Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Diagnostic accuracy of multiplex respiratory pathogen panels for influenza or respiratory syncytial virus infections: systematic review and meta-analysis.

Respiratory syncytial virus (RSV) and influenza viruses are important global causes of morbidity and mortality. We evaluated the diagnostic accuracy of the Luminex NxTAG respiratory pathogen panels (RPPs)™ (index) against other RPPs (comparator) for detection of RSV and influenza viruses. Studies comparing human clinical respiratory samples tested with the index and at least one comparator test were included. A random-effect latent class meta-analysis was performed to assess the specificity and sensitivity of the index test for RSV and influenza. Risk of bias was assessed using the QUADAS-2 tool and certainty of evidence using GRADE. Ten studies were included. For RSV, predicted sensitivity was 99% (95% credible interval [CrI] 96-100%) and specificity 100% (95% CrI 98-100%). For influenza A and B, predicted sensitivity was 97% (95% CrI 89-100) and 98% (95% CrI 88-100) respectively; specificity 100% (95% CrI 99-100) and 100% (95% CrI 99-100), respectively. Evidence was low certainty. Although index sensitivity and specificity were excellent, comparators' performance varied. Further research with clear patient recruitment strategies could ascertain performance across different populations.Protocol Registration: Prospero CRD42021272062.

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.

Prevention of unintentional injuries in children under five years.

We looked at existing recommendations for preventing unintentional injuries in children under five years of age, and we attempted to identify the main sources used as evidence for formulating these recommendations.We conducted a literature search up to the 18th October 2019 by using key terms and manual search in selected sources. We summarized the recommendations and source of the evidence in tables for each of five areas of unintentional injuries: road traffic injuries, drowning, poisoning, thermal injuries, falls.In 2008, the World Health Organization (WHO) published a comprehensive report with strategies for child injury prevention for the European region. More recently, the WHO published several guidance documents focused on one area such as drowning, usually with a global focus. The PrevInfad workgroup (Spanish Association of Primary Care Pediatrics) updated their document on road safety in April 2019, providing recommendations and a summary of the existing evidence. Preventive strategies for injuries in childhood are mainly based on surveillance data and the identification of risk factors. The key strategies for preventing unintentional injuries are a combination of environmental and behaviour modification, that can be achieved through engineering, enforcement and education. Consequently, for this kind of strategies, it is important to evaluate the effectiveness of both the intervention itself, and the way the intervention is advised to parents and caretakers so that there is good compliance of the recommendation.

Newborn pulse oximetry screening for critical congenital heart defects.

We looked at existing recommendations and supporting evidence addressing the effectiveness of pulse oximetry effective for detecting critical congenital heart defects (CCHDs) in newborns. We also looked at the impact of timing of oximetry and the site of testing in the accuracy of screening, and at the potential harms and limitations of pulse oximetry screening,We conducted a literature search up to the 13th of August 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.Current evidence supports consistent accuracy for detection of CCHDs in newborns by pulse oximetry screening in addition to antenatal ultrasonography and clinical examination. Overall, early diagnosis of CCHD with pulse oximetry is judged to be beneficial and cost-effective, and potential harms associated with false-positive tests are not serious, while missing CCHDs and other serious diseases detected by hypoxaemia in absence of pulse oximetry screening can lead to serious consequences. The site of testing (post-ductal versus pre- and post-ductal) had no significant effect on sensitivity nor specificity for detection of CCHDs.

Vision screening in newborns and early childhood.

We looked at existing recommendations and supporting evidence on the effectiveness of screening for visual disorders in newborns and small infants, and in children between six months and five years of age.We conducted a literature search up to the 5th of August 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendations when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported on the accuracy of screening tests for detecting visual alterations; the efficacy of treatment for improving visual acuity, school performance, and quality of life; and potential harms derived from vision screening and treating visual alterations.Although there is little evidence supporting its validity and effectiveness, examining all newborns for congenital cataract and retinoblastoma through the red reflex examination is widely accepted due to the severity of both diseases and the good outcomes reached by early detection and treatment.Overall, there is a moderate certainty of evidence that visual screening in children between three and five years provides a moderate net benefit, as assessed by the US Preventive Services Task Force: vision screening tests are accurate for detecting amblyopia and its risk factors, and their treatment is associated with visual improvement. There is uncertain evidence on whether vision screening in children under three years of age provides net benefits. Among populations with a low prevalence of vision abnormalities, screening the youngest is associated with an increased rate of false positives, leading to unnecessary additional assessment.

Sudden infant death syndrome prevention.

We looked at existing recommendations and supporting evidence for successful strategies to prevent the sudden infant death syndrome (SIDS).We conducted a literature search up to the 14th of December 2020 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.Current evidence supports statistical associations between risk factors and SIDS, but there is globally limited evidence by controlled studies assessing the effect of the social promotion strategies to prevent SIDS through knowledge, attitude and practices, due to obvious ethical reasons. A dramatic decline in SIDS incidence has been observed in many countries after the introduction of "Back to Sleep" campaigns for prevention of SIDS. All infants should be placed to sleep in a safe environment including supine position, a firm surface, no soft objects and loose bedding, no head covering, no overheating, and room-sharing without bed-sharing. Breastfeeding on demand and the use of pacifier during sleep time protect against SIDS and should be recommended. Parents should be advised against the use of tobacco, alcohol and illicit drugs during gestation and after birth.

Vitamin K prophylaxis in newborns.

We looked at existing recommendations and supporting evidence on the effectiveness of vitamin K given after birth in preventing the haemorrhagic disease of the newborn (HDN).We conducted a literature search up to the 10th of December 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.All newborns should receive vitamin K prophylaxis, as it has been proven that oral and intramuscular prophylactic vitamin K given after birth are effective for preventing classical HDN. There are no randomized trials looking at the efficacy of vitamin K supplement on late HDN. There are no randomized trials comparing the oral and intramuscular route of administration of prophylactic vitamin K in newborns. From older trials and surveillance data, it seems that there is no significant difference between the intramuscular and the oral regimens for preventing classical and late HDN, provided that the oral regimen is duly completed. Evidence assessing vitamin K prophylaxis in preterm infants is scarce.

Screening of iron deficiency anaemia in early childhood.

We looked at existing recommendations and supporting evidence on the effectiveness of universal screening of iron deficiency anaemia (IDA) in children under five years of age for improving growth, cognitive function, and psychomotor development. We assessed the accuracy of the screening tests for detecting IDA, the efficacy of existing treatment for children with IDA, and the potential harms associated with screening and treatment.We conducted a literature search up to the 18th of August 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.There is no suitable test for IDA screening that is non-invasive with high accuracy for detecting IDA and there is uncertainty whether IDA in children causes cognitive and psychomotor delays. There is a lack of evidence on the effects of routine screening for IDA in asymptomatic children under five years of age on growth, cognitive and psychomotor development outcomes.Universal screening of IDA in children under five years of age is not recommended by most organisations such as the Spanish Association of Primary Care Paediatrics, the United Kingdom National Screening Committee, and the United States Preventive Services Task Force, but is recommended by the American Academy of Paediatrics. However, selective screening of IDA is recommended in infants and children with risk factors including prematurity, low birth weight, and dietary risk factors.

Screening for autistic spectrum disorder in early childhood.

We looked at existing recommendations and supporting evidence on the effectiveness of screening young children for autistic spectrum disorder (ASD) for improving short- and long-term outcomes.We conducted a literature search up to the 8th of November 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.There are discrepancies among the recommendations given by different institutions on universal screening for ASD in children. Some recommend that all children should be screened with an ASD-specific instrument during well-child visits at ages 18 and 24 months in conjunction with ongoing developmental surveillance and broadband developmental screening; some conclude that the current evidence is insufficient to assess the balance of benefits and harms of screening for ASD in young children for whom no concerns of ASD have been raised by their parents or a clinician; and others recommend against universal screening, but for a screening among children with high risks.There is adequate evidence that ASD screening tools applied to children between 12 and 36 months accurately identify those with ASD. There is some evidence showing benefit of early interventions applied to children with ASD, from children identified with developmental concern by their family, teacher or clinicians. We found no evidence on the effectiveness of interventions applied to children with ASD detected through screening.

Vitamin D prophylaxis in infancy.

We looked at existing recommendations and supporting evidence on the effectiveness of vitamin D supplementation in infancy for reducing vitamin D deficiency and for preventing rickets and infections. We also looked at optimal dose of vitamin D and the age until which vitamin D supplementation is beneficial.We conducted a literature search up to the 17th of July 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.A daily dose of 400 international units of vitamin D in infants has shown to be effective for improving bone health and preventing rickets. Evidence is more robust in groups of infants and children at risk. Vitamin D supplementation is well tolerated, and not associated with toxicity. Higher doses have not shown to add benefit while it could potentially cause toxic blood levels and hypercalcemia. Adequate levels of vitamin D might not be achieved with lower daily doses. Universal vitamin D supplementation starting shortly after birth, regardless of the mode of feeding and until 12 months of age, is strongly recommended. Beyond 12 months of age vitamin D supplementation is recommended only in groups of children at risk.

Screening for language and speech delay in children under five years.

We looked at existing recommendations and supporting evidence on the effectiveness of universal screening for language and speech delay in children under 5 years of age for short- and long-term outcomes.We conducted a literature search up to the 20th of November 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported on the accuracy of the screening tests for detecting language and speech delay, the efficacy of existing interventions for children with language and speech delay, and the potential harms associated with screening and the associated interventions.Several screening tools are used to assess language and speech delay with a wide variation in their accuracy. Targeted interventions improve some measures of speech and language delay and disorders. However, there is no evidence on the effectiveness of such interventions in children detected by screening with no specific concerns about their speech or language before screening. There is no evidence assessing whether universal screening for language and speech delay in a primary care setting improves short and long-term outcomes (including speech and language outcomes and other outcomes). Finally, there is no evidence on the harms of screening for language and speech delay in primary care settings, and there is limited evidence assessing the potential harms of interventions.

Prophylaxis of caries with fluoride for children under five years.

We looked at existing recommendations and supporting evidence on the effectiveness and potential harms of the different fluoride interventions in preventing dental caries in children under 5 years of age.We conducted a literature search up to the 12th of September 2019 by using key terms and manual search in selected sources. We summarized the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported.Water fluoridation has been widely implemented worldwide for several decades and evidence shows it reduces the prevalence of dental caries. Salt or milk fluoridation are other collective fluoride interventions that are also effective to prevent dental caries in children. The evidence of effects of oral fluoride supplements for caries prevention is limited and inconsistent. The use of fluoride toothpastes has consistently been proven to be effective in the prevention of dental caries. The evidence for the effects of the different levels of fluoride concentration in toothpastes is more limited. Topical fluorides (gels and varnishes) are effective in preventing dental caries and are mainly recommended to children with high risk of dental caries. Early childhood intake of fluoride supplements and fluoride level of 0.7 ppm (ppm) in drinking water are associated with the risk of dental fluorosis, ranging from minor forms to severe forms that are of aesthetic concerns.

Supporting recommendations for childhood preventive interventions for primary health care: elaboration of evidence synthesis and lessons learnt.

BACKGROUND: Recommendations to prevent morbidity and mortality in children was a high priority for the editorial group of a WHO pocket book for primary health care in the European region. However, the benefit of preventive interventions is not always clear and recommendations differ across countries and institutions. Here, we summarize the existing recommendations and the most recent evidence on ten selected preventive interventions applied to children under five years to inform this group. In addition, we reflect on the process and challenges of developing these summaries. METHODS: For each intervention, we systematically searched for current recommendations from the WHO, the United States Preventive Services Task Force, the workgroup PrevInfad from the Spanish Association of Primary Care Pediatrics, the Centers of Disease Control and Prevention, and the National Institute for Health and Care Excellence. Then, we systematically searched the sources above and the Cochrane library for relevant systematic reviews. For each topic, we reported the recommendations and the strength of the recommendation when and as reported by the authors. We summarized the main findings of systematic reviews with the certainty of the evidence as reported. Categorising the ten preventive interventions in three groups allowed narrative comparisons between similar types of interventions and between groups. RESULTS AND DISCUSSION: For the single interventions of providing vitamins D and K and topical fluoride there is overall a high degree of consensus between institutions for the evidence of their effectiveness. For the multiple interventions to prevent sudden infant death syndrome and unintentional injuries consensus was more variable as evidence of effectiveness is harder to ascertain. For the screening interventions the summaries of recommendations and evidence varied too. While institutions generally agreed in recommending for vision screening and against universal screening for language and speech delay and iron deficiency, they had some differences for pulse oximetry and autism. The transparent and independent process shed light upon how institutions use existing evidence in their settings - common and different positions were accounted for and became visible. We also identified gaps and duplications of research. Our approach was a crucial starting point for developing the respective sections in the pocket book.

Pneumococcal nasopharyngeal carriage among Bhutanese children hospitalized with clinical pneumonia: serotypes and viral co-infection.

BACKGROUND: Pneumococcal nasopharyngeal colonization (PNC) generally precedes pneumococcal disease. The purpose of this study was to determine the prevalence of PNC and to identify the pneumococcal serotypes circulating among Bhutanese children under five years of age admitted with clinical pneumonia, before the introduction of pneumococcal conjugate vaccine (PCV13) in the country. We also aimed to contribute to the understanding of the interplay between PNC and viral co-infection among this population. METHODS: This was a prospective study conducted at the Jigme Dorji Wangchuck National Referral Hospital in Bhutan over 12 consecutive months. Children aged 2 to 59 months admitted with WHO-defined clinical pneumonia were eligible for recruitment. We collected blood for bacterial culture and molecular identification of S. pneumoniae, and nasopharyngeal washing for screening of respiratory viruses, and for the detection and capsular typing of S. pneumoniae by real-time polymerase chain reaction (RT-PCR). RESULTS: Overall, 189 children were recruited, and PNC was tested in 121 of them (64.0%). PNC was found in 76/121 children (62.8%) and S. pneumoniae was identified in blood (both by culture and RT-PCR) in a single child. Respiratory viruses were detected in a similar proportion among children with (62/70; 88.6%) and without PNC (36/40; 90.0%; p = 1.000), but rhinovirus detection was less common among children with PNC (20/70; 28.6% versus 19/40; 47.5%; p = 0.046). Capsular typing identified 30 different serotypes. Thirty-nine children (51.3%) were colonised with two to five different serotypes. A third of the children presented with serotypes considered highly invasive. Over half of the children (44/76; 57.9%) were carrying at least one serotype included in PCV13. CONCLUSIONS: This study provides baseline information on the status of PNC among Bhutanese children admitted with clinical pneumonia prior to the introduction of PCV13, which is valuable to monitor its potential impact. PCV13 could theoretically have averted up to 58% of the pneumococcal infections among the children in this study, suggesting a future role for the vaccine to significantly reduce the burden associated with S. pneumoniae in Bhutan.

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.

MVA85A vaccine to enhance BCG for preventing tuberculosis.

BACKGROUND: Tuberculosis causes more deaths than any other infectious disease globally. Bacillus Calmette-Guérin (BCG) is the only available vaccine, but protection is incomplete and variable. The modified Vaccinia Ankara virus expressing antigen 85A (MVA85A) is a viral vector vaccine produced to prevent tuberculosis. OBJECTIVES: To assess and summarize the effects of the MVA85A vaccine boosting BCG in humans. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register; Central Register of Controlled Trials (CENTRAL); MEDLINE (PubMed); Embase (Ovid); and four other databases. We searched the WHO ICTRP and ClinicalTrials.gov. All searches were run up to 10 May 2018. SELECTION CRITERIA: We evaluated randomized controlled trials of MVA85A vaccine given with BCG in people regardless of age or HIV status. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the eligibility and risk of bias of trials, and extracted and analyzed data. The primary outcome was active tuberculosis disease. We summarized dichotomous outcomes using risk ratios (RR) and risk differences (RD), with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses. Where meta-analysis was inappropriate, we summarized results narratively. MAIN RESULTS: The search identified six studies relating to four Phase 2 randomized controlled trials enrolling 3838 participants. Funding was by government bodies, charities, and philanthropic donors. Five studies included infants, one of them infants born to HIV-positive mothers. One study included adults living with HIV. All trials included authors from Oxford University who led the laboratory development of the vaccine. Participants received intradermal MVA85A after BCG in some studies, and before selective deferred BCG in HIV-exposed infants.The largest trial in 2797 African children was well conducted with low risk of bias for most parameters. Risk of bias was uncertain for selective reporting because there were no precise case definition endpoints for active tuberculosis published prior to the trial analysis.MVA85A added to BCG compared to BCG alone probably has no effect on the risk of developing microbiologically confirmed tuberculosis (RR 0.97, 95% CI 0.58 to 1.62; 3439 participants, 2 trials; moderate-certainty evidence), or the risk of starting on tuberculosis treatment (RR 1.10, 95% CI 0.92 to 1.33; 3687 participants, 3 trials; moderate-certainty evidence). MVA85A probably has no effect on the risk of developing latent tuberculosis (RR 1.01, 95% CI 0.85 to 1.21; 3831 participants, 4 trials; moderate-certainty evidence). Vaccinating people with MVA85A in addition to BCG did not cause life-threatening serious adverse effects (RD 0.00, 95% CI -0.00 to 0.00; 3692 participants, 3 trials; high-certainty evidence). Vaccination with MVA85A is probably associated with an increased risk of local skin adverse effects (3187 participants, 3 trials; moderate-certainty evidence), but not systemic adverse effect related to vaccination (144 participants, 1 trial; low-certainty evidence). This safety profile is consistent with Phase 1 studies which outlined a transient, superficial reaction local to the injection site and mild short-lived symptoms such as malaise and fever. AUTHORS' CONCLUSIONS: MVA85A delivered by intradermal injection in addition to BCG is safe but not effective in reducing the risk of developing tuberculosis.

Congenital Multidrug-resistant Tuberculosis in a Neonate: A Case Report.

Multidrug-resistant tuberculosis (MDR-TB) is a well-identified raising public health concern worldwide. However, the data available on MDR-TB in children and particularly in the neonate age group are limited. Congenital tuberculosis (TB) is rare, and its diagnosis is challenging because of non-specific manifestations. The choice of anti-tubercular drugs is difficult because of the lack of international consensus as a consequence of the scarcity of evidence-based data on this age group. We hereby present a case from Bhutan of a 23-day-old male neonate with congenital MDR-TB. His mother was diagnosed with disseminated TB, and treatment was commenced 11 days post-partum. Congenital transmission of TB was suspected, as direct postnatal transmission was unlikely and thorough screening of contacts for TB was negative. In this case, the mother's MDR-TB status was revealed only after her newborn's MDR-TB diagnosis.

Six-month therapy for abdominal tuberculosis.

BACKGROUND: Tuberculosis (TB) of the gastrointestinal tract and any other organ within the abdominal cavity is abdominal TB, and most guidelines recommend the same six-month regimen used for pulmonary TB for people with this diagnosis. However, some physicians are concerned whether a six-month treatment regimen is long enough to prevent relapse of the disease, particularly in people with gastrointestinal TB, which may sometimes cause antituberculous drugs to be poorly absorbed. On the other hand, longer regimens are associated with poor adherence, which could increase relapse, contribute to drug resistance developing, and increase costs to patients and health providers. OBJECTIVES: To compare six-month versus longer drug regimens to treat people that have abdominal TB. SEARCH METHODS: We searched the following electronic databases up to 2 September 2016: the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase (accessed via OvidSP), LILACS, INDMED, and the South Asian Database of Controlled Clinical Trials. We searched the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) and ClinicalTrials.gov for ongoing trials. We also checked article reference lists. SELECTION CRITERIA: We included randomized controlled trials (RCTs) that compared six-month regimens versus longer regimens that consisted of isoniazid, rifampicin, pyrazinamide, and ethambutol to treat adults and children that had abdominal TB. The primary outcomes were relapse, with a minimum of six-month follow-up after completion of antituberculous treatment (ATT), and clinical cure at the end of ATT. DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials, extracted data, and assessed the risk of bias in the included trials. For analysis of dichotomous outcomes, we used risk ratios (RR) with 95% confidence intervals (CIs). Where appropriate, we pooled data from the included trials in meta-analyses. We assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: We included three RCTs, with 328 participants, that compared six-month regimens with nine-month regimens to treat adults with intestinal and peritoneal TB. All trials were conducted in Asia, and excluded people with HIV, those with co-morbidities and those who had received ATT in the previous five years. Antituberculous regimens were based on isoniazid, rifampicin, pyrazinamide, and ethambutol, and these drugs were administered daily or thrice weekly under a directly observed therapy programme. The median duration of follow-up after completion of treatment was between 12 and 39 months.Relapse was uncommon, with two cases among 140 participants treated for six months, and no events among 129 participants treated for nine months. The small number of participants means we do not know whether or not there is a difference in risk of relapse between the two regimens (very low quality evidence). At the end of therapy, there was probably no difference in the proportion of participants that achieved clinical cure between six-month and nine-month regimens (RR 1.02, 95% CI 0.97 to 1.08; 294 participants, 3 trials, moderate quality evidence). For death, there were 2/150 (1.3%) in the six-month group and 4/144 (2.8%) in the nine-month group. All deaths occurred in the first four months of treatment, so was not linked to the duration of treatment in the included trials. Similarly, the number of participants that defaulted from treatment was small in both groups, and there may be no difference between them (RR 0.50, 95% CI 0.10 to 2.59; 294 participants, 3 trials, low quality evidence). Only one trial reported on adherence to treatment, with only one participant allocated to the nine-month regimen presenting poor adherence to treatment. We do not know whether six-month regimens are associated with fewer people experiencing adverse events that lead to treatment interruption (RR 0.53, 95% CI 0.18 to 1.55; 318 participants, 3 trials, very low quality evidence). AUTHORS' CONCLUSIONS: We found no evidence to suggest that six-month treatment regimens are inadequate for treating people that have intestinal and peritoneal TB, but numbers are small. We did not find any incremental benefits of nine-month regimens regarding relapse at the end of follow-up, or clinical cure at the end of therapy, but our confidence in the relapse estimate is very low because of size of the trials. Further research is required to make confident conclusions regarding the safety of six-month treatment for people with abdominal TB. Larger studies that include HIV-positive people, with long follow-up for detecting relapse with reliability, would help improve our knowledge around this therapeutic question.

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.