Mannose-binding lectin variant associated with severe malaria in young African children

Mannose-binding lectin (MBL) is a serum protein which initiates innate immune responses to microbial pathogens by binding to non-self surface oligosaccharides. MBL deficiency is the most common congenital immunodeficiency of human and has been shown to predispose to infections, particularly in children and immune compromised. In a matched case-control study among 870 Ghanaian children, we examined the influence of six polymorphisms of the MBL2 gene on Plasmodium falciparum infection and severe malaria. A missense mutation resulting in low MBL activity (MBL2*C) was found in 35% of healthy controls, but in 42% of asymptomatically infected children (P=0.01), and in 46% of patients with severe malaria (P=0.007). Heterozygosity for MBL2*C was associated with increased odds of infection (odds ratio (OR), 1.6; 95% confidence interval (CI), 1.1-2.1), severe malaria (OR, 1.7; 95% CI, 1.2-2.4), and of severe anemia in particular (OR, 2.3; 95% CI, 1.4-3.8). The population attributable fraction of severe malaria cases attributable to MBL2*C heterozygosity was 17%. Our results suggest that the MBL pathway of the complement system is a critical determinant of both, susceptibility to P. falciparum infection and manifestation of severe malaria, particularly in young children in whom specific immune responses are weak or absent.     

Development of renal scars in children: missed opportunities in management. South Bedfordshire Practitioners' Group.

OBJECTIVE--To assess the antecedent medical care of children with renal scars. DESIGN--Retrospective study of both general practice and hospital records. SETTING--12 Group practices in south Bedfordshire and the radiology and paediatric outpatient departments of a district general hospital. SUBJECTS--23 Children with renal scars (six boys, 17 girls) from the 12 group practices, identified from outpatient, radiology, and general practice records. MAIN OUTCOME MEASURES--Number of children in whom a diagnosis of urinary tract infection had been made without prior examination of a mid-stream specimen of urine; number of children who had had a confirmed urinary tract infection that had not been investigated further; number who had experienced delays in investigation or referral; and number who had received inadequate follow up. RESULTS--In all, 11 of the children had received suboptimal medical care, but the management of the other 12 could not have been better. The most common error was failure to investigate possible urinary tract infections, but follow up of confirmed infections was also inadequate. These problems occurred in hospital as well as in general practice. CONCLUSION--Opportunities for intervention had been missed in nearly half of this sample of children with renal scars.     

Severe disease in children hospitalized with a diagnosis of Plasmodium vivax in south-eastern Pakistan

ABSTRACT: BACKGROUND: Infection by Plasmodium vivax has been considered rarely threatening to life, but recent studies challenge this notion. This study documented the frequency and character of severe illness in paediatric patients admitted to a hospital in south-eastern Pakistan with a laboratory-confirmed diagnosis of vivax malaria. METHODS: An observational study of all 180 paediatric patients admitted with any diagnosis of malaria during 2010 was conducted: 128 P. vivax; 48 Plasmodium falciparum; and four mixed infections of these species. Patients were classified as having severe illness with any of the following indicators: Glascow coma scale <11; >2 convulsions; haemoglobin <5g/dL; thrombocytes <50,000/mL; blood glucose <45mg%; >70 breaths/min; or intravenous antimalarial therapy. Additionally, 64 patients with a diagnosis of vivax malaria were treated during 2009, and the 21 of these having severe illness were included in analyses of the frequency and character of severe illness with that diagnosis. RESULTS: During 2010, 39 (31%) or 37 (77%) patients with a diagnosis of P. vivax or P. falciparum were classified as having severe disease. Including the 2009 records of 64 patients having vivax malaria, a total of 60 (31%) patients with severe illness and a diagnosis of P. vivax were available. Altered mental status (Glascow coma scale score <11; or >2 convulsions) dominated at 54% of the 83 indicators of severe illness manifest among the patients with vivax malaria, as was true among the 37 children with a diagnosis of falciparum malaria and being severely ill; 58% of the 72 indicators of severe disease documented among them. No statistically significant difference appeared in frequencies of any other severe disease indicators between patients diagnosed with vivax or falciparum malaria. Despite such similarities, a diagnosis of falciparum malaria nonetheless came with 3.8-fold (95% CI = 1.8- 8.1) higher risk of presenting with severe illness, and 8.0-fold (95% CI = 2.1-31) greater likelihood of presenting with three or more severe disease indicators. Two patients did not survive hospitalization, one each with a diagnosis of falciparum or vivax malaria. CONCLUSIONS: Vivax malaria caused a substantial burden of potentially life-threatening morbidity on a paediatric ward in a hospital in south-eastern Pakistan.     

Characteristics of children admitted to hospital with acute SARS-CoV-2 infection in Canada in 2020

Background:Risk factors for severe outcomes of SARS-CoV-2 infection are not well established in children. We sought to describe pediatric hospital admissions associated with SARS-CoV-2 infection in Canada and identify risk factors for more severe disease.Methods:We conducted a national prospective study using the infrastructure of the Canadian Paediatric Surveillance Program (CPSP). Cases involving children who were admitted to hospital with microbiologically confirmed SARS-CoV-2 infection were reported from Apr. 8 to Dec. 31 2020, through weekly online questionnaires distributed to the CPSP network of more than 2800 pediatricians. We categorized hospital admissions as related to COVID-19, incidental, or for social or infection control reasons and determined risk factors for disease severity in hospital.Results:Among 264 hospital admissions involving children with SARS-CoV-2 infection during the 9-month study period, 150 (56.8%) admissions were related to COVID-19 and 100 (37.9%) were incidental infections (admissions for other reasons and found to be positive for SARS-CoV-2 on screening). Infants (37.3%) and adolescents (29.6%) represented most cases. Among hospital admissions related to COVID-19, 52 (34.7%) had critical disease, 42 (28.0%) of whom required any form of respiratory or hemodynamic support, and 59 (39.3%) had at least 1 underlying comorbidity. Children with obesity, chronic neurologic conditions or chronic lung disease other than asthma were more likely to have severe or critical COVID-19.Interpretation:Among children who were admitted to hospital with SARS-CoV-2 infection in Canada during the early COVID-19 pandemic period, incidental SARS-CoV-2 infection was common. In children admitted with acute COVID-19, obesity and neurologic and respiratory comorbidities were associated with more severe disease.

As of Dec. 31, 2020, Canada had 581 427 confirmed cases of SARS-CoV-2 infection.¹ Similar to other countries, most confirmed infections were in adults, in part because of initial testing policies that targeted older and at-risk populations, as well as prolonged societal containment measures to minimize children’s risk of exposure. Although fewer SARS-CoV-2 infections in children were reported relative to adults during Canada’s first waves of the pandemic,² recent surges in pediatric cases across North America have challenged the notion that children are infected at a lower frequency than adults.^3,4 However, the severity of infection in children appears to be substantially lower, with fewer overall hospital admissions reported and substantially lower mortality compared with adults.^5,6Although risk factors for more severe outcomes of COVID-19 have been well described in adults,⁷ similar risks are less well described in children.⁸ Experience with other viral respiratory infections, including influenza and respiratory syncytial virus, has shown that patient-level factors can increase risk for severe disease in children.^9,10 Understanding populations at risk for severe disease is essential for developing evidence-informed testing strategies, recommendations around reducing exposure (including guidance informing in-person schooling) and potential prioritization of SARS-CoV-2 vaccines in children.To date, few published data have characterized admissions to hospital with SARS-CoV-2 infection among children in Canada. We sought to describe pediatric hospital admissions associated with acute SARS-CoV-2 infection in Canada and identify risk factors for severe disease among children admitted to hospital.     

Challenges in the Diagnosis of Iron Deficiency in Children Exposed to High Prevalence of Infections

Background

While WHO guidelines recommend iron supplements to only iron-deficient children in high infection pressure areas, these are rarely implemented. One of the reasons for this is the commonly held view that iron supplementation increases the susceptibility to some infectious diseases including malaria. Secondly, currently used markers to diagnose iron deficiency are also modified by infections. With the objective of improving iron deficiency diagnosis and thus, its management, we evaluated the performance of iron markers in children exposed to high infection pressure.

Methodology/Principal Findings

Iron markers were compared to bone marrow findings in 180 anaemic children attending a rural hospital in southern Mozambique. Eighty percent (144/180) of the children had iron deficiency by bone marrow examination, 88% (155/176) had an inflammatory process, 66% (119/180) had moderate anaemia, 25% (45/180) severe anaemia and 9% (16/180) very severe anaemia. Mean cell haemoglobin concentration had a sensitivity of 51% and specificity of 71% for detecting iron deficiency. Soluble transferrin receptor (sTfR) and soluble transferrin receptor/log ferritin (TfR-F) index (adjusted by C reactive protein) showed the highest areas under the ROC curve (AUC^ROC) (0.75 and 0.76, respectively), and were the most sensitive markers in detecting iron deficiency (83% and 75%, respectively), but with moderate specificities (50% and 56%, respectively).

Conclusions/Significance

Iron deficiency by bone marrow examination was extremely frequent in these children exposed to high prevalence of infections. However, even the best markers of bone marrow iron deficiency did not identify around a quarter of iron-deficient children. Tough not directly extrapolated to the community, these findings urge for more reliable, affordable and easy to measure iron indicators to reduce the burden of iron deficiency anaemia in resource-poor settings where it is most prevalent.     

Leydig-cell tumour in children: variable clinical presentation, diagnostic features, follow-up and genetic analysis of four cases

BACKGROUND: Testicular tumours are relatively uncommon in infants and children, accounting for only 1-2% of all paediatric solid tumours. Of these approximately 1.5% are Leydig-cell tumours. Further, activating mutations of the luteinizing hormone receptor gene (LHR), as well as of the G protein genes, such as Gsalpha (gsp) and Gialpha (gip2) subunits, and cyclin-dependent kinase gene 4(CDK4) have been associated with the development of several endocrine neoplasms. AIMS/METHODS: In this report, the clinical variability of Leydig-cell tumours in four children is described. The LHR-, gsp-, gip2- and CDK4 genes were investigated to establish the possible molecular pathogenesis of the variable phenotype of the Leydig-cell tumours. RESULTS: No activating mutations in these genes were found in the four Leydig-cell tumours studied. Therefore, the absence of activating mutations in LHR, as well as in both the 'hot spot' regions for activating mutations within the G-alpha subunits and in the regulatory 'hot spot' on the CDK4 genes in these tumours indicates molecular heterogeneity among Leydig-cell tumours. CONCLUSION: Four children with a variable phenotype caused by Leydig-cell tumours are described. A molecular analysis of all the 'activating' genes and mutational regions known so far was performed, but no abnormalities were found. The lessons learnt from these clinically variable cases are: perform ultrasound early and most importantly, consider discrepancies between testicular swelling, tumour size and androgen production.     

Dengue infection in children in Ratchaburi, Thailand: a cohort study. II. Clinical manifestations

Background

Dengue infection is one of the most important mosquito-borne diseases. More data regarding the disease burden and the prevalence of each clinical spectrum among symptomatic infections and the clinical manifestations are needed. This study aims to describe the incidence and clinical manifestations of symptomatic dengue infection in Thai children during 2006 through 2008.

Study Design

This study is a school-based prospective open cohort study with a 9,448 person-year follow-up in children aged 3–14 years. Active surveillance for febrile illnesses was done in the studied subjects. Subjects who had febrile illness were asked to visit the study hospital for clinical and laboratory evaluation, treatment, and serological tests for dengue infection. The clinical data from medical records, diary cards, and data collection forms were collected and analyzed.

Results

Dengue infections were the causes of 12.1% of febrile illnesses attending the hospital, including undifferentiated fever (UF) (49.8%), dengue fever (DF) (39.3%) and dengue hemorrhagic fever (DHF) (10.9%). Headache, anorexia, nausea/vomiting and myalgia were common symptoms occurring in more than half of the patients. The more severe dengue spectrum (i.e., DHF) had higher temperature, higher prevalence of nausea/vomiting, abdominal pain, rash, diarrhea, petechiae, hepatomegaly and lower platelet count. DHF cases also had significantly higher prevalence of anorexia, nausea/vomiting and abdominal pain during day 3–6 and diarrhea during day 4–6 of illness. The absence of nausea/vomiting, abdominal pain, diarrhea, petechiae, hepatomegaly and positive tourniquet test may predict non-DHF.

Conclusion

Among symptomatic dengue infection, UF is most common followed by DF and DHF. Some clinical manifestations may be useful to predict the more severe disease (i.e., DHF). This study presents additional information in the clinical spectra of symptomatic dengue infection.     

Concanavalin A binding to HIV envelope protein is less sensitive to mutations in glycosylation sites than monoclonal antibody 2G12

Many mannose-binding proteins inhibit divergent strains of human immunodeficiency virus type 1 (HIV-1) in in vitro models of viral infectivity, suggesting that targeting mannose residues in vaccine applications might offset the strain restriction typically observed in antibody responses to HIV vaccine preparations. Concanavalin A (ConA) behaves like neutralizing antibodies that do not interfere with CD4 binding of gp120 but rather with later events in virus entry. The design of mannose-based vaccines, therefore, depends on understanding the mode of binding of ConA to the envelope protein in comparison with other mannose-binding proteins. Here, we further compare the binding affinity and fine specificity of ConA for the envelope protein to that of the human antibody 2G12. The 2G12 antibody is of unusual structure recognizing a cluster of 12 linked mannose residues associated with Man9GlcNAc2. Molecular structure comparison for Man9GlcNAc2 recognition by ConA and 2G12 indicates that 2G12 has a more restricted specificity to high mannose glycans of gp120 which correlates with kinetic analysis assessed by surface plasmon resonance (SPR) and ConA inhibits 2G12 binding to gp120 but 2G12 does not inhibit ConA binding to gp120. ConA binding to Env proteins from four different HIV strains proves significantly less sensitive to mutations in the glycosylation sites than 2G12 binding to the proteins. Thus, antibodies directed toward mannose epitopes reactive with ConA may prove to be more effective in the long run to thwart HIV infection and transmission.     

Measured bronchodilator use in preschool children with asthma.

OBJECTIVE--To investigate how parents use bronchodilator treatment for relief of symptoms when treating their asthmatic preschool children. DESIGN--A commercial electromechanical timer device was attached to a large volume spacer to record the time and date of each use of inhaled bronchodilator over two months. The recorded time and dates were compared with symptoms noted in an asthma diary card. SETTING--Large paediatric teaching hospital in Glasgow. SUBJECTS--29 preschool children with moderately severe asthma attending a specialist paediatric asthma clinic. MAIN OUTCOME MEASURES--Inhaler use measured by the timer device; symptoms and inhaler use recorded by parents in a daily asthma diary. RESULTS--Satisfactory data were obtained in 22 of the 29 children; the median number of study days was 53 (range 18-77). Asthmatic symptoms were recorded on a median of 30 (3-77) days. Bronchodilator was used on a median of 19 (2-73) days, or on 63% (7-100%) of days when symptoms occurred. The median number of puffs used in a day was 1 (range 0-100) and was significantly related to symptom severity in only 14 of the 22 children. In only two of the 22 children was bronchodilator given more frequently than four hourly, and only five children ever used more than 12 puffs a day. CONCLUSIONS--The frequency of parental administration of bronchodilator treatment was variable and not closely related to the parent''s record of symptom severity. Parents often recorded symptoms in their children but did not treat them.     

New renal scarring in children who at age 3 and 4 years had had normal scans with dimercaptosuccinic acid: follow up study.

OBJECTIVE: To determine up to what age children remain at risk of developing a new renal scar from a urinary tract infection. DESIGN: Follow up study. Families of children who had normal ultrasound scans and scanning with dimercaptosuccinic acid (DMSA) after referral with a urinary tract infection when aged 3 (209) or 4 (220) were invited to bring the children for repeat scans 2-11 years later. A history of infections since the original scan was obtained for children not having a repeat scan. SETTING: Teaching hospital. SUBJECTS: Children from three health districts in whom a normal scan had been obtained at age 3-4 years in 1985-1992 because of a urinary tract infection. MAIN OUTCOME MEASURE: Frequency of new renal scars in each age group. RESULTS: In each group, about 97% of children either had repeat scanning (over 80%) or were confidently believed by their general practitioner or parent not to have had another urinary infection. The rate of further infections since the original scan was similar in the 3 and 4 year old groups (48/176 (27%)) and 55/179 (31%)). Few children in either group known to have had further urinary infections did not have repeat scanning (3/209 (1.4%) and 4/220 (1.8%)). In the 3 year old group, 2.4% (5/209) had one or more new kidney scars at repeat scanning (one sided 95% confidence interval up to 5.0%), whereas none of the 4 year olds did (one sided 95% confidence interval up to 1.4%). The children who developed scars were all aged under 3.4 years when scanned originally. CONCLUSIONS: Children with a urinary tract infection but unscarred kidneys after the third birthday have about a 1 in 40 risk of developing a scar subsequently, but after the fourth birthday the risk is either very low or zero. Thus the need for urinary surveillance is much reduced in a large number of children.     

Five Years Experience of Clostridium difficile Infection in Children at a UK Tertiary Hospital: Proposed Criteria for Diagnosis and Management

Background

Clostridium difficile infection (CDI) is associated with significant morbidity and mortality in adults. There is increasing evidence of the pathogenic role of C. difficile in the paediatric population. We sought to ascertain the clinical presentation and severity of CDI in children at our institution and develop criteria to aid management.

Methods

Clinical data was retrospectively collected from all children (0–16 yrs) with a positive C. difficile toxin result over a 5-year period. National adult guidelines were used to assess the severity and management of CDI.

Results

Seventy-five patients were included with a mean age of 2.97 years. Forty-nine were hospital onset, 22 community onset and 4 healthcare-associated. The most common co-morbidity among the hospital onset infections was malignancy. Gastrointestinal conditions were most common among community onset infections. Fifty-five cases (73.3%) had received antibiotics in the preceding month, 7 (9.3%) had cow’s milk intolerance and 9 (12%) had co-infection with another gut pathogen. According to national adult guidelines 57 cases (76%) were categorised as severe. Thirty cases received oral metronidazole, two patients required intensive care and one patient had a sub-total colectomy for pseudomembranous colitis. No mortality was observed.

Discussion

We confirm the association of paediatric CDI with co-morbidities such as haematological and solid organ malignancies, recent antibiotic use and hospitalisation. We observed an association between cows milk protein intolerance and C. difficile. The use of adult criteria overestimated severity of disease in this cohort, as most cases experienced a mild course of illness with low morbidity and no mortality. This indicates that adult scoring criteria are not useful in guiding management and we propose specific criteria for children.     

Novel Alleles of the Chemokine-Receptor Gene CCR5

The CCR5 gene encodes a cell-surface chemokine-receptor molecule that serves as a coreceptor for macrophage-tropic strains of HIV-1. Mutations in this gene may alter expression or function of the protein product, thereby altering chemokine binding/signaling or HIV-1 infection of cells that normally express CCR5 protein. Indeed, homozygotes for a 32-bp deletion allele of CCR5 (CCR5-delta 32), which causes a frameshift at amino acid 185, are relatively resistant to HIV-1 infection. Here we report the identification of 16 additional mutations in the coding region of the CCR5 gene, all but 3 of which are codon altering or "nonsynonymous." Most mutations were rare (found only once or twice in the sample); five were detected exclusively among African Americans, whereas eight were observed only in Caucasians. The mutations included 11 codon-altering nonsynonymous variants, one trinucleotide deletion, one chain-termination mutant, and three synonymous mutations. The high predominance of codon-altering alleles among CCR5 mutants (14/17 [81%], including CCR5-delta 32) is consistent with an adaptive accumulation of function-altering alleles for this gene, perhaps as a consequence of historic selective pressures.     

M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage

Increased vascular permeability is a key feature of inflammatory conditions. In severe infections, leakage of plasma from the vasculature induces a life-threatening hypotension. Streptococcus pyogenes, a major human bacterial pathogen, causes a toxic shock syndrome (STSS) characterized by excessive plasma leakage and multi-organ failure. Here we find that M protein, released from the streptococcal surface, forms complexes with fibrinogen, which by binding to beta2 integrins of neutrophils, activate these cells. As a result, neutrophils release heparin binding protein, an inflammatory mediator inducing vascular leakage. In mice, injection of M protein or subcutaneous infection with S. pyogenes causes severe pulmonary damage characterized by leakage of plasma and blood cells. These lesions were prevented by treatment with a beta2 integrin antagonist. In addition, M protein/fibrinogen complexes were identified in tissue biopsies from a patient with necrotizing fasciitis and STSS, further underlining the pathogenic significance of such complexes in severe streptococcal infections.     

Molecular analysis of repeated methicillin-resistant Staphylococcus aureus infections in children

Background

Methicillin-resistant Staphylococcus aureus (MRSA) is a major pathogen that causes severe morbidity and mortality in hospitalized patients. It is unclear whether repeated MRSA infections in pediatric patients are caused by relapse of previous infecting strains or by acquiring new strains from extrinsic sources. The study aimed to define the genetic relatedness of MRSA isolates from children with repeated infections.

Methodology/Principal Findings

Children with multiple MRSA infections during 2004–2006 were identified in a teaching hospital. Repeated infections were confirmed by chart review and the responsible isolates were genotyped and screened for Panton-Valentine leukocidin (PVL) genes. Two consecutive episodes comprised an infection pair, and strain relatedness was defined for each pair as indistinguishable, highly related, or distinct if the isolates were of the same subtype, the same genotype, or different genotype, respectively. A total of 114 episodes comprising 66 infection pairs were identified in 48 children. The interval of infection pairs ranged from 15 days to 346 days, with a median duration of 57.5 days. Genotypings classified all isolates into 7 genotypes and 31 subtypes. Of 66 pairs, 46 (69.7%), 13 (19.7%) and 7 (10.6%) pairs were caused by indistinguishable, highly related and distinct strains, respectively. Subsequent infections caused by indistinguishable strains were more common for PVL-positive strains (17/18, 94.4%) than for PVL-negative strains (29/48, 60.4%, P = 0.007). The strain relatedness was not affected by the durations of interval between infections.

Conclusions/Significance

Most repeated MRSA infections in children are caused by indistinguishable strains even after a long period of interval, suggesting that persistent carriage and relapse of initial infecting strains were responsible for the majority of recurrent MRSA infections.     

Glycosylation of the phosphate binding protein, PstS, in Streptomyces coelicolor by a pathway that resembles protein O-mannosylation in eukaryotes

Previously mutations in a putative protein O -mannosyltransferase (SCO3154, Pmt) and a polyprenol phosphate mannose synthase (SCO1423, Ppm1) were found to cause resistance to phage, φC31, in the antibiotic producing bacteria Streptomyces coelicolor A3(2). It was proposed that these two enzymes were part of a protein O-glycosylation pathway that was necessary for synthesis of the phage receptor. Here we provide the evidence that Pmt and Ppm1 are indeed both required for protein O-glycosylation. The phosphate binding protein PstS was found to be glycosylated with a trihexose in the S. coelicolor parent strain, J1929, but not in the pmt ⁻ derivative, DT1025. Ppm1 was necessary for the transfer of mannose to endogenous polyprenol phosphate in membrane preparations of S. coelicolor . A mutation in ppm1 that conferred an E218V substitution in Ppm1 abolished mannose transfer and glycosylation of PstS. Mass spectrometry analysis of extracted lipids showed the presence of a glycosylated polyprenol phosphate (PP) containing nine repeated isoprenyl units (C₄₅-PP). S. coelicolor membranes were also able to catalyse the transfer of mannose to peptides derived from PstS, indicating that these could be targets for Pmt in vivo .     

Candidate Human Genetic Polymorphisms and Severe Malaria in a Tanzanian Population

Human genetic background strongly influences susceptibility to malaria infection and progression to severe disease and death. Classical genetic studies identified haemoglobinopathies and erythrocyte-associated polymorphisms, as protective against severe disease. High throughput genotyping by mass spectrometry allows multiple single nucleotide polymorphisms (SNPs) to be examined simultaneously. We compared the prevalence of 65 human SNP''s, previously associated with altered risk of malaria, between Tanzanian children with and without severe malaria. Five hundred children, aged 1–10 years, with severe malaria were recruited from those admitted to hospital in Muheza, Tanzania and compared with matched controls. Genotyping was performed by Sequenom MassArray, and conventional PCR was used to detect deletions in the alpha-thalassaemia gene. SNPs in two X-linked genes were associated with altered risk of severe malaria in females but not in males: heterozygosity for one or other of two SNPs in the G6PD gene was associated with protection from all forms of severe disease whilst two SNPs in the gene encoding CD40L were associated with respiratory distress. A SNP in the adenyl cyclase 9 (ADCY9) gene was associated with protection from acidosis whilst a polymorphism in the IL-1α gene (IL1A) was associated with an increased risk of acidosis. SNPs in the genes encoding IL-13 and reticulon-3 (RTN3) were associated with increased risk of cerebral malaria. This study confirms previously known genetic associations with protection from severe malaria (HbS, G6PD). It identifies two X-linked genes associated with altered risk of severe malaria in females, identifies mutations in ADCY9, IL1A and CD40L as being associated with altered risk of severe respiratory distress and acidosis, both of which are characterised by high serum lactate levels, and also identifies novel genetic associations with severe malaria (TRIM5) and cerebral malaria(IL-13 and RTN3). Further studies are required to test the generality of these associations and to understand their functional consequences.