Severe imported falciparum malaria among adults requiring intensive care: a retrospective study at the hospital for tropical diseases, London.

BACKGROUND: Malaria is the commonest imported infection in the UK. Malaria requiring ICU admission has a reported mortality of up to 25%. The relationship between ethnicity, immunity, and risk of malaria is complex. The Malaria Score for Adults (MSA) and Coma Acidosis Malaria (CAM) score have recently been proposed to risk stratify patients with malaria. METHODS: Retrospective study of patients with WHO severe falciparum malaria admitted to ICU at the Hospital for Tropical Diseases, London, UK. The relationship between clinical variables and risk of death or a prolonged ICU stay were examined with logistic regression. The predictive value of the MSA and CAM score were calculated. RESULTS: 124 patients were included. Cerebral malaria and acute kidney injury occurred earlier (median day 1) than acute respiratory distress syndrome (median day 3). Six patients had community acquired bacterial co-infection. Eight patients were co-infected with HIV, five of whom were newly diagnosed. The positive predictive value of a CAM score ≥2 or an MSA ≥5 for death were 12% and 22% respectively. Five patients died. No variable was significantly associated with risk of death. There were no significant differences between individuals raised in endemic countries compared to non-endemic countries. CONCLUSIONS: Mortality in patients managed in a specialist centre was low. Patients who died succumbed to complications associated with a prolonged stay on ICU rather than malaria per se. The clinical usefulness of the MSA and CAM score was limited. Co-infection with HIV was relatively common but compared to studies in children, bacteraemia was uncommon. The relationship between ethnicity and immunity to severe disease is complex.

Novel pfdhps haplotypes among imported cases of Plasmodium falciparum malaria in the United Kingdom.

Treatment of acute malaria caused by Plasmodium falciparum may include long-half-life drugs, such as the antifolate combination sulfadoxine-pyrimethamine (SP), to provide posttreatment chemoprophylaxis against parasite recrudescence or delayed emergence from the liver. An unusual case of P. falciparum recrudescence in a returned British traveler who received such a regimen, as well as a series of 44 parasite isolates from the same hospital, was analyzed by PCR and direct DNA sequencing for the presence of markers of parasite resistance to chloroquine and antifolates. The index patient harbored a mixture of wild-type and resistant pfdhfr and pfdhps alleles upon initial presentation. During his second malaria episode, he harbored only resistant parasites, with the haplotypes IRNI (codons 51, 59, 108, and 164) and SGEAA (codons 436, 437, 540, 581, and 613) at these two loci, respectively. Analysis of isolates from 44 other patients showed that the pfdhfr haplotype IRNI was common (found in 81% of cases). The SGEAA haplotype of pfdhps was uncommon (found only in eight cases of East African origin [17%]). A previously undescribed mutation, I431V, was observed for seven cases of Nigerian origin, occurring as one of two haplotypes, VAGKGS or VAGKAA. The presence of this mutation was also confirmed in isolates of Nigerian origin from the United Kingdom Malaria Reference Laboratory. The presence of the pfdhps haplotype SGEAA in P. falciparum parasites of East African origin appears to compromise the efficacy of treatment regimens that include SP as a means to prevent recrudescence. Parasites with novel pfdhps haplotypes are circulating in West Africa. The response of these parasites to chemotherapy needs to be evaluated.

Clinical and Diagnostic Features of 413 Patients Treated for Imported Strongyloidiasis at the Hospital for Tropical Diseases, London.

This study describes the clinical features of a cohort of imported cases of strongyloidiasis and the performance of standard diagnostic techniques for this condition. A total of 413 cases were identified, of whom 86 had microscopically proven infection. In proven cases, 23% had normal eosinophil counts, 19% had negative Strongyloides-specific serology, and 9.3% had normal blood counts and were seronegative. Serological testing was less sensitive for returning travelers (46.2%) than for migrants (89.7%). Immunosuppression, including human T-cell lymphotropic virus 1, was significantly associated with proven infection after controlling for age, presence of symptoms, duration of infection, and eosinophilia (OR 5.60, 95% CI 1.54-20.4). Patients with proven infection had lower serology values than those diagnosed with strongyloidiasis on the basis of positive serology and eosinophilia alone (P = 0.016). Symptomatic patients were significantly younger, had a shorter presumed duration of infection, and lower serology values. These data suggest a correlation between immunologic control of strongyloidiasis and the amplitude of the humoral response.

Imported Plasmodium falciparum malaria: are patients originating from disease-endemic areas less likely to develop severe disease? A prospective, observational study.

Just more than 2,000 cases of Plasmodium falciparum malaria are reported in the United Kingdom annually, with a mortality rate of approximately 1%. Some studies suggest that patients with malaria who originate from disease-endemic areas are less likely to develop severe disease; such patients are often treated at home. We have prospectively examined 99 patients with imported P. falciparum malaria and categorized them according to severity as defined by World Health Organization criteria. There was no significant difference between those who developed severe disease and those who did not in terms of their ethnicity, residence in a malaria-endemic area, or history of previous episodes of malaria. To assume a patient has clinical immunity to malaria simply because they originate from or have lived for a long time in a malaria-endemic area may be inappropriate and unsafe.

Geographical and temporal trends in imported infections from the tropics requiring inpatient care at the Hospital for Tropical Diseases, London - a 15 year study.

BACKGROUND: Understanding geographic and temporal trends in imported infections is key to the management of unwell travellers. Many tropical infections can be managed as outpatients, with admission reserved for severe cases. METHODS: We prospectively recorded the diagnosis and travel history of patients admitted between 2000 and 2015. We describe the common tropical and non-tropical infectious diseases and how these varied based on region, reason for travel and over time. RESULTS: A total of 4362 admissions followed an episode of travel. Falciparum malaria was the most common diagnosis (n=1089). Among individuals who travelled to Africa 1206/1724 (70.0%) had a tropical diagnosis. The risk of a tropical infection was higher among travellers visiting friends and relatives than holidaymakers (OR 2.8, p<0.001). Among travellers to Asia non-tropical infections were more common than tropical infections (349/782, 44.6%), but enteric fever (117, 33.5%) of the tropical infections and dengue (70, 20.1%) remained important. The number of patients admitted with falciparum malaria declined over the study but those of enteric fever and dengue did not. CONCLUSIONS: Most of those arriving from sub-Saharan Africa with an illness requiring admission have a classical tropical infection, and malaria still predominates. In contrast, fewer patients who travelled to Asia have a tropical diagnosis but enteric fever and dengue remain relatively common. Those visiting friends and relatives are most likely to have a tropical infection.

The effect of mass administration of sulfadoxine-pyrimethamine combined with artesunate on malaria incidence: a double-blind, community-randomized, placebo-controlled trial in The Gambia.

A double-blind, community-randomized, placebo-controlled trial was conducted in a rural area of The Gambia between June and December 1999 to test whether a reduction in the infectious reservoir can reduce malaria transmission. Overall 14,017 (85%) individuals living in the study area were treated with either placebo or sulfadoxine-pyrimethamine (SP) combined with a single dose of artesunate (AS). Following the mass drug administration (MDA) 1375 children aged 6 months to 10 years were kept under surveillance for clinical malaria in 18 villages throughout the 1999 malaria transmission season. During a 20-week surveillance period 637 episodes of malaria were detected. The mean incidence rate was 2.5/100 child-weeks in the placebo villages, and 2.3/100 child-weeks in villages that received SP + AS. The mean rate ratio, adjusted for individual and village-level covariates, was 0.91 (95% CI 0.68-1.22, P = 0.49). During the first 2 months of surveillance, the malaria incidence was lower in treated villages. After 2 months the incidence was slightly higher in the MDA group but this was not statistically significant. Overall, no benefit of the MDA could be detected. The reason for the absence of an impact on malaria transmission is probably the very high basic reproductive number of malaria, and the persistence of mature gametocytes, which are not affected by AS treatment.

Needles and the damage done: reasons for admission and financial costs associated with injecting drug use in a Central London Teaching Hospital.

OBJECTIVES: To establish the clinical reasons for inpatient admissions among injecting drug users. To determine the frequency of behavioural issues during their care and to estimate the financial implications of injecting drug use to the health service. METHODS: Retrospective cohort study at University College London Hospital. Clinical, laboratory and financial data were extracted from case notes and electronic records. The cost of each admission was compared to the income received for the period of care. RESULTS: 124 injecting drug users required 191 admissions between 2005 and 2009. Skin and soft tissue infections (58%) and pneumonia (18%) were the commonest reasons for admission. Bacteraemia at admission was often not accompanied by an inflammatory response. Exposure to HIV (4%), hepatitis B (49%) and C (84%) was common. Drug misuse (16%) during admission was frequent. The cost to the NHS of treating soft tissue infections in drug users was approximately £77 million per annum. After a median follow-up of 40 months, 10 patients (8%) had died. All deaths were attributable to drug use. CONCLUSIONS: Bacterial and viral infections are largely responsible for the significant mortality and morbidity of injecting drug users presenting to secondary care. The financial burden to the NHS is substantial.

Chloroquine-resistant Plasmodium falciparum infections among UK travellers returning with malaria after chloroquine prophylaxis.

OBJECTIVES: We sought to identify chloroquine-resistant Plasmodium falciparum parasites among 66 travellers who presented in the UK with malaria. METHODS: A multiplex real-time PCR assay was devised to identify wild-type and two distinct chloroquine-resistance-associated alleles of the pfcrt gene. RESULTS: Those with documented use of chloroquine/proguanil prophylaxis were more likely to carry parasites with resistance-associated alleles of pfcrt than were patients who had been using antimalarials other than chloroquine (92.9% versus 37.5%; P = 0.011). We also found evidence that people reporting optimum compliance with chloroquine prophylaxis during malaria exposure were more common among malaria cases than were those reporting optimum compliance with other regimens (OR 3.85, 95% CI 1.61-9.69; P = 0.0008). CONCLUSIONS: Chloroquine, known to be failing as therapy for falciparum malaria worldwide, is also failing to provide adequate malaria prophylaxis for travellers.

New perspectives on the fatty liver of kwashiorkor - abstract

Samples of liver were examined from eight patients who died from protein-calorie malnutrition, and compared with biopsies taken at various stages of recovery from seven other patients. All specimens were taken from patients admitted to the Tropical Metabolism Research Unit, at Mona. Liver samples for electron microscopy were obtained within one hour of death, fixed in 2.5 per cent glutaraldehyde, passed through 1 per cent osmium tetroxide, dehydrated through graded ethanols, and embedded in Maraglas. Sections for electron microscopy were stained with lead citrate. The cells from recovering patients showed normal organization, apart from some increase in residual bodies, and prominent intramitochondrial swelling, and influx of calcium into the matrix. There were also canalicular and intracytoplasmic cholestasis, abundant lipid droplets, loss of glycogen reserves, scanty endoplasmic reticulum and Golgi membranes, focal cytoplasmic degradation, and depletion of peroxisomes. The depletion of peroxisomes may be an important factor in the accumulation of lipids, as they normally carry out beta-oxidation on long-chain fatty acids. They also contribute to cellular defences against free radicals. The disorganisation of cellular organelles is consistent with free radical damage and terminal anoxia (AU)

Peroxisomes and the fatty liver of malnutrition: an hypothesis 1-3

Peroxisomes play a role in hepatic á-oxidation of fat, a process that results in the production of hydrogen per-oxide. The fatty infiltration of the liver that occurs in severely malnourished children remains unexplained. We observed an almost total absence of peroxisomes in the hepatocytes of these children. We suggest that lack of available peroxisomes could contribute to the development of fatty liver.(AU)

Peroxisomes and the hepatic pathology of childhood malnutrition

Liver specimens obtained immediately after death from eight severly malnourished children were examined by electron microscopy, and compared with seven liver biopsy specimens from children who recovered from malnutrition. The liver cells from the fatal cases showed mitochondrial swelling, with coarse densities in the matrix, cholestasis, depletion of the endoplasmic reticulum and Golgi apparatus, diminished glycogen stores, prominent lipid deposits and focal cytoplasmic degradation. The nucleoli were enlarged. There was marked reducation in peroxisomes. In contrast, the biopsies from recovering children showed good cellular organisation, and a normal frequency of peroxisomes. Multiple factors, including sepsis, may lead to depletion of peroxisomes. Loss of peroximes may interrupt beta-oxidation of long-chain fatty acids and accentuate the accumulation of lipid. Moreover, a reduction in the concentration of catalase may remove one avenue for the detoxification of free radicals. As the concentration of other anti-oxidants, notably glutathione, is also reduced, free radical damage may occur, leading to lipid peroxidation of membranes, mitochondrial damage, pump failure and influx of water and electrolyted into the cell (AU)

Peroxisomes and the hepatic pathology of childhood malnutrition

Liver specimens obtained immediately after death from eight severly malnourished children were examined by electron microscopy, and compared with seven liver biopsy specimens from children who recovered from malnutrition. The liver cells from the fatal cases showed mitochondrial swelling, with coarse densities in the matrix, cholestasis, depletion of the endoplasmic reticulum and Golgi apparatus, diminished glycogen stores, prominent lipid deposits and focal cytoplasmic degradation. The nucleoli were enlarged. There was marked reducation in peroxisomes. In contrast, the biopsies from recovering children showed good cellular organisation, and a normal frequency of peroxisomes. Multiple factors, including sepsis, may lead to depletion of peroxisomes. Loss of peroximes may interrupt beta-oxidation of long-chain fatty acids and accentuate the accumulation of lipid. Moreover, a reduction in the concentration of catalase may remove one avenue for the detoxification of free radicals. As the concentration of other anti-oxidants, notably glutathione, is also reduced, free radical damage may occur, leading to lipid peroxidation of membranes, mitochondrial damage, pump failure and influx of water and electrolyted into the cell.

The acute phase response in severely malnourished children - abstract

The acute phase response is a non-specific reaction to tissue injury, in which the liver plays a central role. We examined the acute phase response in 52 severely malnourished children by measuring the serum levels of C-Reactive Protein (CRP) and Serum Amyloid A (SAA), using an ELISA technique. Blood was taken both at admission and following a controlled stress, namely, Triple (DPT) Vaccine. Four children died. The surviving children received DPT either at admission (n=16) or early in recovery (time B) (n=32). All the children received a second vaccination with DPT once they had regained > 90 percent weight-for-height (discharge) (n=48). Both acute phase proteins responded in tandem. The admission values were elevated in only 44 percent of the children for CRP and 20 percent for SAA, despite clinical evidence of infection. The magnitude of the response of both acute phase proteins to DPT given at admission or at time B was significantly less than at discharge (p < 0.05). Even at discharge, approximately 20 percent of the children did not have the expected response. Children with oedematous malnutrition were less likely to respond than non-oedematous children. We suggest that, firstly, severly malnourished children are unable to mount an effective acute phase response, which may have functional implications. Secondly, that the inability to synthesize acute phase proteins represents one manifestation of the hepatic dysfunction that occurs in severe malnutrition (AU)

The effect of DPT inoculation on the hormonal control of glucose homeostasis in children recovered from malnutrition

The effect of a controlled stress (DPT inoculation) on the hormonal control of glucose homeostasis was investigated in children nutritionally rehabilitated from severe malnutrition. The age range of the 15 children studied was 6-26 months. Plasma insulin (INS), growth hormone (GH) and interleukin-1 (IL-1) were measured by radioimmunoassay; plasma glucose (GLU) by a glucoseoxidase method; and red cell insulin binding ( percentSB) was determined, using A-14 monoiodinated insulin. Measurements were made on two occasions: (T-O) at 10 a.m.,12 hr before DPT inoculation, and (T-36) 36 hr. after inoculation. On both occasions, 4 hr post-prandial blood samples were used, and the mean body temperature(T) on the day of the test was determined. Red cell insulin binding ( percentSB) was significantly higher at T-36 than at T-O (16.8 ñ 1.7 vs 12.1 ñ 1.2 (14), p=0.005). (Results were expressed as mean ñ SEM, numbers of paired observations in parentheses). The higher percentSB after DPT was accompanied by an increase in the number of receptor sites (S) (29.05 ñ 6.5 vs 15.6 ñ 2.5 (14),p=0.025). However, insulin receptor affinity (K x 10(9)M(-1)) was decreased 0.7 ñ 0.1 vs 1.5 ñ 0.3(14), p=0.008). There were no significant differences in the plasma levels of insulin, glucose and interleukin-1, but plasma growth hormone (æU/ml) was increased after DPT, (18.0 ñ 3.0 vs 11.5 ñ 1.2 (13), p=0.04). Body temperature (§C) was also significantly increased after DPT,(99.9 ñ 0.4 vs 98.3 ñ 0.2(14), p=0.006). The change in plasma glucose from T-O to T-36 tended to be associated with both a change in plasma insulin (p=0.06) and plasma growth hormone (p=0.07). Increased insulin binding, as one index of increased insulin sensitivity during fever, can contribute to a reduction in blood glucose. However, the elevation in plasma growth hormone cold buffer the hypoglycaemic effect of insulin, and help to maintain glucose homeostasis (AU)

Febrile response in malnutrition

The febrile response to a standard dose of triple (DPT) vaccine was assessed in sixteen malnourished children before and after recovery. Increase in temperature was significantly lower in the malnourished children (p<0.005) (AU)

Ultrasonographic assessment of the extent of hepatic steatosis in severe malnutrition

Ultrasonographic, blinded assessment was made of the extent of hepatic steatosis in 55 children with severe malnutrition: undernutrion (n=6), marasmus (n=18), marasmic-kwashiorkor (n=17), and kwashiorkor (n=14). The children were examined on admission, in early recovery (considered as baseline), and again discharge. Eleven healthy control children and eight of the previously malnourished children were studied as comparison groups. Both oedematous and non-oedematous malnourished children had significantly more steatosis than the comparison groups at each time. Children with oedematous malnutrition had significantly greater steatosis than non-oedematous children at admission, Half of the non-oedematous malnourished children had appreciable hepatic steatosis at both admission and at baseline. Hepatic fat was only slowly mobilised. The rate constant was 1.4 ñ 0.3 percent/day. One quarter of the children did not change steatosis grades during the period they were in hospital. There was no overall correlation between the extent of steatosis and liver size. Hepatic steatosis in childhood malnutrition is not confined to oedematous children: it is frequently present in marasmic and under-nourished children. Its extent is not necessarily related to the degree of hepatomegaly and accumulated lipid is only slowly mobilised (AU)

The effect of the level of dietary protein, carbohydrate and fat on urea kinetics in young children during rapid catch-up weight gain

The kinetics of urea metabolism were measured in children recovering from severe malnutrition. For a period of up to 10 d they receive one of four diets which provided 711 kj (170 kcal)/kg per d. Two groups received a diet with a high protein:energy (P:E) ratio of 10.6 percent (HP), enriched with either fat (HP/F) or maize starch and sucrose HP/C). Two groups received a diet with a low P:E ratio of 8.8 percent (LP), enriched with either fat (LP/F) or maize starch and sucrose (LP/C). The rate of weight gain on the HP diets was significsntly greater than on the LP diets. There was no difference in urea production between any of the four diets: HP/F 1.23 (se 0.12), HP/C 1.37 (se 0.14), LP/F 1.64 (se 0.22) LP/C 1.15 (se 0.15) mmol nitrogen/kg per h. On the HP diets urea excretion was 0.77 (se0.07) mmol N/kg per h, 61 percent of production. There was significantly less urea excreted in the urine on diet LP/C than on LP/F (0.36 (se0.05) and 0.64 (se 0.04)mmol N/kg per h respectively). A significantly greater percentage of the urea production was hydrolysed on the LP diets (61 percent) compared with the HP diets (39 percent), with the consequence that 50 percent of urea-N produced was available for synthetic activity on the LP diets compared with 30 percent on the HP diets. The increase in the urea hydrolysed on the LP diets was equivalent in magnitude to the decreased intake of N, so that overall intake plus hydrolysis did not differ between the LP and HP diets. Crude N balance was similiar on diets HP/F, HP/C and LP/C, but was significantly reduced on diet LP/F. These results show that there is an accommodation in urea kinetics during rapid catch-up weight gain, which becomes evident when the P:E ratio of 8.8 percent, protein is limiting for catch-up growth. When the intake has a P:E ratio of 8.8 percent the pattern of urea kinetics can be modified by the relative proportion of fat and carbohydrate in the diet. The measurement of urea kinetics provides a useful approach to the definition of the adequacy of the protein in the diet. (AU)

Is there an acute-phase response in steady-state sickle cell disease?

Metabolic and serum changes during steady-state homozygous sicle cell (SS) disease are consistent with an acute-phase response and raise the possibility that inflammation occurs in SS disease even during the steady state. To test this hypothesis, we measured concentrations of acute phase reactants in patients with SS disease, in patients with sickle cell haemoglobin C (SC) disease, and in normal (AA) control subjects. The concentrations of C-reactive protein and serum amyloid A were increased above 10 mg/L and 5mg/L, respectively (our definition of an acute-phase response) in 18 percent (26/143) of subjects with SS disease even when they were symptom free, in 17 percent (6/35) of subjects with SC disease, and in 1 percent (1/80) of AA controls (p<0.001). We suggest that subclinical vaso-occlusion may generate a covert inflammatory response and that the cytokine mediators of this response may contribute to the metabolic abnormalities and growth failure in sickle cell disease.(AU)

The relationship between red cell glutathione and hepatic steatosis in malnourished Jamaican children - abstract

Low levels of red cell glutathione (a scavenger of free radicals) have been previously shown to correlate well with the presence of oedema in malnourished children. We addressed the possibility that they may also correlate with the extent of hepatic steatosis. Thirty-three children were studied on three occasions - on admission, in early weight gain and at discharge. Ultrasonography was used to assess hepatic fat. The oedematous children had significantly more hepatic fat on admission than the non-oedmatous (p<0.01), but no child had a normal ultrasound. We found a significant inverse relationship (r = -0.53, p<0.001) between hepatic fat and the level of red cell glutathione that disappeared over time. We conclude that, firstly, hepatic steatosis occurs commmonly in even non-oedematous malnourished children. Secondly, this is associated with low levels of glutathione which may have aetiological implications (AU)

Vitamin E status in oedematous and non-oedematous malnourished children - abstract

The antioxidant function of vitamin E is essential for maintaining the integrity of cell membranes. During the early phase of recovery from severe malnutrition, we measured the plasma levels of Vitamin E in 58 children on admission (A), and after metabolic recovery (B). A total of 19 marasmic children, and 34 with oedematous malnutrition (19 with marasmic-kwashiorkor and 15 with kwashiorkor) were studied. A further group of 5 oedematous children who were clinically assessed as extremely sick received daily vitamin E supplements. The children were all fed on the same dietary regimen. The results indicated that although vitamin E intake was greater in the non-oedematous (marasmic) children, the rate of change of concentration in the plasma did not differ between the two groups. This could possibly be attributed to a difference in the absorption or utilization of the vitamin between the groups. In the group receiving supplements, there was a significant increase in plasma vitamin E concentration between A and B. However, the rate of increase and the concentration at B did not differ from that in the two groups of unsupplemented children. We conclude that in malnourished children: (1) plasma viatmin E levels are low on admission, (2) values normalize by time B, and (3) supplementation with alpha-tocopherol in oil did not affect the rate of increase in plasma vitamin E. The supplement did not seem to be bioavailable (AU)