Pediatric Drug-resistant Tuberculosis Research Articles

Effect of delamanid on interim outcomes of bacteriological conversion amongst pediatric drug resistant tuberculosis cases in India.

To determine the bacteriological conversion rate after 6 months of Delamanid (DLM) based treatment in children with drug-resistant tuberculosis (DR-TB) and determine factors associated with bacteriological conversion. This is a descriptive retrospective study done in children between the age of 6-17 years with DR-TB who received DLM-based therapy from October 2018 to May 2021. The drug resistance pattern of TB was detected using Xpert RIF/MTB and phenotypic drug sensitivity testing (DST) on TB-MGIT culture reports. Follow-up sputum TB MGIT culture was carried out monthly after DLM initiation for 6 months. Factors associated with sputum bacteriological conversion such as age, gender, pulmonary TB (PTB) versus disseminated TB, unilateral or bilateral lung involvement, type of DR-TB, prior treatment failure, and type of DR-TB regimen were analyzed. Sixty patients received DLM of which two had extrapulmonary TB (EPTB) and sputum conversion could not be assessed. The mean age at presentation was 12.69 ± 3.03 years. Five patients (8.3%) died while on DLM treatment. On follow-up, 8 (13.7%) out of 58 patients had no sputum bacteriological conversion after 6 months of DLM initiation of which three patients were on salvage therapy; 46 (79.3%) had sputum bacteriological conversion within 6 months of DLM initiation. Sputum bacteriological conversion rate was almost 80% at the end of 6 months of DLM-based treatment.

Pediatric Drug-Resistant Tuberculosis: The Current and Future Prospects for Management and Prevention.

In the continued battle against one of the oldest enemies known to mankind, Mycobacterium tuberculosis (MTB), the emergence of drug resistance to antituberculosis drugs among children poses multiple challenges for early detection and treatment. Molecular diagnostics and newer drugs like bedaquiline and delamanid have strengthened the armamentarium and helped design convenient, safe, and child-friendly therapeutic regimens against drug-resistant tuberculosis (TB). Preventive strategies like treatment of TB infection among children living in close contact with patients with drug-resistant TB and effective vaccines against TB are currently in the investigative stages of development and implementation. In addition to the implementation of recent novel diagnostics and treatment modalities, effective psychosocial and nutritional support, as well as dedicated monitoring for compliance and adverse effects, are crucial determinants for successful treatment outcomes in these children.

Burden of drug-resistant pulmonary tuberculosis in Pakistani children: A cross-sectional study

Introduction: The incidence of drug-resistant tuberculosis (TB) is rapidly increasing worldwide. Children in high TB burden countries are rapidly being reported to be affected by Mycobacterium tuberculosis resistant to isoniazid and rifampicin. The aim of this study is to evaluate the pattern of drug sensitivity among children suffering with TB. Methods: Known cases of pulmonary TB, with sputum smear positive for acid-fast bacilli after two months of compliance to 1st line anti-tuberculous therapy were included after gaining informed consent. Specimens used for drug sensitivity testing were either sputum or bronchoalveolar lavage. Patient age, gender, history of TB contact, and duration of treatment were also recorded. Data was entered and analyzed using SPSS v.22. Results: Fifty children, 32 male (64%) and 18 female (36%) were included in the study. Their mean age was 12.84 ± 2.54 years. History of household TB contact was positive in 29 (58%) children. Among 1st line anti-tuberculous therapy, rifampicin resistance was highest at 33/50 (66%), and resistance to streptomycin and ethambutol were the lowest (6/50; 12%). There were 18 (36%) children with multidrug-resistant tuberculosis (MDR-TB). A positive history of household TB contact (either resistant or non-resistant) was seen to have a statistically significant impact on incidence of MDR-TB (p value=0.03) Conclusion: Pediatric drug-resistant TB is a rising concern. Awareness programs on national and international levels are needed to educate general population regarding the importance of preventing TB household contact, especially amongst children. With the selected method used to identify mainly older children with drug resistance, the yield for drug-resistant TB was found to be high.

Burden of drug-resistant pulmonary tuberculosis in Pakistani children: A cross-sectional study

Introduction: The incidence of drug-resistant tuberculosis (TB) is rapidly increasing worldwide. Children in high TB burden countries are rapidly being reported to be affected by multidrug-resistant TB (resistant to isoniazid and rifampicin). The aim of this study is to evaluate the pattern of drug sensitivity among children suffering with TB. Methods: Known cases of pulmonary TB, with sputum smear positive even after two months of compliance to 1st line anti-tuberculous therapy were included after gaining informed consent. Specimens used for drug sensitivity analysis were either sputum or bronchoalveolar lavage. Patient age, gender, history of TB contact, and duration of treatment were also recorded. Data was entered and analyzed using SPSS v.22. Results: There were 32 male (64%) and 18 female (36%) children in the study. Their mean age was 12.84 ± 2.54 years. History of household TB contact was positive in 29 (58%) children. Among 1st line anti-tuberculous therapy, ethambutol and streptomycin were most sensitive (n=44; 88%). Rifampin was least sensitive (n=17; 34%). There were 32 (64%) children with multidrug-resistant tuberculosis (MDR-TB). A positive history of household TB contact (either resistant or non-resistant) was seen to have a statistically significant impact on incidence of MDR-TB (p value=0.03) Conclusion: Pediatric drug-resistant TB is a rising concern. Awareness programs on national and international levels are needed to educate the general population regarding the importance of preventing TB household contact, especially amongst children.

Increasing Prevalence of Pediatric Drug-resistant Tuberculosis in Mumbai, India, and Its Outcome.

The prevalence and type of Drug resistant tuberculosis (DR-TB) was evaluated pre- and post-2013, and outcome was studied. Descriptive retrospective study. Children were defined as having DR-TB on the basis of GeneXpert or line probe assay and/or drug susceptibility testing (DST) of M. tuberculosis grown on culture or from contact's DST. The prevalence of DR-TB was 110 of 1145 cases (9.6%), which showed an increase, compared with 5.6% pre-2010 and 7% in 2010-2013 (P = 0.014408). Twenty-two children (20%) had pulmonary-TB and 88 (80%) had extra-pulmonary-TB with disseminated-TB being the most common presentation in 31 children (28.18%). Ninety-six children (87.3%) were bacteriologically confirmed TB cases, and 14 (12.7%) were clinically diagnosed-TB and treated as per contact DST. Eight cases (7.2%) were monoresistant, 7 (6.3%) polyresistant, MDR-TB seen in 28 patients (25.45%), 32 (29.09%) had pre-XDR-TB, 9 (8.18%) had XDR-TB and 12 (10.9%) were rifampicin resistant. Ethionamide resistance increased from 26.1% pre-2013 to 60.8% post-2013 (P = 0.014408) and ofloxacin resistance rose from 30.4% pre-2010, to 47.6% in 2010-2013 and 56.9% post-2013 (P = 0.080863). Moxifloxacin resistance showed an acute rise from 8.7% pre-2010, to 46% in 2010-2013 and 57% post-2013 (P = 0.000275). Thirty-three patients (30%) had completed their treatment, 21 (19.09%) were lost to follow-up and 56 (50.09%) patients are still on treatment. DR-TB is increasing in Mumbai, India. Based on the DST results, individualised therapy would be recommended.

Prevalence, diagnosis and treatment status of pediatric drug-resistant tuberculosis

Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis, which threats the health of children worldwide.Accompany with the increase of drug-resistance tuberculosis, great challenging has arose in the prevention and treatment of tuberculosis.Nowadays, the diagnosis and treatment of drug-resistance tuberculosis is still difficult in pediatric patients.Based on molecular diagnosis, fast detect as well as reliable treatment of drug-resistance tuberculosis become available.Currently, the principle of drug-resistant tuberculosis treatment in children is essentially similar to adults.In this review, the mechanism, diagnosis and treatment of pediatric drug resistance tuberculosis were discussed. Key words: Child; Drug-resistance tuberculosis; Prevalence; Mechanisms of drug-resistance; Diagnosis; Treatment

Research progress of molecular diagnosis in pediatric drug-resistant tuberculosis

With the increasing of incidence rate of pediatric drug-resistant tuberculosis in recent years, pe-diatric tuberculosis as a threat to global childhood public health was serious disease and attracted more and more pediatrician concern.Pediatric tuberculosis often can′t result to typical clinical symptoms and imaging findings because its quantity of tubercle bacillus was little in lesions of infection, meanwhile, golden standard mycobacterium tuberculosis detection was time-consuming and low positive rate, pediatric tuberculosis can′t get timely diagnosis and therapy, molecular diagnostic techniques of pediatric drug-resistant tuberculosis got widely clinical application and development for its advantage of rapid, accurate, efficiency and easy operation etc, several common molecular diagnostic techniques in pediatric drug-resistant tuberculosis were summarized, which would provide useful guidance for molecular diagnose of pediatric drug-resistant tuberculosis. Key words: Molecular diagnosis; Drug-resistant tuberculosis; Child

Tuberculosis treatment for children: An update

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.

The Rate of Drug-Resistant Tuberculosis in Korean Children and Adolescents Since 2007.

The incidence of drug-resistant tuberculosis (DR-TB) in pediatric populations is a critical indicator of national TB management and treatment strategies. Limited data exist regarding the rate of pediatric DR-TB. In this study, we aimed to analyze the status of DR-TB in Korean children from 2007 to 2013. We analyzed specimens submitted to the Korean Institute of Tuberculosis using Mycobacterium tuberculosis culture and drug susceptibility tests (DSTs) from January 2007 through December 2013. Specimens from patients ≤ 19 years of age were included. Among the 2,690 cases, 297 cases were excluded because of insufficient data, leaving 2,393 cases for the final analysis. In total, resistance to one or more TB drugs was 13.5%. The resistance rates of each of the drugs were as follows: isoniazid (INH) 10.2%, rifampin (RFP) 5.1%, ethambutol (EMB) 3.7%, and pyrazinamide (PZA) 3.1%. The resistance rate of multidrug-resistant TB (MDR-TB) was 4.2%, and that of extensively drug-resistant TB (XDR-TB) was 0.8%. The overall drug resistance rate demonstrated significant increase throughout the study period (P < 0.001) but showed no significant difference compared to previous study from 1999 to 2007. The drug resistance rate of PZA in ≤ 15 years of age group was significantly greater than that of > 15 years (P < 0.001). The drug resistance rate has increased throughout the study period.

Epidemiology and Clinical Characteristics of Pediatric Drug-Resistant Tuberculosis in Chongqing, China.

To gain insight into the epidemiology of childhood drug resistant tuberculosis (DR-TB) in China that has the second largest burden of TB and the largest number of multidrug resistant (MDR) TB cases in the world, we performed the cross-sectional study to investigate drug resistance of four first-line anti-TB drugs (isoniazid, rifampicin, streptomycin and ethambutol) using Mycobacterium tuberculosis isolates from 196 culture-confirmed pediatric TB cases diagnosed in the Children’s Hospital of Chongqing Medical University, China during 2008–2013. Univariate and multivariate logistic regression analyses were performed to assess the associations between patient demographic and clinical characteristics and DR-and MDR-TB, respectively. Twenty-eight percent (56/196) of the study patients exhibited resistance to at least one of the four first-line anti-TB drugs tested. MDR was found in 4.6% (9/196) of the study patients. More than half (5/9, 55.6%) of the MDR cases were from a single county of Chongqing. A significant association was found between being acid-fast bacilli-smear negative and DR-TB (adjusted OR, 2.33; 95% CI, 1.13–4.80) and between having concurrent thoracic-extrathoracic involvement and MDR-TB (adjusted OR, 9.49; 95% CI, 1.05–85.92), respectively. The findings of this study indicate that the rate of DR is high among pediatric TB patients in Chongqing and suggest an urgent need for studies to identify MDR transmission hotspots in Chongqing, thereby contributing to the control DR- and MDR-TB epidemics in China. The study also generates new insight into the pathogenesis of DR and MDR M. tuberculosis strains and highlights the importance of studying childhood TB to the goal of global TB control.

Challenges and solutions to implementing drug-resistant tuberculosis programmes for children in Central Asia.

Guidelines for children with drug-resistant tuberculosis (DR-TB) tend to focus on individual patient care; there is little guidance for national tuberculosis programmes (NTPs) on how to plan, implement and integrate DR-TB services for children. In 2013, through the paediatric tuberculosis (TB) programme started by the Tajikistan Ministry of Health and Médecins Sans Frontières in 2011, 21 children became the first to be treated for multidrug-resistant tuberculosis (MDR-TB) in Tajikistan. We describe the challenges encountered in establishing the programme and the solutions to these challenges, and propose a framework to guide the implementation of paediatric DR-TB care. This framework could prove useful for other NTPs in resource-limited settings.

Piero Periti Review Article Award 2014

Background:Drug-resistant tuberculosis (DR-TB) is emerging as an increasing problem worldwide and no consensus has been reached about the management of children contacts of DR-TB cases.Objective:To evaluate the role of post-exposure chemoprophylaxis in paediatric DR-TB contacts, focusing on literature findings and recommendations from existing international guidelines.Methods:We conducted a literature search of the Cochrane Library, MEDLINE by PubMed and EMBASE from database inception through September 2012, using an appropriate search strategy.Results:Eighteen articles were included: four retrospective and two prospective population studies, eight international guidelines and four narrative reviews.Conclusions:General agreement exists that preventive therapy could be beneficial in specific high-risk groups, including immunocompromised children and those aged < 5 years. However, no consensus exists on the use of preventive therapy in older or immunocompetent children and on which regimen should be preferred.

Commentary: A targets framework: Dismantling the invisibility trap for children with drug-resistant tuberculosis

Tuberculosis (TB) is an airborne infectious disease that is both preventable and curable, yet it kills more than a million people every year. Children are highly vulnerable, but often invisible casualties. Drug-resistant forms of TB are on the rise globally, and children are as vulnerable as adults but less likely to be counted as cases of drug-resistant disease if they become sick. Four factors make children with drug-resistant TB 'invisible': first, the nature of the disease in children; second, deficiencies in existing diagnostic tools; third, overreliance on these tools; and fourth, our collective failure to deploy one effective tool for finding and treating children - contact investigation. We describe a nascent science-advocacy network - the Sentinel Project on Pediatric Drug-Resistant Tuberculosis - whose goal is to end child deaths from this disease. Provisional annual targets, focused on children exposed at home to multidrug-resistant TB, to be updated every year, constitute a framework to focus attention and collective actions at the community, national, and global levels. The targets in two age groups, under 5 and 5-14 years old, tell us the number of: (i) children who require complete evaluation for TB disease and infection; (ii) children who require treatment for TB disease; and (iii) children who would benefit from preventive therapy.

Completeness and accuracy of electronic recording of paediatric drug-resistant tuberculosis in Cape Town, South Africa.

Cape Town, South Africa. To assess the completeness and accuracy of electronic recording of drug-resistant tuberculosis (DR-TB) in children. Retrospective cohort study. All children aged <15 years treated for DR-TB during 2012 were included, with clinical data collected from routine health services. Matching was performed between clinical data and an extracted data set from an electronic register for DR-TB (EDR.web), and data sources were compared. Seventy-seven children were identified clinically, of whom only 49 (64%) were found in EDR.web. Most data in EDR.web were complete and accurate, but there were some internal inconsistencies for confirmed TB. Only 4.4% of all EDR.web entries were children. Only two thirds of children clinically treated for DR-TB were recorded in the electronic reporting system, suggesting under-reporting. We also found a lower than expected prevalence of childhood DR-TB, probably suggesting both under-diagnosis and under-recording of DR-TB in children. Clinicians at facility level should be able to access the electronic reporting system, and data transfer between clinical paper-based and electronic sources should be simplified. Cross-linking between electronic registers for drug-susceptible and DR-TB or consolidation of registers could improve the accuracy of recording. Improved recording and reporting of DR-TB in children is needed.

Outcomes of children treated for tuberculosis with second-line medications in Georgia, 2009–2011

Drug-resistant tuberculosis (DR-TB) is a major public threat in countries of the former Soviet Union, including Georgia. There are few studies of pediatric DR-TB cases, especially at a national level. To report the characteristics and treatment outcomes of pediatric multidrug-resistant TB (MDR-TB) cases in Georgia. We extracted data on all pediatric (age <16 years) MDR-TB cases notified in Georgia from 2009 to 2011. We assessed the baseline and treatment characteristics and treatment outcomes of this cohort. Between 2009 and 2011, there were 45 notified pediatric DR-TB cases in Georgia. Just over half had previously received anti-tuberculosis treatment and the median age was 7.7 years. Time from diagnosis to treatment was short (median 16 days), and the median length of treatment was 20.2 months. Of those not still on treatment, 77.1% (95%CI 61.0-87.9) had a successful outcome. One of the first reports of pediatric DR-TB treatment outcomes at a national level, this study demonstrates that successful outcomes can be achieved.

Consensus Statement on Research Definitions for Drug-Resistant Tuberculosis in Children

Few children with drug-resistant (DR) tuberculosis (TB) are identified, diagnosed, and given an appropriate treatment. The few studies that have described this vulnerable population have used inconsistent definitions. The World Health Organization (WHO) definitions used for adults with DR-TB and for children with drug-susceptible TB are not always appropriate for children with DR-TB. The Sentinel Project on Pediatric Drug-Resistant Tuberculosis was formed in 2011 as a network of experts and stakeholders in childhood DR-TB. An early priority was to establish standardized definitions for key parameters in order to facilitate study comparisons and the development of an evidence base to guide future clinical management. This consensus statement proposes standardized definitions to be used in research. In particular, it suggests consistent terminology, as well as definitions for measures of exposure, drug resistance testing, previous episodes and treatment, certainty of diagnosis, site and severity of disease, adverse events, and treatment outcome.

Caring for Children with Drug-Resistant Tuberculosis

The management of children with drug-resistant tuberculosis (DR-TB) is challenging, and it is likely that in many places, the roll-out of molecular diagnostic testing will lead to more children being diagnosed. There is a limited evidence base to guide optimal treatment and follow-up in the pediatric population; in existing DR-TB guidelines, the care of children is often relegated to small "special populations" sections. This article seeks to address this gap by providing clinicians with practical advice and guidance. This is achieved through review of the available literature on pediatric DR-TB, including research studies and international guidelines, combined with consensus opinion from a team of experts who have extensive experience in the care of children with DR-TB in a wide variety of contexts and with varying resources. The review covers treatment initiation, regimen design and treatment duration, management of comorbid conditions, treatment monitoring, adverse events, adherence promotion, and infection control, all within a multidisciplinary environment.

Pediatric Drug-Resistant Tuberculosis

This article was based on a presentation given at the 26th International Pediatric Association Conference of Pediatrics, Johannesburg, South Africa, 4–9 August 2010. In 2009, there were 9.4 million new cases of tuberculosis (TB) globally, and, of these, approximately 1 million were pediatric cases. Drug-resistant TB makes up a relatively small proportion of new TB cases, but is much more likely in previously treated cases. Pediatric TB remains difficult to diagnose micro-biologically, with the result that detection of drug-resistant TB in children is an ongoing challenge. Since children diagnosed with TB predominantly represent recently acquired TB infection, they provide an important indication of drug-resistant TB prevalence and transmission within their communities. Drug-resistant TB is essentially a man-made problem, which consumes large amounts of healthcare resources. Recent technologic advances may pave the way to more rapid and accurate diagnosis of TB in children. Similarly, these advances are likely to result in improved detection of drug-resistant pediatric TB isolates. The treatment of pediatric drug-resistant TB requires prolonged courses of expensive and potentially toxic drugs, many of which are not available in child-friendly formulations. New anti-TB drugs are at various stages of pre-clinical development and will hopefully allow for shorter, more effective treatment regimens in the not too distant future. HIV-infected children are at extremely high risk for TB acquisition and subsequent progression to symptomatic disease; therefore, many cases of pediatric drug-resistant TB occur in HIV-infected children. This often results in complicated pharmacologic regimens (including anti-TB and antiretroviral drugs) that are difficult to comply with and may have unpredictable interactions. There are limited reports of long-term clinical outcomes of children diagnosed with drug-resistant TB, but improvements in the diagnosis and pharmacologic management of these cases have the potential to improve the quality of care offered to these children.

Drug-resistant Tuberculosis

Drug-resistant Mycobacterium tuberculosis (TB) infection represents a serious and growing problem. For patients infected or suspected of being infected with multidrug or extensively drug-resistant TB, several medications have to be given simultaneously for prolonged periods. Here, we review the literature on treatment and monitoring of adverse effects of pediatric drug-resistant TB therapy in a high resource, low TB burden setting.

Multi-drug Resistant Childhood Tuberculosis

Emergence of drug resistant tuberculosis is one of the major challenges faced by health community globally. Tuberculosis is an important cause of morbidity and mortality among children in endemic areas, yet little is known regarding epidemiology of pediatric tuberculosis and even far lesser information is available about epidemiology, diagnosis, management and treatment outcome of drug resistant tuberculosis in children. Despite limited data and difficulties in its management, drug resistant tuberculosis can be successfully treated even in resource poor settings with proper use of existing technologies. A high index of suspicion and early drug susceptibility testing is the key to early diagnosis and good treatment outcome. Difficulties in establishing the diagnosis, drug toxicities and absence of pediatric formulations add challenges to the management of Pediatric MDR TB Cases. Active research is required to answer the unresolved issues of finding optimal diagnostic tools, treatment regimens and duration and chemoprophylaxis in pediatric drug resistant tuberculosis.