The United Kingdom Primary Immune Deficiency (UKPID) registry 2012 to 2017.

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.

Clinical and immunological overlap between autoimmune lymphoproliferative syndrome and common variable immunodeficiency.

Autoimmune lymphoproliferative syndrome (ALPS) is mainly caused by defects in the CD95 pathway. Raised CD3+TCRαß+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.

Transfusion for respiratory distress in life-threatening childhood malaria.

We have prospectively collected information during resuscitation in 24 children with life-threatening malaria. All had clinical respiratory distress and 16 were severely anemic (hemoglobin < or = 5 g/dL) on admission. Central venous pressure (CVP) measurements were normal (< or = 5 cm of water) prior to treatment but all had a metabolic acidosis. The geometric mean lactate level was significantly higher in children admitted with severe anemia than in those without severe anemia (11.2 mmol/l versus 4.2 mmol/l; P = 0.009). Hypovolemia (a CVP on admission < 0 cm of water) was associated, although not significantly, with a higher admission plasma creatinine concentration (94 mumol/l versus 64 mumol/l; P = 0.06) and probably contributed to the severely reduced creatinine clearances (0-39 ml/min/1.73 ml2) found in 12 of the 13 children in whom this was assessed in the first 24 hr. Treatment resulted in a rapid decrease in blood lactate in 16 of the 13 children in whom this was assessed in the first 24 hr. Treatment resulted in a rapid decrease in blood lactate in 16 of the 20 children transfused, which was most dramatic in severely anemic children, who were rapidly resuscitated. In nonanemic children, early and rapid administration of normal saline usually resulted in both metabolic and clinical improvement. However, in three children, two of whom died, acidosis persisted despite resuscitation. Metabolic acidosis often accounts for respiratory distress in life-threatening childhood malaria. Severe anemia and hypovolemia appear to play major roles in its pathogenesis, are readily treatable, and there appears to be little risk of congestive cardiac failure even with an aggressive approach to fluid replacement.

Cerebrospinal fluid studies in children with cerebral malaria: an excitotoxic mechanism?

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.

Deep breathing in children with severe malaria: indicator of metabolic acidosis and poor outcome.

Despite the frequent association of respiratory symptoms and signs with malarial morbidity and mortality in sub-Saharan Africa, the value of individual symptoms and signs has rarely been assessed. We have prospectively examined the association of individual clinical findings with the summary diagnosis of respiratory distress, outcome, and the presence of metabolic acidosis in children admitted with severe malaria to a Kenyan district hospital. Respiratory distress was present in 119 of the 350 children included in the study and in 23 of the 30 deaths (relative risk = 6.5, 95% confidence interval = 2.8-14.4). The features of a history of dyspnea, nasal flaring, and indrawing or deep breathing (Kussmaul's respiration) were individually most closely associated with the summary diagnosis of respiratory distress. Of these, deep breathing, which was sensitive (91%) and specific (83%) for the presence of severe metabolic acidosis (base excess < or = -12), is the best candidate sign to represent the prognostically important syndrome of malarial respiratory distress. Therefore, it warrants further prospective evaluation in different clinical settings and areas of different malaria endemicity.

Seizures and status epilepticus in childhood cerebral malaria.

Prolonged, multiple seizures complicate a high proportion of cases of childhood cerebral malaria, and several studies have shown an association between these and neurological sequelae. We prospectively studied 65 patients (38 female) admitted to Kilifi Hospital in 1994. Electroencephalographic recordings (EEGs) were made at 12-hourly intervals, with continuous recordings made on a cerebral function analysing monitor (CFAM). Survivors were seen one month after discharge. Cerebral computerized tomography was performed on children with neurological sequelae. Sixty-two percent of patients had seizures following admission, of whom half had an episode of status epilepticus. Fifty-two percent of seizures were partial motor, 34% generalized tonic-clonic, and 14% partial with secondary generalization. In 22%, coma appeared to be due to a prolonged postictal state. Ten children had subtle motor seizures. Posterior parieto-temporal discharges were the most common EEG finding. Seven children died, eight developed neurological sequelae, and 50 (77%) recovered fully. Status epilepticus was associated with the development of neurological sequelae. Prolonged, multiple seizures may play an important part in the pathogenesis of coma in childhood cerebral malaria, and are likely to contribute to both the morbidity and mortality of this disease.

Acidosis in severe childhood malaria.

Data were prospectively collected on 306 Kenyan children, including blood gases in 258 (75%). Severe malaria caused a predominantly high-anion-gap metabolic acidosis in at least 43% of children. Children with coma and respiratory distress (CM + RD) had greater evidence of renal dysfunction, lower mean pH and higher mean plasma osmolality than those with respiratory distress (RD) or coma (CM) as isolated findings (mean urea 10.7 vs. 6.0 vs. 4.3 mmol/l; mean creatinine 97 vs. 74 vs. 58 mumol/l; mean osmolality 301 vs. 288 vs. 283 mosmol/l; and mean pH 7.16 vs. 7.29 vs. 7.39, respectively, p < 0.001 for each comparison of CM + RD vs. RD or CM). In addition, children with CM + RD had a higher mean blood lactate (6.7 vs. 3.3 mmol/l, p < 0.001), a lower mean haemoglobin (5.5 vs. 7.0 g/dl, p = 0.002) and a lower mean age (26.4 vs. 41.9 months, p < 0.001) than children with CM and accounted for 15/24 (63%) of all deaths. These and previous data implicate hypovolaemia and renal impairment in the pathogenesis of metabolic acidosis in severe childhood malaria. In children who are acidotic, anaemia is strongly associated with lactic acidaemia and may therefore contribute to its pathogenesis. These data also imply that coma in acidotic children (CM + RD) and those with an isolated encephalopathy (CM) may result from quite different pathophysiological mechanisms.

The influence of alanine infusion on glucose production in 'malnourished' African children with falciparum malaria.

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.

Abnormal respiratory patterns in childhood cerebral malaria.

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.

Towards optimal regimens of parenteral quinine for young African children with cerebral malaria: the importance of unbound quinine concentration.

Young African children with severe malaria are given quinine using a regimen designed for Thai adults. We measured quinine in the blood, plasma and plasma water of young children in Kenya after rapid intravenous and intramuscular dosing, and calculated the therapeutic range of unbound quinine. The peak plasma quinine concentration after rapid intravenous dosing was 12.3 +/- 3.7 mg/L (mean +/- SD), 43% higher than in adults given the same regimen previously; this was due to a smaller apparent volume of distribution in the children. The therapeutic range of unbound quinine was calculated as 0.2-2.0 mg/L. Simulations of unbound quinine were made for the standard quinine regimen: unbound drug concentrations rose above the therapeutic range after each dose. The possible risks of quinine-induced visual impairment are discussed. Alternative, lower dose regimens for young African children with severe malaria are described.

An open randomized trial of artemether versus quinine in the treatment of cerebral malaria in African children.

We have compared the efficacy of artemether versus quinine as treatment for cerebral malaria in children in an open randomized clinical trial in Kenya. Children admitted to hospital with coma and Plasmodium falciparum parasitaemia were treated with either intramuscular artemether (3.2 mg/kg loading dose followed by 1.6 mg/kg daily) or intravenous quinine (20 mg/kg loading dose followed by 10 mg/kg every 8 h). Both drugs were well tolerated and no significant adverse effect was observed. Parasite clearance times (50% and 90%) were shorter in patients treated with artemether (median times [h], with interquartile ranges in brackets, were: 50%, 7.3 [4.2-12.4] vs. 15.5 [9-22]; 90%, 16.9 [13.2-25] vs. 28.5 [22-35]; P < 0.0001). The total mortality in 160 children with cerebral malaria was 16.25%, with no overall significant difference between the 2 treatment groups. In a subgroup of children with respiratory distress, mortality was higher in those treated with artemether (43.7% vs. 11.1%, P < 0.05). The frequency of neurological sequelae and clinical recovery times were similar in both treatment groups. We conclude that there would currently be no advantage in replacing quinine with artemether for the treatment of cerebral malaria in African children.

Epileptic seizures and malaria in Kenyan children.

Between October 1990 and November 1991 data were collected on the frequency, causes, and nature of epileptic seizures in children admitted to the paediatric ward at Kilifi District Hospital, Kenya, from a defined study area. During this period, 1324 children were studied, of whom 15.8% had seizures as part of their illness. Malaria was by far the commonest cause of seizures, accounting for 69.0%; no other single condition caused more than 4.4%. The proportion of respiratory infections complicated by seizures was 4.0% compared to 31.3% for malaria. Only 25% of malaria-related epileptic seizures were associated with cerebral malaria; the remainder were associated with otherwise uncomplicated malaria and, in this group, 84% had complex seizures, with 47% being partial and over 70% repetitive. There was no relationship with fever, with 54% of observed seizures occurring at rectal temperatures below 38 degrees C. The minimum community incidence of complex seizures in association with non-cerebral malaria was 5.8 per 1000 per year. Complex epileptic seizures in association with otherwise uncomplicated malaria are common and may be a significant cause of longer term morbidity in malaria endemic areas.

The relationship between glucose production and plasma glucose concentration in children with falciparum malaria.

The pathophysiology of hypoglycaemia in children with acute falciparum malaria, a frequent and serious complication, is unknown due to absence of data on glucose kinetics. We investigated the correlation between basal glucose production and plasma glucose concentration in 20 children (8 girls) with acute, uncomplicated falciparum malaria by infusion of [6,6-2H2]glucose. Median plasma glucose concentration was 4.5 (range 2.1-6.5) mmol/L and the median glucose production 5.0 (range 4.1-8.4) mg/kg/min. There was a positive correlation between basal glucose production and plasma glucose concentration (r = 0.53, P = 0.016). There was no correlation between the rate of glucose production and the plasma concentrations of alanine, lactate, counter-regulatory hormones or cytokines. It was concluded that, in children with acute uncomplicated falciparum malaria, endogenous glucose production is an important determinant of plasma glucose concentration, contrary to previous findings in adults with malaria, in whom peripheral uptake seems to be more important than glucose production in determining plasma glucose concentration.

The disposition of intramuscular artemether in children with cerebral malaria; a preliminary study.

The disposition of intramuscular artemether (AM) was studied in 26 Kenyan children with cerebral malaria. Antimalarial activity determined by bioassay was compared with total plasma AM plus dihydroartemisinin (DHA) determined by high power liquid chromatography (HPLC). Therapeutic levels were achieved in most subjects (21/26) within 1 h of receiving intramuscular AM (3.2 mg/kg), with close correlation between bioassay and HPLC measurements (r = 0.706). However, there was marked inter-individual variation, antimalarial activity was undetectable in 5 subjects ('non-absorbers'), and plasma concentrations were lower in subject with respiratory distress. The 50% parasite clearance time was significantly longer in non-absorbers (mean = 13.1 h, SD = 10.8 vs. mean = 7.8 h, SD = 5.5; P = 0.013). We conclude that the bioavailability of intramuscular AM in children with severe malaria may be highly variable, particularly in the presence of respiratory distress, and may be associated with an inadequate therapeutic response.

Periodicity and space-time clustering of severe childhood malaria on the coast of Kenya.

Traditionally malaria epidemiology has focused on factors such as parasite rates and vector dynamics without specific reference to disease. There are limited comprehensive data on malaria as a life-threatening event in African children. We have identified, through hospital surveillance, 581 episodes of severe malaria in residents of a defined area on the Kenya coast over a period of 3 years. This represents an absolute minimum risk of developing severe malaria by the fifth birthday of 1 in 15. The presentation of severe malaria showed marked seasonality, but the timing and magnitude of these fluctuations varied considerably between years. A satellite navigational system was used to define the exact location of the home of each severe malaria case. Space-time clustering of severe malaria was evident in this community. Seasonal peaks in incidence of severe malaria may comprise discrete mini-epidemics. In contrast, parasite rates in the community varied little during the course of the surveillance. The monitoring of disease, as opposed to parasitization, in children may result in more effective targeting of intervention resources.

A single dose of intramuscular sulfadoxine-pyrimethamine as an adjunct to quinine in the treatment of severe malaria: pharmacokinetics and efficacy.

It has been suggested that sulfadoxine-pyrimethamine (SD/PM) may be useful in the treatment of severe malaria since it could enhance the killing of parasites by quinine (QN) and it can be given as a single intramuscular injection. Eighty Kenyan children with severe malaria were allocated at random to receive either intramuscular QN alone (quinine dihydrochloride 20 mg salt/kg as a loading dose, followed by 10 mg salt/kg 12 hourly for a total of 6 doses) or the same QN regimen plus one intramuscular injection of SD/PM (sulfadoxine 25 mg/kg, pyrimethamine 1.25 mg/kg). There was no difference in time to defervescence, aparasitaemia, or 50% reduction in parasitaemia, parasite elimination half-life, or mortality between the 2 groups. In addition, the concentrations of SD and PM were measured in 14 children and of QN in 8 of these children. Concentrations needed to achieve synergy against PM-resistant strains of Plasmodium falciparum were achieved in all of the children with severe malaria within the first hour and maintained for more than 72 h. SD/PM did not perturb the pharmacokinetics of QN.

The management of severe malaria in children: a review.

We have attempted to summarise an approach to management of severe malaria from our experience and that of others from published data in this review. This represents our current state of knowledge and practices which may change as research continues in this field. It also represents what we feel should be the minimum aim in treating severe malaria even at district hospital level. It focuses on practical issues encountered when admitting such patients: initial assessment, immediate supportive management, use of transfusion, appropriate anti-malarial treatment and ongoing management.

Febrile seizures: an update.

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

Hyponatraemia and dehydration in severe malaria.

The prevalence and likely cause of hyponatraemia in severe childhood malaria were investigated. One hundred and thirty two children, 47 of whom had cerebral malaria, were prospectively recruited and serial simple indices of fluid and electrolyte balance and renal function monitored during admission. In 55%, hyponatraemia (sodium < 135 mmol/l) was present on admission. Hyponatraemia was pronounced (sodium < or = 130 mmol/l) in 21%, and these children gained less weight during admission (mean weight gain 2.4% v 4.3%) than children with a normal sodium (135-145 mmol/l). Overall, 31% of survivors were at least moderately dehydrated on admission (5% weight gain by discharge). These children had higher plasma urea concentrations on admission (6.1 v 4.5 mmol/l) and were more acidotic (mean base excess -12.1 v -8.0) than children who were not dehydrated. There were changes in simple indices of renal function between admission and discharge in children who survived (creatinine 65.7 v 37.9 mumol/l and urea 5.5 v 1.9 mmol/l). The results suggest that dehydration is common in severe childhood malaria, that it may contribute to mild impairment in renal function, and that hyponatraemic children are less water depleted, showing appropriate rather than inappropriate secretion of antidiuretic hormone.