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 > or =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.     

Exposure to open tuberculosis on a neonatal unit

The mother of a baby on the neonatal intensive care unit was found to have untreated open pulmonary tuberculosis. Tuberculin skin testing and chemoprophylaxis was offered to selected mothers and babies, depending on level of exposure. One of 3 mothers sharing a room with the index mother and 2 of 20 mothers whose babies were on the neonatal unit subsequently converted to tuberculin and were given isoniazid chemoprophylaxis. Isoniazid chemoprophylaxis was given to 13 exposed babies, none of whom tuberculin converted. Two babies were treated empirically for tuberculosis.     

Evaluation of young children in household contact with adult multidrug-resistant pulmonary tuberculosis cases.

BACKGROUND: The prevention and management of multidrug-resistant (MDR) tuberculosis has received much attention, but little attention has been given to children with MDR tuberculosis or children in contact with adults with MDR tuberculosis. The aim of this study was to determine the prevalence of tuberculous infection and disease in childhood contacts of adults with MDR pulmonary tuberculosis. METHOD: All children <5 years of age in household contact with 75 recently diagnosed adults with MDR pulmonary tuberculosis were evaluated. Evaluation included clinical examination, tuberculin skin test, chest radiography and culture for Mycobacterium tuberculosis from gastric aspirates. RESULTS: One hundred twenty-eight children, median age 27 months, were evaluated. Fifty children had recent contact with other adult tuberculosis cases. Sixty-six children previously had chemoprophylaxis or treatment of whom 36 defaulted treatment or received insufficient chemoprophylaxis. One child had HIV infection. Forty-seven children were classified as noninfected, 66 were considered infected only (Mantoux test, > or = 15 mm) and 15 had disease. Three children, who had not previously received antituberculosis drugs, had positive cultures for M. tuberculosis; all were multidrug-resistant. CONCLUSION: This study documents the transmission of multidrug-resistant M. tuberculosis to childhood contacts, the development of disease in these contacts and the importance of knowing the index case's M. tuberculosis susceptibility pattern in choosing a proper treatment regimen for the childhood contact.     

儿童结核病的预防研究进展

近年来结核发病率有所回升,估计全球有1/3的人群有无症状的潜伏结核感染.目前普遍使用卡介苗接种计划,卡介苗对儿童结核病有良好的预防作用,但由于其诱导的免疫反应持续时间有限,也有预防失败的情况出现,故研究者开始探索新型的抗结核疫苗,如突变减毒活菌株、亚单位疫苗、DNA疫苗,并取得一定成果.对于纯结核蛋白衍化物皮内试验阳性...     

BCG, tuberculin skin-test results and asthma prevalence in school children in North London

OBJECTIVE: To test whether there is any relationship between asthma prevalence and BCG immunization or tuberculin skin text reaction. DESIGN: Cross-sectional survey. SETTING: Secondary school in Haringey, North London, U.K. SUBJECTS: 780 children aged 11-18 years (median 13.35 years). INTERVENTIONS: Administration of tuberculin skin text and questionnaire. MAIN OUTCOME MEASURES: Diagnosis of asthma, presence of nocturnal cough, exercise-induced wheeze or wheeze with viral respiratory infections; diameter of induration with tuberculin skin text; history of BCG immunization. RESULTS: 57 of 629 children (8.5%) had a significantly positive Mantoux reaction (>or=15 millimeters of induration). Children with and without a history of BCG immunization did not differ significantly in prevalence of asthma diagnosis (11.8% vs 14.1%, p > 0.6), exercise-induced wheeze (16.9% vs 21.2%, p>0.4), viral induced wheeze (15.4% vs 7%, p>0.6) or nocturnal cough (32.3% vs 32.7%, p> 0.6). We also found no significant correlation of the prevalence of asthma diagnosis or symptoms with diameter of Mantoux test reaction. CONCLUSION: There is no evidence of an effect of BCG immunization or tuberculin reactivity on the incidence of asthma in secondary school children in Haringey, North London and the exposure to tuberculosis is high in these children.     

Reduced incidence of tuberculosis by prophylactic chemotherapy in subjects showing strong reactions to tuberculin testing.

The introduction of chemoprophylaxis with rifampicin and isoniazid in 1981 significantly reduced the incidence of tuberculosis. Between 1978 and 1981 children accounted for 136 of 642 notified cases, and this was reduced to 55 of 418 between 1982 and 1986. This effect was most obvious among children from the Indian subcontinent who comprised 80.2% of the children treated. The incidence among white children was not affected. Few side effects occurred and only two of 339 (0.6%) later developed clinical tuberculosis. Chemoprophylaxis plays an important part in the management of tuberculosis in a district with a high incidence of the disease.     

T-cell-based diagnosis of neonatal multidrug-resistant latent tuberculosis infection

Young children exposed to tuberculosis have a high risk of progression to severe tuberculosis disease, but diagnosis of recent infection is hindered by the poor sensitivity of the tuberculin skin test. Whether new blood tests can detect latent infection in this vulnerable group is unknown because there is no gold standard. We monitored a tuberculin skin test-negative infant whose mother had infectious multidrug-resistant tuberculosis with enzyme-linked immunospot, a blood test that enumerates Mycobacterium tuberculosis-specific T cells. The enzyme-linked immunospot test became persistently positive by 6 months, and 18 months later the child developed active tuberculosis despite appropriate chemoprophylaxis. At this point, the magnitude of the enzyme-linked immunospot response increased >10-fold. Our findings demonstrate that this blood test detected latent infection with dormant, yet viable, bacilli and illustrate how enzyme-linked immunospot could improve diagnosis of childhood tuberculosis infection.     

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.     

Connatal tuberculosis in an extremely low birth weight infant: case report and management of exposure to tuberculosis in a neonatal intensive care unit

A case of connatal tuberculosis in an extremely low birth weight infant is reported. The patient was a female with a birth weight of 973 g born in the 27th week of pregnancy. She developed respiratory distress and signs of infection immediately after birth, which did not respond to mechanical ventilation, antibiotics, and corticosteroid therapy. Connatal tuberculosis was confirmed at 48 days of age by isolation of Mycobacterium tuberculosis from the infant's tracheal aspirate and the mother's menstrual discharge. The infant died of respiratory failure at 90 days of age. Mantoux tuberculin skin tests (TST) were performed on 99 infants, 144 medical staff members, and two family members. TST conversion occurred in three medical staff members, and preventive therapy with isoniazid was initiated. Eight exposed infants had normal chest X-rays and negative gastric aspirates for acid-fast bacilli and all received preventive isoniazid therapy. No case of tuberculosis developed during the 2-year follow-up period. Conclusion Connatal tuberculosis should be considered in neonatal respiratory infection resistant to antibiotics. Prevention of transmission of tuberculosis on the neonatal intensive care unit by chemoprophylaxis is important. Received: 14 March 2000 / Accepted: 13 September 2000     

Comparison of the prevalence of tuberculosis infection in BCG vaccinated versus nonvaccinated school age children

OBJECTIVE: To compare the prevalence of tuberculosis infection in BCG vaccinated versus non-vaccinated school age children in a tuberculosis endemic region. DESIGN: Cross-sectional, case control, school based survey. SETTING: Government lower primary school in Palakkad District, Kerala. METHODS: Tuberculosis infection was determined by tuberculin testing in 418 school children aged 5 to 9 years, utilizing a differential outcome variable definition for BCG vaccinated and unvaccinated children, in a tuberculosis endemic area with moderate vaccination coverage. Nutritional status was calculated using weight for age and weight for height criteria. RESULTS: Tuberculin positivity rate in unvaccinated children (24%) was significantly higher than in the vaccinated (9.7%) (P<0.001, RR: 2.9). Overall prevalence rate of tuberculosis infection was 15.5%. Boys had significantly higher vaccination rates than girls (P < 0.001). No association was found between tuberculin reaction size and age or nutritional status. CONCLUSIONS: BCG vaccination is associated with significant protection against the acquisition of Mycobacterium tuberculosis infection in childhood. This finding highlights the importance of universal implementation of BCG vaccination in children in tuberculosis endemic regions.     

Pediatric tuberculosis pyramid and its fate with and without chemotherapy/chemoprophylaxis

The latest available information on total and infectious cases of tuberculosis in the country and also large number of sputum positive cases being detected annually, particularly after the involvement of multipurpose workers in the primary health care programme for the control of tuberculosis, is presented. The consequences of the large pool of infectious cases in the population lead to spread of bacilli to children with development of primary infection in them. These children with primary infection, specially high risk group in infancy and early childhood, get serious complications of the disease. It may be emphasized that BCG vaccination cannot prevent the lodgement of tubercle bacilli in the lung but can only contain or restrict haematogenous spread. Inspite of increasing coverage of infants with BCG vaccination there are an increasing number of cases of intrathoracic tuberculosis, particularly various groups of mediastinal nodes. However, to a lesser extent haematogenous complications do occur in malnourished children, as BCG has a limited value in preventing serious complications in children with malnutrition. The clinical pattern of pediatric tuberculosis has also changed in vaccinated and partly or inadequately drug treated children. Hence, chemoprophylasis/ chemotherapy to prevent complications of primary infection has been tried. Even relatively privileged children in developed countries are reported to have complications of primary infection to an extent of 10 to 15%, as per the studies all over world. So preventive chemoprophylaxls, preferably with two bactericidal drugs, should be considered as the main strategy for controlling primary infection. Chemoprophylaxis with two drugs should be used as incidence of isoniazid resistant bacilli has increased. All concerned with child health should consider the strategy of treatment of primary infection in high risk children by chemoprophylaxis by starting a large multicentric trial both in urban and rural areas, as a part and parcel of primary health care intervention already in practice for cases of sputum positive pulmonary tuberculosis.     

Effect of BCG vaccine on tuberculin skin tests in 1-6-year-old children

Bacillus Calmette Guerin (BCG) vaccination used in the prevention of tuberculosis may cause problems in interpreting the tuberculin skin test (TST), which is commonly used in the diagnosis of infection. A limited number of studies have been undertaken to investigate how length of time after BCG vaccination affects TST results. TST induration values of unvaccinated children were compared with those of children vaccinated once in order to determine the changes in TST responses after BCG vaccination. Mantoux TSTs were administered to 1145 children aged 1-6 y and induration was measured at 72 h. BCG scar status and average TST induration diameters were identified for each age group. CONCLUSION: Average TST induration in vaccinated children is significantly higher than that in unvaccinated children, and in the vaccinated group there is no statistically significant difference between induration values in the different age groups. BCG vaccination at the age of 0-2 mo affects TST for a long period and this condition does not change until 6 y of age.     

Failure of chemoprophylaxis with standard antituberculosis agents in child contacts of multidrug-resistant tuberculosis cases

BACKGROUND: There is little published information on optimal chemoprophylaxis for children with multidrug-resistant tuberculosis (MDR-TB) contacts. Current guidelines of World Health Organization suggest that isoniazid (INH), the standard first-line chemoprophylaxis, be used for those exposed to MDR-TB. METHODS: This is a retrospective review of medical records of 5 children residing in the Western Cape Province, South Africa, who developed MDR-TB while receiving conventional chemoprophylaxis with either INH or a combination of INH, rifampin, and pyrazinamide. RESULTS: Adult MDR-TB source cases were identified for all children and resistance patterns of patient and source case isolates matched in all cases. The median age of the patients was 0.4 years. One patient participated in a trial of INH chemoprophylaxis for HIV-infected children. Four HIV-uninfected infants presented with TB-related symptoms several months after being given chemoprophylaxis because of a known source case. Stigmata of TB were cough >3 weeks in 4, weight loss or a history of failing to thrive in 3, fever in 2 infants, and reported night sweats in 1. Chest radiographs at diagnosis revealed lymphadenopathy, lobar opacification, and airway narrowing. All patients were treated for varying time periods at a TB referral institution in the Western Cape. CONCLUSIONS: Standard, first-line anti-TB agents were inadequate to prevent MDR-TB in children exposed to MDR-TB contacts. Second-line chemoprophylaxis, reflecting the susceptibility profile of the source case's isolate, with at least 2 drugs with activity against the drug-resistant isolate for 6-12 months should be considered.     

Neonatal BCG vaccine and response to the tuberculin test in BCG vaccinated children in contact with tuberculosis patients in Recife, Brazil

This case-control study analyses the association between the tuberculin response and the neonatal BCG vaccine in 330 children under 15 who are home contacts of tuberculosis patients, taking into account risk factors for the transmission of infection. Interviews were conducted with 330 children, their parents or legal guardians. Chest X-rays were taken and the tuberculin test (TT) applied using 0.1 ml of PPD RT23, taking an induration reading of > or = 10 mm as the cut-off point for a positive test result. Prior BCG vaccination was ascertained by observing the presence of a scar on the deltoid region of the right arm. Six children were excluded because they had signs/symptoms of pulmonary tuberculosis, thereby reducing the final sample to 324 children. The multivariate analysis showed that being exposed to a patient with pulmonary lesions with cavities (OR = 3.14; CI: 1.59-6.20; p = 0.000), a positive sputum smear (OR = 3.65; CI: 1.52-8.78; p = 0.002) or a positive culture (OR = 4.42; CI: 1.39-14.1; p = 0.005), being under five (OR = 0.47; CI: 0.22-0.99; p = 0.045) are independently associated with a positive TT. The fact that a prior BCG scar is not associated with a positive response to the TT indicates the need to re-open discussion of the guidelines which exist in many poor countries where tuberculosis is still a serious public health problem. Such guidelines include those issued by the Brazilian Ministry of Health, which considers the child under 15 in contact with a tuberculosis case to be infected only if there is a TT of 10 mm or more and the child received no prior BCG vaccination.     

Unintended consequences: mandatory tuberculin skin testing and severe isoniazid hepatotoxicity

After mandatory school-enrollment tuberculin skin testing, a 4-year-old girl who was at low risk for Mycobacterium tuberculosis infection had severe isoniazid hepatotoxicity that was managed with a liver transplant. Although severe isoniazid hepatotoxicity is very uncommon in children, this case emphasizes the need to limit skin testing to persons who have a risk factor for infection and to educate parents on how to monitor for adverse effects during treatment.     

Antituberculosis chemoprophylaxis in children

OBJECTIVE: To present a review of the indications of antituberculosis chemoprophylaxis in childhood, based on Brazilian official rules of the National Program for the Control of Tuberculosis of the Ministry of Health and the new tendencies pointed by the Brazilian Consensus on Tuberculosis. METHODS: Articles on the theme were selected from Medline and publications of the Ministry of Health. RESULTS: The chemoprophylaxis is an effective and safe form of prevention of tuberculosis in childhood. It does not conflict with the BCG vaccination program, because it aims at avoiding that tuberculosis infection develops into disease. CONCLUSIONS: International proposals an recent national tendencies recommend the expansion of chemoprophylaxis indications in childhood. Thus measures that expand its use in our country are needed.     

BCG vaccination in India and tuberculosis in children: Newer facets

With the extended programme of immunisation and since 1985 the universal programme of immunisation and the coverage status of BCG vaccination in India has been very good, although it is still unsatisfactory in the eastern states. It is emphasized that BCG vaccination cannot prevent natural tuberculous infection of the lungs and its local complications, although it reduces the haematogenous complications of primary infection. However, this is not true for malnourished children who, inspite of BCG vaccination, develop serious, and often fatal types of tuberculosis such as miliary, meningitic and disseminated tuberculosis. The tuberculin anergy in malnourished children, is mainly responsible for high morbidity and mortality. BCG vaccinated, well-nourished children manifest modified patterns of tuberculous disease, following infection. The most important manifestation is the increased incidence of intrathoracic tuberculosis, specially enlargement of the various groups of mediastinal nodes and their local complications. Localisation of the disease by T cell immunity, due to BCG vaccination is responsible for this and the much lower incidence of haemotological complications such as neurotuberculosis and disseminated disease. In these children, the clinical picture of neurotuberculosis is also modified, with a tendency for more localised involvement of the brain and meninges. Similarly, vaccinated children may present with hepatomegaly, splenomegaly or isolated organ disease. It is important to relearn the new patterns of tuberculosis disease seen in vaccinated, non-malnourished children, and to a lesser extent in children with grade 1 to 2 protein energy malnutrition (PEM). With these limitations of BCG vaccination, other strategies like chemoprophylaxis need multicentric trials in high risk children, in different parts of the country.     

Active surveillance for tuberculosis in Wales: 1996-2003.

AIMS: To estimate the incidence of active tuberculosis (TB) and study the use of chemoprophylaxis for latent TB in children in Wales, and to identify potential areas for improving prevention and management. METHODS: Active surveillance for TB in children aged 0-15 years from July 1996 to December 2003, using the Welsh Paediatric Surveillance Scheme. RESULTS: A total of 232 children, 102 with active TB (2.3 per 100 000) and 130 with latent TB (2.9 per 100 000), were identified. Nearly half (45%) belonged to ethnic minorities (19% were of black African origin), a much higher proportion than the base population. Pulmonary disease was the most common presentation (47%), including six (9%) children who were sputum smear positive. There were 10 cases of disseminated TB, nearly all in white children under 10 years of age. Less than two thirds of eligible children (27/46, 59%) were known to have received BCG immunisation. The source of infection was an adult household contact in most cases, but was not known in 44 cases, particularly among teenagers. Four community outbreaks occurred during the surveillance period, including three in high schools. CONCLUSION: TB incidence in children in Wales remains low, but the epidemiology is changing with an increasing proportion of cases in black African children. The high proportion of patients with disseminated TB is of particular concern. TB in teenagers was often associated with school outbreaks. Many eligible children do not receive BCG immunisation, indicating further scope for prevention.     

Tuberculin test in the diagnosis of childhood tuberculosis: Analysis of quantitative and qualitative features

OBJECTIVE: To evaluate the role of the tuberculin test in the diagnosis of tuberculosis in children. METHODS: Test diagnosis study; Tuberculin test with PPD Rt 23 (2 UT) was performed in 158 children, distributed in 2 groups: 101 no tuberculous, BCG vaccinated children and 57 tuberculous ones (diagnosis by clinical-radiological and epidemiological features). The interpretation of the tuberculin test was made by quantitative analysis (Mantoux test) and qualitative analysis (Koch and Listeria phenomena). RESULTS: Using cutoff = 10mm in Mantoux test, we found sensitivity of 85.9% and specificity of 86.1%. The qualitative analysis (Koch phenomenon), showed sensitivity of 77.2% and specificity of 98%. CONCLUSION: The qualitative analysis of the tuberculin test was useful in the diagnosis of tuberculosis in children, associated to the Mantoux test interpretation.     

Newer diagnostic modalities for tuberculosis

The gold standard for diagnosis of tuberculosis is demonstration of mycobacteria from various body fluids. This is often not possible in children due to pauci-bacillary nature of illness. Significant improvement in understanding of molecular biology ofMycobacterium tuberculosis has led to development of newer diagnostic techniques of tuberculosis. Polymerase chain reaction (PCR) is an emerging diagnostic tool for diagnosis of TB in children. However, its role in day-to-day clinical practice needs to be defined. A negative PCR never eliminates possibility of tuberculosis, and a positive result is not always confirmatory. The PCR may be useful in evaluating children with significant pulmonary disease when diagnosis is not readily established by other means, and in evaluating immunocompromised children (HIV infection) with pulmonary disease. In the absence of good diagnostic methods for tuberculosis, a lot of interest has been generated in serodiagnosis. ELISA has been used to detect antibodies to various purified or complex antigens ofM. tuberculosis in children. Despite a large number of studies published over the past several years, serology has found little place in the routine diagnosis of tuberculosis in children, even though it is rapid and does not require specimen from the site of disease. Sensitivity and specificity depend on the antigen used, gold standard for the diagnosis of tuberculosis and the type of tubercular infection. Though most of these tests have high specificity, their sensitivity is poor. In addition, these tests may be influenced by factors such as age, prior BCG vaccination and exposure to environmental mycobacteria. The serological tests, theoretically, may not be able to differentiate between infection and disease. At present, serodiagnosis does not appear to have any role in diagnosis of childhood pulmonary tuberculosis. A new test (QuantiFERON-TB or QFT) that measures the release of interferon-gamma in whole blood in response to stimulation by purified protein derivative is comparable with the tuberculin skin testing to detect latent tubercular infection, and is less affected by BCG vaccination. It can also discriminate responses due to nontuberculous mycobacteria, and avoids variability and subjectivity associated with placing and reading the tuberculin skin test. Polymerase chain reaction based test for identification of katG and rpoB mutation which are associated with isoniazid and rifampicin resistance may help in early identification of drug resistance in mycobacterium.