Identifying critically ill children in Malawi: A modified qSOFA score for low-resource settings.

In low-resource settings, a reliable bedside score for timely identification of children at risk of dying, could help focus resources and improve survival. The rapid bedside Liverpool quick Sequential Organ Failure Assessment (LqSOFA) uses clinical parameters only and performed well in United Kingdom cohorts. A similarly quick clinical assessment-only score has however not yet been developed for paediatric populations in sub-Saharan Africa. In a development cohort of critically ill children in Malawi, we calculated the LqSOFA scores using age-adjusted heart rate and respiratory rate, capillary refill time and Blantyre Coma Scale, and evaluated its prognostic performance for mortality. An improved score, the Blantyre qSOFA (BqSOFA), was developed (omitting heart rate, adjusting respiratory rate cut-off values and adding pallor), subsequently validated in a second cohort of Malawian children, and compared with an existing score (FEAST-PET). Prognostic performance for mortality was evaluated using area under the receiver operating characteristic curve (AUC). Mortality was 15.4% in the development (N = 493) and 22.0% in the validation cohort (N = 377). In the development cohort, discriminative ability (AUC) of the LqSOFA to predict mortality was 0.68 (95%-CI: 0.60-0.76). The BqSOFA and FEAST-PET yielded AUCs of 0.84 (95%-CI:0.79-0.89) and 0.83 (95%-CI:0.77-0.89) in the development cohort, and 0.74 (95%-CI:0.68-0.79) and 0.76 (95%-CI:0.70-0.82) in the validation cohort, respectively. We developed a simple prognostic score for Malawian children based on four clinical parameters which performed as well as a more complex score. The BqSOFA might be used to promptly identify critically ill children at risk of dying and prioritize hospital care in low-resource settings

Severe anemia in Malawian children

Background Severe anemia is a major cause of sickness and death in African children, yet the causes of anemia in this population have been inadequately studied. Methods We conducted a case-control study of 381 preschool children with severe anemia (hemoglobin concentration, <5.0 g per deciliter) and 757 preschool children without severe anemia in urban and rural settings in Malawi. Causal factors previously associated with severe anemia were studied. The data were examined by multivariate analysis and structural equation modeling. Results Bacteremia (adjusted odds ratio, 5.3; 95% confidence interval [CI], 2.6 to 10.9), malaria (adjusted odds ratio, 2.3; 95% CI, 1.6 to 3.3), hookworm (adjusted odds ratio, 4.8; 95% CI, 2.0 to 11.8), human immunodeficiency virus infection (adjusted odds ratio, 2.0; 95% CI, 1.0 to 3.8), the G6PD(sup -202/-376) genetic disorder (adjusted odds ratio, 2.4; 95% CI, 1.3 to 4.4), vitamin A deficiency (adjusted odds ratio, 2.8; 95% CI, 1.3 to 5.8), and vitamin B(sub 12) deficiency (adjusted odds ratio, 2.2; 95% CI, 1.4 to 3.6) were associated with severe anemia. Folate deficiency, sickle cell disease, and laboratory signs of an abnormal inflammatory response were uncommon. Iron deficiency was not prevalent in case patients (adjusted odds ratio, 0.37; 95% CI, 0.22 to 0.60) and was negatively associated with bacteremia. Malaria was associated with severe anemia in the urban site (with seasonal transmission) but not in the rural site (where malaria was holoendemic). Seventy-six percent of hookworm infections were found in children under 2 years of age. Conclusions There are multiple causes of severe anemia in Malawian preschool children, but folate and iron deficiencies are not prominent among them. Even in the presence of malaria parasites, additional or alternative causes of severe anemia should be considere

Estimating the Fitness Cost of Escape from HLA Presentation in HIV-1 Protease and Reverse Transcriptase

Human immunodeficiency virus (HIV-1) is, like most pathogens, under selective pressure to escape the immune system of its host. In particular, HIV-1 can avoid recognition by cytotoxic T lymphocytes (CTLs) by altering the binding affinity of viral peptides to human leukocyte antigen (HLA) molecules, the role of which is to present those peptides to the immune system. It is generally assumed that HLA escape mutations carry a replicative fitness cost, but these costs have not been quantified. In this study, we assess the replicative cost of mutations which are likely to escape presentation by HLA molecules in the region of HIV-1 protease and reverse transcriptase. Specifically, we combine computational approaches for prediction of in vitro replicative fitness and peptide binding affinity to HLA molecules. We find that mutations which impair binding to HLA-A molecules tend to have lower in vitro replicative fitness than mutations which do not impair binding to HLA-A molecules, suggesting that HLA-A escape mutations carry higher fitness costs than non-escape mutations. We argue that the association between fitness and HLA-A binding impairment is probably due to an intrinsic cost of escape from HLA-A molecules, and these costs are particularly strong for HLA-A alleles associated with efficient virus control. Counter-intuitively, we do not observe a significant effect in the case of HLA-B, but, as discussed, this does not argue against the relevance of HLA-B in virus control. Overall, this article points to the intriguing possibility that HLA-A molecules preferentially target more conserved regions of HIV-1, emphasizing the importance of HLA-A genes in the evolution of HIV-1 and RNA viruses in general

Specific Receptor Usage in Plasmodium falciparum Cytoadherence Is Associated with Disease Outcome

Our understanding of the basis of severe disease in malaria is incomplete. It is clear that pathology is in part related to the pro-inflammatory nature of the host response but a number of other factors are also thought to be involved, including the interaction between infected erythrocytes and endothelium. This is a complex system involving several host receptors and a major parasite-derived variant antigen (PfEMP1) expressed on the surface of the infected erythrocyte membrane. Previous studies have suggested a role for ICAM-1 in the pathology of cerebral malaria, although these have been inconclusive. In this study we have examined the cytoadherence patterns of 101 patient isolates from varying clinical syndromes to CD36 and ICAM-1, and have used variant ICAM-1 proteins to further characterise this adhesive phenotype. Our results show that increased binding to CD36 is associated with uncomplicated malaria while ICAM-1 adhesion is raised in parasites from cerebral malaria cases

Severe anaemia is not associated with HIV-1 <it>env </it>gene characteristics in Malawian children

Abstract Background Anaemia is the most common haematological complication of HIV and associated with a high morbidity and a poor prognosis. The pathogenesis of HIV-associated anaemia is poorly understood and may include a direct effect of HIV on erythropoiesis. In vitro studies have suggested that specific HIV strains, like X4 that uses the CXCR4 co-receptor present on erythroid precursors, are associated with diminished erythropoiesis. This co-receptor affinity is determined by changes in the hypervariable loop of the HIV-1 envelope genome. In a previous case-control study we observed an association between HIV and severe anaemia in Malawian children that could not be fully explained by secondary infections and micronutrient deficiencies alone. We therefore explored the possibility that alterations in the V1-V2-V3 fragment of HIV-1 were associated with severe anaemia. Methods Using peripheral blood nucleic acid isolates of HIV-infected children identified in the previous studied we assessed if variability of the V1-V2-V3 region of HIV and the occurrence of X4 strains were more common in HIV-infected children with (cases, n = 29) and without severe anaemia (controls, n = 30). For 15 cases bone marrow isolates were available to compare against peripheral blood. All children were followed for 18 months after recruitment. Results Phylogenetic analysis showed that HIV-1 subtype C was present in all but one child. All V1-V2-V3 characteristics tested: V3 charge, V1-V2 length and potential glycosylation sites, were not found to be different between cases and controls. Using a computer model (C-PSSM) four children (7.8%) were identified to have an X4 strain. This prevalence was not different between study groups (p = 1.00). The V3 loop characteristics for bone marrow and peripheral blood isolates in the case group were identical. None of the children identified as having an X4 strain developed a (new) episode of severe anaemia during follow up. Conclusion The prevalence of X4 strains in these young HIV-1-subtype-C-infected children that were most likely vertically infected and naïve to anti-retroviral therapy can be considered high compared to previous results from Malawi. It is unlikely that V1-V2-V3 fragment characteristics and HIV co-receptor affinity is an important feature in the development of severe anaemia in Malawian children.</p

Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children-2

Mia (cases, Hb<p><b>Copyright information:</b></p><p>Taken from "Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children"</p><p>http://www.biomedcentral.com/1471-2334/8/26</p><p>BMC Infectious Diseases 2008;8():26-26.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2311312.</p><p></p

Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children-4

(cases, Hb<p><b>Copyright information:</b></p><p>Taken from "Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children"</p><p>http://www.biomedcentral.com/1471-2334/8/26</p><p>BMC Infectious Diseases 2008;8():26-26.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2311312.</p><p></p

Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children-3

Ent in children with severe anaemia (cases, Hb<p><b>Copyright information:</b></p><p>Taken from "Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children"</p><p>http://www.biomedcentral.com/1471-2334/8/26</p><p>BMC Infectious Diseases 2008;8():26-26.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2311312.</p><p></p

Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children-0

, Hb<p><b>Copyright information:</b></p><p>Taken from "Severe anaemia is not associated with HIV-1 gene characteristics in Malawian children"</p><p>http://www.biomedcentral.com/1471-2334/8/26</p><p>BMC Infectious Diseases 2008;8():26-26.</p><p>Published online 29 Feb 2008</p><p>PMCID:PMC2311312.</p><p></p