scholarly journals Improving the diagnosis of severe malaria in African children using platelet counts and plasma PfHRP2 concentrations

2021 ◽  
Author(s):  
James A Watson ◽  
Sophie A Uyoga ◽  
Perpetual Wanjiku ◽  
Johnstone Makale ◽  
Gideon M Nyutu ◽  
...  
Keyword(s):  
Platelet Count ◽  
Severe Malaria ◽  
Falciparum Malaria ◽  
Latent Class Models ◽  
Severe Illness ◽  
Bacterial Disease ◽  
Platelet Counts ◽  
African Children ◽  
Cell Counts ◽  
Severe Falciparum Malaria

Background Severe falciparum malaria is difficult to diagnose accurately in children in high transmission settings. Platelet counts and plasma concentrations of P. falciparum histidine-rich protein-2 (PfHRP2) are potential biomarkers to increase diagnostic accuracy. Methods We fitted Bayesian latent class models to platelet counts and PfHRP2 concentrations in 2,649 patients enrolled in four studies of severe illness in three countries (Bangladesh, Kenya, and Uganda). We estimated receiver operating characteristic curves and compared parasite densities, haematocrits, total white blood cell counts, blood culture positivity rates, and haemoglobin S genotypes (HbAS and HbSS) across the subgroups defined by the probabilistic models. Findings The platelet count and the plasma PfHRP2 concentration have substantial diagnostic value in severe malaria. In severely ill patients with clinical features consistent with severe malaria, a combined platelet count ≤150,000 per μL and a plasma PfHRP2 concentration ≥1,000 ng/mL had an estimated sensitivity of 74\% and specificity of 93\% in identifying `true' severe falciparum malaria. We estimate one third of African children enrolled in the two clinical studies of severe malaria had another cause of severe illness. Under the model, patients with severe malaria had higher parasite densities, lower haematocrits, lower rates of invasive bacterial disease, and a lower prevalence of both HbAS and HbSS than children misdiagnosed. Mortality in `true' severe malaria was consistent across the African sites at ≈10%. Interpretation Studies of severe falciparum malaria in African children would be improved by including only patients with platelet counts ≤150,000 per μL and plasma PfHRP2 concentrations ≥1,000 ng/mL. Funding Wellcome

scholarly journals 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

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.

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

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Grace Mzumara ◽  
Stije Leopold ◽  
Kevin Marsh ◽  
Arjen Dondorp ◽  
Eric O. Ohuma ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Metabolic Acidosis ◽  
Falciparum Malaria ◽  
Model Building ◽  
Statistical Significance ◽  
Severe Metabolic Acidosis ◽  
African Countries ◽  
Prognostic Features ◽  
African Children ◽  
Severe Falciparum Malaria

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.

scholarly journals Thrombocytopenia in Malaria- a retrospective study

2015 ◽  
Vol 10 (1) ◽  
pp. 25-28
Author(s):  
Susane Giti ◽  
Md Mizanur Rahman ◽  
Md Saiful Islam ◽  
Ahmed Fayezi Bin Saad ◽  
Mohammed Nuruzzaman Bhuiyan
Keyword(s):  
Plasmodium Falciparum ◽  
Blood Cell ◽  
Falciparum Malaria ◽  
Vivax Malaria ◽  
Armed Forces ◽  
Severe Thrombocytopenia ◽  
Cross Sectional ◽  
Platelet Counts ◽  
Cell Counts ◽  
Blood Cell Counts

Introduction: Malaria is usually associated with low blood cell counts and mild to moderate thrombocytopenia is a common association. The cause of thrombocytopenia is poorly understood, but the immune-mediated lysis, sequestration in the spleen and diminished platelet production by the bone marrow have all been postulated. Objectives: This study was carried out to evaluate the degree of thrombocytopenia in patients suffering from malaria. Methods: This retrospective cross-sectional analytical study was conducted at Armed Forces Institute of Pathology (AFIP), over a period of one-year from January 2012 to December 2012. A total 81 cases of malaria parasite positive on peripheral blood film were studied by full blood counts (FBC) with automated haematology analyzer Sysmex 1800i. Thick and thin smears were stained with Giemsa and Leishman stains and examined by haematologist. Data was analyzed using the SPSS version 10.0. Results: Out of 81 patients, all were male. Mean age was 24.3 years (Mean+2SD:24.3±10.7) with a range of 23-42 years. Plasmodium falciparum was detected in 61(75.3%) cases, P. vivax in 16 (19.8%) and mixed infection in 04 (4.9%) cases. Haemoglobin values in patients of malaria with thrombocytopenia and without thrombocytopenia were 10.8±3.2 g/dl and 12.2±2.6 g/dl respectively. White blood cell counts in patients with and without thrombocytopenia were 6.2±4.3X109/L and 9.3±5.2X109/L respectively. 25 JAFMC Bangladesh. Vol 10, No 1 (June) 2014 Out of 81 patients, 23 (28.4%) had normal platelet counts, and 58 (71.6%) had thrombocytopenia. Platelet counts in patients with malaria with and without thrombocytopenia were 48.1±25.3X109/L and 199±45.4X109 respectively. The mild, moderate and severe thrombocytopenia were found in 44 (75.9%), 09 (15.5%) and 05 (8.6%) cases respectively. Platelet counts of <20X109/L were noted in only 8.6% cases of falciparum malaria and none in vivax malaria. Conclusion: The study found high frequency of mild to moderate thrombocytopenia in the Plasmodium falciparum and plasmodium vivax malaria. Although thrombocytopenia is uncommon in malaria, its presence is not a distinguishing feature between the two types. Finding of thrombocytopenia in a patient with fever is of diagnostic help as it raises the suspicion of malaria. Thrombocytopenia of <20X109/L can occur in P. vivax malaria although it is statistically more common with P. falciparum malaria. The above findings can have therapeutic implications in context of avoiding unnecessary platelet infusions with the relatively benign course in P. vivax malaria. DOI: http://dx.doi.org/10.3329/jafmc.v10i1.22899 Journal of Armed Forces Medical College Bangladesh Vol.10(1) 2014

Moderate Pharmacological Platelet Count Reduction Limits Thrombus Formation without Hemostatic Impairment in Primates

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1033-1033
Author(s):  
Erik I Tucker ◽  
Ulla M Marzec ◽  
Sawan Hurst ◽  
András Gruber ◽  
Stephen R Hanson
Keyword(s):  
Platelet Count ◽  
Platelet Function ◽  
Thrombus Formation ◽  
Significant Risk ◽  
Platelet Counts ◽  
Thrombosis Model ◽  
Cell Counts ◽  
Increased Risk ◽  
Platelet Deposition ◽  
Av Shunt

Abstract Despite the established contribution of platelets to thrombotic cardiovascular disorders, documented in part by the effectiveness of platelet function inhibitors and the increased risk of thrombosis associated with high normal and supranormal platelet counts, relationships between circulating platelet count and thrombotic events remain largely undefined. Since the initiation and propagation of arterial, platelet-dependent thrombus must depend upon platelet count, albeit in a manner that could be nonlinear, we hypothesized that reducing platelet count within the normal range would produce an anti-thrombotic benefit with minimal effects on hemostasis. To test this hypothesis, we reduced the platelet count in baboons (n=4) by targeting the megakaryocyte growth and development factor thrombopoietin (TPO). A polyclonal anti-TPO autoantibody (anti-TPOab) was purified from the serum of a baboon that developed thrombocytopenia following recombinant TPO injections. The IC50 of the purified IgG fraction was found to be 0.76 μg/ml, determined using a proliferation assay with a TPO-dependent cell line. An i.v. bolus of the anti-TPO antiserum, 30–35 ml infused into baboons, resulted in a transient, &gt;60% decrease in the circulating platelet count after 2–3 weeks. Other blood cell counts were unaffected vs. baseline values. The effect of platelet count reduction on thrombogenesis was evaluated using an established baboon arteriovenous (AV) shunt thrombosis model. Accumulation of 111-Indium-labeled platelets and 125-Iodine-labeled fibrinogen were measured within a 4 mm i.d. thrombogenic vascular graft segment that was deployed into a chronic AV shunt for 60 min. Blood flow was maintained at 100 ml/min, producing an arterial wall shear rate of 265 sec−1. Standard template bleeding times (BTs) were used to assess hemostatic impairment at various platelet counts. Platelet count reductions, ranging from 46–61% (normal levels averaging 352,000 ± 61,000 platelets/μl), reduced platelet deposition onto the graft surface by 46–68% (vs. control values of 4.1 ± 0.9 x 109 platelets deposited, n=9). Similarly, thrombus fibrin accumulation was reduced by 14–39% (vs. control values of 2.2 ± 0.4 mgs of deposited fibrin). Thrombus formation was not affected acutely by anti-TPOab administration, but correlated directly with circulating platelet numbers. As expected, BTs were not significantly prolonged until platelet counts fell below ~100,000 cells/μl. In contrast, single dose aspirin (32 mg/kg) at normal platelet counts did not significantly reduce graft associated platelet deposition in this model but doubled the BTs to 6.8 ± 2.6 min (vs. control values of 3.4 ± 0.9 min). With further reduction in platelet counts to 90,000 ± 30,000 platelets/μL, BTs were only slightly prolonged (5.6 ± 1.7 min, n=5). When platelet counts averaged 74,000 ± 20,000 platelets/μl in animals given ASA, BTs averaged only 9.4 ± 2.7 min (n=5). Thus ASA produced a hemostatic impairment that was approximately fixed (i.e., a BT prolongation of 3–4 min) and not disproportionately prolonged at reduced platelet counts. Thus specific lowering of the platelet count by pharmacologic inhibition of megakaryocytopoiesis may be an effective anti-thrombotic strategy in populations currently treated with conventional anti-platelet agents. Since direct inhibitors of platelet function produce a significant risk of bleeding, inhibition of platelet production may represent a safer approach for reducing the pro-thrombotic capacity of the circulating platelet pool.

2-O, 3-O-Desulfated Heparin (ODSH) Mitigates Chemotherapy-Induced Thrombocytopenia (CIT) by Blocking the Negative Paracrine Effect of Platelet Factor 4 (PF4) On Megakaryopoiesis

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 386-386 ◽  
Author(s):  
Michele Lambert ◽  
Samriddhi S Sharma ◽  
Liqing Xiao ◽  
Stephen Marcus ◽  
Mortimer Poncz
Keyword(s):  
Platelet Count ◽  
Steady State ◽  
Unfractionated Heparin ◽  
Clinical Studies ◽  
Myelosuppressive Chemotherapy ◽  
Platelet Counts ◽  
Cell Counts ◽  
Count Recovery

Abstract Abstract 386 Thrombocytopenia is a significant complication of myelosuppressive chemotherapy treatments, which are a mainstay in cancer therapy. We and others have previously shown that PF4 is a negative paracrine affecting megakaryocyte number in culture. In murine studies we showed that platelet PF4 levels are inversely related to steady-state platelet counts and is a major contributor to the duration and severity of CIT. Recently, we have shown that PF4 influences both steady-state platelet count and platelet count recovery in pediatric patients treated for acute lymphoblastic leukemia. Pre-clinical studies in murine models suggest that blocking the effect of PF4 (using polyclonal anti-PF4 antibodies) can mitigate the effect of PF4 on megakaryopoiesis and results in a shortened time to platelet count recovery and higher nadir platelet count. Heparin is known to bind PF4 tightly and can clear PF4 from the vascular endothelium. Pre-clinical studies using heparin to mitigate CIT failed to show an effect, but were limited by dose considerations due to the anti-coagulant effect of unfractionated heparin (UFH) and likely by the inability of this highly negative polysaccharide to reach the intramedullary space in high enough amounts to alter available PF4. ODSH does not exhibit the same effect as unfractionated heparin (UFH) in enhancing antithrombin effects and may allow studies of non-anticoagulant pharmacologic effects of heparin. For example, ODSH retains UFH's anti-inflammatory effects and its ability to bind tightly to PF4. In preliminary results of a clinical trial using ODSH in conjunction with myelosuppressive chemotherapy in patients with metastatic pancreatic cancer, there was a striking lack of clinically significant CIT as will be reported separately at this meeting. This prompted our evaluation of whether ODSH affects CIT and modulates platelet count recovery and whether this is through its interaction with PF4. We first examined the ability of ODSH to prevent the PF4 effect on megakaryopoiesis in vitro. Using a megakaryocyte colony assay, we show that PF4 treatment of PF4null murine megakaryocytes decreases megakaryocyte colony numbers (54±3% control vs. 23±6% PF4-treated, p<0.001) and treatment with ODSH completely blocks the PF4 effect (55±9% ODSH/PF4-treated, p<0.001 vs. PF4-treated). This suggested that the major mechanism by which ODSH prevents CIT is through inhibition of the PF4 effect. We then examined the effect of ODSH on liquid murine bone marrow culture and showed that ODSH treatment (50 μg/mL) was able to improve cell counts in the presence of added recombinant human PF4 (50 μg/mL) (9.2±3.3 × 104 cells/mL in PF4-treated cells vs. 19.3±4.2 × 104 cells/mL in ODSH+PF4-treated cells, p<0.01). Finally, we examined the in vivo effect of ODSH on CIT in a murine model of chemotherapy in transgenic mice that overexpress human (h) PF4. In these hPF4 mice, endogenous PF4 levels significantly affect enhances the degree and duration of 5FU-induced CIT. We previously reported that treatment of animals with anti-hPF4 antibodies was able to completely abolish the PF4 effect. Using the same model, injecting 180 mg/kg 5-fluourouracil (5-FU) intraperitoneally on day 0, we examined the effect on platelet counts of treatment with 2 clinically relevant doses of ODSH (25 mg/kg/dose) given subcutaneously 30 minutes and 24 hours after injection of 5-FU. hPF4 mice treated with 5-FU and ODSH had a higher platelet count nadir (70±14% versus vs. 44±1% of baseline). The nadir platelet count in the ODSH-treated mice was similar to that in mPF4null mice (57±20% of baseline). In addition, animals treated with ODSH recovered approximately 2 days earlier. In summary, ODSH mitigates CIT resulting in decreased severity and duration of thrombocytopenia. These studies suggest that this effect is mediated in large part by PF4 as in vitro experiments show that ODSH completely blocks the effect of PF4 on megakaryopoiesis. The in vivo studies support that sufficient ODSH reaches the marrow to block intramedullary-released PF4 and prevents its inhibition of megakaryopoiesis. This drug is already in clinical trials in humans and may be the first clinically relevant inhibitor of CIT. Further studies will examine its effect in other thrombocytopenic settings. Disclosures: Marcus: Paringenix: Employment, Equity Ownership.

Severe malaria is associated with a deficiency of von Willebrand factor cleaving protease, ADAMTS13

2010 ◽  
Vol 103 (01) ◽  
pp. 181-187 ◽  
Author(s):  
Prakaykaew Charunwatthana ◽  
Sophie Cohen ◽  
Bert-Jan van den Born ◽  
Joost Meijers ◽  
Emran Yunus ◽  
...  
Keyword(s):  
Severe Malaria ◽  
Falciparum Malaria ◽  
Von Willebrand Factor ◽  
Activity Levels ◽  
Adamts13 Activity ◽  
Life Threatening ◽  
Von Willebrand ◽  
Willebrand Factor ◽  
Severe Falciparum Malaria ◽  
Normal Controls

SummarySevere falciparum malaria remains a major killer in tropical countries. Central in the pathophysiology is mechanical obstruction in the micro-circulation caused by cytoadherence and sequestration of parasitized erythrocytes. However, the pathogenesis of many features complicating severe malaria, including coma, renal failure and thrombocytopenia, remains incompletely understood. These disease manifestations are also key features of thrombotic thrombocytopenic purpura, a life-threatening disease strongly associated with a deficiency of the von Willebrand factor (VWF) cleaving protease, ADAMTS13. We measured plasma ADAMTS13 activity, VWF antigen and VWF propeptide levels in 30 patients with severe falciparum malaria, 12 patients with uncomplicated falciparum malaria and 14 healthy Bangladeshi controls. In patients with severe malaria ADAMTS13 activity levels were markedly decreased in comparison to normal controls (mean [95%CI]: 23% [20–26] vs. 64% [55–72]) and VWF antigen and propeptide concentrations were significantly elevated (VWF antigen: 439% [396–481] vs. 64% [46–83]; VWF propeptide: 576% [481–671] vs. 69% [59–78]). In uncomplicated malaria VWF levels were also increased compared to healthy controls but ADAMTS13 activity was normal. The results suggest that decreased ADAMTS13 activity in combination with increased VWF concentrations may contribute to the complications in severe malaria.

scholarly journals Atypical brain response to novelty in rural African children with a history of severe falciparum malaria

2010 ◽  
Vol 296 (1-2) ◽  
pp. 88-95 ◽  
Author(s):  
Michael Kihara ◽  
Michelle de Haan ◽  
Harrun H. Garrashi ◽  
Brian G.R. Neville ◽  
Charles R.J.C. Newton
Keyword(s):  
Falciparum Malaria ◽  
Brain Response ◽  
African Children ◽  
History Of ◽  
Severe Falciparum Malaria
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