Co-trimoxazole or multivitamin multimineral supplement for post-discharge outcomes after severe anaemia in African children: a randomised controlled trial

Background Severe anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes. Methods Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second nonsequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete. Findings From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79–1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86–1·32; p=0·56). We found no evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180, 489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate group (HR 0·95, 95% CI 0·84–1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children in the no co-trimoxazole group (1·01, 0·89–1·15; p=0·85) had had one or more serious adverse events. Most serious adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions). Interpretation Neither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa

Genomic investigations of unexplained acute hepatitis in children

Since its first identification in Scotland, over 1,000 cases of unexplained paediatric hepatitis in children have been reported worldwide, including 278 cases in the UK1. Here we report an investigation of 38 cases, 66 age-matched immunocompetent controls and 21 immunocompromised comparator participants, using a combination of genomic, transcriptomic, proteomic and immunohistochemical methods. We detected high levels of adeno-associated virus 2 (AAV2) DNA in the liver, blood, plasma or stool from 27 of 28 cases. We found low levels of adenovirus (HAdV) and human herpesvirus 6B (HHV-6B) in 23 of 31 and 16 of 23, respectively, of the cases tested. By contrast, AAV2 was infrequently detected and at low titre in the blood or the liver from control children with HAdV, even when profoundly immunosuppressed. AAV2, HAdV and HHV-6 phylogeny excluded the emergence of novel strains in cases. Histological analyses of explanted livers showed enrichment for T cells and B lineage cells. Proteomic comparison of liver tissue from cases and healthy controls identified increased expression of HLA class 2, immunoglobulin variable regions and complement proteins. HAdV and AAV2 proteins were not detected in the livers. Instead, we identified AAV2 DNA complexes reflecting both HAdV-mediated and HHV-6B-mediated replication. We hypothesize that high levels of abnormal AAV2 replication products aided by HAdV and, in severe cases, HHV-6B may have triggered immune-mediated hepatic disease in genetically and immunologically predisposed children

Transfusion and Treatment of severe anaemia in African children (TRACT): a study protocol for a randomised controlled trial

Background In sub-Saharan Africa, where infectious diseases and nutritional deficiencies are common, severe anaemia is a common cause of paediatric hospital admission, yet the evidence to support current treatment recommendations is limited. To avert overuse of blood products, the World Health Organisation advocates a conservative transfusion policy and recommends iron, folate and anti-helminthics at discharge. Outcomes are unsatisfactory with high rates of in-hospital mortality (9–10 %), 6-month mortality and relapse (6 %). A definitive trial to establish best transfusion and treatment strategies to prevent both early and delayed mortality and relapse is warranted. Methods/Design TRACT is a multicentre randomised controlled trial of 3954 children aged 2 months to 12 years admitted to hospital with severe anaemia (haemoglobin < 6 g/dl). Children will be enrolled over 2 years in 4 centres in Uganda and Malawi and followed for 6 months. The trial will simultaneously evaluate (in a factorial trial with a 3 x 2 x 2 design) 3 ways to reduce short-term and longer-term mortality and morbidity following admission to hospital with severe anaemia in African children. The trial will compare: (i) R1: liberal transfusion (30 ml/kg whole blood) versus conservative transfusion (20 ml/kg) versus no transfusion (control). The control is only for children with uncomplicated severe anaemia (haemoglobin 4–6 g/dl); (ii) R2: post-discharge multi-vitamin multi-mineral supplementation (including folate and iron) versus routine care (folate and iron) for 3 months; (iii) R3: post-discharge cotrimoxazole prophylaxis for 3 months versus no prophylaxis. All randomisations are open. Enrolment to the trial started September 2014 and is currently ongoing. Primary outcome is cumulative mortality to 4 weeks for the transfusion strategy comparisons, and to 6 months for the nutritional support/antibiotic prophylaxis comparisons. Secondary outcomes include mortality, morbidity (haematological correction, nutritional and infectious), safety and cost-effectiveness. Discussion If confirmed by the trial, a cheap and widely available ‘bundle’ of effective interventions, directed at immediate and downstream consequences of severe anaemia, could lead to substantial reductions in mortality in a substantial number of African children hospitalised with severe anaemia every year, if widely implemented. Trial registration Current Controlled Trials ISRCTN84086586, Approved 11 February 201

Cotrimoxazole or multi-mineral multi-vitamins to improve post-discharge outcomes following severe anaemia in African children: a randomised controlled trial

Background Severe anaemia is a leading cause of paediatric admission to hospital in Africa; post-discharge outcomes remain poor, with high 6-month mortality (8%) and re-admission (17%). We aimed to investigate post-discharge interventions that might improve outcomes. Methods Within the two-stratum, open-label, multicentre, factorial randomised TRACT trial, children aged 2 months to 12 years with severe anaemia, defined as haemoglobin of less than 6 g/dL, at admission to hospital (three in Uganda, one in Malawi) were randomly assigned, using sequentially numbered envelopes linked to a second nonsequentially numbered set of allocations stratified by centre and severity, to enhanced nutritional supplementation with iron and folate-containing multivitamin multimineral supplements versus iron and folate alone at treatment doses (usual care), and to co-trimoxazole versus no co-trimoxazole. All interventions were administered orally and were given for 3 months after discharge from hospital. Separately reported randomisations investigated transfusion management. The primary outcome was 180-day mortality. All analyses were done in the intention-to-treat population; follow-up was 180 days. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN84086586, and follow-up is complete. Findings From Sept 17, 2014, to May 15, 2017, 3983 eligible children were randomly assigned to treatment, and followed up for 180 days. 164 (4%) were lost to follow-up. 1901 (95%) of 1997 assigned multivitamin multimineral supplement, 1911 (96%) of 1986 assigned iron and folate, and 1922 (96%) of 1994 assigned co-trimoxazole started treatment. By day 180, 166 (8%) children in the multivitamin multimineral supplement group versus 169 (9%) children in the iron and folate group had died (hazard ratio [HR] 0·97, 95% CI 0·79–1·21; p=0·81) and 172 (9%) who received co-trimoxazole versus 163 (8%) who did not receive co-trimoxazole had died (HR 1·07, 95% CI 0·86–1·32; p=0·56). We found no evidence of interactions between these randomisations or with transfusion randomisations (p>0·2). By day 180, 489 (24%) children in the multivitamin multimineral supplement group versus 509 (26%) children in the iron and folate group (HR 0·95, 95% CI 0·84–1·07; p=0·40), and 500 (25%) children in the co-trimoxazole group versus 498 (25%) children in the no co-trimoxazole group (1·01, 0·89–1·15; p=0·85) had had one or more serious adverse events. Most serious adverse events were re-admissions, occurring in 692 (17%) children (175 [4%] with at least two re-admissions). Interpretation Neither enhanced supplementation with multivitamin multimineral supplement versus iron and folate treatment or co-trimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa

Cotrimoxazole or multi-mineral multi-vitamins to improve post-discharge outcomes following severe anaemia in African children: a randomised controlled trial

Background: Severe anaemia (haemoglobin0.2). By day180, 489(24%) MVMM vs 509(26%) iron/folate had experienced one or more SAEs (HR=0.95 (0.84- 1.07), p=0.40) and 500(25%) cotrimoxazole vs 498(25%) no cotrimoxazole (HR=1.01 (0.89,1.15) p=0.85). Most SAEs were readmissions, occurring in 692(17%) children (175(4%) with ≥2 readmissions). Interpretation: Neither enhanced supplementation with MVMM versus iron/folate treatment or cotrimoxazole prophylaxis improved 6-month survival. High rates of hospital re-admission suggest that novel interventions are urgently required for severe anaemia, given the burden it places on overstretched health services in Africa

Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines

Inflammatory responses in SARS-CoV-2 associated Multisystem Inflammatory Syndrome and Kawasaki Disease in children: An observational study

Multisystem Inflammatory Syndrome in Children (MIS-C) is a severe inflammatory disease in children related to SARS-CoV-2 with multisystem involvement including marked cardiac dysfunction and clinical symptoms that can resemble Kawasaki Disease (KD). We hypothesized that MIS-C and KD might have commonalities as well as unique inflammatory responses and studied these responses in both diseases. In total, fourteen children with MIS-C (n=8) and KD (n=6) were included in the period of March-June 2020. Clinical and routine blood parameters, cardiac follow-up, SARS-CoV-2-specific antibodies and CD4+ T-cell responses, and cytokine-profiles were determined in both groups. In contrast to KD patients, all MIS-C patients had positive Spike protein-specific CD3+CD4+ T-cell responses. MIS-C and KD patients displayed marked hyper-inflammation with high expression of serum cytokines, including the drug-targetable interleukin (IL)-6 and IFN-γ associated chemokines CXCL9, 10 and 11, which decreased at follow-up. No statistical differences were observed between groups. Clinical outcomes were all favourable without cardiac sequelae at 6 months follow-up. In conclusion, MIS-C and KD-patients both displayed cytokine-associated hyper-inflammation with several high levels of drug-targetable cytokines

Immune cell phenotyping data.

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Patients Characteristics.

Patients Characteristics.</p

Serum proteins levels, 2Log fold expression compared to healthy controls.

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