Identifying prognostic factors of severe metabolic acidosis and uraemia in African children with severe falciparum malaria: a secondary analysis of a randomized trial

Abstract Background Severe metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. Methods A retrospective analysis of the ‘Artesunate versus quinine in the treatment of severe falciparum malaria in African children’ (AQUAMAT) trial was conducted to identify clinical features of severe metabolic acidosis and uraemia in 5425 children from nine African countries. Separate models were fitted for uraemia and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis and uraemia. Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. Results There were 2296 children identified with severe metabolic acidosis and 1110 with uraemia. Prognostic features of severe metabolic acidosis among them were deep breathing (OR: 3.94, CI 2.51–6.2), hypoglycaemia (OR: 5.16, CI 2.74–9.75), coma (OR: 1.72 CI 1.17–2.51), respiratory distress (OR: 1.46, CI 1.02–2.1) and prostration (OR: 1.88 CI 1.35–2.59). Features associated with uraemia were coma (3.18, CI 2.36–4.27), Prostration (OR: 1.78 CI 1.37–2.30), decompensated shock (OR: 1.89, CI 1.31–2.74), black water fever (CI 1.58. CI 1.09–2.27), jaundice (OR: 3.46 CI 2.21–5.43), severe anaemia (OR: 1.77, CI 1.36–2.29) and hypoglycaemia (OR: 2.77, CI 2.22–3.46) Conclusion Clinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and uraemia were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.

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Identifying Prognostic Factors of Severe Metabolic Acidosis and Acute Kidney Injury in African Children with Severe Falciparum Malaria: A Secondary Analysis of A Randomised Trial

10.21203/rs.3.rs-148298/v1 ◽

2021 ◽

Author(s):

Grace Wezi Mzumara ◽

Stije Stije Leopold ◽

Kevin Marsh ◽

Arjen Dondorp ◽

Eric Ohuma ◽

...

Keyword(s):

Acute Kidney Injury ◽

Prognostic Factors ◽

Metabolic Acidosis ◽

Falciparum Malaria ◽

Kidney Injury ◽

Severe Anaemia ◽

Severe Metabolic Acidosis ◽

Prognostic Features ◽

African Children ◽

Severe Falciparum Malaria

Abstract IntroductionSevere metabolic acidosis and acute kidney injury are major causes of mortality in children with severe malaria but are often underdiagnosed in low resource settings. MethodsWe conducted a retrospective analysis of the ‘Artesunate vs Quinine in the treatment of severe falciparum malaria in African children’ (AQUAMAT) trial to identify clinical features of severe metabolic acidosis and acute kidney injury in 5425 children from nine African countries. Separate models were fitted for acute kidney injury and severe metabolic acidosis. Separate univariable and multivariable logistic regression were performed to identify prognostic factors for severe metabolic acidosis (SMA) and acute kidney injury (AKI). Both analyses adjusted for the trial arm. A forward selection approach was used for model building of the logistic models and a threshold of 5% statistical significance was used for inclusion of variables into the final logistic model. Model performance was assessed through calibration, discrimination, and internal validation with bootstrapping. ResultsThere were 2296 children identified with Severe metabolic acidosis and 1110 with Acute Kidney Injury. Prognostic features of SMA among them were: deep breathing (OR: 5.41, CI: 4.26 – 6.89), hypoglycaemia (OR: 5.22, CI: 3.80 – 7.18), AKI (OR: 3.99, CI: 3.30 – 4.81), coma ( OR: 1.79 CI: 1.36 – 2.35), respiratory distress (OR: 1.49, CI: 1.21 – 1.83), prostration (OR: 1.64 CI: 1.30 – 2.03) and severe anaemia (OR: 1.40, CI: 1.11 – 1.77). Features associated with AKI were; older children(OR: 1.20, CI: 1.15 – 1.25), coma (2.47, CI: 1.78 – 3.42), Prostration (OR: 1.52 CI: 1.14 – 2.02), decompensated shock (OR: 1.74, CI: 1.15 – 2.63), black water fever (CI: 1.81. CI: 1.22 – 2.69), jaundice (OR: 3.31 CI: 2.01 – 5.47), SMA (OR: 4.02 CI:3.30 – 4.89), mild anaemia (OR: 1.36, CI: 1.05 – 1.76), severe anaemia (OR: 1.48, CI: 1.11 – 1.96), hypoglycaemia (OR: 2.02, CI: 1.58 – 2.59), hypernatremia (OR: 5.74, CI: 2.69 – 12.26) and hyperkalaemia (OR: 5.31. CI: 4.15 – 6.80). ConclusionClinical and laboratory parameters representing contributors and consequences of severe metabolic acidosis and acute kidney injury were independently associated with these outcomes. The model can be useful for identifying patients at high risk of these complications where laboratory assessments are not routinely available.

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Population pharmacokinetics of artemether and dihydroartemisinin following single intramuscular dosing of artemether in African children with severe falciparum malaria

British Journal of Clinical Pharmacology ◽

10.1046/j.1365-2125.2003.01986.x ◽

2003 ◽

Vol 57 (2) ◽

pp. 146-152 ◽

Cited By ~ 32

Author(s):

Sadik Mithwani ◽

Leon Aarons ◽

Gilbert O. Kokwaro ◽

Oneeb Majid ◽

Simon Muchohi ◽

...

Keyword(s):

Population Pharmacokinetics ◽

Falciparum Malaria ◽

African Children ◽

Severe Falciparum Malaria

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Results of subset analyses on overall survival (OS) from study CA184-043: Ipilimumab (Ipi) versus placebo (Pbo) in post-docetaxel metastatic castration-resistant prostate cancer (mCRPC).

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.4_suppl.2 ◽

2014 ◽

Vol 32 (4_suppl) ◽

pp. 2-2 ◽

Cited By ~ 9

Author(s):

Charles G. Drake ◽

Eugene D. Kwon ◽

Karim Fizazi ◽

Alberto Bossi ◽

Alfons JM van den Eertwegh ◽

...

Keyword(s):

Prognostic Factors ◽

Statistical Significance ◽

Progression Free Survival ◽

Castration Resistant Prostate Cancer ◽

Free Survival ◽

Prognostic Features ◽

Castration Resistant ◽

Kaplan Meier ◽

To Receive ◽

Clinical Trial Information

2 Background: The CA184-043 phase 3 study did not reach statistical significance for its primary endpoint of OS (HR=0.85, p=0.053). However, antitumor activity was observed in other efficacy endpoints, including progression-free survival. Prespecified subset analyses were performed to understand if any prognostic features may identify mCRPC patients (pts) more likely to benefit from Ipi treatment. Methods: 799 pts were randomized to receive a single dose of radiotherapy (RT) followed by either Ipi (N=399) or Pbo (N=400). Prespecified subset analyses based on Kaplan-Meier/Cox methodology were performed using known prognostic factors for OS in mCRPC. Results: Prespecified subset analyses suggested that Ipi may be more active in pts with favorable prognostic factors, including no visceral disease, alkaline phosphatase <1.5 ULN, and hemoglobin ≥11 g/dL (Table). The safety profile in this study was consistent with previous reports of Ipi. Conclusions: Based on these subset analyses, Ipi added to RT appears to have greater activity than RT alone in pts with a favorable prognostic profile. These results support continued investigation of Ipi in the ongoing CA184-095 study in chemotherapy-naive mCRPC pts. Clinical trial information: NCT00861614. [Table: see text]

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A Rapidly Fatal Case of Severe Falciparum Malaria Complicated with High-Level Metabolic Acidosis

Kansenshogaku zasshi ◽

10.11150/kansenshogakuzasshi1970.74.491 ◽

2000 ◽

Vol 74 (5) ◽

pp. 491-496

Author(s):

Yuriko SAITO ◽

Mikio TAKAMORI ◽

Mikio KIMURA

Keyword(s):

Metabolic Acidosis ◽

Falciparum Malaria ◽

Fatal Case ◽

High Level ◽

Severe Falciparum Malaria

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The prognostic and diagnostic value of intraleukocytic malaria pigment: an individual patient data pooled meta-analysis of 32,000 patients with severe falciparum malaria in Africa and Asia

10.1101/2021.11.30.21267052 ◽

2021 ◽

Author(s):

Ketsanee Srinamon ◽

James A Watson ◽

Kamolrat Silamut ◽

Benjamas Intharabut ◽

Nguyen Hoan Phu ◽

...

Keyword(s):

Systematic Review ◽

Severe Malaria ◽

Falciparum Malaria ◽

Peripheral Blood ◽

Prognostic Value ◽

Individual Patient Data ◽

Risk Of Death ◽

African Children ◽

Malaria Pigment ◽

Severe Falciparum Malaria

AbstractBackgroundSevere falciparum malaria is a major cause of death in tropical countries, particularly in African children. Accurate diagnosis and prognostic assessment are critical to clinical management.MethodsThe prognostic value of the malaria parasite count, and the proportions of polymorphonuclear leukocytes (PMNs) and monocytes (PMMs) containing malaria pigment in peripheral blood films were assessed in three randomized controlled trials conducted in severe malaria patients; two in Southeast Asia (AQ Vietnam; n=483 and SEAQUAMAT; n=1,330) and one in Africa (AQUAMAT; n=4,211). Following a systematic review of the literature, we incorporated these data into an individual patient data meta-analysis including published data from the Severe Malaria in African children (SMAC) network (n=25,845) and a study from Mali (n=166).FindingsThe proportion of pigment containing PMNs on peripheral blood films was strongly positively correlated with prognosis (odds-ratio for in-hospital mortality for a tenfold increase: 2.53 [95% CI: 2.13-3.00], p = 10−26). The meta-analytic odds-ratio estimate for in-hospital death in patients with >5% pigment containing PMNs compared with lower values was 2.67 (95% CI: 2.08-3.42; p = 10−14). Particularly in African children, the proportion of pigment containing PMNs added substantially to the prognostic assessment from simple bedside examination, and also to the conventional parasite count. In all analyses, the proportion of pigment containing monocytes had a lower prognostic value.InterpretationMicroscopy assessment of the proportion of pigment containing PMNs in a blood film is simple and rapid, and should be performed in all patients hospitalised with suspected severe malaria. Patients with >5% pigment containing PMNs have more than double the risk of death.OtherFunded by Wellcome. The systematic review was registered prospectively on PROS-PERO, number CRD42021284527Research in contextEvidence before this studySevere falciparum malaria remains a major cause of preventable childhood mortality in sub-Saharan Africa. In 2019 there were an estimated 274,000 deaths in children under 5 years. Rapidly identifying patients at the greatest risk of death and providing effective treatment is essential to saving lives. Based on data from our prospective studies of strictly defined severe falciparum malaria in Vietnamese adults, the proportions of peripheral blood neutrophils and monocytes containing malaria pigment (haemozoin) was proposed as a prognostic factor for mortality. We carried out a systematic review on PubMed of all articles published between database inception and October 11, 2021, using search terms “intraleukocytic pigment” and “severe malaria”. In addition to papers published by our research group, we found two other studies that reported the prognostic value of intraleukocytic pigment counts in severe malaria cohorts of at least 100 patients: the SMAC network study, the largest published cohort study conducted in over 25,000 African children with suspected severe malaria, and a cohort of 172 children from Mali. The SMAC study reported that intraleukocytic malaria pigment counts were not a useful predictor of outcome in African children diagnosed with severe malaria. This differed from the results from the Malian study and our original study in Vietnamese adults.Added value of this studyWe provide new data on the prognostic value of intraleukocytic malaria pigment counts in over 6,000 adults and children with a strict diagnosis of severe falciparum malaria studied prospectively in Asia and Africa. These patients were enrolled in three of the largest randomised controlled trials in severe malaria. These randomised trials have provided the main evidence base for current global therapeutic recommendations. Our data show that there is substantial prognostic value in counting intraleukocytic malaria pigment. This was significantly greater for neutrophil rather than monocyte associated pigment. Pooling all the individual patient data showed that the prognostic value was consistent across studies and countries, despite the substantial differences in study populations and study designs. Having more than 5% pigment containing neutrophils was associated with over double the risk of death from severe falciparum malaria.Implications of all the available evidenceIntraleukocytic malaria pigment counts have sub-stantial prognostic value in severe falciparum malaria. The proportion of neutrophils containing malaria pigment should be counted in thin blood films in all patients with suspected severe malaria. Patients with over 5% of pigment containing neutrophils have a high risk of death.

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