Publications
258 results found
Obonyo NG, Byrne L, Tung J-P, et al., 2019, Pre-clinical study protocol: Blood transfusion in endotoxaemic shock, MethodsX, Vol: 6, Pages: 1124-1132, ISSN: 2215-0161
The Surviving Sepsis Campaign (SCC) and the American College of Critical Care Medicine (ACCM) guidelines recommend blood transfusion in sepsis when the haemoglobin concentration drops below 7.0 g/dL and 10.0 g/dL respectively, while the World Health Organisation (WHO) guideline recommends transfusion in septic shock ‘if intravenous (IV) fluids do not maintain adequate circulation’, as a supportive measure of last resort. Volume expansion using crystalloid and colloid fluid boluses for haemodynamic resuscitation in severe illness/sepsis, has been associated with adverse outcomes in recent literature. However, the volume expansion effect(s) following blood transfusion for haemodynamic circulatory support, in severe illness remain unclear with most previous studies having focused on evaluating effects of either different RBC storage durations (short versus long duration) or haemoglobin thresholds (low versus high threshold) pre-transfusion.• We describe the protocol for a pre-clinical randomised controlled trial designed to examine haemodynamic effect(s) of early volume expansion using packed RBCs (PRBCs) transfusion (before any crystalloids or colloids) in a validated ovine-model of hyperdynamic endotoxaemic shock.• Additional exploration of mechanisms underlying any physiological, haemodynamic, haematological, immunologic and tissue specific-effects of blood transfusion will be undertaken including comparison of effects of short (≤5 days) versus long (≥30 days) storage duration of PRBCs prior to transfusion.
Maitland K, 2019, Emergency fluid bolus therapy studies: first do no harm., Archives of Disease in Childhood, Vol: 104, Pages: 409-410, ISSN: 1468-2044
Uyoga S, Mpoya A, Olupot-Olupot P, et al., 2019, Haematological quality and age of donor blood issued for paediatric transfusion to four hospitals in sub-Saharan Africa, Vox Sanguinis, Vol: 114, Pages: 340-348, ISSN: 0042-9007
Background and ObjectivesPaediatric blood transfusion for severe anaemia in hospitals in sub-Saharan Africa remains common. Yet, reports describing the haematological quality of donor blood or storage duration in routine practice are very limited. Both factors are likely to affect transfusion outcomes. Materials and MethodsWe undertook 3 audits examiningthe distribution of pack types, haematological quality and storage duration of donor blood used in a paediatric clinical trial of blood at four hospitals in Africa (Uganda and Malawi). ResultsThe overall distribution of whole blood, packed cells(plasma-reduced by centrifugation) and red cell concentrates (RCC) (plasma-reduced by gravity-dependent sedimentation)used in a randomised trial was 40.7% (N=1215), 22.4% (N=669) and 36.8% (N=1099) respectively.The first audit found similar median haematocrits of 57.0% (50.0,74.0), 64.0% (52.0,72.5;p=0.238vs whole blood) and 56.0% (48.0,67.0;p=0.462) in whole blood, RCCand packed cells respectively, which resulted from unclear pack labelling by blood transfusion services (BTS). Retraining of the BTS, hospital blood banks and clinical teams led to, in subsequent audits, significant differences in medianhaematocrit and haemoglobins across the 3 pack types and values within expected ranges. Median storage duration time was 12 days (IQR 6,19) with 18.2% (537/2964) over 21 days in storage. Initially, 9 (2.8%)packswere issued past the recommended duration of storage, dropping to 0.3%(N=7) in the third audit post training. ConclusionThe study highlights the importance of close interactions and education between BTS and clinical services and the importance of haemovigilence to ensure safe transfusion practice.
Passmore MR, Obonyo NG, Byrne L, et al., 2019, Fluid resuscitation with 0.9% saline alters haemostasis in an ovine model of endotoxemic shock, Thrombosis Research: vascular obstruction, hemorrhage and hemostasis, Vol: 176, Pages: 39-45, ISSN: 0049-3848
IntroductionFluid resuscitation is a cornerstone of severe sepsis management, however there are many uncertainties surrounding the type and volume of fluid that is administered. The entire spectrum of coagulopathies can be seen in sepsis, from asymptomatic aberrations to fulminant disseminated intravascular coagulation (DIC). The aim of this study was to determine if fluid resuscitation with saline contributes to the haemostatic derangements in an ovine model of endotoxemic shock.Materials and methodsTwenty-one adult female sheep were randomly divided into no endotoxemia (n = 5) or endotoxemia groups (n = 16) with an escalating dose of lipopolysaccharide (LPS) up to 4 μg/kg/h administered to achieve a mean arterial pressure below 60 mmHg. Endotoxemia sheep received either no bolus fluid resuscitation (n = 8) or a 0.9% saline bolus (40 mL/kg over 60 min) (n = 8). No endotoxemia, saline only animals (n = 5) underwent fluid resuscitation with a 0.9% bolus of saline as detailed above. Hemodynamic support with vasopressors was initiated if needed, to maintain a mean arterial pressure (MAP) of 60-65 mm Hg in all the groups.ResultsRotational thromboelastometry (ROTEM®) and conventional coagulation biomarker tests demonstrated sepsis induced derangements to secondary haemostasis. This effect was exacerbated by saline fluid resuscitation, with low pH (p = 0.036), delayed clot initiation and formation together with deficiencies in naturally occurring anti-coagulants antithrombin (p = 0.027) and Protein C (p = 0.001).ConclusionsEndotoxemia impairs secondary haemostasis and induces changes in the intrinsic, extrinsic and anti-coagulant pathways. These changes to haemostasis are exacerbated following resuscitation with 0.9% saline, a commonly used crystalloid in clinical settings.
Brent B, Obonyo N, Akech S, et al., 2019, Assessment of myocardial function in Kenyan children with severe, acute malnutrition, Jama Network Open, Vol: 2, ISSN: 2574-3805
Importance Mortality among African children hospitalized with severe malnutrition remains high, with sudden, unexpected deaths leading to speculation about potential cardiac causes. Malnutrition is considered high risk for cardiac failure, but evidence is limited.Objective To investigate the role of cardiovascular dysfunction in African children with severe, acute malnutrition (SAM).Design, Setting, and Participants A prospective, matched case-control study, the Cardiac Physiology in Malnutrition (CAPMAL) study, of 88 children with SAM (exposed) vs 22 severity-matched patients without SAM (unexposed) was conducted between March 7, 2011, and February 20, 2012; data analysis was performed from October 1, 2012, to March 1, 2016.Exposures Echocardiographic and electrocardiographic (ECG) recordings (including 7-day Holter monitoring) at admission, day 7, and day 28.Main Outcomes and Measures Findings in children with (cases) and without (controls) SAM and in marasmus and kwashiorkor phenotypes were compared.Results Eighty-eight children (52 with marasmus and 36 with kwashiorkor) of the 418 admitted with SAM and 22 severity-matched controls were studied. A total of 63 children (57%) were boys; median age at admission was 19 months (range, 12-39 months). On admission, abnormalities more common in cases vs controls included severe hypokalemia (potassium <2.5 mEq/L) (18 of 81 [22%] vs 0%), hypoalbuminemia (albumin level <3.4 g/dL) (66 of 88 [75%] vs 4 of 22 [18%]), and hypothyroidism (free thyroxine level <0.70 ng/dL or thyrotropin level >4.2 mU/L) (18 of 74 [24%] vs 1 of 21 [5%]) and were associated with typical electrocardiographic changes (T-wave inversion: odds ratio, 7.3; 95% CI, 1.9-28.0; P = .001), which corrected as potassium levels improved. Fourteen children with SAM (16%) but no controls died. Myocardial mass was lower in cases on admission but not by day 7. Results of the Tei Index, a measure of global cardiac function, were within
Olupot-Olupot P, Prevatt N, Engoru C, et al., 2019, Evaluation of the diagnostic accuracy and cost of different methods for the assessment of severe anaemia in hospitalised children in Eastern Uganda [version 2; referees: 3 approved], Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background: Severe anaemia in children requiring hospital admission is a major public health problem in malaria-endemic Africa. Affordable methods for the assessment of haemoglobin have not been validated against gold standard measures for identifying those with severe anaemia requiring a blood transfusion, despite this resource being in short supply. Methods: We conducted a prospective descriptive study of hospitalized children aged 2 months – 12 years at Mbale and Soroti Regional Referral Hospitals, assessed to have pallor at triage by a nurse and two clinicians. Haemoglobin levels were measured using the HemoCue ® Hb 301 system (gold standard); the Haemoglobin Colour Scale; calorimetric and Sahli’s methods. We report clinical assessments of the degree of pallor, clinicians’ intention to transfuse, inter-observer agreement, limits of agreement using the Bland-Altman method, and the sensitivity and specificity of each method in comparison to HemoCue ® Results: We recruited 322 children assessed by the admitting nurse as having severe (164; 51.0%), moderate (99; 30.7%) or mild (57; 17.7%) pallor. Agreement between the clinicians and the nurse were good: Clinician A Kappa=0.68 (0.60–0.76) and Clinician B Kappa=0.62 (0.53–0.71) respectively ( P <0.0001 for both). The nurse, clinicians A and B indicated that of 94/116 (81.0%), 83/121 (68.6%) and 93/120 (77.5%) respectively required transfusion. HemoCue ® readings indicated anaemia as mild (Hb10.0–11.9g/dl) in 8/292 (2.7%), moderate (Hb5.0–9.9g/dl) in 132/292 (45.2%) and severe (Hb<5.0g/dl) in 152/292 (52.1%). Comparing to HemoCue® the Sahli’s method performed best in estimation of severe anaemia, with sensitivity 84.0% and specificity 87.9% and a Kappa score of 0.70 (0.64–0.80). Conclusions : Clinical assessment of severe pallor results has a low specificity for the diagnosis of severe anaemia. To target blood transfusion Hb measurement by eit
Silaba M, Ooko M, Bottomley C, et al., 2019, The impact of 10-valent Pneumococcal Conjugate Vaccine on theincidence of radiologically-confirmed pneumonia and clinically-definedpneumonia in Kenyan children: an interrupted time series analysis, The Lancet Global Health, Vol: 7, Pages: e337-e346, ISSN: 2214-109X
BackgroundPneumococcal conjugate vaccines (PCV) are highly protective against invasive pneumococcal disease caused by vaccine serotypes but the burden of pneumococcal disease in developing countries is dominated by pneumonia, most of which is non-bacteraemic. We examined the impact of 10-valent PCV on pneumonia incidence.MethodsWe linked prospective hospital surveillance for clinically-defined WHO severe or very-severe pneumonia at Kilifi County Hospital from 2002-2015 to population surveillance at Kilifi Health and Demographic Surveillance System, comprising 45,000 children aged <5 years. Chest radiographs were read according to a WHO standard. A 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PCV10) was introduced in Kenya in January 2011. In Kilifi, there was a 3-dose catch-up campaign for infants and a 2-dose catch-up campaign for children aged 1-4 years between January and March 2011. We estimated the impact of PCV10 on the incidence of clinically-defined and radiologically-confirmed pneumonia through interrupted time series analysis accounting for seasonal and temporal trends.FindingsAt the start of the study, in 2002/3, the incidence of admission with clinically-defined pneumonia was 21·7/1000/year in children aged 2-59 months. By the end of the catch-up campaign, 61·1% of children aged 2-11 months had received ≥2 doses and 62·3% of children aged 12-59 months had received ≥1 dose of PCV10. Across the whole 13-years of surveillance the incidence of clinically-defined pneumonia declined by 0.5% per month, independent of vaccine introduction; in contrast, there was no secular trend in the incidence of radiologically-confirmed pneumonia over 8 years of study.After adjusting for secular trend and season, incidence rate ratios for admission with radiologically-confirmed pneumonia, clinically-defined pneumonia, and diarrhoea (control condition), associated temporally with PCV10 introduction and th
Uyoga S, Macharia A, Ndila C, et al., 2019, The indirect health effects of malaria estimated from health advantages of the sickle cell trait, Nature Communications, Vol: 10, ISSN: 2041-1723
Most estimates of the burden of malaria are based on its direct impacts; however, its true burden is likely to be greater because of its wider effects on overall health. Here we estimate the indirect impact of malaria on children’s health in a case-control study, using the sickle cell trait (HbAS), a condition associated with a high degree of specific malaria resistance, as a proxy indicator for an effective intervention. We estimate the odds ratios for HbAS among cases (all children admitted to Kilifi County Hospital during 2000–2004) versus community controls. As expected, HbAS protects strongly against malaria admissions (aOR 0.26; 95%CI 0.22–0.31), but it also protects against other syndromes, including neonatal conditions (aOR 0.79; 0.67–0.93), bacteraemia (aOR 0.69; 0.54–0.88) and severe malnutrition (aOR 0.67; 0.55–0.83). The wider health impacts of malaria should be considered when estimating the potential added benefits of effective malaria interventions.
Maitland K, Ohuma E, Mpoya A, et al., 2019, Informing thresholds for paediatric transfusion in Africa: the need for a trial [version 1; peer review: 2 approved with reservations], Wellcome Open Research, Vol: 4, Pages: 1-23, ISSN: 2398-502X
Background : Provision of adequate supplies of donor blood for paediatric transfusion remains a challenge. Guidelines recommend restrictive transfusion practices, based on expert opinion. We examined whether survival among children admitted to hospital varied by admission haemoglobin status and whether this was influenced by malaria infection and/or transfusion. Methods : A retrospective analysis in an unselected population of children admitted to a rural district hospital in Kenya over an 8-year period. We describe baseline parameters with respect to categories of anaemia and outcome (in-hospital death) with respect to haemoglobin, malaria and transfusion status. Results : Among 29,226 admitted children, 1,143 (3.9%) had profound anaemia (Hb <4g/dl) and 3,469 (11.9%) had severe anaemia (Hb 4-6g/d). In-hospital mortality was; 97/1,143 (8.5%) in those with Hb<4g/dl and 164/2,326 (7.1%) in those with severe anaemia (Hb ≥4.0-<6g/dl). Admission Hb <3g/dl was associated with higher risk of death versus those with higher Hbs (OR=2.41 (95%CI: 1.8 - 3.24; P<0.001), increasing to OR=6.36, (95%CI: 4.21–9.62; P<0.001) in malaria positive children. Conversely, mortality in non-malaria admissions was unrelated to Hb level. Transfusion was associated with a non-significant improvement in outcome if Hb<3g/dl (malaria-only) OR 0.72 (95%CI 0.29 - 1.78), albeit the number of cases were too few to show a statistical difference. For those with Hb levels above 4g/dl, mortality was significantly higher in those receiving a transfusion compared to the non-transfused group. For non-malarial cases, transfusion did not affect survival-status, irrespective of baseline Hb level compared to children who were not transfused at higher Hb levels. Conclusion : Although severe and complicated anaemia is common among children admitted to hospital in sSA (~16%), our data do not indicate that outcome is improved by transfusion irrespective of malaria status. Given the limi
Talbert A, Ngari M, Bauni E, et al., 2019, Mortality after inpatient treatment for diarrhea in children: a cohort study, BMC Medicine, Vol: 17, ISSN: 1741-7015
BackgroundThere is an increasing recognition that children remain at elevated risk of death following discharge from health facilities in resource-poor settings. Diarrhea has previously been highlighted as a risk factor for post-discharge mortality.MethodsA retrospective cohort study was conducted to estimate the incidence and demographic, clinical, and biochemical features associated with inpatient and 1-year post-discharge mortality amongst children aged 2–59 months admitted with diarrhea from 2007 to 2015 at Kilifi County Hospital and who were residents of Kilifi Health and Demographic Surveillance System (KHDSS). Log-binomial regression was used to identify risk factors for inpatient mortality. Time at risk was from the date of discharge to the date of death, out-migration, or 365 days later. Post-discharge mortality rate was computed per 1000 child-years of observation, and Cox proportion regression used to identify risk factors for mortality.ResultsTwo thousand six hundred twenty-six child KHDSS residents were admitted with diarrhea, median age 13 (IQR 8–21) months, of which 415 (16%) were severely malnourished and 130 (5.0%) had a positive HIV test. One hundred twenty-one (4.6%) died in the hospital, and of 2505 children discharged alive, 49 (2.1%) died after discharge: 21.4 (95% CI 16.1–28.3) deaths per 1000 child-years. Admission with signs of both diarrhea and severe pneumonia or severe pneumonia alone had a higher risk of both inpatient and post-discharge mortality than admission for diarrhea alone. There was no significant difference in inpatient and post-discharge mortality between children admitted with diarrhea alone and those with other diagnoses excluding severe pneumonia. HIV, low mid-upper arm circumference (MUAC), and bacteremia were associated with both inpatient and post-discharge mortality. Signs of circulatory impairment, sepsis, and abnormal electrolytes were associated with inpatient but not post-discharge mo
Consortium H, Drake L, Frost G, et al., 2019, Health outcomes in Undernutrition: the role of Nutrients, Gut dysfunction and the gut microbiome (HUNGer), Health outcomes in Undernutrition: the role of Nutrients, Gut dysfunction and the gut microbiome (HUNGer), Publisher: Imperial College London
The HUNGer consortium is comprised of a multi-disciplinary, multi-national consortium of world leading researchers, with expertise in physiology and nutrition, through to clinical research, public health and agriculture in LMIC settings. The HUNGer consortium was awarded the MRC Confidence in Global Nutrition and Health award in 2018.The HUNGer consortium is developing a programme of work that will directly address United Nations Sustainable Development Goal 2 (SDG-2): End hunger, achieve food security and improve nutrition, and promote sustainable agriculture. We believe there are a number of critical unanswered questions regarding the role of the gut in undernutrition, which if answered could significantly improve the effective management and prevention of undernutrition.The following document represents the consensus opinion of the HUNGer consortium concerning the key challenges that currently limit the effective management and prevention of undernutrition and the most promising potential solutions.
Tshilolo L, Tomlinson G, Williams TN, et al., 2019, Hydroxyurea for children with sickle cell anemia in sub-Saharan Africa, New England Journal of Medicine, Vol: 380, Pages: 121-131, ISSN: 0028-4793
BackgroundHydroxyurea is an effective treatment for sickle cell anemia, but few studies have been conducted in sub-Saharan Africa, where the burden is greatest. Coexisting conditions such as malnutrition and malaria may affect the feasibility, safety, and benefits of hydroxyurea in low-resource settings.MethodsWe enrolled children 1 to 10 years of age with sickle cell anemia in four sub-Saharan countries. Children received hydroxyurea at a dose of 15 to 20 mg per kilogram of body weight per day for 6 months, followed by dose escalation. The end points assessed feasibility (enrollment, retention, and adherence), safety (dose levels, toxic effects, and malaria), and benefits (laboratory variables, sickle cell–related events, transfusions, and survival).ResultsA total of 635 children were fully enrolled; 606 children completed screening and began receiving hydroxyurea at a mean (±SD) dose of 17.5±1.8 mg per kilogram per day. The retention rate was 94.2% at 3 years of treatment. Hydroxyurea therapy led to significant increases in both the hemoglobin and fetal hemoglobin levels. Dose-limiting toxic events regarding laboratory variables occurred in 5.1% of the participants, which was below the protocol-specified threshold for safety. During the treatment phase, 20.6 dose-limiting toxic effects per 100 patient-years occurred, as compared with 20.7 events per 100 patient-years before treatment. As compared with the pretreatment period, the rates of clinical adverse events decreased with hydroxyurea use, including rates of vaso-occlusive pain (98.3 vs. 44.6 events per 100 patient-years; incidence rate ratio, 0.45; 95% confidence interval [CI], 0.37 to 0.56), nonmalaria infection (142.5 vs. 90.0 events per 100 patient-years; incidence rate ratio, 0.62; 95% CI, 0.53 to 0.72), malaria (46.9 vs. 22.9 events per 100 patient-years; incidence rate ratio, 0.49; 95% CI, 0.37 to 0.66), transfusion (43.3 vs. 14.2 events per 100 patient-years; incidence rate ratio, 0
Kityo C, Szubert AJ, Siika A, et al., 2018, Raltegravir-intensified initial antiretroviral therapy in advanced HIV disease in Africa: A randomised controlled trial, PLoS Medicine, Vol: 15, Pages: 1-20, ISSN: 1549-1277
BackgroundIn sub-Saharan Africa, individuals infected with HIV who are severely immunocompromised have high mortality (about 10%) shortly after starting antiretroviral therapy (ART). This group also has the greatest risk of morbidity and mortality associated with immune reconstitution inflammatory syndrome (IRIS), a paradoxical response to successful ART. Integrase inhibitors lead to significantly more rapid declines in HIV viral load (VL) than all other ART classes. We hypothesised that intensifying standard triple-drug ART with the integrase inhibitor, raltegravir, would reduce HIV VL faster and hence reduce early mortality, although this strategy could also risk more IRIS events.Methods and findingsIn a 2×2×2 factorial open-label parallel-group trial, treatment-naive adults, adolescents, and children >5 years old infected with HIV, with cluster of differentiation 4 (CD4) <100 cells/mm3, from eight urban/peri-urban HIV clinics at regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe were randomised 1:1 to initiate standard triple-drug ART, with or without 12-week raltegravir intensification, and followed for 48 weeks. The primary outcome was 24-week mortality, analysed by intention to treat. Of 2,356 individuals screened for eligibility, 1,805 were randomised between 18 June 2013 and 10 April 2015. Of the 1,805 participants, 961 (53.2%) were male, 72 (4.0%) were children/adolescents, median age was 36 years, CD4 count was 37 cells/mm3, and plasma viraemia was 249,770 copies/mL. Fifty-six participants (3.1%) were lost to follow-up at 48 weeks. By 24 weeks, 97/902 (10.9%) raltegravir-intensified ART versus 91/903 (10.2%) standard ART participants had died (adjusted hazard ratio [aHR] = 1.10 [95% CI 0.82–1.46], p = 0.53), with no evidence of interaction with other randomisations (pheterogeneity > 0.7) and despite significantly greater VL suppression with raltegravir-intensified ART at 4 weeks (343/836 [41.0%] versus 113/841 [13.4%] with
Passmore MR, Byrne L, Obonyo NG, et al., 2018, Inflammation and lung injury in an ovine model of fluid resuscitated endotoxemic shock, Respiratory Research, Vol: 19, ISSN: 1465-9921
BackgroundSepsis is a multi-system syndrome that remains the leading cause of mortality and critical illness worldwide, with hemodynamic support being one of the cornerstones of the acute management of sepsis. We used an ovine model of endotoxemic shock to determine if 0.9% saline resuscitation contributes to lung inflammation and injury in acute respiratory distress syndrome, which is a common complication of sepsis, and investigated the potential role of matrix metalloproteinases in this process.MethodsEndotoxemic shock was induced in sheep by administration of an escalating dose of lipopolysaccharide, after which they subsequently received either no fluid bolus resuscitation or a 0.9% saline bolus. Lung tissue, bronchoalveolar fluid (BAL) and plasma were analysed by real-time PCR, ELISA, flow cytometry and immunohistochemical staining to assess inflammatory cells, cytokines, hyaluronan and matrix metalloproteinases.ResultsEndotoxemia was associated with decreased serum albumin and total protein levels, with activated neutrophils, while the glycocalyx glycosaminoglycan hyaluronan was significantly increased in BAL. Quantitative real-time PCR studies showed higher expression of IL-6 and IL-8 with saline resuscitation but no difference in matrix metalloproteinase expression. BAL and tissue homogenate levels of IL-6, IL-8 and IL-1β were elevated.ConclusionsThis data shows that the inflammatory response is enhanced when a host with endotoxemia is resuscitated with saline, with a comparatively higher release of inflammatory cytokines and endothelial/glycocalyx damage, but no change in matrix metalloproteinase levels.
Olupot-Olupot P, Prevatt N, Engoru C, et al., 2018, Evaluation of the diagnostic accuracy and cost of different methods for the assessment of severe anaemia in hospitalised children in Eastern Uganda [version 1; peer review: 2 approved, 1 approved with reservations], Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background: Severe anaemia in children requiring hospital admission is a major public health problem in malaria-endemic Africa. Affordable methods for the assessment of haemoglobin have not been validated against gold standard measures for identifying those with severe anaemia requiring a blood transfusion, despite this resource being in short supply. Methods: We conducted a prospective descriptive study of hospitalized children aged 2 months – 12 years at Mbale and Soroti Regional Referral Hospitals, assessed to have pallor at triage by a nurse and two clinicians. Haemoglobin levels were measured using the HemoCue ® Hb 301 system (gold standard); the Haemoglobin Colour Scale; calorimetric and Sahli’s methods. We report clinical assessments of the degree of pallor, clinicians’ intention to transfuse, inter-observer agreement, limits of agreement using the Bland-Altman method, and the sensitivity and specificity of each method in comparison to HemoCue ® Results: We recruited 322 children assessed by the admitting nurse as having severe (164; 51.0%), moderate (99; 30.7%) or mild (57; 17.7%) pallor. Agreement between the clinicians and the nurse were good: Clinician A Kappa=0.68 (0.60–0.76) and Clinician B Kappa=0.62 (0.53–0.71) respectively ( P <0.0001 for both). The nurse, clinicians A and B indicated that of 94/116 (81.0%), 83/121 (68.6%) and 93/120 (77.5%) respectively required transfusion. HemoCue ® readings indicated anaemia as mild (Hb10.0–11.9g/dl) in 8/292 (2.7%), moderate (Hb5.0–9.9g/dl) in 132/292 (45.2%) and severe (Hb<5.0g/dl) in 152/292 (52.1%). Comparing to HemoCue® the Sahli’s method performed best in estimation of severe anaemia, with sensitivity 84.0% and specificity 87.9% and a Kappa score of 0.70 (0.64–0.80). Conclusions : Clinical assessment of severe pallor results has a low specificity for the diagnosis of severe anaemia. To target blood transfusion Hb measurement by eit
Walsh K, Calder N, Olupot-Olupot P, et al., 2018, Modifying Intestinal Integrity and Micro Biome in Severe Malnutrition with Legume-Based Feeds (MIMBLE 2.0): protocol for a phase II refined feed and intervention trial [version 1; referees: 2 approved], Wellcome Open Research, Vol: 3, Pages: 95-95, ISSN: 2398-502X
Background: Changes in intestinal mucosal integrity and gut microbial balance occur in severe acute malnutrition (SAM), resulting in treatment failure and adverse clinical outcomes (gram-negative sepsis, diarrhoea and high case-fatality). Transient lactose intolerance, due to loss of intestinal brush border lactase, also complicates SAM, thus milk based feeds may not be optimal for nutritional rehabilitation. Since the gut epithelial barrier can be supported by short chain fatty acids, derived from microbiota fermentation by particular fermentable carbohydrates, we postulated that an energy-dense nutritional feed comprising of legume-based fermentable carbohydrates, incorporated with lactose-free versions of standard World Health Organization (WHO) F75/F100 nutritional feeds will enhance epithelial barrier function in malnourished children, reduce and promote resolution of diarrhoea and improve overall outcome. Methods: We will investigate in an open-label trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference <11.5cm and/or presence of kwashiorkor. Children will be randomised to a lactose-free, chickpea-enriched feed containing 2 kcal/ml, provided in quantities to match usual energy provision (experimental) or WHO standard treatment F75 (0.75 kcal/ml) and F100 (1 kcal/ml) feeds on a 1:1 basis, conducted at Mbale Regional Referral Hospital nutritional rehabilitation unit. The primary outcomes are change in MUAC at day 90 and survival to day 90. Secondary outcomes include: i) moderate to good weight gain (>5 g/kg/day), ii) de novo development of diarrhoea (>3 loose stools/day), iii) time to diarrhoea resolution (if >3 loose stools/day), and iv) time to oedema resolution (if kwashiorkor) and change in intestinal biomarkers (faecal calprotectin). Discussion: We hypothesize that, if introduced early in the management of malnutrition, such lactose-free, fermentable carbohydrate-based feeds, could safely and cheaply improve global outco
Walsh K, Calder N, Olupot-Olupot P, et al., 2018, Modifying Intestinal Integrity and MicroBiome in Severe Malnutrition with Legume-Based Feeds (MIMBLE 2.0): protocol for a phase II refined feed and intervention trial, Wellcome Open Research, Vol: 3, ISSN: 2398-502X
Background: Changes in intestinal mucosal integrity and gut microbial balance occur in severe acute malnutrition (SAM), resulting in treatment failure and adverse clinical outcomes (gram-negative sepsis, diarrhoea and high case-fatality). Transient lactose intolerance, due to loss of intestinal brush border lactase, also complicates SAM, thus milk based feeds may not be optimal for nutritional rehabilitation. Since the gut epithelial barrier can be supported by short chain fatty acids, derived from microbiota fermentation by particular fermentable carbohydrates, we postulated that an energy-dense nutritional feed comprising of legume-based fermentable carbohydrates, incorporated with lactose-free versions of standard World Health Organization (WHO) F75/F100 nutritional feeds will enhance epithelial barrier function in malnourished children, reduce and promote resolution of diarrhoea and improve overall outcome. Methods: We will investigate in an open-label trial in 160 Ugandan children with SAM, defined by mid-upper arm circumference <11.5cm and/or presence of kwashiorkor. Children will be randomised to a lactose-free, chickpea-enriched feed containing 2 kcal/ml, provided in quantities to match usual energy provision (experimental) or WHO standard treatment F75 (0.75 kcal/ml) and F100 (1 kcal/ml) feeds on a 1:1 basis, conducted at Mbale Regional Referral Hospital nutritional rehabilitation unit. The primary outcomes are change in MUAC at day 90 and survival to day 90. Secondary outcomes include: i) moderate to good weight gain (>5 g/kg/day), ii) de novo development of diarrhoea (>3 loose stools/day), iii) time to diarrhoea resolution (if >3 loose stools/day), and iv) time to oedema resolution (if kwashiorkor) and change in intestinal biomarkers (faecal calprotectin). Discussion: We hypothesize that, if introduced early in the management of malnutrition, such lactose-free, fermentable carbohydrate-based feeds, could safely and cheaply improve global outco
Ndila C, Uyoga S, Macharia A, et al., 2018, Human candidate gene polymorphisms and malaria in Kilifi, Kenya: A case-control association study, The Lancet Haematology, Vol: 5, Pages: e333-e345, ISSN: 2352-3026
BackgroundHuman genetic factors are important determinants of malaria risk. We investigated associations between multiple candidate polymorphisms—many related to the structure or function of red blood cells—and risk for severe Plasmodium falciparum malaria and its specific phenotypes, including cerebral malaria, severe malaria anaemia, and respiratory distress.MethodsWe did a case-control study in Kilifi County, Kenya. We recruited as cases children presenting with severe malaria to the high-dependency ward of Kilifi County Hospital. We included as controls infants born in the local community between Aug 1, 2006, and Sept 30, 2010, who were part of a genetics study. We tested for associations between a range of candidate malaria-protective genes and risk for severe malaria and its specific phenotypes. We used a permutation approach to account for multiple comparisons between polymorphisms and severe malaria. We judged p values less than 0·005 significant for the primary analysis of the association between candidate genes and severe malaria.FindingsBetween June 11, 1995, and June 12, 2008, 2244 children with severe malaria were recruited to the study, and 3949 infants were included as controls. Overall, 263 (12%) of 2244 children with severe malaria died in hospital, including 196 (16%) of 1233 with cerebral malaria. We investigated 121 polymorphisms in 70 candidate severe malaria-associated genes. We found significant associations between risk for severe malaria overall and polymorphisms in 15 genes or locations, of which most were related to red blood cells: ABO, ATP2B4, ARL14, CD40LG, FREM3, INPP4B, G6PD, HBA (both HBA1 and HBA2), HBB, IL10, LPHN2 (also known as ADGRL2), LOC727982, RPS6KL1, CAND1, and GNAS. Combined, these genetic associations accounted for 5·2% of the variance in risk for developing severe malaria among individuals in the general population. We confirmed established associations between severe malaria and sickle-cell tra
Ominde M, Sande J, Ooko M, et al., 2018, Reliability and validity of the World Health Organization reading standards for paediatric chest radiographs used in the field in an impact study of Pneumococcal Conjugate Vaccine in Kilifi, Kenya, PLoS ONE, Vol: 13, ISSN: 1932-6203
BackgroundRadiologically-confirmed pneumonia (RCP) is a specific end-point used in trials of Pneumococcal Conjugate Vaccine (PCV) to estimate vaccine efficacy. However, chest radiograph (CXR) interpretation varies within and between readers. We measured the repeatability and reliability of paediatric CXR interpretation using percent agreement and Cohen’s Kappa and the validity of field readings against expert review in a study of the impact of PCV on pneumonia.MethodsCXRs were obtained from 2716 children admitted between 2006 and 2014 to Kilifi County Hospital, Kilifi, Kenya, with clinically-defined severe or very-severe pneumonia. Five clinicians and radiologists attended a three-day training course on CXR interpretation using a WHO standard. All CXRs were read once by two local primary readers. Discordant readings and 13% of concordant readings were arbitrated by a panel of three expert radiologists. To assess repeatability, a 5% median random sample was presented twice. Sensitivity and specificity of the primary readers’ interpretations was estimated against the ‘gold-standard’ of the arbitrators’ results.ResultsOf 2716 CXRs, 2 were uninterpretable and 159 were evaluated twice. The percent agreement and Kappa for RCP were 89% and 0.68 and ranged between 84–97% and 0.19–0.68, respectively, for all pathological findings. Intra-observer repeatability was similar to inter-observer reliability. Sensitivities of the primary readers to detect RCP were 69% and 73%; specificities were 96% and 95%.ConclusionIntra- and inter-observer agreements on interpretations of radiologically-confirmed pneumonia are fair to good. Reasonable sensitivity and high specificity make radiologically-confirmed pneumonia, determined in the field, a suitable measure of relative vaccine effectiveness.
Byrne L, Obonyo NG, Diab SD, et al., 2018, Unintended consequences; fluid resuscitation worsens shock in an ovine model of endotoxemia, American Journal of Respiratory and Critical Care Medicine, Vol: 198, Pages: 1043-1054, ISSN: 1073-449X
Background: Fluid resuscitation is widely considered a life saving intervention in septic shock however recent evidence has questioned both its safety and efficacy in sepsis. This study sought to compare fluid resuscitation with vasopressors with vasopressors alone in a hyperdynamic model of ovine endotoxemia. Methods: Endotoxemic shock was induced in sixteen sheep after which they received fluid resuscitation with 40mls/kg of 0.9% saline or commenced haemodynamic support with protocolized noradrenaline and vasopressin. Microdialysis catheters were inserted into the arterial circulation, heart, brain, kidney and liver to monitor local metabolism. Blood samples were recovered to measure serum inflammatory cytokines, creatinine, troponin, ANP, BNP and hyaluronan. All animals were monitored and supported for 12 hours after fluid resuscitation. Results: After resuscitation animals receiving fluid resuscitation required significantly more noradrenaline to maintain the same mean arterial pressure in the subsequent 12 hours (68.9mg vs. 39.6mg p=0.04). Serum cytokines were similar between groups. Atrial natriuretic peptide increased significantly after fluid resuscitation compared to animals managed without fluid resuscitation (335ng/mL (256-382) vs. 233ng/mL (144 – 292) p 0.04). Cross-sectional time series analysis showed the rate of increase of the glycocalcyx glycosaminoglycan hyaluronan was greater in the fluid resuscitated group over the course of the study (p=0.02) Conclusion: Fluid resuscitation resulted in a paradoxical increase in vasopressor requirement. Additionally, It did not result in improvements in any of the measured microcirculatory or organ specific markers measured. The increase in vasopressor requirement seen may have been due to endothelial/glycocalyx damage secondary to ANP mediated glycocalyx shedding.
Houston KA, George EC, Maitland K, 2018, Implications for paediatric shock management in resource-limited settings: a perspective from the FEAST trial, Critical Care, Vol: 22, ISSN: 1364-8535
BackgroundAlthough the African “Fluid Expansion as Supportive therapy” (FEAST) trial showed fluid resuscitation was harmful in children with severe febrile illness managed in resource-limited hospitals, the most recent evidence reviewed World Health Organization (WHO) guidelines continue to recommend fluid boluses in children with shock according to WHO criteria “WHO shock”, arguing that the numbers included in the FEAST trial were too small to provide reasonable certainty.MethodsWe re-analysed the FEAST trial results for all international definitions for paediatric shock including hypotensive (or decompensated shock) and the WHO criteria. In addition, we examined the clinical relevance of the WHO criteria to published and unpublished observational studies reporting shock in resource-limited settings.ResultsWe established that hypotension was rare in children with severe febrile illness complicating only 29/3170 trial participants (0.9%). We confirmed that fluid boluses were harmful irrespective of the definitions of shock including the very small number with WHO shock (n = 65). In this subgroup 48% of bolus recipients died at 48 h compared to 20% of the non-bolus control group, an increased absolute risk of 28%, but translating to an increased relative risk of 240% (p = 0.07 (two-sided Fisher’s exact test)). Examining studies describing the prevalence of the stringent WHO shock criteria in children presenting to hospital we found this was rare (~ 0.1%) and in these children mortality was very high (41.5–100%).ConclusionsThe updated WHO guidelines continue to recommend boluses for a very limited number of children presenting at hospital with the strict definition of WHO shock. Nevertheless, the 3% increased mortality from boluses seen across FEAST trial participants would also include this subgroup of children receiving boluses. Recommendations aiming to differentiate WHO shock from other definitions will invariably lead to
Mallewa J, Szubert AJ, Mugyenyi P, et al., 2018, Effect of ready-to-use supplementary food on mortality in severely immunocompromised HIV-infected individuals in Africa initiating antiretroviral therapy (REALITY): an open-label, parallel-group, randomised controlled trial, Lancet HIV, Vol: 5, Pages: E231-E240, ISSN: 2405-4704
BackgroundIn sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing ready-to-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only.MethodsWe did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per μL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5–12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16–18 kg/m2 or BMI-for-age Z scores <–3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary
Opi DH, Swann O, Macharia A, et al., 2018, Two complement receptor one alleles have opposing associations with cerebral malaria and interact with ethalassaemia, eLife, Vol: 7, ISSN: 2050-084X
Malaria has been a major driving force in the evolution of the human genome. In sub-Saharan African populations, two neighbouring polymorphisms in the Complement Receptor One (CR1) gene, named Sl2 and McCb, occur at high frequencies, consistent with selection by malaria. Previous studies have been inconclusive. Using a large case-control study of severe malaria in Kenyan children and statistical models adjusted for confounders, we estimate the relationship between Sl2 and McCb and malaria phenotypes, and find they have opposing associations. The Sl2 polymorphism is associated with markedly reduced odds of cerebral malaria and death, while the McCb polymorphism is associated with increased odds of cerebral malaria. We also identify an apparent interaction between Sl2 and α+thalassaemia, with the protective association of Sl2 greatest in children with normal α-globin. The complex relationship between these three mutations may explain previous conflicting findings, highlighting the importance of considering genetic interactions in disease-association studies.
Lisping M, Skoglund P, Spriggs M, et al., 2018, Population turnover in remote oceania shortly after initial settlement, Current Biology, Vol: 28, Pages: 1157-1165.e7, ISSN: 1879-0445
Ancient DNA from Vanuatu and Tonga dating to about 2,900–2,600 years ago (before present, BP) has revealed that the “First Remote Oceanians” associated with the Lapita archaeological culture were directly descended from the population that, beginning around 5000 BP, spread Austronesian languages from Taiwan to the Philippines, western Melanesia, and eventually Remote Oceania. Thus, ancestors of the First Remote Oceanians must have passed by the Papuan-ancestry populations they encountered in New Guinea, the Bismarck Archipelago, and the Solomon Islands with minimal admixture [1]. However, all present-day populations in Near and Remote Oceania harbor >25% Papuan ancestry, implying that additional eastward migration must have occurred. We generated genome-wide data for 14 ancient individuals from Efate and Epi Islands in Vanuatu from 2900–150 BP, as well as 185 present-day individuals from 18 islands. We find that people of almost entirely Papuan ancestry arrived in Vanuatu by around 2300 BP, most likely reflecting migrations a few hundred years earlier at the end of the Lapita period, when there is also evidence of changes in skeletal morphology and cessation of long-distance trade between Near and Remote Oceania [2, 3]. Papuan ancestry was subsequently diluted through admixture but remains at least 80%–90% in most islands. Through a fine-grained analysis of ancestry profiles, we show that the Papuan ancestry in Vanuatu derives from the Bismarck Archipelago rather than the geographically closer Solomon Islands. However, the Papuan ancestry in Polynesia—the most remote Pacific islands—derives from different sources, documenting a third stream of migration from Near to Remote Oceania.
Post FA, Szubert AJ, Prendergast AJ, et al., 2018, Causes and timing of mortality and morbidity smong late presenters dtarting antiretroviral therapy in the REALITY trial, Clinical Infectious Diseases, Vol: 66, Pages: S132-S139, ISSN: 1058-4838
BackgroundIn sub-Saharan Africa, 20%–25% of people starting antiretroviral therapy (ART) have severe immunosuppression; approximately 10% die within 3 months. In the Reduction of EArly mortaLITY (REALITY) randomized trial, a broad enhanced anti-infection prophylaxis bundle reduced mortality vs cotrimoxazole. We investigate the contribution and timing of different causes of mortality/morbidity.MethodsParticipants started ART with a CD4 count <100 cells/µL; enhanced prophylaxis comprised cotrimoxazole plus 12 weeks of isoniazid + fluconazole, single-dose albendazole, and 5 days of azithromycin. A blinded committee adjudicated events and causes of death as (non–mutually exclusively) tuberculosis, cryptococcosis, severe bacterial infection (SBI), other potentially azithromycin-responsive infections, other events, and unknown.ResultsMedian pre-ART CD4 count was 37 cells/µL. Among 1805 participants, 225 (12.7%) died by week 48. Fatal/nonfatal events occurred early (median 4 weeks); rates then declined exponentially. One hundred fifty-four deaths had single and 71 had multiple causes, including tuberculosis in 4.5% participants, cryptococcosis in 1.1%, SBI in 1.9%, other potentially azithromycin-responsive infections in 1.3%, other events in 3.6%, and unknown in 5.0%. Enhanced prophylaxis reduced deaths from cryptococcosis and unknown causes (P < .05) but not tuberculosis, SBI, potentially azithromycin-responsive infections, or other causes (P > .3); and reduced nonfatal/fatal tuberculosis and cryptococcosis (P < .05), but not SBI, other potentially azithromycin-responsive infections, or other events (P > .2).ConclusionsEnhanced prophylaxis reduced mortality from cryptococcosis and unknown causes and nonfatal tuberculosis and cryptococcosis. High early incidence of fatal/nonfatal events highlights the need for starting enhanced-prophylaxis with ART in advanced disease.
Aramburo A, Todd J, George EC, et al., 2018, Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa, BMC Medicine, Vol: 16, ISSN: 1741-7015
BackgroundHyperlactataemia (HL) is a biomarker of disease severity that predicts mortality in patients with sepsis and malaria. Lactate clearance (LC) during resuscitation has been shown to be a prognostic factor of survival in critically ill adults, but little data exist for African children living in malaria-endemic areas.MethodsIn a secondary data analysis of severely ill febrile children included in the Fluid Expansion as Supportive Therapy (FEAST) resuscitation trial, we assessed the association between lactate levels at admission and LC at 8 h with all-cause mortality at 72 h (d72). LC was defined as a relative lactate decline ≥ 40% and/or lactate normalisation (lactate < 2.5 mmol/L).ResultsOf 3170 children in the FEAST trial, including 1719 children (57%) with Plasmodium falciparum malaria, 3008 (95%) had a baseline lactate measurement, 2127 (71%) had HL (lactate ≥ 2.5 mmol/L), and 1179 (39%) had severe HL (≥ 5 mmol/L). Within 72 h, 309 children (10.3%) died, of whom 284 (92%) had baseline HL. After adjustment for potential confounders, severe HL was strongly associated with mortality (Odds Ratio (OR) 6.96; 95% CI 3.52, 13.76, p < 0.001). This association was not modified by malaria status, despite children with malaria having a higher baseline lactate (median 4.6 mmol/L vs 3 mmol/L; p < 0.001) and a lower mortality rate (OR = 0.42; p < 0.001) compared to non-malarial cases. Sensitivity and specificity analysis identified a higher lactate on admission cut-off value predictive of d72 for children with malaria (5.2 mmol/L) than for those with other febrile illnesses (3.4 mmol/L). t 8 h, 2748/3008 survivors (91%) had a lactate measured, 1906 (63%) of whom had HL on admission, of whom 1014 (53%) fulfilled pre-defined LC criteria. After adjustment for confounders, LC independently predicted survival after 8 h (OR 0.24; 95% CI 0.14, 0.42; p < 0.001). Absence of LC (< 10%) at 8 h was strongly associated w
Siika A, McCabe L, Bwakura-Dangarembizi M, et al., 2018, Late presentation with HIV in Africa: phenotypes, risk, and risk stratification in the REALITY trial, Clinical Infectious Diseases, Vol: 66, Pages: S140-S146, ISSN: 1058-4838
© 2018 World Health Organization. Background. Severely immunocompromised human immunodefciency virus (HIV)-infected individuals have high mortality shortly afer starting antiretroviral therapy (ART). We investigated predictors of early mortality and "late presenter" phenotypes. Methods. Te Reduction of EArly MortaLITY (REALITY) trial enrolled ART-naive adults and children =5 years of age with CD4 counts < 100 cells/μL initiating ART in Uganda, Zimbabwe, Malawi, and Kenya. Baseline predictors of mortality through 48 weeks were identifed using Cox regression with backwards elimination (exit P > .1). Results. Among 1711 included participants, 203 (12%) died. Mortality was independently higher with older age; lower CD4 count, albumin, hemoglobin, and grip strength; presence of World Health Organization stage 3/4 weight loss, fever, or vomiting; and problems with mobility or self-care at baseline (all P < .04). Receiving enhanced antimicrobial prophylaxis independently reduced mortality (P =.02). Of fve late-presenter phenotypes, Group 1 (n = 355) had highest mortality (25%; median CD4 count, 28 cells/μL), with high symptom burden, weight loss, poor mobility, and low albumin and hemoglobin. Group 2 (n = 394; 11% mortality; 43 cells/μL) also had weight loss, with high white cell, platelet, and neutrophil counts suggesting underlying inflammation/infection. Group 3 (n = 218; 10% mortality) had low CD4 counts (27 cells/μL), but low symptom burden and maintained fat mass. Te remaining groups had 4%-6% mortality. Conclusions. Clinical and laboratory features identifed groups with highest mortality following ART initiation. A screening tool could identify patients with low CD4 counts for prioritizing same-day ART initiation, enhanced prophylaxis, and intensive follow-up.
Kotlyar S, Olupot-Olupot P, Nteziyaremye J, et al., 2018, Assessment of myocardial function and injury by echocardiography and cardiac biomarkers in African children with severe Plasmodium falciparum malaria, Pediatric Critical Care Medicine, Vol: 19, Pages: 179-185, ISSN: 1529-7535
Objective: Perturbed hemodynamic function complicates severe malaria. The FEAST trial demonstrated that fluid resuscitation, involving children with severe malaria, was associated with increased mortality, primarily due to cardiovascular collapse, suggesting that myocardial dysfunction may have a role. The aim of this study was to characterize cardiac function in children with severe malaria. Design: A prospective observational study with clinical, laboratory and echocardiographic data collected at presentation (T0) and 24 hours (T1) in children with severe malaria. Cardiac Index (CI) and Ejection Fraction (EF) were calculated at T0 and T1. Cardiac Troponin I (cTnI) and Brain-Naturetic-Peptide (BNP) were measured at T0. We compared clinical and echocardiographic parameters in children with and without severe anemia [Hb < 5mg/dl] (SMA) at T0 and T1.Setting: Mbale Regional Referral Hospital.Patients: Children aged 3 months–12 years with severe falciparum malaria. Interventions: usual careMeasurements and Main Results: We enrolled 104 children, median age 23.3 months, including 61 children with SMA. cTnI levels were elevated (>0.1ng/ml) in n=50, (48%); and median BNP was within normal range (69.1pg/ml, IQR 48.4-90.8). At T0, median CI was significantly higher in the SMA vs. non-SMA group (6.89 vs. 5.28 L/min/m2) (p=0.001), which normalized in both groups at T1 (5.60 vs 5.13 L/min/m2) (p=0.452). CI negatively correlated with hemoglobin, r = -0.380 (p<0.001). Four patients (3.8%) had evidence of depressed cardiac systolic function (EF <45%). Overall, 6 children died, none developed pulmonary oedema, biventricular failure or required diuretic treatment. Conclusions: Elevation of CI, due to increased stroke volume, in severe malaria is a physiological response to circulatory compromise and correlates with anemia. Following whole blood transfusion and antimalarial therapy, CI in SMA returns to normal. The majority (>96%) of children with severe malar
Idro MA, Brown N, Maitland K, 2018, Rapid intravenous rehydration of children with severe acute gastroenteritis: a systematic review and meta-analysis., BMC Pediatrics, Vol: 18, ISSN: 1471-2431
BackgroundThe World Health Organization (WHO) recommends rapid intravenous rehydration, using fluid volumes of 70-100mls/kg over 3–6 h, with some of the initial volume given rapidly as initial fluid boluses to treat hypovolaemic shock for children with acute gastroenteritis (AGE) and severe dehydration. The evidence supporting the safety and efficacy of rapid versus slower rehydration remains uncertain.MethodsWe conducted a systematic review of randomised controlled trials (RCTs) on 11th of May 2017 comparing different rates of intravenous fluid therapy in children with AGE and moderate or severe dehydration, using standard search terms. Two authors independently assessed trial quality and extracted data. Non-RCTs and non-English articles were excluded. The primary endpoint was mortality and secondary endpoints included adverse events (safety) and treatment efficacy.Main resultsOf the 1390 studies initially identified, 18 were assessed for eligibility. Of these, 3 studies (n = 464) fulfilled a priori criteria for inclusion; most studied children with moderate dehydration and none were conducted in resource-poor settings. Volumes and rates of fluid replacement varied from 20 to 60 ml/kg given over 1-2 h (fast) versus 2-4 h (slow). There was substantial heterogeneity in methodology between the studies with only one adjudicated to be of high quality. There were no deaths in any study. Safety endpoints only identified oedema (n = 6) and dysnatraemia (n = 2). Pooled analysis showed no significant difference between the rapid and slow intravenous rehydration groups for the proportion of treatment failures (N = 468): pooled RR 1.30 (95% CI: 0.87, 1.93) and the readmission rates (N = 439): pooled RR 1.39 (95% CI: 0.68, 2.85).ConclusionsDespite wide implementation of WHO Plan C guideline for severe AGE, we found no clinical evaluation in resource-limited settings, and only limited evaluation of the r
Taylor RW, Naw HK, Maitland K, et al., 2018, Single low-dose primaquine for blocking transmission of Plasmodium falciparum malaria – a proposed model-derived age-based regimen for sub-Saharan Africa, BMC Medicine, Vol: 16, ISSN: 1741-7015
Background: In 2012, the World Health Organization recommended blocking the transmission of Plasmodiumfalciparum with single low-dose primaquine (SLDPQ, target dose 0.25 mg base/kg body weight), withouttesting for glucose-6-phosphate dehydrogenase deficiency (G6PDd), when treating patients with uncomplicatedfalciparum malaria. We sought to develop an age-based SLDPQ regimen that would be suitable for sub-Saharan Africa.Methods: Using data on the anti-infectivity efficacy and tolerability of primaquine (PQ), the epidemiology of anaemia,and the risks of PQ-induced acute haemolytic anaemia (AHA) and clinically significant anaemia (CSA), we prospectivelydefined therapeutic-dose ranges of 0.15–0.4 mg PQ base/kg for children aged 1–5 years and 0.15–0.5 mg PQ base/kgfor individuals aged ≥6 years (therapeutic indices 2.7 and 3.3, respectively). We chose 1.25 mg PQ base for infants aged6–11 months because they have the highest rate of baseline anaemia and the highest risks of AHA and CSA. Wemodelled an anthropometric database of 661,979 African individuals aged ≥6 months (549,127 healthy individuals,28,466 malaria patients and 84,386 individuals with other infections/illnesses) by the Box–Cox transformation powerexponential and tested PQ doses of 1–15 mg base, selecting dosing groups based on calculated mg/kg PQ doses. Results: From the Box–Cox transformation power exponential model, five age categories were selected: (i) 6–11 months(n = 39,886, 6.03%), (ii) 1–5 years (n = 261,036, 45.46%), (iii) 6–9 years (n = 20,770, 3.14%), (iv) 10–14 years (n = 12,155, 1.84%)and (v) ≥15 years (n = 328,132, 49.57%) to receive 1.25, 2.5, 5, 7.5 and 15 mg PQ base for corresponding median (1st and99th centiles) mg/kg PQ base of: (i) 0.16 (0.12–0.25), (ii) 0.21 (0.13–0.37), (iii) 0.25 (0.16–0.38), (iv) 0.26 (0.15–0.38) and (v) 0.27(0.17–0.40). The proportions of individuals predicted to re
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