The Challenges of Combining Clinical Work with Research in Bhutan: A Changing Status Quo

Health research is imperative for continuously improving care, this is unquestionable. Knowing that research is costly and time consuming, can a country use the research findings from another country or does every country have to produce their own data? With the amount of studies published every day, it is essential for policy-makers and clinicians to have the knowledge and skills to identify reliable data that translates into evidence-based policies and practice. It is important to acknowledge when the findings identified by previous research can be applicable to another setting or population so that redundant research is avoided. Having said that, local data are needed for multiple purposes. To monitor progress made at a national level based on health indicators, to determine the burden of diseases and identify their characteristics, and to better describe local problems so that tailored solutions can be offered are some examples of why reliable local data are needed. ‘Because local health problems often require local solutions, each country should be a producer as well as a consumer of research’ reminded the WHO in 2013

Characterization of pneumonia among children under five years of age hospitalized in Thimphu, Bhutan

[eng] The general objective of this thesis was to describe the epidemiology, aetiology, clinical presentation, and radiological findings of pneumonia among Bhutanese children to better characterize childhood pneumonia in Bhutan and to contribute to the understanding of this disease in the local context. This thesis also aimed to assess the diagnostic and prognostic performance of host-response biomarkers alone, combined, or in addition to clinical scoring scales to risk-stratify children hospitalized with pneumonia and predict their outcome. The first article acknowledges the need for local research in Bhutan and comments on the specific challenges experienced when trying to conduct it. The second article is a systematic review that summarizes current knowledge around childhood pneumonia in Bhutan and identifies knowledge gaps in this area. The findings of this review were used as the starting point to guide further research and to establish the objectives of the Respiratory Infections in Bhutanese Children (RIBhuC) study. We reported the findings of the RIBhuC study in articles 3 to 6 of this thesis. In brief, the RIBhuC study took place between 1 July 2017 and 30 June 2018. We prospectively enrolled all children between 2 and 59 months admitted to the Jigme Dorji Wangchuck National Referral Hospital (JDWNRH) in Thimphu with WHO-defined clinical pneumonia, provided parents or caregivers consented to study participation. On admission, we performed a comprehensive physical examination, including anthropometric and vital signs measurements. We recorded demographic and clinical data from medical files and through family interviews. We performed an antero-posterior chest radiograph within 24 hours of admission and classified children according to radiological findings following WHO radiological criteria. We collected blood samples upon enrolment or as soon as possible after enrolment for haematology, biochemistry, and bacterial culture, and two drops of blood on filter paper for the identification of Streptococcus pneumoniae by realtime polymerase chain reaction (RT-PCR). In addition, we measured plasma levels of eleven host-response biomarkers, including six markers of immune and endothelial activation: interleukin-6 (IL-6), interleukin-8 (IL-8), soluble triggering receptor expressed on myeloid cells-1 (sTREM-1), soluble tumour necrosis factor receptor 1 (sTNFR1), angiopoietin-2 (Angpt-2), and soluble fms-like tyrosine kinase 1 (sFlt1). Finally, we collected respiratory samples through nasopharyngeal washing for the molecular identification of seventeen respiratory viruses and four atypical bacteria and the detection and capsular typing of Streptococcus pneumoniae. The third article describes the aetiological profile and the demographic and clinical characteristics of this cohort of children admitted with WHO-defined clinical pneumonia. The fourth article reports data on the prevalence of pneumococcal nasopharyngeal carriers and on the pneumococcal serotypes circulating among Bhutanese children with clinical pneumonia before the introduction of the pneumococcal conjugate vaccine in the country. We identified and compared respiratory viruses among children with and without pneumococcal nasopharyngeal colonization to contribute to the understanding of the interplay between pneumococcal nasopharyngeal colonization and viral coinfections. The fifth article describes the radiological findings of the RIBhuC cohort and the differences in radiological outcomes by demographic characteristics, aetiology, clinical features, and host-response biomarker levels. We also evaluated the utility of hostresponse biomarkers in discerning between bacterial and viral pneumonia, taking radiological endpoint pneumonia as a proxy for bacterial aetiology. The sixth and last article of this thesis assessed the performance of a wide range of clinical characteristics, laboratory testing, clinical scoring scales, and host-response biomarkers to risk-stratify children with clinical pneumonia in Bhutan and predict their outcome.[spa] El objetivo principal de esta tesis fue identificar y reducir las lagunas de conocimiento sobre la epidemiologia, la etiologia, la presentacion clinica y los hallazgos radiologicos de la neumonia infantil en Butan para caracterizar esta enfermedad y contribuir a su comprension en el contexto local. Esta tesis tambien tuvo como objetivo evaluar el rol diagnostico y pronostico de ciertos biomarcadores por si solos, combinados o en adicion a escalas de puntuacion clinica para estratificar el riesgo de los ninos hospitalizados con neumonia y predecir su resultado clinico. El primer artículo senala la necesidad de realizar investigacion a nivel local y comenta los desafios especificos encontrados en un pais como Butan para llevarla a cabo. El segundo artículo es una revision sistematica que resume el conocimiento actual sobre la neumonia infantil en Butan y que identifica las lagunas de conocimiento en este campo. Se utilizaron los resultados de esta revision y las carencias de conocimiento para enfocar los objetivos del estudio RIBhuC (del ingles Respiratory Infections in Bhutanese Children). Se detallan los principales hallazgos del estudio RIBhuC en los artículos 3 a 6 de esta tesis. El estudio RIBhuC se llevo a cabo entre el 1 de julio del 2017 y el 30 de junio del 2018 en el Hospital Nacional de Referencia Jigme Dorji Wangchuck, en Thimphu. Se recluto prospectivamente a todos los ninos entre 2 y 59 meses ingresados por neumonia clinica segun los criterios de la OMS, siempre que los padres o cuidadores aceptaran participar en el estudio. Al ingreso, se realizo un examen fisico completo incluyendo mediciones antropometricas y toma de signos vitales. Se recogieron datos demograficos y clinicos mediante entrevistas con los familiares y a partir del expediente medico. Se realizo una radiografia de torax anteroposterior en las primeras 24 horas del ingreso y se 20 clasificaron los ninos segun los criterios radiologicos de la OMS. Se recogieron muestras de sangre en el momento del reclutamiento, o lo antes posible despues del reclutamiento, para analisis de hematologia y bioquimica, cultivo bacteriano, e identificacion de Streptococcus pneumoniae mediante la reaccion en cadena de la polimerasa en tiempo real a partir de dos gotas de sangre recogidas en papel de filtro. Tambien se midieron los niveles plasmaticos de once biomarcadores de respuesta del huesped, incluyendo seis marcadores de activacion endotelial e inmune: la interleucina-6 (IL-6), la interleucina-8 (IL-8), el receptor de activacion soluble expresado en celulas mieloides-1 (sTREM-1), el receptor soluble del factor de necrosis tumoral 1 (sTNFR1), la angiopoyetina-2 (Angpt-2), y la tirosina quinasa-1 soluble similar a fms (sFlt1). Finalmente, se recogieron muestras respiratorias mediante lavado nasofaringeo para la identificacion molecular de 17 virus respiratorios y 4 bacterias atipicas, asi como para la deteccion y tipificacion capsular neumococica. El tercer artículo describe el perfil etiologico y las caracteristicas demograficas y clinicas de esta cohorte de ninos butaneses ingresados con neumonia clinica. El cuarto artículo presenta la prevalencia de portadores nasofaringeos neumococicos y los serotipos neumococicos circulantes entre los ninos butaneses ingresados con neumonia clinica antes de la introduccion de la vacuna antineumococica conjugada en el pais. Comparamos la prevalencia y tipos de virus respiratorios entre ninos con y sin colonizacion nasofaringea neumococica para contribuir a la comprension de la interaccion entre la colonizacion nasofaringea neumococica y las coinfecciones virales. El quinto artículo describe los hallazgos radiologicos y evalua las diferencias en cuanto a caracteristicas demograficas, etiologicas, clinicas y niveles de biomarcadores segun las caracteristicas radiologicas. En este articulo, tambien se evalua la utilidad de biomarcadores para diferenciar entre neumonia bacteriana y viral, considerando el hallazgo de neumonia radiologica (condensacion, derrame pleural o ambos) como indicador de neumonia bacteriana. El sexto y último artículo de esta tesis evalua el rendimiento de caracteristicas clinicas, pruebas de laboratorio, escalas de puntuacion clinica y biomarcadores para estratificar el riesgo pronostico de los ninos con neumonia clinica en el momento del ingreso y predecir su resultado clinico

The impact of mass deworming programmes on schooling and economic development: an appraisal of long-term studies

Background Documents from advocacy and fund-raising organizations for child mass deworming programmes in low and middle-income countries cite unpublished economic studies claiming long-term effects on health, schooling and economic development. Methods To summarise and appraise these studies, we searched for and included all long-term follow-up studies, based on cluster-randomized trials included in a 2015 Cochrane review on deworming. We used Cochrane methods to assess risk of bias, and appraised the credibility of the main findings. Where necessary we contacted study authors for clarifications. Results We identified three studies (Baird 2016, Ozier 2016, and Croke 2014), evaluating effects more than nine years after cluster-randomized trials in Kenya and Uganda. Baird and Croke evaluate short additional exposures to deworming programmes in settings where all children were dewormed multiple times. Ozier evaluates potential spin-off effects to infants living in areas with school-based deworming. None of the studies used pre-planned protocols, or blinded the analysis to treatment allocation. Baird 2016 has been presented on-line in six iterations. It is at high risk of reporting bias and selective reporting, and there are substantive changes between versions. The main cited effects on secondary school attendance and job sector allocation are from post-hoc sub-group analyses, which the study was not powered to assess. The study finds no evidence of effect on nutritional status, cognitive tests, or school grades achieved, but these are not reported in the abstracts. Ozier 2016 has been presented on-line in four iterations, without substantive differences between versions. Higher cognitive test scores were associated with deworming but were only beyond the play of chance with inclusion of the non-randomised data. The size of the stated effect seems inconsistent with the short and indirect nature of the exposure to deworming, and a causal pathway for this effect is unclear. Croke 2014 utilizes a data set unrelated to the base trial to report improvements in English and maths test scores. The analysis is at high risk of attrition bias, due to loss of clusters, and is substantially underpowered to assess these effects. Conclusion In the context of reliable epidemiological methods, all three studies are at risk of substantial methodological bias. They therefore help in generating hypothesis, but should not be considered reliable evidence of effects

Rapid diagnostic tests for plague

Background Plague is a severe disease associated with high mortality. Late diagnosis leads to advance stage of the disease with worse outcomes and higher risk of spread of the disease. A rapid diagnostic test (RDT) could help in establishing a prompt diagnosis of plague. This would improve patient care and help appropriate public health response. Objectives To determine the diagnostic accuracy of the RDT based on the antigen F1 (F1RDT) for detecting plague in people with suspected disease. Search methods We searched the CENTRAL, Embase, Science Citation Index, Google Scholar, the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov up to 15 May 2019, and PubMed (MEDLINE) up to 27 August 2019, regardless of language, publication status, or publication date. We handsearched the reference lists of relevant papers and contacted researchers working in the field. Selection criteria We included cross‐sectional studies that assessed the accuracy of the F1RDT for diagnosing plague, where participants were tested with both the F1RDT and at least one reference standard. The reference standards were bacterial isolation by culture, polymerase chain reaction (PCR), and paired serology (this is a four‐fold difference in F1 antibody titres between two samples from acute and convalescent phases). Data collection and analysis Two review authors independently selected studies and extracted data. We appraised the methodological quality of each selected studies and applicability by using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS‐2) tool. When meta‐analysis was appropriate, we used the bivariate model to obtain pooled estimates of sensitivity and specificity. We stratified all analyses by the reference standard used and presented disaggregated data for forms of plague. We assessed the certainty of the evidence using GRADE. Main results We included eight manuscripts reporting seven studies. Studies were conducted in three countries in Africa among adults and children with any form of plague. All studies except one assessed the F1RDT produced at the Institut Pasteur of Madagascar (F1RDT‐IPM) and one study assessed a F1RDT produced by New Horizons (F1RDT‐NH), utilized by the US Centers for Disease Control and Prevention. We could not pool the findings from the F1RDT‐NH in meta‐analyses due to a lack of raw data and a threshold of the test for positivity different from the F1RDT‐IPM. Risk of bias was high for participant selection (retrospective studies, recruitment of participants not consecutive or random, unclear exclusion criteria), low or unclear for index test (blinding of F1RDT interpretation unknown), low for reference standards, and high or unclear for flow and timing (time of sample transportation was longer than seven days, which can lead to decreased viability of the pathogen and overgrowth of contaminating bacteria, with subsequent false‐negative results and misclassification of the target condition). F1RDT for diagnosing all forms of plague F1RDT‐IPM pooled sensitivity against culture was 100% (95% confidence interval (CI) 82 to 100; 4 studies, 1692 participants; very low certainty evidence) and pooled specificity was 70.3% (95% CI 65 to 75; 4 studies, 2004 participants; very low‐certainty evidence). The performance of F1RDT‐IPM against PCR was calculated from a single study in participants with bubonic plague (see below). There were limited data on the performance of F1RDT against paired serology. F1RDT for diagnosing pneumonic plague Performed in sputum, F1RDT‐IPM pooled sensitivity against culture was 100% (95% CI 0 to 100; 2 studies, 56 participants; very low‐certainty evidence) and pooled specificity was 71% (95% CI 59 to 80; 2 studies, 297 participants; very low‐certainty evidence). There were limited data on the performance of F1RDT against PCR or against paired serology for diagnosing pneumonic plague. F1RDT for diagnosing bubonic plague Performed in bubo aspirate, F1RDT‐IPM pooled sensitivity against culture was 100% (95% CI not calculable; 2 studies, 1454 participants; low‐certainty evidence) and pooled specificity was 67% (95% CI 65 to 70; 2 studies, 1198 participants; very low‐certainty evidence). Performed in bubo aspirate, F1RDT‐IPM pooled sensitivity against PCR for the caf1 gene was 95% (95% CI 89 to 99; 1 study, 88 participants; very low‐certainty evidence) and pooled specificity was 93% (95% CI 84 to 98; 1 study, 61 participants; very low‐certainty evidence). There were no data providing data on both F1RDT and paired serology for diagnosing bubonic plague. Authors' conclusions Against culture, the F1RDT appeared highly sensitive for diagnosing either pneumonic or bubonic plague, and can help detect plague in remote areas to assure management and enable a public health response. False positive results mean culture or PCR confirmation may be needed. F1RDT does not replace culture, which provides additional information on resistance to antibiotics and bacterial strains

Pneumonia in Bhutanese children: what we know, and what we need to know.

Background Pneumonia is the single largest cause of death in under-five children worldwide. We conducted a systematic review to identify the knowledge gaps around childhood pneumonia in Bhutan. Methods We searched PubMed, ScienceDirect and Google scholar from conception to 3rd December 2018, World Health Organization, UNICEF, Bhutan’s Ministry of Health and other local databases for relevant reports. We included any report describing pneumonia in Bhutanese children with regards to the burden of the disease, aetiology, related risk factors, clinical and prognostic characteristics, surveillance systems and national preventive strategies. Two review authors identified the records. We summarized the findings narratively. Results We included 44 records. Although with notable decreasing trends, pneumonia is still accountable for a high burden and mortality rate in Bhutanese children. The national surveillance system focuses mainly on influenza identification but has recently introduced other viral aetiology to monitor. We found very scarce or no data with regard to the bacterial aetiology, related risk factors and clinico-radiological and prognostic characteristics. Conclusion There is a dearth of data regarding the epidemiological, microbiological, clinical and radiological characteristics of pneumonia in children in Bhutan, leading to challenges while implementing evidence-based management and effective national preventive strategies

Six months therapy for tuberculous meningitis.

BACKGROUND Tuberculous meningitis (TBM) is the main form of tuberculosis that affects the central nervous system and is associated with high rates of death and disability. Most international guidelines recommend longer antituberculous treatment (ATT) regimens for TBM than for pulmonary tuberculosis disease to prevent relapse. However, longer regimens are associated with poor adherence, which could contribute to increased relapse, development of drug resistance, and increased costs to patients and healthcare systems. OBJECTIVES To compare the effects of short-course (six months) regimens versus prolonged-course regimens for people with tuberculous meningitis (TBM). SEARCH METHODS We searched the following databases up to 31 March 2016: the Cochrane Infectious Diseases Group Specialized Register; the Cochrane Central Register of Controlled Trials (CENTRAL), published in the Cochrane Library; MEDLINE; EMBASE; LILACS; INDMED; and the South Asian Database of Controlled Clinical Trials. We searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov for ongoing trials. We also checked article reference lists and contacted researchers in the field. SELECTION CRITERIA We included randomized controlled trials (RCTs) and prospective cohort studies of adults and children with TBM treated with antituberculous regimens that included rifampicin for six months or longer than six months. The primary outcome was relapse, and included studies required a minimum of six months follow-up after completion of treatment. DATA COLLECTION AND ANALYSIS Two review authors (SJ and HR) independently assessed the literature search results for eligibility, and performed data extraction and 'Risk of bias' assessments of the included studies. We contacted study authors for additional information when necessary. Most data came from single arm cohort studies without a direct comparison so we pooled the findings for each group of cohorts and presented them separately using a complete-case analysis. We assessed the quality of the evidence narratively, as using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was inappropriate with no direct comparisons between short- and prolonged-course regimens. MAIN RESULTS Four RCTs and 12 prospective cohort studies met our inclusion criteria, and included a total of 1881 participants with TBM. None of the included RCTs directly compared six months versus longer regimens, so we analysed all data as individual cohorts to obtain relapse rates in each set of cohorts.We included seven cohorts of participants treated for six months, with a total of 458 participants. Three studies were conducted in Thailand, two in South Africa, and one each in Ecuador and Papua New Guinea between the 1980s and 2009. We included 12 cohorts of participants treated for longer than six months (ranging from eight to 16 months), with a total of 1423 participants. Four studies were conducted in India, three in Thailand and one each in China, South Africa, Romania, Turkey and Vietnam, between the late 1970s and 2011.The proportion of participants classified as having stage III disease (severe) was higher in the cohorts treated for six months (33.2% versus 16.9%), but the proportion with known concurrent HIV was higher in the cohorts treated for longer (0/458 versus 122/1423). Although there were variations in the treatment regimens, most cohorts received isoniazid, rifampicin, and pyrazinamide during the intensive phase.Investigators achieved follow-up beyond 18 months after completing treatment in three out of the seven cohorts treated for six months, and five out of the 12 cohorts treated for eight to 16 months. All studies had potential sources of bias in their estimation of the relapse rate, and comparisons between the cohorts could be confounded.Relapse was an uncommon event across both groups of cohorts (3/369 (0.8%) with six months treatment versus 7/915 (0.8%) with longer), with only one death attributed to relapse in each group.Overall, the proportion of participants who died was higher in the cohorts treated for longer than six months (447/1423 (31.4%) versus 58/458 (12.7%)). However, most deaths occurred during the first six months in both treatment cohorts, which suggested that the difference in death rate was not directly related to duration of ATT but was due to confounding. Clinical cure was higher in the group of cohorts treated for six months (408/458 (89.1%) versus longer than six months (984/1336 (73.7%)), consistent with the observations for deaths.Few participants defaulted from treatment with six months treatment (4/370 (1.1%)) versus longer treatment (8/355 (2.3%)), and adherence was not well reported. AUTHORS' CONCLUSIONS In all cohorts most deaths occurred in the first six months; and relapse was uncommon in all participants irrespective of the regimen. Further inferences are probably inappropriate given this is observational data and confounding is likely. These data are almost all from participants who are HIV-negative, and thus the inferences will not apply to the efficacy and safety of the six months regimens in HIV-positive people. Well-designed RCTs, or large prospective cohort studies, comparing six months with longer treatment regimens with long follow-up periods established at initiation of ATT are needed to resolve the uncertainty regarding the safety and efficacy of six months regimens for TBM

WHO guidelines for plague management: revised recommendations for the use of rapid diagnostic tests, fluoroquinolones for case management and personal protective equipment for prevention of post-mortem transmission.

Plague has killed millions of people during the past 25 centuries (1), and the disease reappeared in several countries during the 1990s. Consequently, plague was categorized as a re-emerging disease (2). Human plague outbreaks continue to be reported, including an outbreak of pneumonic plague in Madagascar in 2017 (2–4). Plague is an acute bacterial infection caused by Yersinia pestis. Although effective antimicrobials are available, plague still has high mortality because most outbreaks take place in remote places, where proper diagnosis and treatment remain challenging (2). Early identification of the disease is crucial to ensure prompt treatment and better outcomes. Pneumonic plague is highly contagious and of particular concern because of the high risk of triggering epidemics. Thus, plague is both a medical and a public health emergency. These guidelines were developed in accordance with the WHO handbook for guideline development (5). A WHO Steering Group, led by the responsible technical officer, developed the draft scope of the guidelines and the key questions to be addressed. The Steering Group selected the members of the Guideline Development Group (GDG) to ensure diverse areas of expertise were represented, including clinicians, microbiologists, public health professionals, researchers and an anthropologist. The Steering Group also commissioned technical advisers to lead the Evidence Review Team and provide methodological support

Plague Transmission from Corpses and Carcasses

Knowing whether human corpses can transmit plague will inform policies for handling the bodies of those who have died of the disease. We analyzed the literature to evaluate risk for transmission of Yersinia pestis, the causative agent of plague, from human corpses and animal carcasses. Because we could not find direct evidence of transmission, we described a transmission pathway and assessed the potential for transmission at each step. We examined 3 potential sources of infection: body fluids of living plague patients, infected corpses and carcasses, and body fluids of infected corpses. We concluded that pneumonic plague can be transmitted by intensive handling of the corpse or carcass, presumably through the inhalation of respiratory droplets, and that bubonic plague can be transmitted by blood-to-blood contact with the body fluids of a corpse or carcass. These findings should inform precautions taken by those handling the bodies of persons or animals that died of plague