at our MDR TB clinic or TB hospital were recalled and appropriate treatment was started. Follow up was done for as long as possible. Results: Thirty nine children, median age 4.5 years at first TB diagnosis and 6.2 years on MDR culture confirmation, were seen. Delay in starting appropriate MDR treatment after TB diagnosis was a median of 2 days if MDR TB source cases were taken into account, but 246 days if the drug susceptibility pattern of the source case was not considered, and 283 days if there was no known tuberculosis source case. Correlation between the drug susceptibility results of the child’s and adult source case’s isolates was 68%. Seventeen children had smear positive tuberculosis, of whom 13 had cavitatory pulmonary disease. Eight children had central nervous system TB. Thirty six children were treated for MDR tuberculosis, of whom four died. Conclusions: Obtaining a detailed contact history is essential as a delay in starting appropriate MDR antituberculosis treatment has potentially serious consequences.

Disseminated bacille Calmette-Guérin disease in HIV-infected South African infants

OBJECTIVE To determine the population-based incidence of disseminated bacille Calmette-Guérin (BCG) disease in HIV-infected infants (aged <or= 1 year) in a setting with a high burden of tuberculosis and HIV infection coupled with a well-functioning programme for the prevention of HIV infection in infants. METHODS The numerator, or number of new cases of disseminated BCG disease, was derived from multicentre surveillance data collected prospectively on infants with a confirmed HIV infection during 2004-2006. The denominator, or total number of HIV-infected infants who were BCG-vaccinated, was derived from population-based estimates of the number of live infants and from reported maternal HIV infection prevalence, vertical HIV transmission rates and BCG vaccination rates. FINDINGS The estimated incidences of disseminated BCG disease per 100 000 BCG-vaccinated, HIV-infected infants were as follows: 778 (95% confidence interval, CI: 361-1319) in 2004 (vertical HIV transmission rate: 10.4%); 1300 (95% CI: 587-2290) in 2005 (transmission rate: 6.1%); and 1013 (95% CI: 377-1895) in 2006 (transmission rate: 5.4%). The pooled incidence over the study period was 992 (95% CI: 567-1495) per 100 000. CONCLUSION Multicentre surveillance data showed that the risk of disseminated BCG disease in HIV-infected infants is considerably higher than previously estimated, although likely to be under-estimated. There is an urgent need for data on the risk-benefit ratio of BCG vaccination in HIV-infected infants to inform decision-making in settings where HIV infection and tuberculosis burdens are high. Safe and effective tuberculosis prevention strategies are needed for HIV-infected infants.

Diagnostic aspects of cervical lymphadenopathy in children in the developing world: a study of 1,877 surgical specimens

Abstract. Chronic cervical lymphadenopathy is a common clinical problem frequently requiring surgical biopsy. To evaluate the characteristics of surgically excised cervical lymph nodes (LN) in children in a developing country, we studied 1,332 children less than 15 years old (1,877 surgically removed cervical LNs) over a 23-year period (1976–1999). Indications for biopsy included failure to respond to antibiotic therapy, rapid increase in size, hard, matted LNs in the preauricular, supraclavicular, and posterior triangle of the neck, and difficulty in diagnosis. Clinical and pathological characteristics investigated included age, malignancy, and granulomatous disease such as tuberculosis (tbc). The mean age was 7 years (tbc 5.8/neoplastic disease 8.5 years). Twenty LNs (1.5%) were histologically normal. There were 637 (47.8%) with nonspecific reactive lymphoid hyperplasia and 484 with chronic granulomatous changes (36.3%). Tuberculous lymphadenitis was confirmed in 332 of these (25%). In 181 (54.5%) Mycobacterium tuberculosis was cultured and a further 149 had acid-fast bacilli. Other granulomatous diseases identified included sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfmann disease) (3), syphilis (4), yaws (2), and toxoplasmosis (1). No mycobacteria other than M. tuberculosis were encountered. More than two-thirds (108) of 154 patients with neoplastic LN involvement had a lymphoma; in a further 10 lymphadenopathy was associated with leukemia. Pyogenic organisms were identified in 32, and 5 were positive for human immunodeficiency virus, 1 of whom had Kaposis sarcoma. A second pathology was identified in 18 of the 637 cases of reactive lymphoid hyperplasia (3 with tuberculosis); in 15 (1.3%) a diagnosis of lymphoma was made from other sites (pleural fluid, etc.) within 6 months of initial biopsy. This represents a diagnostically difficult subgroup requiring further investigation. Chronic lymphadenopathy in children in developing countries has a high incidence of infective causes, including a significant incidence of M. tuberculosis. The incidence of serious pathology in more than one-half of the cervical LNs examined justifies aggressive surgical investigation.

Adherence to isoniazid preventive chemotherapy: a prospective community based study

Background: Current international guidelines recommend 6–9 months of isoniazid (INH) preventive chemotherapy to prevent the development of active tuberculosis in children exposed to a susceptible strain of M tuberculosis. However, this is dependent on good adherence and retrospective studies have indicated that adherence to unsupervised INH preventive chemotherapy is poor. Aim: To prospectively document adherence to six months of unsupervised INH monotherapy and outcome in children with household exposure to an adult pulmonary tuberculosis index case. Methods: From February 2003 to January 2005 in two suburbs of Cape Town, South Africa, all children <5 years old in household contact with an adult pulmonary tuberculosis index case were screened for tuberculosis and given unsupervised INH preventive chemotherapy once active tuberculosis was excluded. Adherence and outcome were monitored. Results: In total, 217 index cases from 185 households were identified; 274 children <5 years old experienced household exposure, of whom 229 (84%) were fully evaluated. Thirty eight children were treated for tuberculosis and 180 received preventive chemotherapy. Of the children who received preventive chemotherapy, 36/180 (20%) completed ⩾5 months of unsupervised INH monotherapy. During the subsequent surveillance period six children developed tuberculosis: two received no preventive chemotherapy, and four had very poor adherence. Conclusion: Adherence to six months of unsupervised INH preventive chemotherapy was poor. Strategies to improve adherence, such as using shorter duration multidrug regimens and/or supervision of preventive treatment require further evaluation, particularly in children who are at high risk to progress to disease following exposure.

Pharmacokinetics of Isoniazid, Rifampin, and Pyrazinamide in Children Younger than Two Years of Age with Tuberculosis: Evidence for Implementation of Revised World Health Organization Recommendations

ABSTRACT The World Health Organization (WHO) recently issued revised first-line antituberculosis (anti-TB) drug dosage recommendations for children. No pharmacokinetic studies for these revised dosages are available for children <2 years. The aim of the study was to document the pharmacokinetics of the first-line anti-TB agents in children <2 years of age comparing previous and revised WHO dosages of isoniazid (INH; 5 versus 10 mg/kg/day), rifampin (RMP; 10 versus 15 mg/kg/day), and pyrazinamide (PZA; 25 versus 35 mg/kg/day) and to investigate the effects of clinical covariates, including HIV coinfection, nutritional status, age, gender, and type of tuberculosis (TB), and the effect of NAT2 acetylator status. Serum INH, PZA, and RMP levels were prospectively assessed in 20 children <2 years of age treated for TB following the previous and the revised WHO dosage recommendations. Samples were taken prior to dosing and at 0.5, 1.5, 3, and 5 h following dosing. The maximum drug concentration in serum (Cmax), the time to Cmax (tmax), and the area under the concentration-time curve (AUC) were calculated. Eleven children had pulmonary and 9 had extrapulmonary TB. Five were HIV infected. The mean Cmax (μg/ml) following the administration of previous/revised dosages were as follows: INH, 3.19/8.11; RMP, 6.36/11.69; PZA, 29.94/47.11. The mean AUC (μg·h/ml) were as follows: INH, 8.09/20.36; RMP, 17.78/36.95; PZA, 118.0/175.2. The mean Cmax and AUC differed significantly between doses. There was no difference in the tmax values achieved. Children less than 2 years of age achieve target concentrations of first-line anti-TB agents using revised WHO dosage recommendations. Our data provided supportive evidence for the implementation of the revised WHO guidelines for first-line anti-TB therapy in young children.