Clinical profile of drug resistant tuberculosis in children

This Cross-sectional observational study was conducted to determine the clinical profile of drug-resistant tuberculosis in children. Patients were classified as monoresistant TB, polyresistant TB, multidrug resistant (MDR)-TB and extensively drug resistant (XDR — TB). We coined a term called as Partial XDR-TB when isolates of Mycobacterium tuberculosis were confirmed to be resistant in vitro to be MDR along with either a fluoroquinolone or an aminoglycoside resistance (apart from streptomycin). Of 500 children analysed, 34 (6.8%) had drug resistant TB. Mean age of presentation was 6.8±3.2 years (Male: Female ratio 13:21). 18 (52.9%) children had been treated for tuberculosis in the past (1 defaulted), 7 patients had been in contact with an adult suffering from drug resistant TB and 3 patients (10.3%) were HIV co-infected. Fourteen children (41.2 %) had MDR TB, 11 (32.4 %) had Partial XDR, 1 each (2.9 %) had polyresistant TB and XDR TB. Clinical features of DR-TB are similar in all age groups. Past history of TB with treatment with antitubercular agents, and contact with adults suffering with drug-resistant TB are important risk factors in development of drug-resistant -TB in children.     

Outcome of HIV infected children with culture confirmed tuberculosis.

BACKGROUND: Tuberculosis (TB) is an important disease in human immunodeficiency virus (HIV) infected children living in regions where TB is endemic. There are limited data on the outcome of culture confirmed TB in HIV infected children. AIMS AND METHODS: To describe the outcome on TB therapy and overall mortality in HIV infected children with culture confirmed TB through a retrospective cohort study. RESULTS: Eighty seven children, median age 24 months, contributed to 93 TB episodes; six children had two confirmed episodes. Pulmonary disease (PTB) was present in 71 episodes (76.3%), extrapulmonary disease (EPTB) in 43 (46.2%), and of these, both PTB and EPTB were present in 21 (22.6%). There was cure based on bacteriological and/or radiological criteria in 54 episodes (58.1%). Eighteen children died during TB therapy and there were a total of 34 deaths (39.1%). In univariate analysis (n = 87 patients), severe malnutrition, age < or =1 year, and a negative tuberculin skin test were significant risk factors for death during TB therapy. In multivariate survival analysis (n = 87 patients), HIV disease category, severe malnutrition at diagnosis, and lack of cure at the end of TB therapy were significantly associated with overall mortality. CONCLUSION: In the absence of antiretroviral therapy, HIV infected children with confirmed TB have poor outcomes on antituberculosis therapy and are at high risk of death during and after completion of antituberculosis therapy, especially due to non-TB related causes. There is an urgent need to optimise and monitor antituberculosis therapy in HIV infected children and to improve access to TB and other preventative therapy.     

A clinical approach to paediatric tuberculosis in Canada

OBJECTIVE:

To review clinical aspects of management of tuberculosis (TB) infection and disease in Canadian children in the context of the global TB epidemic and the rising incidence of drug-resistant TB.

DATA SOURCES:

Original and review articles pertinent to: epidemiology of TB globally and in Canada; management of latent TB infection and TB disease in children; diagnostic tests for latent TB infection and TB disease; and management of drug-resistant TB disease. Multiple Medline searches were used including combinations of the MeSH terms ‘Tuberculosis*’ (and its multiple subheadings), ‘Child*’, ‘Drug Resistance’, ‘Mycobacterium tuberculosis*’ and ‘Canada/epidemiology*’. Select relevant textbooks were reviewed.

DATA SELECTION AND EXTRACTION:

The articles were analyzed from the perspective of clinicians managing children in Canada today, and from our experience of managing children with TB in Southern Ontario.

DATA SYNTHESIS:

TB in Canada is largely a disease of the foreign-born and their children, but continues to occur in aboriginal children. Drug resistance is increasing globally and in Canada. Most children with TB disease in Canada are asymptomatic and found through contact tracing. False positive skin tests are frequent where TB prevalence is low.

CONCLUSIONS:

Obtain source case drug sensitivities when treating TB contacts and those with latent TB infection. Obtain cultures before treating TB disease and treat disease with at least four antituberculous drugs while awaiting sensitivities. Use Directly Observed Therapy for TB disease. Confine TB skin testing to children at high risk for TB infection or disease, including contacts of infectious patients and recent immigrants. A team approach and infection control measures including environmental controls are important in managing TB disease.     

Outcome of HIV infected children with culture confirmed tuberculosis

Background: Tuberculosis (TB) is an important disease in human immunodeficiency virus (HIV) infected children living in regions where TB is endemic. There are limited data on the outcome of culture confirmed TB in HIV infected children. Aims and Methods: To describe the outcome on TB therapy and overall mortality in HIV infected children with culture confirmed TB through a retrospective cohort study. Results: Eighty seven children, median age 24 months, contributed to 93 TB episodes; six children had two confirmed episodes. Pulmonary disease (PTB) was present in 71 episodes (76.3%), extrapulmonary disease (EPTB) in 43 (46.2%), and of these, both PTB and EPTB were present in 21 (22.6%). There was cure based on bacteriological and/or radiological criteria in 54 episodes (58.1%). Eighteen children died during TB therapy and there were a total of 34 deaths (39.1%). In univariate analysis (n = 87 patients), severe malnutrition, age ⩽1 year, and a negative tuberculin skin test were significant risk factors for death during TB therapy. In multivariate survival analysis (n = 87 patients), HIV disease category, severe malnutrition at diagnosis, and lack of cure at the end of TB therapy were significantly associated with overall mortality. Conclusion: In the absence of antiretroviral therapy, HIV infected children with confirmed TB have poor outcomes on antituberculosis therapy and are at high risk of death during and after completion of antituberculosis therapy, especially due to non-TB related causes. There is an urgent need to optimise and monitor antituberculosis therapy in HIV infected children and to improve access to TB and other preventative therapy.     

Advances in diagnosis and therapy of childhood tuberculosis

Tuberculosis remains a major health problem worldwide. Recently developed diagnostic blood tests may supplant or supplement TB skin test in some settings. Emergence of drug-resistant strains remains a global concern. New anti-tuberculous agents are being developed and are greatly needed. There is mounting evidence that BCG has significant effectiveness in prevention, but development of improved vaccines for tuberculosis should remain a priority.     

Drug-resistant tuberculosis in two children in Greece: Report of the first extensively drug-resistant case

Extensively drug-resistant (XDR) tuberculosis (TB) represents a serious and growing problem in both endemic and non-endemic countries. We describe a 2.5-year-old girl with XDR-pulmonary TB and an 18-month-old boy with pre-XDR-central nervous system TB. Patients received individualized treatment with second-line anti-TB agents based on genotypic and phenotypic drug susceptibility testing results. Both children achieved culture conversion 3 months and 1 month after treatment initiation, respectively. The child with XDR-pulmonary TB showed evidence of cure while treatment adverse events were managed without treatment interruption. The child with pre-XDR-central nervous system TB after 6-month hospitalization with multiple infectious complications had a dismal end due to hepatic insufficiency possibly related to anti-TB treatment. This is the first report of children with pre-XDR and XDR TB in Greece, emphasizing the public health dimensions and management complexity of XDR TB.     

Tuberculosis and human immunodeficiency virus co-infection in children: management challenges

The pattern of childhood human immunodeficiency virus (HIV) and tuberculosis (TB) infection mirror these epidemics in the adult population. The number of children co-infected with HIV and TB is rising, and the incidence of congenital and neonatal TB is similarly increasing. In addition, the emergence of multidrug resistant TB and extensively drug-resistant TB has occurred within the context of a high prevalence of HIV and TB. The diagnosis of TB has always been difficult in children and is compounded by HIV co-infection. The clinical symptoms in both diseases are similar, and the radiological changes may be non-specific. Treatment of both conditions in children is a challenge due to drug interactions and problems with adherence. In most developing countries, there are few medicines specifically tested and manufactured for children, with few stable syrup formulations. Thus antituberculosis and antiretroviral tablets have to be divided, giving rise to unpredictable dosing and the possible emergence of resistance. To reduce the morbidity and mortality of TB and HIV, existing childhood TB programmes must be strengthened, and antiretroviral drug therapy and mother-to-child transmission programmes scaled up. An increased emphasis on childhood TB, with early diagnosis and treatment, must be a priority. The provision of isoniazid prophylaxis to HIV-infected children exposed to an adult case of TB or, in areas with a high prevalence of TB, to HIV-infected children (irrespective of a TB contact) may be effective in reducing the morbidity and mortality from childhood TB.     

干扰素释放试验对儿童隐性结核感染的诊断价值

隐性结核感染是指已经感染结核杆菌,但尚未出现临床症状和胸片异常表现者,常用结核菌素皮肤试验(TST)来进行诊断。但TST在卡介苗接种者或非结核分枝杆菌感染者中会出现假阳性,而免疫低下或婴幼儿中常出现假阴性,因此急需寻找敏感性及特异性更高的方法进行隐性结核感染的判断。最近,干扰素释放试验越来越受到人们的关注,并在有些国家已经作为TST诊断隐性结核感染的替代或确认方法。该方法比TST特异性高,不受卡介苗接种和其他非结核分枝杆菌感染的影响;其敏感性在免疫正常者与结核菌素试验相似,在免疫抑制的患者中敏感性高于TST。提示干扰素释放试验在诊断隐性结核感染中有很好的应用前景,但还不能完全替代TST。     

Childhood tuberculosis: old and new vaccines

The world is witnessing an escalation of the tuberculosis (TB) epidemic, particularly in sub-Saharan Africa and South-East Asia. The problem has been compounded by the evolution of the human immunodeficiency virus pandemic, the increase in multidrug-resistant TB and the emergence of extensively drug-resistant TB. This has led to renewed interest in vaccines aimed at preventing tuberculosis. The current Bacille Calmette-Guérin (BCG) vaccine prevents the invasive complications of childhood tuberculosis, such as meningitis and miliary disease, but provides variable protection against adult pulmonary disease. This review discusses the history of the BCG vaccine, the reasons for its variable efficacy, protective immunity and TB, and the evolution of and obstacles to development of new candidate vaccines. Several new TB vaccines have demonstrated promising results in animal models; a number have gone into phase I clinical trials in humans, and it is anticipated that phase III trials will commence by 2009. Licensing of an effective new TB vaccine by 2015 is thus a possibility.     

Risk factors for human immunodeficiency virus infection in Ethiopian children with tuberculosis.

BACKGROUND: Separate risk factors for HIV infection and for tuberculosis (TB) are well-studied, but it is unclear whether these risk factors still apply in the new epidemiologic situation of dual infection. This study examines risk factors associated with seropositivity for HIV in Ethiopian children with clinical TB. METHODS: A prospective, controlled study of children with TB diagnosed in Addis Ababa from December 11, 1995, to January 28, 1997, in which HIV-positive children were compared with HIV-negative children with regard to sociodemographic background, previous medical history and vaccination. RESULTS: HIV prevalence among children with clinical TB was 11.2%. High educational status of mothers, low age, loss of one or two parents and earlier Calmette-Guérin bacillus (BCG) vaccination of the child were factors independently related to HIV infection. CONCLUSION: Factors associated with HIV infection among children with clinical TB include higher education of parents, higher income and better living conditions. The HIV epidemic might thus modify traditional risk factors for tuberculosis. It might also decrease the overall effect of BCG vaccination given that BCG did not provide protection in children infected with HIV. An expected increase of dually infected children who are younger, more in need of hospitalization and often lacking one or both parents will put an additional burden on the Ethiopian health care system.     

Current concepts of childhood tuberculosis

Tuberculosis (TB) is a social disease with medical implications. An estimated one-third of the world's population (2 billion people) is infected with the tubercle bacilli. In the year 2000 alone, an estimated 8.3 million new cases of TB occurred, of which 884,019 (10.7%) were in children. Of the total, 659,379 (75%) occurred in 22 high-burden countries, most of which were resource-poor. Despite a growing body of literature demonstrating the substantial impact made by addressing childhood TB, current guidelines are geared toward the treatment and control of TB in adults. This review focuses on TB disease among children younger than 15 years of age, the standard World Health Organization category for TB in children. The purpose of this work is to review the epidemiology, pathophysiology, and clinical presentation of childhood TB. The challenges of accurate surveillance, confirmation of diagnoses, and effective treatment of childhood TB in resource-poor settings are highlighted.     

Recurrent culture-confirmed tuberculosis in human immunodeficiency virus-infected children

INTRODUCTION: Recurrent tuberculosis (TB) is more common among human immunodeficiency virus (HIV)-infected than HIV-uninfected adults. There are limited data regarding recurrence of TB in children. OBJECTIVE: To determine the occurrence of recurrent TB in HIV-infected children with culture-confirmed tuberculosis. METHODS: HIV-infected children with culture-confirmed TB, identified from 1992 to 2000, were followed until February 2004 for further confirmed TB episodes 6 months or more after completion of previous antituberculosis therapy. Clinical data and results of special investigations were recorded. Restriction fragment length polymorphism (RFLP) analysis of Mycobacterium tuberculosis isolates was done when possible. RESULTS: Of 87 children, 9 had a second episode; 2 of these had a third episode of confirmed TB. Adherence to treatment was good in 8; 2 experienced hepatotoxicity, and regimens were changed. Chest radiographs were normal in only 2 children after first treatment completion. Bacteriologic cure was documented in 7 episodes before recurrence. RFLP analysis showed 3 children infected with the same strain (relapse) and 1 child with a different strain between episodes 1 and 3 (reinfection). Two further cases had reinfection based on epidemiologic data and drug susceptibility test results. Full comparison of strains by RFLP was not possible because of the unavailability of isolates of the first episode in 5 cases. CONCLUSION: Recurrent TB in HIV-infected children is common in a high burden TB setting. Both relapse and reinfection occur.     

Risk factors for TB infection and disease in young childhood contacts in Malawi

BACKGROUND: Screening of children in household contact with smear-positive tuberculosis (TB) is universally recommended but seldom practiced in resource-poor settings. It has huge potential to reduce the burden of TB disease in children, particularly if streamlined to focus on those at greatest risk.AIMS: To assess the prevalence of infection and disease amongst children aged < or = 5 yrs in household contact with smear-positive TB. To identify which source case characteristics are risk factors for infection. METHODS: A prospective, hospital-based audit was conducted over a 17-mth period in Southern Malawi. Smear-positive adults were identified and encouraged to bring their children to the outpatient clinic, in accordance with the national TB programme guidelines. Full assessment was performed, including tuberculin skin test. RESULTS: 195 children aged < or = 5 yrs who were contacts of 161 source cases were assessed. Prevalences of TB infection and disease were high (45% and 23%, respectively). The likelihood of a child being infected was significantly greater with increasing smear-positivity of the source case, and also if the source case were female (OR 2.25, 95% CI 1.19-4.27, p = 0.01). CONCLUSIONS: The high prevalence of TB infection and disease in child contacts attending this hospital-based clinic supports the current policy of contact-screening in Malawi. However, community-based studies are needed to provide a more accurate assessment of prevalence and risks for child contacts.     

Pyridoxal‐5‐phosphate plasma concentrations in children receiving tuberculosis chemotherapy including isoniazid

Aim: Little is known about pyridoxine nutriture of children treated with isoniazid (INH) regimens. This study documents plasma pyridoxal 5′‐phosphate (PLP) concentrations in children, HIV‐infected and HIV‐uninfected, receiving INH regimens. Methods: Children from the Western Cape of South Africa hospitalized for tuberculosis (TB) management were studied. Plasma PLP concentrations were determined on enrolment, 1‐month after commencing TB treatment, and again after 4‐month’s treatment. The children received a supplement meeting pyridoxine requirements. Results: Nineteen HIV‐infected and 33 HIV‐uninfected children received INH (dosage range 4–20 mg/kg) daily. Mean PLP plasma concentrations on enrolment were 8.32 (SD 6.75) ng/mL and 11.28 (SD 3.02) ng/mL in HIV‐infected and HIV‐uninfected children, respectively (p = 0.11) and after 4‐month’s treatment 6.75 (SD 2.71) ng/mL and 14.76 (SD 7.96) ng/mL (p < 0.001). On enrolment 9 (50%) HIV‐infected and 5 (15%) HIV‐uninfected children (p = 0.016) had suboptimal PLP concentrations (<6 ng/mL); after 4‐month’s treatment 8 (42%) and 2 (6%) (p = 0.004). Conclusion: Plasma PLP concentrations in children treated for TB were low on enrolment in HIV‐infected and HIV‐uninfected children; after 4‐month’s treatment low values were still common in HIV‐infected children. Additional pyridoxine supplementation of malnourished children treated for tuberculosis is advisable, particularly those HIV‐infected.     

Tuberculosis treatment in children: The changing landscape

Traditionally children have been treated for tuberculosis (TB) based on data extrapolated from adults. However, we know that children present unique challenges that deserve special focus. New data on optimal drug selection and dosing are emerging with the inclusion of children in clinical trials and ongoing research on age-related pharmacokinetics and pharmacodynamics. We discuss the changing treatment landscape for drug-susceptible and drug-resistant paediatric tuberculosis in both the most common (intrathoracic) and most severe (central nervous system) forms of disease, and address the current knowledge gaps for improving patient outcomes.     

Multidrug-resistant tuberculous meningitis in children in Durban, South Africa

BACKGROUND: Tuberculous meningitis (TBM) is the most frequent manifestation of central nervous system tuberculosis (TB) and is more common in children than in adults. The diagnosis of TBM in children is difficult because signs and symptoms are vague. Information about drug resistant TB in children is scarce, and there is no published information on drug resistant TBM in children. METHODS: This is a retrospective review of medical records of children with culture-confirmed multidrug-resistant tuberculous meningitis (MDR-TBM) at King George V Hospital in Durban, South Africa. RESULTS: Between 1992 and 2003, there were 8 children with MDR-TBM; 6 were HIV infected and 2 were HIV negative. Only one child survived. The diagnosis was made posthumously in almost all the children. DISCUSSION: The changes in the cerebrospinal fluid (CSF) in early TBM can be nonspecific and can change rapidly; therefore, CSF studies should always include culture and susceptibility testing. Factors that contributed to the high mortality were disseminated TB, HIV infection, delay in diagnosis and treatment, the absence of a standardized approach to the management of MDR-TBM and the poor CSF penetration of most MDR-TB drugs. MDR-TB therapy should be considered if there is a history of TB: a MDR-TB contact or a poor clinical response to TB therapy despite adequate adherence to treatment. Early diagnosis is important because TBM in children is often associated with a grave outcome.     

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.     

Actualización del tratamiento de la tuberculosis en niños

Tuberculosis (TB) is the most important infectious disease all over the world, with a high morbidity and mortality. Pediatric tuberculosis has been a neglected epidemic, due to the difficulties in assessing its global impact, reduced incidence and lower infectivity compared to adults. In 2015, the WHO reported 1 million cases of paediatric TB and 169,000 deaths. In Europe, the emergence of MDR TB is a major concern, representing 16% of the new diagnosis in Eastern Europe. In 2014, it was estimated that about 219,000 children were infected by MDR-TB-strains in Europe, and 2,120 developed the disease. Spain is the Western European country with more paediatric cases, with an incidence 4.3/100,000 inhabitants in 2014. Paediatric tuberculosis mortality in Spain is rare, but extra-pulmonary disease is associated with significant complications. The prevalence of paediatric drug resistant TB in Spain is over 4%, higher than the estimated incidence in adult population, representing mayor difficulties for therapeutic intervention. These data reveal that paediatric TB is still a Public Health priority in our country.The difficulties in diagnosis and the lack of optimal paediatric drug formulations are the major challenges for controlling the childhood's tuberculosis epidemic. A group of national paeditric TB experts has reviewed the international guidelines and the most recent evidences, and has established new recommendations for the management of paediatric TB contacts, latent infection and active TB disease, especially focused in drug resistant cases. This document replaces the former national guidelines from the Spanish Society for Pediatric Infectios Diseases, although the prior recommendations on the diagnosis remain valid.     

A Relook at Preventive Therapy for Tuberculosis in Children

Preventive therapy for tuberculosis in children is an important strategy to control pediatric TB in addition to early diagnosis and treatment of infectious cases in the community. In low burden countries, it is an important tool for preventing TB at all ages as the opportunities for re-infection are few. In contrast in high burden countries, preventive therapy though effective in preventing occurrence of disease among infected, can not prevent re-infection—an event of fairly high occurrence in these settings. Children under 5 years of age or immuno-compromised children of any age who have the highest risk of developing infection and disease when exposed are the main focus for preventive therapy in high burden settings. A 6 months therapy with INH continues to be the preferred modality of preventive therapy as efforts are being made to identify a short course preventive therapy using Rifampicin and other drugs.     

Impact of human immunodeficiency virus 1 infection on clinical presentation,treatment outcome and survival in a cohort of Ethiopian children with tuberculosis

BACKGROUND: Childhood tuberculosis (TB) is difficult to diagnose reliably because signs and symptoms are nonspecific and sputum for direct microscopy is difficult to obtain, especially in very young children. This diagnostic dilemma is thought to have increased with the HIV pandemic. Few studies on treatment outcome of dually infected children in high endemic countries have been reported. This study examines the impact of HIV infection on clinical presentation, diagnostic criteria and treatment outcome of TB in Ethiopian children. METHODS: A prospective cohort study of children with TB diagnosed in Addis Ababa from December 1995 to January 1997 in which HIV-positive children were compared with HIV-negative children with regard to medical history, signs and symptoms, nutritional status, chest radiography, tuberculin skin test, response to TB treatment and final outcome. Mycobacterium tuberculosis was cultured in children with pulmonary manifestations. RESULTS: HIV-positive children were younger, were underweight and had a 6-fold higher mortality than HIV-negative children. The tuberculin skin test was less sensitive and chest radiography was less specific in HIV-infected patients. Adherence to treatment was high (96%), and the cure rate was 58% for HIV-positive and 89% for HIV-negative TB patients. CONCLUSION: HIV-positive children are at risk of diagnostic error as well as delayed diagnosis of TB. TB manifestations are more severe and progression to death is more rapid than in HIV-negative children. Weight for age may be used to identify children at high risk of a fatal outcome.