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Article ; Online: Identification of a Novel Clinical Phenotype of Severe Malaria using a Network-Based Clustering Approach.

Cominetti, Ornella / Smith, David / Hoffman, Fred / Jallow, Muminatou / Thézénas, Marie L / Huang, Honglei / Kwiatkowski, Dominic / Maini, Philip K / Casals-Pascual, Climent

Scientific reports

2018 Volume 8, Issue 1, Page(s) 12849

Abstract: The parasite Plasmodium falciparum is the main cause of severe malaria (SM). Despite treatment with antimalarial drugs, more than 400,000 deaths are reported every year, mainly in African children. The diversity of clinical presentations associated with ... ...

Abstract	The parasite Plasmodium falciparum is the main cause of severe malaria (SM). Despite treatment with antimalarial drugs, more than 400,000 deaths are reported every year, mainly in African children. The diversity of clinical presentations associated with SM highlights important differences in disease pathogenesis that often require specific therapeutic options. The clinical heterogeneity of SM is largely unresolved. Here we report a network-based analysis of clinical phenotypes associated with SM in 2,915 Gambian children admitted to hospital with Plasmodium falciparum malaria. We used a network-based clustering method which revealed a strong correlation between disease heterogeneity and mortality. The analysis identified four distinct clusters of SM and respiratory distress that departed from the WHO definition. Patients in these clusters characteristically presented with liver enlargement and high concentrations of brain natriuretic peptide (BNP), giving support to the potential role of circulatory overload and/or right-sided heart failure as a mechanism of disease. The role of heart failure is controversial in SM and our work suggests that standard clinical management may not be appropriate. We find that our clustering can be a powerful data exploration tool to identify novel disease phenotypes and therapeutic options to reduce malaria-associated mortality.
MeSH term(s)	Anemia/etiology ; Biomarkers ; Child ; Child, Preschool ; Female ; Humans ; Malaria/complications ; Malaria/diagnosis ; Malaria/mortality ; Malaria/parasitology ; Malaria, Falciparum/diagnosis ; Malaria, Falciparum/mortality ; Malaria, Falciparum/parasitology ; Male ; Neural Networks, Computer ; Phenotype ; Plasmodium falciparum ; Severity of Illness Index
Chemical Substances	Biomarkers
Language	English
Publishing date	2018-08-27
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-018-31320-w
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Article ; Online: The effect of blood transfusion on outcomes among African children admitted to hospital with Plasmodium falciparum malaria: a prospective, multicentre observational study.

Ackerman, Hans / Ayestaran, Aintzane / Olola, Christopher H O / Jallow, Muminatou / Agbenyega, Tsiri / Bojang, Kalifa / Roberts, David J / Krishna, Sanjeev / Kremsner, Peter G / Newton, Charles R / Taylor, Terrie / Valim, Clarissa / Casals-Pascual, Climent

The Lancet. Haematology

2020 Volume 7, Issue 11, Page(s) e789–e797

Abstract: Background: Infection with Plasmodium falciparum leads to severe malaria and death in approximately 400 000 children each year in sub-Saharan Africa. Blood transfusion might benefit some patients with malaria but could potentially harm others. The aim ... ...

Abstract	Background: Infection with Plasmodium falciparum leads to severe malaria and death in approximately 400 000 children each year in sub-Saharan Africa. Blood transfusion might benefit some patients with malaria but could potentially harm others. The aim of this study was to estimate the association between transfusion and death among children admitted to hospital with P falciparum malaria. Methods: In this prospective, multicentre observational study, we analysed admissions to six tertiary care hospitals in The Gambia, Malawi, Gabon, Kenya, and Ghana that participated in the Severe Malaria in African Children network. Patients were enrolled if they were younger than 180 months and had a Giemsa-stained thick blood smear that was positive for P falciparum. Blood transfusion (whole blood at a target volume of 20 mL per kg) was administered at the discretion of the responsible physicians who were aware of local and international transfusion guidelines. The primary endpoint was death associated with transfusion, which was estimated using models adjusted for site and disease severity. We also aimed to identify factors associated with the decision to transfuse. The exploratory objective was to estimate optimal haemoglobin transfusion thresholds using generalised additive models. Findings: Between Dec 19, 2000, and March 8, 2005, 26 106 patients were enrolled in the study, 25 893 of whom had their transfusion status recorded and were included in the primary analysis. 8513 (32·8%) patients received a blood transfusion. Patients were followed-up until discharge from hospital for a median of 2 days (IQR 1-4). 405 (4·8%) of 8513 patients who received a transfusion died compared with 689 (4·0%) of 17 380 patients who did not receive a transfusion. Transfusion was associated with decreased odds of death in site-adjusted analysis (odds ratio [OR] 0·82 [95% CI 0·71-0·94]) and after adjusting for the increased disease severity of patients who received a transfusion (0·50 [0·42-0·60]). Severe anaemia, elevated lactate concentration, respiratory distress, and parasite density were associated with greater odds of receiving a transfusion. Among all study participants, transfusion was associated with improved survival when the admission haemoglobin concentration was up to 77 g/L (95% CI 65-110). Among those with impaired consciousness (Blantyre Coma Score ≤4), transfusion was associated with improved survival at haemoglobin concentrations up to 105 g/L (95% CI 71-115). Among those with hyperlactataemia (blood lactate ≥5·0 mmol/L), transfusion was not significantly associated with harm at any haemoglobin concentration-ie, the OR of death comparing transfused versus not transfused was less than 1 at all haemoglobin concentrations (lower bound of the 95% CI for the haemoglobin concentration at which the OR of death equals 1: 90 g/L; no upper bound). Interpretation: Our findings suggest that whole blood transfusion was associated with improved survival among children hospitalised with P falciparum malaria. Among those with impaired consciousness or hyperlactataemia, transfusion was associated with improved survival at haemoglobin concentrations above the currently recommended transfusion threshold. These findings highlight the need to do randomised controlled trials to test higher transfusion thresholds among African children with severe malaria complicated by these factors. Funding: US National Institute of Allergy and Infectious Diseases.
MeSH term(s)	Anemia/complications ; Antimalarials/therapeutic use ; Blood Transfusion ; Child, Preschool ; Consciousness ; Hemoglobins/analysis ; Hospitalization ; Humans ; Hyperlactatemia/complications ; Infant ; Kenya ; Malaria, Falciparum/complications ; Malaria, Falciparum/drug therapy ; Malaria, Falciparum/mortality ; Malaria, Falciparum/pathology ; Odds Ratio ; Prospective Studies ; Quinine/therapeutic use ; Severity of Illness Index ; Survival Rate ; Tertiary Care Centers ; Treatment Outcome
Chemical Substances	Antimalarials ; Hemoglobins ; Quinine (A7V27PHC7A)
Language	English
Publishing date	2020-10-26
Publishing country	England
Document type	Journal Article ; Multicenter Study ; Observational Study
ISSN	2352-3026
ISSN (online)	2352-3026
DOI	10.1016/S2352-3026(20)30288-X
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Article ; Online: Precision identification of high-risk phenotypes and progression pathways in severe malaria without requiring longitudinal data.

Johnston, Iain G / Hoffmann, Till / Greenbury, Sam F / Cominetti, Ornella / Jallow, Muminatou / Kwiatkowski, Dominic / Barahona, Mauricio / Jones, Nick S / Casals-Pascual, Climent

NPJ digital medicine

2019 Volume 2, Page(s) 63

Abstract: More than 400,000 deaths from severe malaria (SM) are reported every year, mainly in African children. The diversity of clinical presentations associated with SM indicates important differences in disease pathogenesis that require specific treatment, and ...

Abstract	More than 400,000 deaths from severe malaria (SM) are reported every year, mainly in African children. The diversity of clinical presentations associated with SM indicates important differences in disease pathogenesis that require specific treatment, and this clinical heterogeneity of SM remains poorly understood. Here, we apply tools from machine learning and model-based inference to harness large-scale data and dissect the heterogeneity in patterns of clinical features associated with SM in 2904 Gambian children admitted to hospital with malaria. This quantitative analysis reveals features predicting the severity of individual patient outcomes, and the dynamic pathways of SM progression, notably inferred without requiring longitudinal observations. Bayesian inference of these pathways allows us assign quantitative mortality risks to individual patients. By independently surveying expert practitioners, we show that this data-driven approach agrees with and expands the current state of knowledge on malaria progression, while simultaneously providing a data-supported framework for predicting clinical risk.
Language	English
Publishing date	2019-07-10
Publishing country	England
Document type	Journal Article
ISSN	2398-6352
ISSN (online)	2398-6352
DOI	10.1038/s41746-019-0140-y
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Article ; Online: Proteomic profiling of the plasma of Gambian children with cerebral malaria.

Moussa, Ehab M / Huang, Honglei / Thézénas, Marie L / Fischer, Roman / Ramaprasad, Abhinay / Sisay-Joof, Fatou / Jallow, Muminatou / Pain, Arnab / Kwiatkowski, Dominic / Kessler, Benedikt M / Casals-Pascual, Climent

Malaria journal

2018 Volume 17, Issue 1, Page(s) 337

Abstract: Background: Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection. A number of pathological findings have been correlated with pediatric CM including sequestration, platelet accumulation, petechial haemorrhage ... ...

Abstract	Background: Cerebral malaria (CM) is a severe neurological complication of Plasmodium falciparum infection. A number of pathological findings have been correlated with pediatric CM including sequestration, platelet accumulation, petechial haemorrhage and retinopathy. However, the molecular mechanisms leading to death in CM are not yet fully understood. Methods: A shotgun plasma proteomic study was conducted using samples form 52 Gambian children with CM admitted to hospital. Based on clinical outcome, children were assigned to two groups: reversible and fatal CM. Label-free liquid chromatography-tandem mass spectrometry was used to identify and compare plasma proteins that were differentially regulated in children who recovered from CM and those who died. Candidate biomarkers were validated using enzyme immunoassays. Results: The plasma proteomic signature of children with CM identified 266 proteins differentially regulated in children with fatal CM. Proteins from the coagulation cascade were consistently decreased in fatal CM, whereas the plasma proteomic signature associated with fatal CM underscored the importance of endothelial activation, tissue damage, inflammation, haemolysis and glucose metabolism. The concentration of circulating proteasomes or PSMB9 in plasma was not significantly different in fatal CM when compared with survivors. Plasma PSMB9 concentration was higher in patients who presented with seizures and was significantly correlated with the number of seizures observed in patients with CM during admission. Conclusions: The results indicate that increased tissue damage and hypercoagulability may play an important role in fatal CM. The diagnostic value of this molecular signature to identify children at high risk of dying to optimize patient referral practices should be validated prospectively.
MeSH term(s)	Adolescent ; Biomarkers/blood ; Blood Proteins/analysis ; Child ; Child, Preschool ; Female ; Gambia/epidemiology ; Humans ; Infant ; Malaria, Cerebral/genetics ; Malaria, Cerebral/mortality ; Malaria, Falciparum/genetics ; Malaria, Falciparum/mortality ; Male ; Plasmodium falciparum/physiology ; Proteome/analysis ; Proteomics
Chemical Substances	Biomarkers ; Blood Proteins ; Proteome
Language	English
Publishing date	2018-09-24
Publishing country	England
Document type	Journal Article
ZDB-ID	2091229-8
ISSN	1475-2875 ; 1475-2875
ISSN (online)	1475-2875
ISSN	1475-2875
DOI	10.1186/s12936-018-2487-y
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Article ; Online: Investigating the potential for ethnic group harm in collaborative genomics research in Africa: is ethnic stigmatisation likely?

de Vries, Jantina / Jallow, Muminatou / Williams, Thomas N / Kwiatkowski, Dominic / Parker, Michael / Fitzpatrick, Raymond

Social science & medicine (1982)

2012 Volume 75, Issue 8, Page(s) 1400–1407

Abstract: A common assumption in genomics research is that the use of ethnic categories has the potential to lead to ethnic stigmatisation - particularly when the research is done on minority populations. Yet few empirical studies have sought to investigate the ... ...

Abstract	A common assumption in genomics research is that the use of ethnic categories has the potential to lead to ethnic stigmatisation - particularly when the research is done on minority populations. Yet few empirical studies have sought to investigate the relation between genomics and stigma, and fewer still with a focus on Africa. In this paper, we investigate the potential for genomics research to lead to harms to ethnic groups. We carried out 49 semi-structured, open-ended interviews with stakeholders in a current medical genomics research project in Africa, MalariaGEN. Interviews were conducted with MalariaGEN researchers, fieldworkers, members of three ethics committees who reviewed MalariaGEN project proposals, and with members of the two funding bodies providing support to the MalariaGEN project. Interviews were conducted in Kenya, The Gambia and the UK between June 2008 and October 2009. They covered a range of aspects relating to the use of ethnicity in the genomics project, including views on adverse effects of the inclusion of ethnicity in such research. Drawing on the empirical data, we argue that the risk of harm to ethnic groups is likely to be more acute in specific types of genomics research. We develop a typology of research questions and projects that carry a greater risk of harm to the populations included in genomics research. We conclude that the potential of generating harm to ethnic groups in genomics research is present if research includes populations that are already stigmatised or discriminated against, or where the research investigates questions with particular normative implications. We identify a clear need for genomics researchers to take account of the social context of the work they are proposing to do, including understanding the local realities and relations between ethnic groups, and whether diseases are already stigmatised.
MeSH term(s)	Africa ; Cooperative Behavior ; Ethnicity/genetics ; Ethnicity/psychology ; Genetic Research ; Genome-Wide Association Study ; Genomics ; Humans ; Malaria/ethnology ; Malaria/genetics ; Qualitative Research ; Risk Assessment ; Stereotyping
Language	English
Publishing date	2012-06-16
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	4766-1
ISSN	1873-5347 ; 0037-7856 ; 0277-9536
ISSN (online)	1873-5347
ISSN	0037-7856 ; 0277-9536
DOI	10.1016/j.socscimed.2012.05.020
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Article ; Online: Malaria protection due to sickle haemoglobin depends on parasite genotype.

Band, Gavin / Leffler, Ellen M / Jallow, Muminatou / Sisay-Joof, Fatoumatta / Ndila, Carolyne M / Macharia, Alexander W / Hubbart, Christina / Jeffreys, Anna E / Rowlands, Kate / Nguyen, Thuy / Gonçalves, Sónia / Ariani, Cristina V / Stalker, Jim / Pearson, Richard D / Amato, Roberto / Drury, Eleanor / Sirugo, Giorgio / d'Alessandro, Umberto / Bojang, Kalifa A /

Marsh, Kevin / Peshu, Norbert / Saelens, Joseph W / Diakité, Mahamadou / Taylor, Steve M / Conway, David J / Williams, Thomas N / Rockett, Kirk A / Kwiatkowski, Dominic P

Nature

2021 Volume 602, Issue 7895, Page(s) 106–111

Abstract: Host genetic factors can confer resistance against ... ...

Abstract	Host genetic factors can confer resistance against malaria
MeSH term(s)	Alleles ; Animals ; Child ; Female ; Gambia/epidemiology ; Genes, Protozoan/genetics ; Genotype ; Hemoglobin, Sickle/genetics ; Host Adaptation/genetics ; Humans ; Kenya/epidemiology ; Linkage Disequilibrium ; Malaria, Falciparum/blood ; Malaria, Falciparum/epidemiology ; Malaria, Falciparum/parasitology ; Male ; Parasites/genetics ; Plasmodium falciparum/genetics ; Polymorphism, Genetic
Chemical Substances	Hemoglobin, Sickle
Language	English
Publishing date	2021-12-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/s41586-021-04288-3
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Article ; Online: Heterogeneous alleles comprising G6PD deficiency trait in West Africa exert contrasting effects on two major clinical presentations of severe malaria.

Shah, Shivang S / Rockett, Kirk A / Jallow, Muminatou / Sisay-Joof, Fatou / Bojang, Kalifa A / Pinder, Margaret / Jeffreys, Anna / Craik, Rachel / Hubbart, Christina / Wellems, Thomas E / Kwiatkowski, Dominic P

Malaria journal

2016 Volume 15, Page(s) 13

Abstract: Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits considerable allelic heterogeneity which manifests with variable biochemical and clinical penetrance. It has long been thought that G6PD deficiency confers partial protection ... ...

Abstract	Background: Glucose-6-phosphate dehydrogenase (G6PD) deficiency exhibits considerable allelic heterogeneity which manifests with variable biochemical and clinical penetrance. It has long been thought that G6PD deficiency confers partial protection against severe malaria, however prior genetic association studies have disagreed with regard to the strength and specificity of a protective effect, which might reflect differences in the host genetic background, environmental influences, or in the specific clinical phenotypes considered. Methods: A case-control association study of severe malaria was conducted in The Gambia, a region in West Africa where there is considerable allelic heterogeneity underlying expression of G6PD deficiency trait, evaluating the three major nonsynonymous polymorphisms known to be associated with enzyme deficiency (A968G, T542A, and C202T) in a cohort of 3836 controls and 2379 severe malaria cases. Results: Each deficiency allele exhibited a similar trend toward protection against severe malaria overall (15-26% reduced risk); however, in stratifying severe malaria to two of its constituent clinical subphenotypes, severe malarial anaemia (SMA) and cerebral malaria (CM), the three deficiency alleles exhibited trends of opposing effect, with risk conferred to SMA and protection with respect to CM. To assess the overall effect of G6PD deficiency trait, deficiency alleles found across all three loci were pooled. G6PD deficiency trait was found to be significantly associated with protection from severe malaria overall (OR 0.83 [0.75-0.92], P = 0.0006), but this was limited to CM (OR 0.73 [0.61-0.87], P = 0.0005), with a trend toward increased risk for SMA, especially in fully-deficient individuals (OR 1.43 [0.99-2.08], P = 0.056). Sex-stratified testing largely comported with these results, with evidence suggesting that protection by G6PD deficiency trait is conferred to both males and females, though susceptibility to SMA may be restricted to fully-deficient male hemizygotes. Conclusions: In a part of Africa where multiple alleles contribute to expression of G6PD deficiency trait, these findings clarify and extend previous work done in populations where a single variant predominates, and taken together suggest a causal role for G6PD deficiency trait itself with respect to severe malaria, with opposing effects seen on two major clinical subphenotypes.
MeSH term(s)	Adult ; Africa, Western ; Alleles ; Case-Control Studies ; Female ; Genetic Association Studies ; Glucosephosphate Dehydrogenase/genetics ; Humans ; Malaria/diagnosis ; Malaria/enzymology ; Male ; Middle Aged ; Polymorphism, Genetic/genetics
Chemical Substances	Glucosephosphate Dehydrogenase (EC 1.1.1.49)
Language	English
Publishing date	2016-01-07
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, N.I.H., Intramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2091229-8
ISSN	1475-2875 ; 1475-2875
ISSN (online)	1475-2875
ISSN	1475-2875
DOI	10.1186/s12936-015-1045-0
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Article ; Online: Admixture into and within sub-Saharan Africa.

Busby, George Bj / Band, Gavin / Si Le, Quang / Jallow, Muminatou / Bougama, Edith / Mangano, Valentina D / Amenga-Etego, Lucas N / Enimil, Anthony / Apinjoh, Tobias / Ndila, Carolyne M / Manjurano, Alphaxard / Nyirongo, Vysaul / Doumba, Ogobara / Rockett, Kirk A / Kwiatkowski, Dominic P / Spencer, Chris Ca

eLife

2016 Volume 5

Abstract: Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, ... ...

Abstract	Similarity between two individuals in the combination of genetic markers along their chromosomes indicates shared ancestry and can be used to identify historical connections between different population groups due to admixture. We use a genome-wide, haplotype-based, analysis to characterise the structure of genetic diversity and gene-flow in a collection of 48 sub-Saharan African groups. We show that coastal populations experienced an influx of Eurasian haplotypes over the last 7000 years, and that Eastern and Southern Niger-Congo speaking groups share ancestry with Central West Africans as a result of recent population expansions. In fact, most sub-Saharan populations share ancestry with groups from outside of their current geographic region as a result of gene-flow within the last 4000 years. Our in-depth analysis provides insight into haplotype sharing across different ethno-linguistic groups and the recent movement of alleles into new environments, both of which are relevant to studies of genetic epidemiology.
MeSH term(s)	Africa South of the Sahara ; Blacks ; Gene Flow ; Genetic Variation ; Genome, Human ; Haplotypes ; Human Migration ; Humans
Language	English
Publishing date	2016-06-21
Publishing country	England
Document type	Journal Article
ZDB-ID	2687154-3
ISSN	2050-084X ; 2050-084X
ISSN (online)	2050-084X
ISSN	2050-084X
DOI	10.7554/eLife.15266
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Article ; Online: Classical sickle beta-globin haplotypes exhibit a high degree of long-range haplotype similarity in African and Afro-Caribbean populations

Jallow Muminatou / Pinder Margaret / Rockett Kirk / Trafford Clare / Elzein Abier / Hanchard Neil / Harding Rosalind / Kwiatkowski Dominic / McKenzie Colin

BMC Genetics, Vol 8, Iss 1, p

2007 Volume 52

Abstract: Abstract Background The sickle (β s ) mutation in the beta-globin gene (HBB) occurs on five "classical" β s haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the β s allele – a consequence of protection from severe ...

Abstract	Abstract Background The sickle (β s ) mutation in the beta-globin gene (HBB) occurs on five "classical" β s haplotype backgrounds in ethnic groups of African ancestry. Strong selection in favour of the β s allele – a consequence of protection from severe malarial infection afforded by heterozygotes – has been associated with a high degree of extended haplotype similarity. The relationship between classical β s haplotypes and long-range haplotype similarity may have both anthropological and clinical implications, but to date has not been explored. Here we evaluate the haplotype similarity of classical β s haplotypes over 400 kb in population samples from Jamaica, The Gambia, and among the Yoruba of Nigeria (Hapmap YRI). Results The most common β s sub-haplotype among Jamaicans and the Yoruba was the Benin haplotype, while in The Gambia the Senegal haplotype was observed most commonly. Both subtypes exhibited a high degree of long-range haplotype similarity extending across approximately 400 kb in all three populations. This long-range similarity was significantly greater than that seen for other haplotypes sampled in these populations (P < 0.001), and was independent of marker choice and marker density. Among the Yoruba, Benin haplotypes were highly conserved, with very strong linkage disequilibrium (LD) extending a megabase across the β s mutation. Conclusion Two different classical β s haplotypes, sampled from different populations, exhibit comparable and extensive long-range haplotype similarity and strong LD. This LD extends across the adjacent recombination hotspot, and is discernable at distances in excess of 400 kb. Although the multi-centric geographic distribution of β s haplotypes indicates strong subdivision among early Holocene sub-Saharan populations, we find no evidence that selective pressures imposed by falciparum malaria varied in intensity or timing between these subpopulations. Our observations also suggest that cis -acting loci, which may influence outcomes in sickle cell disease, could lie considerable distances away from β-globin.
Keywords	Genetics ; QH426-470 ; Biology (General) ; QH301-705.5 ; Science ; Q ; DOAJ:Genetics ; DOAJ:Biology ; DOAJ:Biology and Life Sciences
Subject code	333
Language	English
Publishing date	2007-08-01T00:00:00Z
Publisher	BioMed Central
Document type	Article ; Online
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Article ; Online: Discovery and validation of biomarkers to guide clinical management of pneumonia in African children.

Huang, Honglei / Ideh, Readon C / Gitau, Evelyn / Thézénas, Marie L / Jallow, Muminatou / Ebruke, Bernard / Chimah, Osaretin / Oluwalana, Claire / Karanja, Henri / Mackenzie, Grant / Adegbola, Richard A / Kwiatkowski, Dominic / Kessler, Benedikt M / Berkley, James A / Howie, Stephen R C / Casals-Pascual, Climent

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

2014 Volume 58, Issue 12, Page(s) 1707–1715

Abstract: Background: Pneumonia is the leading cause of death in children globally. Clinical algorithms remain suboptimal for distinguishing severe pneumonia from other causes of respiratory distress such as malaria or distinguishing bacterial pneumonia and ... ...

Abstract	Background: Pneumonia is the leading cause of death in children globally. Clinical algorithms remain suboptimal for distinguishing severe pneumonia from other causes of respiratory distress such as malaria or distinguishing bacterial pneumonia and pneumonia from others causes, such as viruses. Molecular tools could improve diagnosis and management. Methods: We conducted a mass spectrometry-based proteomic study to identify and validate markers of severity in 390 Gambian children with pneumonia (n = 204) and age-, sex-, and neighborhood-matched controls (n = 186). Independent validation was conducted in 293 Kenyan children with respiratory distress (238 with pneumonia, 41 with Plasmodium falciparum malaria, and 14 with both). Predictive value was estimated by the area under the receiver operating characteristic curve (AUC). Results: Lipocalin 2 (Lpc-2) was the best protein biomarker of severe pneumonia (AUC, 0.71 [95% confidence interval, .64-.79]) and highly predictive of bacteremia (78% [64%-92%]), pneumococcal bacteremia (84% [71%-98%]), and "probable bacterial etiology" (91% [84%-98%]). These results were validated in Kenyan children with severe malaria and respiratory distress who also met the World Health Organization definition of pneumonia. The combination of Lpc-2 and haptoglobin distinguished bacterial versus malaria origin of respiratory distress with high sensitivity and specificity in Gambian children (AUC, 99% [95% confidence interval, 99%-100%]) and Kenyan children (82% [74%-91%]). Conclusions: Lpc-2 and haptoglobin can help discriminate the etiology of clinically defined pneumonia and could be used to improve clinical management. These biomarkers should be further evaluated in prospective clinical studies.
MeSH term(s)	Acute-Phase Proteins ; Area Under Curve ; Biomarkers/blood ; C-Reactive Protein/metabolism ; Case-Control Studies ; Child, Preschool ; Female ; Gambia ; Haptoglobins/metabolism ; Humans ; Infant ; Kenya ; Lipocalin-2 ; Lipocalins/blood ; Malaria, Falciparum/complications ; Male ; Mass Spectrometry ; Pneumonia, Bacterial/blood ; Pneumonia, Bacterial/diagnosis ; Pneumonia, Bacterial/therapy ; Predictive Value of Tests ; Proteomics ; Proto-Oncogene Proteins/blood ; ROC Curve ; Respiratory Insufficiency/blood ; Respiratory Insufficiency/diagnosis ; Respiratory Insufficiency/parasitology ; Severity of Illness Index ; von Willebrand Factor/metabolism
Chemical Substances	Acute-Phase Proteins ; Biomarkers ; Haptoglobins ; LCN2 protein, human ; Lipocalin-2 ; Lipocalins ; Proto-Oncogene Proteins ; von Willebrand Factor ; C-Reactive Protein (9007-41-4)
Language	English
Publishing date	2014-04-02
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1099781-7
ISSN	1537-6591 ; 1058-4838
ISSN (online)	1537-6591
ISSN	1058-4838
DOI	10.1093/cid/ciu202
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