Abstract
Background: Plasmodium falciparum malaria is a leading global killer of children and cause for transfusion in endemic areas. Sequestration cytopenias and microvascular insufficiency are pathologic consequences of the acquired cytoadhesivity of P falciparum-infected red blood cells (iRBC). Parasite-derived surface knobs (PfEMP1) expressed on iRBC promote their binding to blood group ligands on non-infected blood cells and the microvascular endothelium. The purpose of the Cytoadherence in Pediatric Malaria Study (clinicaltrials.gov, NCT 00707200) is to study the association between malaria outcomes and host markers of cytoadhesion.
Methods: This prospective observational study of children with malaria (age 6 m–12 y, HIV-neg) was launched in October 2007 at Mulago Hospital, Uganda. Patients with severe malaria syndromes, as defined by the WHO, were compared with uncomplicated malaria (UM) patients for presenting hematologic features and transfusion practices. Associations between severe malaria syndromes and mortality were also explored.
Results: Over the study’s 1st 7 months, 785 patients were screened, 492 enrolled, and 44 excluded (40 malaria false positives, 4 HIV+). A total of 448 were analyzed (199 severe, 249 UM), including 16 deaths (severe malaria case fatality rate: 8%). Patients were 55% male/45% female. Severe malaria patients were significantly younger than those with UM (2.3 ± 1.9 y, 93% ≤ 5 y, vs 3.5 ± 2.7 y, 76% <5 y), p < 2×10−7. Hematologic features of the patients are summarized in Table 1, illustrating significantly greater derangements in the CBC of severe cases versus UM. In contrast, both groups had a similar sickle trait prevalence and level of parasitemia:
Table 1: Hematologic Features in Uncomplicated Malaria (UM) vs Severe Malaria
UM (n = 249) Severe (n = 199) signifinance WBC Count, × 10 9/L [mean ± sd] 8.1 ± 3.5 12.8 ± 8.1 p = 2.6 × 10−13 Hemoglobin, g/dL [mean ± sd] 9.3 ± 1.5 5.2 ± 2.1 p = 2.1 × 10−71 Severe Malarial Anemia [number, % ], Hb ≥ 5 g/dL 0 (0 %) 130 (65.3 %) χ2 = 226 Platelet Count, × 10 3/μL, [mean ± sd] 160,000 ± 103,000 129,000 ± 98,000 p =.0015 Severe Thrombocytopenia [n, %], Plt ≥ 50,000/μL 17 (6.8 %) 39 (19.6 %) χ2 = 15.3 Sickle Trait on Screen or History [n, %] 11/157 (7.0 %) 12/118 (10.2 %) χ2 =.51 (NS) Quantitative Parasitemia,/μL [median, range] 80,000 (7–10,638,000) 65,000 (60–2,593,000) p =.8 (NS) Hyperparasitemia [n, % ], Parasites ≥250,000/μL 42 (16.9 %) 44 (22.1 %) χ2 = 1.6 (NS)
Among severe cases, severe malarial anemia (SMA) was the most common syndrome (n=130, 65%), followed by lactic acidosis (LA, n=93, 47%), respiratory distress (RD, n=91, 46%), hypoglycaemia (HG, n=22, 23%), cerebral malaria (CM, n=43, 22%), and hypoxia (HO, n=14, 7%). Among fatal cases, RD occurred most commonly (94%), followed by LA (75%), CM (56%), HG (42%), and SMA (only 31%). Overall, RBC transfusions were given to 78% of severe cases, and all but 1 of 130 SMA cases. Despite severe anemia, most received only 1 unit (1.2 ±.5 pediatric units/patient, range 1–3). 83% of transfusions were given for SMA and 10% for RD (without SMA). Significant delays or dose insufficiency of blood products occurred in 5.2% of recipients. ABO non-identical but compatible products were given 10.2% of the time. In unadjusted analysis of severe cases, associations between the hemolytic state of SMA and either hypoxia or respiratory distress (as possible signs of pulmonary hypertension) were not apparent (χ2=.01 and 2.2 respectively). LA was associated with SMA (χ2=4.7, p=.03), but not with the smaller subset of SMA patients with HO (χ2=.61, p=.43). The strongest association occurred between LA and RD (χ2=29.3, p<.0001), tying labored breathing to acidotic respiratory compensation.
Conclusions: Hematologic abnormalities are seen across the entire spectrum of severe and uncomplicated pediatric P falciparum malaria in Uganda, and are most striking in the severe syndromes. Among patients with severe malaria, SMA is the most common feature, while severe thrombocytopenia occurs in up to 20%. SMA is not as predictive of death as either RD, LA, or CM. LA in turn occurs even in the absence of severe anemia and/or hypoxia, highlighting the potential contribution of microvascular ischemia from cytoadhesion. Cytoadhesion between infected red cells and host ligands is thus an appealing area of focus for studies of the pathogenesis of malaria morbidity and mortality in children.
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