This is the second report of the United Kingdom Primary Immunodeficiency (UKPID) registry. The registry will be a decade old in 2018 and, as of August 2017, had recruited 4758 patients encompassing 97% of immunology centres within the United Kingdom. This represents a doubling of recruitment into the registry since we reported on 2229 patients included in our first report of 2013. Minimum PID prevalence in the United Kingdom is currently 5·90/100 000 and an average incidence of PID between 1980 and 2000 of 7·6 cases per 100 000 UK live births. Data are presented on the frequency of diseases recorded, disease prevalence, diagnostic delay and treatment modality, including haematopoietic stem cell transplantation (HSCT) and gene therapy. The registry provides valuable information to clinicians, researchers, service commissioners and industry alike on PID within the United Kingdom, which may not otherwise be available without the existence of a well-established registry.

Loss-of-function mutations of the gene for the integrin α3 (ITGA3) subunit were recently associated with a rare autosomal recessive multiorgan disorder comprising interstitial lung disease, nephrotic syndrome, and junctional epidermolysis bullosa (ILNEB, OMIM#614748) (Has et al., 2012Has C. Sparta G. Kiritsi D. Weibel L. Moeller A. Vega-Warner V. et al.Integrin alpha3 mutations with kidney, lung, and skin disease.N Engl J Med. 2012; 366: 1508-1514Crossref PubMed Scopus (170) Google Scholar). Although integrin α3β1 is known to be an essential integrin in epithelia, including epidermal keratinocytes, alveolar epithelial cells, and podocytes, the clinical features of the human disorder and the underlying molecular pathomechanisms remain poorly understood (Nicolaou et al., 2012Nicolaou N. Margadant C. Kevelam S.H. Lilien M.R. Oosterveld M.J. Kreft M. et al.Gain of glycosylation in integrin alpha3 causes lung disease and nephrotic syndrome.J Clin Invest. 2012; 122: 4375-4387Crossref PubMed Scopus (95) Google Scholar, Sachs and Sonnenberg, 2013Sachs N. Sonnenberg A. Cell-matrix adhesion of podocytes in physiology and disease.Nat Rev Nephrol. 2013; 9: 200-210Crossref PubMed Scopus (100) Google Scholar, Shukrun et al., 2014Shukrun R. Vivante A. Pleniceanu O. Vax E. Anikster Y. Dekel B. et al.A human integrin-alpha3 mutation confers major renal developmental defects.PLoS One. 2014; 9: e90879Crossref PubMed Scopus (18) Google Scholar, Yamada and Sekiguchi, 2013Yamada M. Sekiguchi K. Disease-associated single amino acid mutation in the calf-1 domain of integrin alpha3 leads to defects in its processing and cell surface expression.Biochem Biophys Res Commun. 2013; 441: 988-993Crossref PubMed Scopus (12) Google Scholar). Here, we report on a patient with ILNEB due to an unconventional ITGA3 intronic mutation and show that the pathogenic mechanism involves generation of a new acceptor splice site and of a new interaction site with a splicing regulatory element. The diagnosis of ILNEB was suspected in a 4-month-old male patient, first born to healthy, consanguineous Pakistani parents with no significant family history, because of the concomitant presence of interstitial lung disease with persistent respiratory distress and renal involvement. As the child was critically unwell with no clear diagnosis, it was important to make a precise and rapid diagnosis to inform prognosis and therapeutic decision making. Thus, in a candidate gene approach, ITGA3 mutation analysis was performed (Has et al., 2012Has C. Sparta G. Kiritsi D. Weibel L. Moeller A. Vega-Warner V. et al.Integrin alpha3 mutations with kidney, lung, and skin disease.N Engl J Med. 2012; 366: 1508-1514Crossref PubMed Scopus (170) Google Scholar), after written informed consent and ethical approval. This analysis revealed in the patient a single homozygous unclassified variant, c.1383-11T>A, in intron 9 of ITGA3 (NM_002204.2, NC_000017.11). This variant was present in a heterozygous state in each of the parents (Figure 1a). In addition, it was excluded from 200 control chromosomes and from databases (single nucleotide polymorphism database 141, Exome Variant Server). Given the lack of skin findings in the child at this stage and intronic nature of the variant, it was necessary to substantiate the disease-causing role of this unclassified variant. To expedite the molecular diagnosis, a skin biopsy was obtained from the patient for additional protein and RNA studies. For immunofluorescence staining, a panel of antibodies to proteins of the dermal-epidermal junction zone was used, including the integrin α3 primary antibody P1B5 (Millipore, Darmstadt, Germany) (Has et al., 2012Has C. Sparta G. Kiritsi D. Weibel L. Moeller A. Vega-Warner V. et al.Integrin alpha3 mutations with kidney, lung, and skin disease.N Engl J Med. 2012; 366: 1508-1514Crossref PubMed Scopus (170) Google Scholar). Surprisingly, although clinically no cutaneous fragility was noted, the biopsy taken from an unaffected skin area after gentle rubbing displayed multiple junctional splits. These were indicated by the presence of immunoreactivity for integrin α6 at the blister roof and for laminin α3 and collagen VII at the blister base (Figure 1b). In the patient's skin, there was an absence of immunoreactivity for integrin α3, which stained at the periphery of basal keratinocytes in control skin (Figure 1b). Thus the clinical suspicion was confirmed on a molecular level. By this point, the child had an acute respiratory deterioration and did not survive. Examination just prior revealed the presence of blisters, confirming the skin phenotype associated with ILNEB. To explain the pathogenic role of the identified unclassified variant, we analyzed ITGA3 transcripts expressed in the skin of the patient and a healthy age-matched control. Total RNA was isolated from skin sections using an RNAeasy FFPE kit (QIAGEN, Hilden, Germany), transcribed into cDNA (Fermentas, St. Leon-Rot, Germany), and subjected to quantitative real time PCR and to reverse-transcriptase PCR (Supplementary Table S1 online). Both demonstrated that ITGA3 mRNA was not significantly regulated, but an additional shorter ITGA3 transcript was detected in the patient's skin (Figure 2a). Sequencing of the TopoTA cloned amplicons revealed the normal sequence in all control clones, and seven aberrant transcripts in the patient's skin (37 clones) (Supplementary Table S2 online). These resulted from abnormal splicing of intron 9, exon 9, intron 11, or exon 12. To exclude cloning artifacts, primers spanning abnormal splicing sites were designed and used for nested PCR from the initial reverse-transcriptase PCR. Therewith, the existence of eight abnormal transcripts was confirmed in the skin of the patient, all absent in the control (Supplementary Tables S1 and S2, Figure 2b–e). Capillary electrophoresis and sequencing showed that transcripts 3 and 1 prevailed, whereas the others were minor (Figure 2e, Supplementary Figures S1–S4 online). These results clearly demonstrate that c.1383-11T>A induces complex splicing errors and is disease causing. Two further questions arise: (i) Which is the mechanism behind the complex splicing anomalies identified in situ? (ii) What is the outcome of the in-frame transcripts, in respect to the synthesis of truncated integrin α3 polypeptides? In silico analysis (NetGene2) of c.1383-11T>A predicted creation of an aberrant acceptor splice site (from 0 to 0.41), located nine base pairs upstream of the canonical one, which was validated in situ in transcripts 1, 2, 7, and 8 (Figure 2b and c), whereas at position +57 in intron 9 a cryptic acceptor splice site (score 0.43) is located that is used in transcripts 3 and 4. In addition, predictions of RNA regulatory elements (http://regrna.mbc.nctu.edu.tw) showed that c.1383-11T>A generates a new exonic splicing enhancer, R0621, or exonic splicing enhancer-SRp40, which is recognized by human splicing regulatory protein, SRp40. Exonic splicing enhancers are functional in splicing and are highly specific. The splicing regulatory proteins are a family of highly conserved serine/arginine-rich RNA-binding proteins that act very early in spliceosome assembly (Staknis and Reed, 1994Staknis D. Reed R. SR proteins promote the first specific recognition of pre-mRNA and are present together with the U1 small nuclear ribonucleoprotein particle in a general splicing enhancer complex.Mol Cell Biol. 1994; 14: 7670-7682Crossref PubMed Scopus (244) Google Scholar). They are essential splicing factors (Ge et al., 1991Ge H. Zuo P. Manley J.L. Primary structure of the human splicing factor ASF reveals similarities with Drosophila regulators.Cell. 1991; 66: 373-382Abstract Full Text PDF PubMed Scopus (267) Google Scholar, Krainer et al., 1991Krainer A.R. Mayeda A. Kozak D. Binns G. Functional expression of cloned human splicing factor SF2: homology to RNA-binding proteins, U1 70K, and Drosophila splicing regulators.Cell. 1991; 66: 383-394Abstract Full Text PDF PubMed Scopus (413) Google Scholar) and also regulate the selection of alternative splice sites in a concentration-dependent manner (Zahler et al., 1993Zahler A.M. Neugebauer K.M. Lane W.S. Roth M.B. Distinct functions of SR proteins in alternative pre-mRNA splicing.Science. 1993; 260: 219-222Crossref PubMed Scopus (323) Google Scholar) in part by antagonizing the activity of Heterogeneous nuclear ribonucleoproteins A1 (Mayeda and Krainer, 1992Mayeda A. Krainer A.R. Regulation of alternative pre-mRNA splicing by hnRNP A1 and splicing factor SF2.Cell. 1992; 68: 365-375Abstract Full Text PDF PubMed Scopus (586) Google Scholar). RNA regulatory elements in introns can control splicing of an exon that is kilobases away and long-range RNA-RNA interactions can function over kilobase distances in vivo to mediate the activity of distal enhancers, and such RNA bridges may be the common components of distal regulatory mechanisms in alternative splicing control (Lee and Rio, 2015Lee Y. Rio D.C. Mechanisms and regulation of alternative pre-mRNA splicing.Annu Rev Biochem. 2015; 84: 291-323Crossref PubMed Scopus (681) Google Scholar, Lovci et al., 2013Lovci M.T. Ghanem D. Marr H. Arnold J. Gee S. Parra M. et al.Rbfox proteins regulate alternative mRNA splicing through evolutionarily conserved RNA bridges.Nat Struct Mol Biol. 2013; 20: 1434-1442Crossref PubMed Scopus (206) Google Scholar). On the basis of these, we hypothesize that the mutation c.1383-11T>A deeply alters the splicing machinery through a complex mechanism, including the generation of an aberrant acceptor splice site and a new exonic splicing enhancer (Figure 2f). The putative expression of truncated integrin α3 polypeptides was addressed by in silico prediction of the least affected transcript 1, leading to insertion of three amino acids into the reading frame, p.461_462insLCR. The tertiary structure of the amino acids 82–478 was modeled (http://scratch.proteomics.ics.uci.edu/) (Cheng et al., 2005Cheng J. Randall A.Z. Sweredoski M.J. Baldi P. SCRATCH: a protein structure and structural feature prediction server.Nucleic Acids Res. 2005; 33: W72-W76Crossref PubMed Scopus (742) Google Scholar), and p.461_462insLCR was predicted to significantly alter the conformation of the β-propeller domain that is important for the interaction between α3 and β1 integrin (Campbell and Humphries, 2011Campbell I.D. Humphries M.J. Integrin structure, activation, and interactions.Cold Spring Harb Perspect Biol. 2011; 3Crossref PubMed Scopus (691) Google Scholar) (Figure 2g). We have recently shown that the mutation p.R463W alters the conformation, heterodimerization, and processing of the integrin α3 precursor, preventing its membrane incorporation (Yalcin et al., 2015Yalcin E.G. He Y. Orhan D. Pazzagli C. Emiralioglu N. Has C. Crucial role of posttranslational modifications of integrin alpha3 in interstitial lung disease and nephrotic syndrome.Hum Mol Genet. 2015; 24: 3679-3688PubMed Google Scholar). We hypothesize that p.461_462insLCR has similar consequences, acting as a loss-of-function mutation. Finally, although there was initially no clinical evidence for cutaneous fragility, the analysis of the skin proved to be a powerful tool for the rapid elucidation of the molecular basis of ILNEB. A precise molecular diagnosis for this child's presentation was crucial for making decisions regarding clinical management and end-of-life care. In addition, having a greater understanding of his condition allowed informed discussions regarding recurrence risk and implications for a future pregnancy for this family. The authors state no conflicts of interest. In particular, we thank the family of the patient. We also thank Juna Leppert for excellent technical assistance. The contribution of the "Center for Human Genetics Freiburg" led by Dr Jürgen Kohlhase as a sequencing facility is acknowledged. YH was supported by the Else-Kröner Fresenius foundation and CH by the Deutsche Forschungsgemeinschaft (DFG) CRC/SFB 1140. Download .pdf (1.62 MB) Help with pdf files Supplementary Tables S1 and S2 and Supplementary Figures S1–S4

Background Haemophagocytic lymphohistiocytosis (HLH) is a severe systemic inflammatory condition caused by dysregulation in Natural Killer T cell function. This results in excessive activation and proliferation of lymphocytes and histiocytes which results in a “cytokine storm” and uncontrolled haemophagocytosis. HLH should be considered in cases of unexplained unremitting fevers, sudden onset of cytopaenias, liver dysfunction and clotting abnormalities. It can be associated with rashes, hepatomegaly, splenomegaly and central nervous system symptoms (headache, lethargy, irritability, seizures, coma). Due to the non specific nature of presentation, HLH can often be overlooked, even when patients are extremely unwell. Traditionally, HLH is divided into primary HLH (genetic cause identified), and secondary HLH, which is associated with a variety of conditions (neoplasic, infectious and autoimmune). In autoimmune disease HLH is usually referred to as macrophage activation syndrome (MAS). HLH can be difficult to diagnose and early recognition and prompt treatment is essential to prevent the significant mortality associated with this disorder. Aims To raise awareness of HLH, to outline the complexity of this disorder and the challenges that exist in diagnosis. Methods We present three cases of HLH seen at a tertiary paediatric hospital with a tertiary paediatric rheumatology unit between January and October 2013. In two cases there was MAS associated with systemic juvenile idiopathic arthritis. In one case the diagnosis is likely to be a primary HLH. We outline the presentation and course of the illness and the results of investigations. Results (Image 1) one and two were successfully treated with methylprednisolone and Anakinra (Interleukin – 1 blocker). Patient three initially responded to methylprednisolone however, subsequently eventually required treatment with dexamethosone and cyclosporine HLH protocol. Conclusion HLH or MAS, regardless of terminology preferred, needs prompt recognition and treatment to prevent fatality. We present this series of cases to highlight the complexities and challenges of diagnosis of this condition. It is essential to raise awareness of this condition amongst paediatricians and furthermore to stimulate the development of guidelines that encompass the diagnosis and management of primary and secondary HLH.

There is a clear, documented association between Human Immunodeficiency Virus (HIV) and arthritis in children and young people (CYP). However, this association has not been clearly defined and the arthritis has been seen to resolve with differing management strategies.

Introduction Mild streptococcal infections infection are extremely common, however invasive infections can lead to high mortality. Described in 1982, post streptococcal reactive arthritis (PSRA) has been reported with increasing frequency. Aim We aimed to look at the number of children presenting to a Tertiary Children9s Hospital, with serological significant streptococcal illnesses, diagnoses and antibiotic treatment of those patients. We aimed to identify the patient population with possible Rheumatological conditions, and those who were seen in Rheumatology clinic. Method We looked at the number of patients where Antistreptolysin O test (ASOT) were performed. Results > 400 were reviewed. Patient case notes were reviewed for diagnosis, antibiotics prescribed and duration of treatment. Results Department & Number of patients seen in 2009 Emergency Department 46 700 GP referral unit 4861 General medical clinic new referrals 9776 General medical clinic follow-up 39 915 Rheumatology clinic new referral 19 Rheumatology clinic follow-up 338 ASOT9s ASOT9s January 2009–December 2010=645 N patients=359 N ASOT9s >400=100 (28%) Notes reviewed=95/100 patients Diagnoses & Number of patients Urticaria 11 Tonsillitis 9 Pneumonia/empyema 8 Lymphadenopathy 8 Rheumatological (2 SoJIA, 3 JIA, 2 PSRA, 1 irritable hip) 8 Nephritis/haematuria 7 Dermatology other 7 Recurrent streptococcal illness 5 Vasculitis (HSP 4 Wegeners 1) 5 Asthma/WAVE 4 Chronic Fatigue 3 Meningitis/encephalitis 3 Kawasaki 2 Immunological (PFAFA, Autoimmune) 2 Neurological 2 Fever Unspecified 2 Gastroenterology 2 EBV 2 TB 2 UTI 1 Endocarditis 1 Osteomyelitis 1 N° patients with conditions commonly seen in Rheumatology clinics (Bold above )=25 N° patients seen in the Rheumatology clinic=12 Antibiotics 65/95 were prescribed antibiotics. Length of Antibiotic & Number of Patients 48hrs 1 Up to7 days 15 8–14 days 37 2 weeks–6 weeks 4 >6 weeks 8 Conclusions Less than 1/3 of those patients in whom ASOT9s were performed were significantly raised. 1/4 of patients with positive streptococcal serology had a rheumatological diagnosis, suggesting it is a significant trigger in rheumatological conditions. Learning points ▶Need for education on rational antibiotic policies, allowing appropriate treatment for streptococcal eradication. ▶Possible need for streptococcal screening in rheumatological patients ▶Paediatricians should consider rheumatological conditions in patients with positive results.

Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαβ+CD4-CD8- double negative T cells and impaired T cell apoptosis are hallmarks of the disease. In contrast, the B cell compartment has been less well studied. We found an altered distribution of B cell subsets with raised transitional B cells and reduced marginal zone B cells, switched memory B cells and plasma blasts in most of 22 analyzed ALPS patients. Moreover, 5 out of 66 ALPS patients presented with low IgG and susceptibility to infection revealing a significant overlap between ALPS and common variable immunodeficiency (CVID). In patients presenting with lymphoproliferation, cytopenia, hypogammaglobulinemia and impaired B cell differentiation, serum biomarkers were helpful in addition to apoptosis tests for the identification of ALPS patients. Our observations may indicate a role for apoptosis defects in some diseases currently classified as CVID.

This review focuses on the latest knowledge and understanding of febrile seizures and outlines the more important issues in the management of children who present with an apparent “febrile seizure”. It is not the remit of this paper to discuss the detailed management of febrile seizures. Throughout this review, the words “partial” and “focal” will be used interchangeably and the term “febrile seizure” (FS) will be used, reflecting the proposed changes in the terminology of seizures and epilepsies.1

The pathogenesis of cerebral malaria is poorly understood. One hypothesis is that activation of microglia and astrocytes in the brain might cause the cerebral symptoms by excitotoxic mechanisms. Cerebrospinal fluid was sampled in 97 Kenyan children with cerebral malaria, 85% within 48 hr of admission. When compared with an age-matched reference range, there were large increases in concentrations of the excitotoxin quinolinic acid (geometric mean ratio cerebral malaria/reference population [95% confidence limits] = 14.1 [9.8-20.4], P < 0.001) and total neopterin (10.9 [9.1-13.0], P < 0.001) and lesser increases in tetra-hydrobiopterin, di-hydrobiopterin, and 5-hydroxyindoleacetic acid. There was no change in tryptophan concentration. In contrast, nitrate plus nitrite concentrations were decreased (geometric mean ratio = 0.45 [0.35-0.59], P < 0.001). There was a graded increment in quinolinic acid concentration across outcome groups of increasing severity. The increased concentration of quinolinic acid suggests that excitotoxic mechanisms may contribute to the pathogenesis of cerebral malaria.

Summary The district general hospital (DGH) is a common feature of health service provision in many developing countries. We have used linked demographic and clinical surveillance in a rural community located close to a DGH on the Kenyan coast to define the use and public health significance of essential clinical services provided by it. Of a birth cohort of over 4000 children followed for approximately 6 years, about a third were admitted to hospital at least once. Significantly more children admitted with major infectious diseases such as malaria and acute respiratory tract infections were readmitted with the same condition during the surveillance period than would have been expected by chance. Among surviving admissions, mortality post‐discharge was significantly higher than in the cohort which had not been admitted within 3, 6 and 12 months. Most of the patients who died after discharge had been admitted with a diagnosis of gastroenteritis. Most children admitted to the DGH survive hospitalization and the remaining period of childhood. Despite no clinical trial evidence to support the claim, it seems reasonable to assume that in the absence of intensive clinical management provided by a DGH, a significant proportion of these children would not have survived. However, the DGH is able to define a group of at‐risk children who re‐present with severe complications of infectious disease, and of these several may have underlying conditions not amenable to DGH intervention and continue to have a poor prognosis. Both groups of children represent statistically significant subsets of a rural paediatric community and the future organization and co‐ordination of DGH and primary care services need to work in unison to strengthen the service needs of children at risk.

Hyponatraemia is common in African children with severe malaria, but the cause is unknown, We measured plasma sodium (p[Na]) and arginine vasopressin concentrations (p[AVP]) in 30 consecutive children with severe malaria (19 had cerebral malaria), on admission, at 48 and 96h after admission. Hyponatraemia (p[Na] <130 mmol/l) occurred in 53 per cent of the children and was unrelated to peripheral parasite density, dehydration or abnormal renal function. The highest p[AVP] were seen in patients with cerebral malaria. Overall, p[AVP] declined 96 h after treatment. In children with hyponatraemia (cerebral and non-cerebral), p[AVP] levels were not suppressed and in 67 per cent of cases they were deemed inappropriate. Inappropriate AVP secretion is common in children with severe malaria and may influence fluid therapy after correction of initial dehydration.

Background Seizures commonly complicate cerebral malaria and are associated with an increased risk of death and neurological sequelae. We undertook a randomised study to assess the efficacy of intramuscular phenobarbital in preventing seizures in childhood cerebral malaria.Methods Children with cerebral malaria admitted to one hospital in Kilifi, Kenya, were randomly assigned a single intramuscular dose of phenobarbital (20 mg/kg) or identical placebo. Clinical tolerance was assessed at the start of the trial, with particular reference to respiratory depression and hypotension. Seizures were timed and recorded, and treated in a standard way. Plasma phenobarbital concentrations were measured. Analyses were by intention to treat.Findings 440 children with cerebral malaria were admitted to the hospital; 100 were not recruited to the study. Of the remaining 340 170 received phenobarbital and 170 placebo. The drug was adequately absorbed and well tolerated. Seizure frequency was significantly lower in the phenobarbital group than in the placebo group (18 [11%] vs 46 [27%] children had three or more seizures of any duration; odds ratio 0.32 [95% CI 0.18-0.58]) but mortality was doubled (30 [18%] vs 14 [8%] deaths; 2.39 higher in the phenobarbital group than in the placebo group, and mortality was greatly increased in children who received phenobarbital plus three or more doses of diazepam (odds ratio 31.7 [1.2-814]).Interpretation In children with cerebral malaria, phenobarbital 20 mg/kg provides highly effective seizure prophylaxis but is associated with an unacceptable increase in mortality. Use of this dose cannot, therefore, be recommended.

Of 295 children with cerebral malaria, 117 (40%) had an abnormal respiratory pattern; 15 children exhibited more than one pattern during their clinical course. Four distinct patterns were seen. (i) Deep breathing (80 children); this was associated with severe metabolic acidosis, and resolved following treatment with intravenous fluids and/or blood. (ii) Hypoventilation with nystagmus and salivation (18 children); simultaneous electroencephalographic recording revealed continuous electrical seizure activity, demonstrating that these children were in subtle status epilepticus; anticonvulsant treatment resulted in return to normal of blood gases and recovery of consciousness. (iii) Hyperventilation with extensor posturing (20 children), which was associated with varying degrees of intracranial hypertension. (iv) Periodic respiration (14 children); all had clinical features suggestive of transtentorial herniation, and died following a respiratory arrest. Abnormal respiratory patterns can alert the clinician to complications of cerebral malaria that require treatment. Recognition of these patterns and rapid initiation of appropriate supportive therapy may help to reduce the high mortality rate of this disease.

The causes of death and neurological sequelae in African children with cerebral malaria are obscure. Intracranial pressure (ICP) was monitored and cerebral perfusion pressure (CPP) calculated in 23 Kenyan children with cerebral malaria. Four children had severe intracranial hypertension (ICP >40 mm Hg, CPP <40 mm Hg): two died, one with an ICP of 158 mm Hg and signs of transtentorial herniation, the other one with an ICP of 42 mm Hg and cardiorespiratory arrest. The other two survived with severe neurological sequelae. Nine had intermediate intracranial hypertension (ICP >20 mm Hg, CPP <50 mm Hg) and 10 had mild intracranial hypertension (maximum ICP 10-20 mm Hg); all survived without severe sequelae. Mannitol controlled the ICP in children with intermediate intracranial hypertension, but it did not prevent the development of intractable intracranial hypertension in children with severe intracranial hypertension. Intracranial hypertension is a feature of Kenyan children with cerebral malaria and severe intracranial hypertension is associated with a poor outcome.

By US standards, about half of African children are malnourished, although most appear clinically normal. It is possible that precursor supply for gluconeogenesis is limited to a greater extent in these seemingly malnourished African children than in healthy children, consequently limiting glucose production. Since in malaria peripheral glucose utilization is increased, precursor supply could play an even more critical role in maintaining glucose production in African children suffering from falciparum malaria. We studied the effect of alanine infusion (1.5 mg/kg/min) on glucose production (measured by infusion of [6,6-2H2]glucose) and plasma glucose concentration in 10 consecutive children with acute, uncomplicated falciparum malaria. By US standards, six children were below the 10th percentile of weight for height and seven were below the 10th percentile of height for age. Plasma concentrations of alanine increased during alanine infusion from 153 +/- 21 to 468 +/- 39 mumol/l, whereas plasma lactate concentrations did not change (1.4 +/- 0.2 vs. 1.3 +/- 0.2 mmol/l). Plasma glucose concentration and glucose production did not change during alanine infusion: 4.6 +/- 0.3 vs. 4.5 +/- 0.3 mmol/l and 5.8 +/- 0.4 vs. 5.7 +/- 0.3 mg/kg/min, respectively. Gluconeogenic precursor supply is sufficient for maintainance of glucose production in African children with uncomplicated malaria who are malnourished by US standards.