Jay Achar

Prognostic Indicators for Ebola Patient Survival

Odds of survival were greatest when first Ebola virus–positive blood sample collected had low viral load.

Ebola viral disease and pregnancy

Ebola viral disease’s interaction with pregnancy is poorly understood and remains a particular challenge for medical and para-medical personnel responding to an outbreak. This review article is written with the benefit of hindsight and experience from the largest recorded Ebola outbreak in history. We have provided a broad overview of the issues that arise for pregnant women and for the professionals treating them during an Ebola outbreak. The discussion focuses on the specifics of Ebola infection in pregnancy and possible management strategies, including the delivery of an infected woman. We have also discussed the wider challenges posed to pregnant women and their carers during an epidemic, including the identification of suspected Ebola-infected pregnant women and the impact of the disease on pre-existing health services. This paper outlines current practices in the field, as well as highlighting the gaps in our knowledge and the paramount need to protect the health-care workers directly involved in the management of pregnant women.

New and Repurposed Drugs for Pediatric Multidrug-Resistant Tuberculosis. Practice-based Recommendations

&NA; It is estimated that 33,000 children develop multidrug‐resistant tuberculosis (MDR‐TB) each year. In spite of these numbers, children and adolescents have limited access to the new and repurposed MDR‐TB drugs. There is also little clinical guidance for the use of these drugs and for the shorter MDR‐TB regimen in the pediatric population. This is despite the fact that these drugs and regimens are associated with improved interim outcomes and acceptable safety profiles in adults. This review fills a gap in the pediatric MDR‐TB literature by providing practice‐based recommendations for the use of the new (delamanid and bedaquiline) and repurposed (linezolid and clofazimine) MDR‐TB drugs and the new shorter MDR‐TB regimen in children and adolescents.

Inpatient signs and symptoms and factors associated with death in children aged 5 years and younger admitted to two Ebola management centres in Sierra Leone, 2014: a retrospective cohort study

BACKGROUND Médecins Sans Frontières (MSF) opened Ebola management centres (EMCs) in Sierra Leone in Kailahun in June, 2014, and Bo in September, 2014. Case fatality in the west African Ebola virus disease epidemic has been highest in children younger than 5 years. Clinical data on outcomes can provide important evidence to guide future management. However, such data on children are scarce and disaggregated clinical data across all ages in this epidemic have focussed on symptoms reported on arrival at treatment facilities, rather than symptoms and signs observed during admission. We aimed to describe the clinical characteristics of children aged 5 years and younger admitted to the MSF EMCs in Bo and Kailahun, and any associations between these characteristics and mortality. METHODS In a retrospective cohort study, we included data from children aged 5 years and younger with laboratory-confirmed Ebola virus disease admitted to EMCs between June and December, 2014. We described epidemiological, demographic, and clinical characteristics and viral load (measured using Ebola virus cycle thresholds [Ct]), and assessed their association with death using Cox regression modelling. FINDINGS We included 91 children in analysis; 52 died (57·1%). Case fatality was higher in children aged less than 2 years (76·5% [26/34]) than those aged 2-5 years (45·6% [26/57]; adjusted HR 3·5 [95% CI 1·5-8·5]) and in those with high (Ct<25) versus low (Ct≥25) viral load (81·8% [18/22] vs 45·9% [28/61], respectively; adjusted HR 9·2 [95% CI 3·8-22·5]). Symptoms observed during admission included: weakness 74·7% (68); fever 70·8% (63/89); distress 63·7% (58); loss of appetite 60·4% (55); diarrhoea 59·3% (54); and cough 52·7% (48). At admission, 25% (19/76) of children were afebrile. Signs significantly associated with death were fever, vomiting, and diarrhoea. Hiccups, bleeding, and confusion were observed only in children who died. INTERPRETATION This description of the clinical features of Ebola virus disease over the duration of illness in children aged 5 years and younger shows symptoms associated with death and a high prevalence of distress, with implications for clinical management. Collection and analysis of age-specific data on Ebola is very important to ensure that the specific vulnerabilities of children are addressed. FUNDING No specific funding was received for this study. EB is supported by the National Health and Medical Research Council of Australia.

Off-Label Use of Bedaquiline in Children and Adolescents with Multidrug-Resistant Tuberculosis

We describe 27 children and adolescents <18 years of age who received bedaquiline during treatment for multidrug-resistant tuberculosis. We report good treatment responses and no cessation attributable to adverse effects. Bedaquiline could be considered for use with this age group for multidrug-resistant tuberculosis when treatment options are limited.

Multidrug-Resistant Tuberculosis in Child Successfully Treated with 9-Month Drug Regimen

To the Editor: Approximately 480,000 persons acquired multidrug-resistant tuberculosis (MDR TB) in 2013 (1). Of the 32,000 children who acquire MDR TB annually, few are identified and administered appropriate treatment (2). World Health Organization (WHO)–recommended treatment for MDR TB lasts 20–24 months, including 8 months of daily drug injections (3). Because many children have paucibacillary TB, a shorter protocol may be sufficient, especially for early or nonsevere disease. In Bangladesh, 87% of MDR TB patients who received a 9-month regimen had a favorable outcome; compared with patients who received the WHO regimen, fewer had adverse events or were lost to follow-up (4,5). A randomized controlled trial of this regimen is ongoing (6); however, the trial excludes children, and no detailed data are available for use of this regimen in children. The regimen is being implemented in several countries under operational research conditions (7). Along with the Ministry of Health of Uzbekistan, and in accordance with WHO advice (8), Medecins Sans Frontieres investigated the efficacy, tolerability, and safety of the shortened regimen in Karakalpakstan, Uzbekistan (9), where rates of second-line drug resistance are high (1) and katG-mediated isoniazid resistance predominates. Unlike the Bangladesh study (4), the Karakalpakstan study used moxifloxacin instead of gatifloxacin and included scheduled electrocardiograms (ECGs) and graded assessments of side effects to monitor for safety, including cardiac toxicity. All drugs in the regimen were previously used safely in children (10). For children, limited data are available regarding use of 2 new TB drugs, bedaquiline and delamanid; thus, the shortened regimen could represent the best opportunity to improve their outcomes and access to treatment. We report the successful treatment of MDR TB in a child who received the 9-month drug regimen. This retrospective research fulfilled Medecins Sans Frontieres Ethics Review Board criteria for analysis of existing program data. Written informed consent was provided by the child and his parents. In November 2013, a 14-year-old boy in Karakalpakstan received a diagnosis of pulmonary MDR TB after seeking medical care for a sore throat without cough, fever, weight loss, or major concurrent conditions. His mother (a close contact) had experienced symptoms of pulmonary TB since 2011 and, after a period of self-treatment, received a diagnosis of MDR TB with confirmed absence of preextensively or extensively drug-resistant TB; she completed appropriate treatment in September 2013. In accordance with national guidelines, the boy did not receive treatment for latent TB. Clinical examination of the boy (weight 43 kg, body mass index 17.2 kg/m2) was unremarkable and showed no signs of extrapulmonary disease. A chest radiograph showed a left midzone interstitial infiltrate. Sputum sample testing (Xpert MTB/RIF; Cepheid, Sunnyvale, CA, USA) confirmed rifampin-resistant Mycobacterium tuberculosis. Sputum smear microscopy and liquid-based culture (BACTEC MGIT 960; Becton Dickinson, Franklin Lakes, NJ, USA) were negative. Baseline biochemical, hematologic, and ECG results were within normal limits. Serologic test results were negative for HIV and hepatitis B and C viruses. Together, a history consistent with TB disease, radiographic evidence, and molecular testing results were considered sufficient indication for treatment of MDR TB. After psychosocial counseling and health education sessions, the boy, with his family’s agreement, consented to daily outpatient treatment with isoniazid (400 mg), ethambutol (800 mg), pyrazinamide (1,600 mg), prothionamide (500 mg), moxifloxacin (400 mg), capreomycin (750 mg), and clofazimine (100 mg) beginning in December 2013. Treatment initiation was complicated by drug-associated nausea and vomiting, headache, tinnitus, and abdominal pain. Despite early aggressive management in line with study protocols, occasional vomiting continued. Intensive counseling ensured good adherence; only 3 days were missed. Corrected QT prolongation was excluded by use of ECG monitoring during treatment initiation. After 4 months of treatment, the boy’s sputum smear microscopy and culture results remained negative, so the continuation phase of treatment was initiated. The daily regimen consisted of ethambutol (800 mg), pyrazinamide (1,600 mg), prothionamide (500 mg), moxifloxacin (400 mg), and clofazimine (100 mg). In May 2014, after 6 months of treatment, the boy returned to school while still receiving treatment. In August 2014, the regimen was completed without incident, and at a 6-month follow-up, the boy had not experienced a relapse. According to study protocol, he will be followed for 1 year posttreatment to monitor for relapse. The shortened treatment regimen has several potential benefits for children. The shorter treatment period enables an earlier return to school and social activities, the shorter duration of anti-TB injectable drug use may lessen ototoxicity, and fewer adverse effects and shorter duration could improve treatment adherence. The reluctance to include children in TB research studies may result from difficulties in confirming a diagnosis (due to paucibacillary disease and difficulty in obtaining specimens); such confirmation is often a prerequisite for treatment. Other barriers include lack of second-line TB drug formulations and pharmacokinetic data for children, ethics review issues, and informed and parental consent issues. Clinicians and TB program managers could consider the 9-month treatment regimen for children. We advocate inclusion of children of all ages in research investigating the efficacy and safety of a 9-month regimen and emphasize the importance of separately reporting data for children.

Treatment and outcomes in children with multidrug-resistant tuberculosis: A systematic review and individual patient data meta-analysis

Background An estimated 32,000 children develop multidrug-resistant tuberculosis (MDR-TB; Mycobacterium tuberculosis resistant to isoniazid and rifampin) each year. Little is known about the optimal treatment for these children. Methods and findings To inform the pediatric aspects of the revised World Health Organization (WHO) MDR-TB treatment guidelines, we performed a systematic review and individual patient data (IPD) meta-analysis, describing treatment outcomes in children treated for MDR-TB. To identify eligible reports we searched PubMed, LILACS, Embase, The Cochrane Library, PsychINFO, and BioMedCentral databases through 1 October 2014. To identify unpublished data, we reviewed conference abstracts, contacted experts in the field, and requested data through other routes, including at national and international conferences and through organizations working in pediatric MDR-TB. A cohort was eligible for inclusion if it included a minimum of three children (aged <15 years) who were treated for bacteriologically confirmed or clinically diagnosed MDR-TB, and if treatment outcomes were reported. The search yielded 2,772 reports; after review, 33 studies were eligible for inclusion, with IPD provided for 28 of these. All data were from published or unpublished observational cohorts. We analyzed demographic, clinical, and treatment factors as predictors of treatment outcome. In order to obtain adjusted estimates, we used a random-effects multivariable logistic regression (random intercept and random slope, unless specified otherwise) adjusted for the following covariates: age, sex, HIV infection, malnutrition, severe extrapulmonary disease, or the presence of severe disease on chest radiograph. We analyzed data from 975 children from 18 countries; 731 (75%) had bacteriologically confirmed and 244 (25%) had clinically diagnosed MDR-TB. The median age was 7.1 years. Of 910 (93%) children with documented HIV status, 359 (39%) were infected with HIV. When compared to clinically diagnosed patients, children with confirmed MDR-TB were more likely to be older, to be infected with HIV, to be malnourished, and to have severe tuberculosis (TB) on chest radiograph (p < 0.001 for all characteristics). Overall, 764 of 975 (78%) had a successful treatment outcome at the conclusion of therapy: 548/731 (75%) of confirmed and 216/244 (89%) of clinically diagnosed children (absolute difference 14%, 95% confidence interval [CI] 8%–19%, p < 0.001). Treatment was successful in only 56% of children with bacteriologically confirmed TB who were infected with HIV who did not receive any antiretroviral treatment (ART) during MDR-TB therapy, compared to 82% in children infected with HIV who received ART during MDR-TB therapy (absolute difference 26%, 95% CI 5%–48%, p = 0.006). In children with confirmed MDR-TB, the use of second-line injectable agents and high-dose isoniazid (15–20 mg/kg/day) were associated with treatment success (adjusted odds ratio [aOR] 2.9, 95% CI 1.0–8.3, p = 0.041 and aOR 5.9, 95% CI 1.7–20.5, p = 0.007, respectively). These findings for high-dose isoniazid may have been affected by site effect, as the majority of patients came from Cape Town. Limitations of this study include the difficulty of estimating the treatment effects of individual drugs within multidrug regimens, only observational cohort studies were available for inclusion, and treatment decisions were based on the clinician’s perception of illness, with resulting potential for bias. Conclusions This study suggests that children respond favorably to MDR-TB treatment. The low success rate in children infected with HIV who did not receive ART during their MDR-TB treatment highlights the need for ART in these children. Our findings of individual drug effects on treatment outcome should be further evaluated.

WHO recommendations for multidrug-resistant tuberculosis

2234 www.thelancet.com Vol 388 November 5, 2016 3 Casas EC. Experiences with short MDR-TB regimen in unstable settings. The 46th Union World Conference on Lung Health; Cape Town, South Africa; Dec 2–6, 2015. http://capetown. worldlunghealth.org/programme/ programme-by-type/sponsored-satellitesymposia/pdf/12-Sponsored-satellitesymposium.pdf (accessed June 18, 2016). 4 Casas E, Gashu T, Greig J, et al. 9-month short-course MDR-TB treatment in HIVand non-HIV-co-infected patients in Uzbekistan and Swaziland: interim outcomes of two prospective studies. The 46th Union World Conference on Lung Health; Cape Town, South Africa; Dec 2–6, 2015. http://capetown. worldlunghealth.org/programme/ programme-by-type/e-poster/pdf/EP-03-04Dec.pdf (accessed June 18, 2016). 5 Lalor MK, Greig J, Allamuratova S, et al. Risk factors associated with default from multiand extensively drug-resistant tuberculosis treatment, Uzbekistan: a retrospective cohort analysis. PLoS One 2013; 8: e78364. 6 WHO. Global tuberculosis report 2015. Geneva: WHO, 2015. http://apps.who.int/iris/ bitstream/10665 /191102/1/9789241565059 _eng.pdf (accessed June 18, 2016). the potential benefi t for some patients with multidrug-resistant (MDR) tuberculosis. We wish to address their concern regarding applicability in countries of the former Soviet Union. Interim data (1-year, relapse-free outcomes due in 2017) from our observational study of the shortened regimen in Karakalpakstan, Uzbekistan, contributed to the meta-analysis on which WHO based their recommendations. The Ministry of Health of Karakalpakstan, in partnership with Médecins sans Frontières, chose to pilot the shortened regimen in parallel with the line-probe assay for second-line drugs. This decision was made on the basis of the challenges of maintaining quality patient-centred care when scaling up a 20-month regimen: successful outcomes dropped to 62%; and loss to follow-up increased to 20%. When considering whether to incorporate some or all of the WHO recommendations, national programme managers must balance the benefit of reducing treatment duration for some patients against the extra resources required to identify them. While some settings have high levels of resistance, there remain patients within these contexts who are likely to benefi t from shorter regimens. Keeping patients at the centre of these decisions is key. With global successful treatment outcomes of just 50% for MDR tuberculosis, perhaps the focus should be on who might benefit from the shorter regimen rather than who might not.

Electronic medical records in humanitarian emergencies – the development of an Ebola clinical information and patient management system

By November 2015, the West Africa Ebola epidemic had caused 28598 infections and 11299 deaths in the three countries most affected. The outbreak required rapid innovation and adaptation. Médecins sans Frontières (MSF) scaled up its usual 20-30 bed Ebola management centres (EMCs) to 100-300 beds with over 300 workers in some settings. This brought challenges in patient and clinical data management resulting from the difficulties of working safely with high numbers of Ebola patients. We describe a project MSF established with software developers and the Google Social Impact Team to develop context-adapted tools to address the challenges of recording Ebola clinical information. We share the outcomes and key lessons learned in innovating rapidly under pressure in difficult environmental conditions. Information on adoption, maintenance, and data quality was gathered through review of project documentation, discussions with field staff and key project stakeholders, and analysis of tablet data. In March 2015, a full prototype was deployed in Magburaka EMC, Sierra Leone. Inpatient data were captured on 204 clinical interactions with 34 patients from 5 March until 10 April 2015. Data continued to also be recorded on paper charts, creating theoretically identical record “pairs” on paper and tablet. 83 record pairs for 33 patients with 22 data items (temperature and symptoms) per pair were analysed. The overall Kappa coefficient for agreement between sources was 0.62, but reduced to 0.59 when rare bleeding symptoms were excluded, indicating moderate to good agreement. The time taken to deliver the product was more than that anticipated by MSF (7 months versus 6 weeks). Deployment of the tablet coincided with a dramatic drop in patient numbers and thus had little impact on patient care. We have identified lessons specific to humanitarian-technology collaborative projects and propose a framework for emergency humanitarian innovation. Time and effort is required to bridge differences in organisational culture between the technology and humanitarian worlds. This investment is essential for establishing a shared vision on deliverables, urgency, and ownership of product.

Impact of pyrazinamide resistance on multidrug-resistant tuberculosis in Karakalpakstan, Uzbekistan.

SETTING The World Health Organization (WHO) recommends the inclusion of pyrazinamide (PZA) in treatment regimens for multidrug-resistant tuberculosis (MDR-TB) unless resistance has been confirmed. OBJECTIVE To investigate the association between PZA susceptibility and MDR-TB treatment outcome among patients treated with a PZA-containing regimen and whether the duration of the intensive phase of the PZA-containing regimen affected treatment outcome. DESIGN We conducted a retrospective cohort study including all eligible MDR-TB patients starting treatment in 2003-2013 in the TB programme in Karakalpakstan, Uzbekistan. PZA drug susceptibility testing (DST) using liquid culture was performed, and outcomes were classified according to the WHO 2013 definitions. RESULTS Of 2446 MDR-TB patients included, 832 (34.0%) had an available baseline PZA DST result, 612 (73.6%) of whom were PZA-resistant. We found no association between treatment success and PZA susceptibility (adjusted odds ratio [aOR] 0.86, 95%CI 0.51-1.44, P = 0.6) in patients treated with PZA. Furthermore, among patients with no baseline PZA DST result, no evidence was seen of an association between treatment success and PZA treatment duration (aOR 0.86, 95%CI 0.49-1.51, P = 0.6). CONCLUSION Treatment of MDR-TB with a standard PZA regimen does not appear to improve treatment outcomes, regardless of PZA susceptibility or duration of treatment.