Anaemia and blood transfusion in African children presenting to hospital with severe febrile illness

BACKGROUND: Severe anaemia in children is a leading cause of hospital admission and a major cause of mortality in sub-Saharan Africa, yet there are limited published data on blood transfusion in this vulnerable group. METHODS: We present data from a large controlled trial of fluid resuscitation (Fluid Expansion As Supportive Therapy (FEAST) trial) on the prevalence, clinical features, and transfusion management of anaemia in children presenting to hospitals in three East African countries with serious febrile illness (predominantly malaria and/or sepsis) and impaired peripheral perfusion. RESULTS: Of 3,170 children in the FEAST trial, 3,082 (97%) had baseline haemoglobin (Hb) measurement, 2,346/3,082 (76%) were anaemic (Hb <10 g/dL), and 33% severely anaemic (Hb <5 g/dL). Prevalence of severe anaemia varied from 12% in Kenya to 41% in eastern Uganda. 1,387/3,082 (45%) children were transfused (81% within 8 hours). Adherence to WHO transfusion guidelines was poor. Among severely anaemic children who were not transfused, 52% (54/103) died within 8 hours, and 90% of these deaths occurred within 2.5 hours of randomisation. By 24 hours, 128/1,002 (13%) severely anaemic children had died, compared to 36/501 (7%) and 71/843 (8%) of those with moderate and mild anaemia, respectively. Among children without severe hypotension who were randomised to receive fluid boluses of 0.9% saline or albumin, mortality was increased (10.6% and 10.5%, respectively) compared to controls (7.2%), regardless of admission Hb level. Repeat transfusion varied from ≤2% in Kenya/Tanzania to 6 to 13% at the four Ugandan centres. Adverse reactions to blood were rare (0.4%). CONCLUSIONS: Severe anaemia complicates one third of childhood admissions with serious febrile illness to hospitals in East Africa, and is associated with increased mortality. A high proportion of deaths occurred within 2.5 hours of admission, emphasizing the need for rapid recognition and prompt blood transfusion. Adherence to current WHO transfusion guidelines was poor. The high rates of re-transfusion suggest that 20 mL/kg whole blood or 10 mL/kg packed cells may undertreat a significant proportion of anaemic children. Future evaluation of the impact of a larger volume of transfused blood and optimum transfusion management of children with Hb of <6 g/dL is warranted. Please see related article: http://dx.doi.org/10.1186/s12916-014-0248-5. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12916-014-0246-7) contains supplementary material, which is available to authorized users

WHO guidelines on fluid resuscitation in children: missing the FEAST data.

The World Health Organization recommendations on management of common childhood illnesses affect the lives of millions of children admitted to hospital worldwide. Its latest guidelines,1 released in May 2013, continue to recommend rapid fluid resuscitation for septic shock, even though the only large controlled trial of this treatment (Fluid Expansion as a Supportive Treatment (FEAST) found that it increased the risk of death in African children.2 A subsequent systematic review of bolus resuscitation in children with shock resulting from severe infection also did not support its use.3 Failure to take this evidence into account is not consistent with WHO’s commitment to systematically and transparently assess evidence using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) process when producing guidelines and could endanger the lives of children

Immediate Versus Triggered Transfusion for Children with Uncomplicated Severe Anaemia

Background: The World Health Organization recommends a haemoglobin transfusion threshold of 0.2) nor evidence of differences between groups in re-admissions (p=0.36), serious adverse events (p=0.36) nor in haemoglobin recovery at 180-days (p=0.08). Length-of-stay was mean 0.9 days longer in the triggered group. Conclusions: There was no evidence of differences in clinical outcomes over 6 months with triggered vs immediate transfusion. Triggered transfusion reduced blood-volume requirements by 60% but increased length-of-stay by 20% and required repeated haemoglobin monitoring and surveillance

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]

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 either Hemocue® or Sahli’s method for the cost of USD 4 or and USD 0.25 per test, respectively would be more cost-effective

Farmers, food and climate change: ensuring community-based adaptation is mainstreamed into agricultural programmes

Climate change creates widespread risks for food production. As climate impacts are often locally specific, it is imperative that large-scale initiatives to support smallholder farmers consider local priorities and integrate lessons from successful autonomous adaptation efforts. This article explores how large-scale programmes for smallholder adaptation to climate change might link effectively with community-led adaptation initiatives. Drawing on experiences in Bangladesh, Mozambique, Uganda and India, this article identifies key success factors and barriers for considering local priorities, capacities and lessons in large-scale adaptation programmes. It highlights the key roles of extension services and farmers' organizations as mechanisms for linking between national-level and community-level adaptation, and a range of other success factors which include participative and locally driven vulnerability assessments, tailoring of adaptation technologies to local contexts, mapping local institutions and working in partnership across institutions. Barriers include weak governance, gaps in the regulatory and policy environment, high opportunity costs, low literacy and underdeveloped markets. The article concludes that mainstreaming climate adaptation into large-scale agricultural initiatives requires not only integration of lessons from community-based adaptation, but also the building of inclusive governance to ensure smallholders can engage with those policies and processes affecting their vulnerability

Pharmacokinetics and pharmacodynamics of azithromycin in severe malaria bacterial co-infection in African children (TABS-PKPD): a protocol for a Phase II randomised controlled trial [version 2; peer review: 1 approved with reservations]

BACKGROUND: African children with severe malaria are susceptible to Gram-negative bacterial co-infection, largely non-typhoidal Salmonellae, leading to a substantially higher rates of in-hospital and post-discharge mortality than those without bacteraemia. Current evidence for treating co-infection is lacking, and there is no consensus on the dosage or length of treatment required. We therefore aimed to establish the appropriate dose of oral dispersible azithromycin as an antimicrobial treatment for children with severe malaria and to investigate whether antibiotics can be targeted to those at greatest risk of bacterial co-infection using clinical criteria alone or in combination with rapid diagnostic biomarker tests. METHODS: A Phase I/II open-label trial comparing three doses of azithromycin: 10, 15 and 20 mg/kg spanning the lowest to highest mg/kg doses previously demonstrated to be equally effective as parenteral treatment for other salmonellae infection. Children with the highest risk of bacterial infection will receive five days of azithromycin and followed for 90 days. We will generate relevant pharmacokinetic data by sparse sampling during dosing intervals. We will use population pharmacokinetic modelling to determine the optimal azithromycin dose in severe malaria and investigate azithromycin exposure to change in C-reactive protein, a putative marker of sepsis at 72 hours, and microbiological cure (seven-day), alone and as a composite with seven-day survival. We will also evaluate whether a combination of clinical, point-of-care diagnostic tests, and/or biomarkers can accurately identify the sub-group of severe malaria with culture-proven bacteraemia by comparison with a control cohort of children hospitalized with severe malaria at low risk of bacterial co-infection. DISCUSSION: We plan to study azithromycin because of its favourable microbiological spectrum, its inherent antimalarial and immunomodulatory properties and dosing and safety profile. This study will generate new data to inform the design and sample size for definitive Phase III trial evaluation. REGISTRATION: ISRCTN49726849 (27th October 2017)

Impact of early continuous positive airway pressure in the delivery room (DR-CPAP) on neonates &lt; 1500 g in a low-resource setting: a protocol for a pilot feasibility and acceptability randomized controlled trial

Background Preterm birth is the leading cause of childhood mortality, and respiratory distress syndrome is the predominant cause of these deaths. Early continuous positive airway pressure is effective in high-resource settings, reducing the rate of continuous positive airway pressure failure, and the need for mechanical ventilation and surfactant. However, most deaths in preterm infants occur in low-resource settings without access to mechanical ventilation or surfactant. We hypothesize that in such settings, early continuous positive airway pressure will reduce the rate of failure and therefore preterm mortality. Methods This is a mixed methods feasibility and acceptability, single-center pilot randomized control trial of early continuous positive airway pressure among infants with birthweight 800-1500 g. There are two parallel arms: (i) application of continuous positive airway pressure; with optional oxygen when indicated; applied in the delivery room within 15 min of birth; transitioning to bubble continuous positive airway pressure after admission to the neonatal unit if Downes Score ≥ 4 (intervention), (ii) supplementary oxygen at delivery when indicated; transitioning to bubble continuous positive airways pressure after admission to the neonatal unit if Downes Score ≥ 4 (control). A two-stage consent process (verbal consent during labor, followed by full written consent within 24 h of birth) and a low-cost third-party allocation process for randomization will be piloted. We will use focus group discussions and key informant interviews to explore the acceptability of the intervention, two-stage consent process, and trial design. We will interview healthcare workers, mothers, and caregivers of preterm infants. Feasibility will be assessed by the proportion of infants randomized within 15 min of delivery; the proportion of infants in the intervention arm receiving CPAP within 15 min of delivery; and the proportion of infants with primary and secondary outcomes measured successfully. Discussion This pilot trial will enhance our understanding of methods and techniques that can enable emergency neonatal research to be carried out effectively, affordably, and acceptably in low-resource settings. This mixed-methods approach will allow a comprehensive exploration of parental and healthcare worker perceptions, experiences, and acceptance of the intervention and trial design. Trial registration The study is registered on the Pan African Clinical Trials Registry (PACTR) PACTR202208462613789. Registered 08 August 2022. https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=23888

Transfusion Volume for Children with Severe and LifeThreatening Anaemia

Background: Severe anaemia (haemoglobin37.5C) at screening. 30mls/kg reduced mortality in the 1943(61%) children without fever (28-day HR=0.43 (0.27,0.69) p=0.001), but increased mortality in the 1253(39%) children with fever (HR=1.91 (1.04,3.49) p=0.04). There was no evidence of differences between groups in re-admissions (p=0.38), serious adverse events (p=0.58) nor in haemoglobin recovery at 180-days (p=0.10). Conclusions: Mortality could be reduced by transfusing 30mls/kg whole blood equivalent in children presenting with severe anaemia without fever

Phase II trial of standard versus increased transfusion volume in Ugandan children with acute severe anemia.

BACKGROUND: Severe anemia (SA, hemoglobin 6 g/dl: primary outcome) and 28-day survival. RESULTS: Median admission hemoglobin was 4.2 g/dl (IQR 3.1 to 4.9). Initial volume received followed the randomization strategy in 155 (97%) patients. By 24-hours, 70 (90%) children in the Tx30 arm had corrected SA compared to 61 (74%) in the Tx20 arm; cause-specific hazard ratio = 1.54 (95% confidence interval 1.09 to 2.18, P = 0.01). From admission to day 28 there was a greater hemoglobin increase from enrollment in Tx30 (global P <0.0001). Serious adverse events included one non-fatal allergic reaction and one death in the Tx30 arm. There were six deaths in the Tx20 arm (P = 0.12); three deaths were adjudicated as possibly related to transfusion, but none secondary to volume overload. CONCLUSION: A higher initial transfusion volume prescribed at hospital admission was safe and resulted in an accelerated hematological recovery in Ugandan children with SA. Future testing in a large, pragmatic clinical trial to establish the effect on short and longer-term survival is warranted. TRIAL REGISTRATION: ClinicalTrials.Gov identifier: NCT01461590 registered 26 October 2011

Do Dispersing Monkeys Follow Kin? Evidence from Gray-cheeked Mangabeys (Lophocebus albigena)

Among social vertebrates, immigrants may incur a substantial fitness cost when they attempt to join a new group. Dispersers could reduce that cost, or increase their probability of mating via coalition formation, by immigrating into groups containing first- or second-degree relatives. We here examine whether dispersing males tend to move into groups containing fathers or brothers in gray-cheeked mangabeys (Lophocebus albigena) in Kibale National Park, Uganda. We sampled blood from 21 subadult and adult male mangabeys in 7 social groups and genotyped them at 17 microsatellite loci. Twelve genotyped males dispersed to groups containing other genotyped adult males during the study; in only 1 case did the group contain a probable male relative. Contrary to the prediction that dispersing males would follow kin, relatively few adult male dyads were likely first- or second-degree relatives; opportunities for kin-biased dispersal by mangabeys appear to be rare. During 4 yr of observation, adult brothers shared a group only once, and for only 6 wk. Mean relatedness among adult males sharing a group was lower than that among males in different groups. Randomization tests indicate that closely related males share groups no more often than expected by chance, although these tests had limited power. We suggest that the demographic conditions that allow kin-biased dispersal to evolve do not occur in mangabeys, may be unusual among primates, and are worth further attention