Inpatient management of severe malnutrition: time for a change in protocol and practice.

This review focuses on how to reduce the high mortality of severe acute malnutrition (SAM) in African hospitals. The World Health Organization's 1999 manual for physicians (protocol) has not resulted in case-fatality rates of under 5%, even in published research studies from Africa, far less in district and central hospitals which do not record case-fatality rates. It is suggested that the following eight changes to the protocol need to be considered if we are serious about reducing case-fatality rates in African hospitals: (1) use of low lactose, low osmolality milk feeds during the early stage of treatment, especially for HIV-exposed infants and diarrhoeal cases; (2) more cautious use of high carbohydrate loads (ORS, ReSoMal, sucrose and 10% dextrose) during initial stabilisation; (3) more careful grading up and down of feed volumes according the child's responses during the early rehabilitation phase; (4) rapid rehydration of children in shock with Ringer's lactate, as for well-nourished children, with closer monitoring for heart failure; (5) greater use of 3rd-generation cephalosporin and fluoroquinolone antibiotics (e.g. ceftriaxone, ciprofloxacin) to treat sepsis owing to resistant organisms; (6) consider adding glutamine-arginine supplements as gut-protective agents in addition to zinc and vitamin A; (7) the addition of phosphate to existing potassium and magnesium supplements for those at risk of the refeeding syndrome; and (8) introduce better tools for diagnosis and clearer management of combined HIV and tuberculous infections in infants. Many will argue that these suggestions are unaffordable or impractical. On the contrary, cases of SAM requiring hospital admission need to be allocated more resources, including better nursing care, better diet and better medication. Resources made available for other childhood inpatient services such as ID and HIV dwarf those for severe malnutrition. Of course, prevention is always a better investment, including improving breastfeeding rates, improving complementary feeding practices and using ready-to-use therapeutic foods (RUTF) or similar supplements for those failing to thrive in the community, but SAM is unlikely to disappear from our hospitals, and these children need to be better managed if we are serious about reducing mortality.

Substance P recognition by a subset of human T lymphocytes.

The interaction of substance P with human blood T-lymphocytes, which stimulates T-lymphocyte proliferation, was quantified by both flow cytometric and direct binding assays. Fluorescence-detection flow cytometry recorded the binding of dichlorotriazinylamino-fluorescein-labeled substance P to 21 +/- 10% (mean +/- SD, n = 6) and 35 +/- 8% (n = 2) of human blood T-lymphocytes before and after stimulation with 10 micrograms/ml of phytohemagglutinin, respectively. The suppressor-cytotoxic (leu 2a) and helper-inducer (leu 3a) subsets identified by phycoerythrin-labeled monoclonal antibodies contained substance P-reactive T-lymphocytes at respective mean frequencies of 10 and 18%. [3H]substance P bound rapidly and reversibly to a mean of 7035 +/- 2850 sites/T-lymphocyte, which exhibited a dissociation constant (KD) of 1.85 +/- 0.70 X 10(-7) M (mean +/- SD, n = 5). [D-Pro2,D-Phe7,D-Trp9]substance P inhibited the binding of dichlorotriazinylamino-fluorescein-labeled substance P and [3H]substance P to T-lymphocytes at concentrations that suppressed the proliferative response to substance P. Substance P, eledoisin, and substance K (alpha-neurokinin), which all share with substance P the carboxy-terminal substituent -Gly-Leu-Met-NH2, were more potent than substance P in inhibiting the binding of [3H]substance P to T-lymphocytes, suggesting the importance of this sequence in the interaction. Purified human blood B-lymphocytes, monocytes, polymorphonuclear leukocytes, and platelets, and cultured Hut 78 cutaneous lymphoma T-cells, Jurkat cells, Molt-4 lymphoblasts, and HL-60 and U-937 monocyte-like cells all showed only minimal specific binding of [3H]substance P. The recognition of substance P by T-lymphocytes provides one mechanism for selective modulation of immunity by sensory nerves.

Whole-body protein kinetics in children with kwashiorkor and infection: a comparison of egg white and milk as dietary sources of protein.

This study tested the hypothesis that during treatment of kwashiorkor (including marasmic kwashiorkor) with infection there is a lower rate of amino acid oxidation when the dietary intake of amino acids resembles the amino acid composition of acute phase proteins (APPs). Twenty-two children in Blantyre, Malawi, with kwashiorkor and acute infection were fed an isoenergetic, isonitrogenous diet with either egg white or milk as a protein source. The whole-body amino acid oxidation rate was measured after 24 h by determining the plasma urea rate of appearance, and whole-body protein breakdown and synthesis rates were determined from the plasma leucine rate of appearance. Plasma concentrations of C-reactive protein, alpha1-antitrypsin, tumor necrosis factor alpha (TNF-alpha), and interleukin 6 (IL-6) were determined on admission and at 24 and 48 h. The 11 children who received milk had a lower rate of amino acid oxidation than the children who received egg white (x +/- SD: 137 +/- 65 compared with 195 +/- 66 micromol urea x kg body wt(-1) x h(-1), P < 0.05). No significant differences were found between the two groups in the rate of whole-body protein breakdown or protein synthesis. The TNF-alpha concentration correlated inversely with whole-body protein breakdown and synthesis rates, and the IL-6 concentration correlated directly with C-reactive protein. We conclude that by making the amino acid composition of the diet resemble that of APPs in the treatment of acute kwashiorkor, the rate of amino acid oxidation can be decreased.

Protein metabolism in children with edematous malnutrition and acute lower respiratory infection.

This study tested the hypothesis that wholebody protein kinetics remain low in children with edematous malnutrition and acute infection. Thirteen children with edematous malnutrition and acute infection (subjects) were compared with 14 uninfected children with edematous malnutrition early in recovery (control children). Protein kinetics were determined by using a primed, constant intravenous infusion of [13C]leucine and [15N2]urea in the postabsorptive state. Calculations of rates of whole-body protein synthesis and breakdown were based on the rate of leucine appearance; the rate of leucine oxidation was estimated from the rate of urea appearance. Protein synthesis and breakdown rates were lower in subjects than in control children (97 +/- 30 compared with 153 +/- 67, P < 0.01, and 103 +/- 30 compared with 160 +/- 67 mumol leucine.kg-1.h-1, P < 0.01). No difference was found between the two groups in the rate of urea appearance, but this analysis only had a statistical power of 54%. The absence of the expected increase in the rate of protein turnover during acute infection in edematous malnutrition implies that acute phase proteins are made with a corresponding depletion of muscle, hepatic, and other body proteins such as albumin, and that there may also be a blunting of the acute phase response.

Increased nitric oxide production in acute diarrhoea is associated with abnormal gut permeability, hypokalaemia and malnutrition in tropical Australian aboriginal children.

Australian Aboriginal children hospitalized with diarrhoeal disease have severe manifestations with acidosis, hypokalaemia, osmotic diarrhoea and abnormal small bowel permeability. Nitric oxide (NO) production is increased in diarrhoeal disease, but its relationship to mucosal function and diarrhoeal complications is not known. We examined the relationship between NO production and complications of acute diarrhoea in Aboriginal and non-Aboriginal children between February 1998 and February 2000. We enrolled 318 children admitted to Royal Darwin Hospital into one of three groups: acute diarrhoea, non-diarrhoeal controls with no inflammatory illness, and non-diarrhoeal controls with inflammatory illness. Nitric oxide production was measured by urine nitrate-creatinine (NOx/Cr) excretion on a low nitrate diet. Small bowel intestinal permeability was measured by the lactulose-rhamnose (L/R) ratio on a timed blood specimen. The NOx/Cr ratios were markedly elevated in Aboriginal diarrhoeal cases (geometric mean [GM] = 1.23, 95% confidence interval [95% CI] 1.07-1.44), lowest in non-Aboriginal non-inflammatory controls (GM = 0.13, 95% CI 0.10-0.16) and intermediate in all other groups (GM = 0.35, 95% CI 0.28-0.43). Convalescent levels (day 5) in the Aboriginal diarrhoeal group (GM = 1.02, 95% CI 0.82-1.28) were slower to fall than L/R ratios. Multivariate analysis in the diarrhoeal group indicated that high NO production was associated with abnormal permeability, hypokalaemia and malnutrition, but not with the severity of diarrhoea, acidosis or osmotic diarrhoea. We concluded that increased NO production may contribute to impaired mucosal barrier function and hypokalaemia in acute gastroenteritis, which may be the cost of the known gut-protective and antimicrobial effects mediated by NO in acute intestinal inflammation.

Case management of kwashiorkor: an intervention project at seven nutrition rehabilitation centres in Malawi.

OBJECTIVES: (1) To improve case management of kwashiorkor at seven Nutritional Rehabilitation Centres (NRCs) through 2-4 weekly paediatric supervisory visits. (2) To evaluate the impact of the use of routine tube-feeding and a micronutrient supplement (Nutriset). DESIGN: An intervention project with descriptive clinical data in which Nutriset was introduced halfway through the project, and routine tube-feeding at one NRC was compared to no tube-feeding at a similar one. SETTING: NRCs located at two central hospitals, two district hospitals and three rural clinics in southern Malawi. SUBJECTS: 1625 consecutive kwashiorkor admissions from January-December 1995. RESULTS: The overall case-fatality rate was 24.2% (393/1625), varying by facility level (central 30.5%, district 25.8% and rural 7.5%), reflecting different severity of cases. From ELISA testing and a clinical protocol, we estimate that 21.7% (353/1625) of these kwashiorkor cases were HIV-infected, including 121 breastfed children. Routine tube-feeding was associated with better weight gain (8.24 g/kg/d) than no tube-feeding (4.51 g/kg/d) at central NRCs, but with no reduction in mortality (31.4% vs 30.3%). The introduction of Nutriset was associated with improved weight gain (6.06 vs 4.66 g/kg/d) and a lower mortality (20.8 vs 25.8%), but was confounded by seasonal factors. CONCLUSIONS: From a clinical perspective, HIV infection has transformed kwashiorkor in this part of Africa. Routine tube-feeding was associated with improved body weight gain in the treatment of kwashiorkor. The benefit of paediatric supervision was limited by the infrequency of visits, by constraints of health worker motivation, by a lack of resources and by the severity of disease. Efforts need to focus-not just on case management protocols-but on how to actually improve clinical practice in this setting.

Hospital admissions for wheezing in Polynesian children.

The purpose of this study is to establish a baseline of information about pre-school Polynesian children hospitalised with wheezing attacks. During a one year study period at Wellington Hospital, 19 percent of the acute paediatric admissions under five years were Polynesians with wheezing respiratory disease. Seventy percent of these admissions were in children under 18 months of age, and 38 percent of the children were readmitted during the year. These and other variables are compared to European children hospitalised with wheezing. We conclude that young Polynesian children in New Zealand are especially prone to a different pattern of asthma from European children.

Evaluation of the ARI program: a health facility survey in Simbu, Papua, New Guinea.

The purpose of this health facility survey was to evaluate how the ARI (Acute Respiratory Infection) Program actually works in an everyday, non-research setting. We surveyed 33 clinics and aid posts, including 223 children with ARI and 104 health workers. In this primary health care setting, health workers diagnosed 37% of ARI cases as pneumonia, compared to 69% in the same children assessed independently by trained ARI surveyors using Papua New Guinea case management, which defines fast breathing as > or = 40 per minute for children 1 month to 5 years of age. Agreement between health workers and surveyors was reasonably good (kappa > or = 0.6) for the history of symptoms, but was poor (kappa < 0.3) for diagnoses, treatments and signs such as respiratory rate (RR) and chest indrawing. Health workers counted the RR in only 14% of cases in the survey. In essence, we found that health workers in Simbu are not practising ARI case management. We conclude that case management guidelines which define fast breathing as a rate of > or = 40 per minute classify too many obviously well children as pneumonia. Furthermore, we encountered difficulties in measuring RR accurately, and documented marked inter-observer variation in this setting. Consequently, we are concerned about the ARI Program's excessive reliance on RR and rigid protocols at the expense of clinical sense. Case management guidelines developed for aid post orderlies or village health workers may need to be modified, or used differently by experienced nurses at health centres, who recognize sick children better than by following a standardized protocol. Despite better overall ARI knowledge and practice by nurses, we could demonstrate an impact of the ARI Training Program only on community health workers (CHWs). In order to improve ARI clinical practice, we recommend that the ARI Program in PNG initiates regular on-site clinical supervision of nurses and CHWs at health centres.

Seasonal variation of paediatric diseases in The Gambia, west Africa.

In a 3-year prospective study of 9584 consecutive paediatric admissions to the Royal Victoria Hospital in Banjul, The Gambia, we examined the impact of seasonal variations in childhood diseases. The four principal diseases (falciparum malaria, pneumonia, gastro-enteritis and malnutrition) all peaked in September to October following the rainy season. The mortality rate was also higher in the rainy season than in the dry season. Of the 1525 children with cerebral malaria, 83% were admitted during the extended rainy season from July to December. With the emergence of chloroquine-resistant malaria over the 3 years, there was a 27% annual increase in severe anaemia owing to malaria. The median age of malarial anaemia (23 months) was significantly younger than that of cerebral malaria (42 months). Malnutrition peaked immediately following the annual rainy season epidemics of bacterial gastro-enteritis but was not associated with the cool dry season rotavirus outbreaks. Rainy season diarrhoea was also associated with more persistent diarrhoea, an older mean age and a higher mortality. Meningitis was caused by either pneumococcus or Haemophilus influenzae in 64% of cases, of whom 19% were 0-2 months of age. Causes of death in hospital showed good agreement with Gambian community studies. We conclude that analysis of hospital data in a developing country can give accurate information on childhood morbidity and mortality patterns which can be used to set priorities for health care interventions. Seasonal variation is a cardinal feature of paediatric diseases in this part of Africa, and accentuates the vulnerability of children in poor families.

Potassium supplementation in kwashiorkor.

BACKGROUND: Kwashiorkor is an edimatous form of severe malnutrition and is the predominant form of childhood malnutrition in Malawi. Potassium depletion is common and contributes to the high mortality. The aim of this study was to determine if high potassium supplementation improves the outcome of kwashiorkor treatment. METHODS: We performed a randomised, double-blind, placebo-controlled, clinical trial of high potassium supplementation in 99 children with kwashiorkor. Controls (n = 51) received a standard potassium intake of 4.7 mmol/kg/day. The intervention group (n = 48) received 7.7 mmol/kg/day. All cases (intervention and control groups) were treated in the hospital-based Nutrition Rehabilitation Center and received a standard treatment regime of mild feeds, mineral and vitamin supplements, and antibiotics. RESULTS: There was no significant difference in length of hospitalization, or time for resolution of oedema between groups. The case-fatality rate was reduced by 33% in the high potassium intervention group (13/48) compared to controls (21/51). There was a significant reduction in late deaths (13 in controls vs 3 in intervention group; odds ratio 5.3, 95% confidence interval 1.2-31.0) but no difference in early deaths (0-5 days). The intervention group also had significantly fewer presumed septic episodes (3 vs 18, odds ratio 8.9, confidence interval 2.2-50.9), respiratory symptoms, and new skin ulcerations than controls. CONCLUSIONS: The high potassium supplementation reduced mortality and significant morbidity in kwashiorkor. This may be due to improved myocardial and immune function from earlier repletion of intracellular potassium. We recommend that the standard potassium supplement for the initial phase of treatment of kwashiorkor be increased from 4 to 8 mmol/kg/day.

Intensive nursing care of kwashiorkor in Malawi.

The case fatality rate for children with kwashiorkor in central hospitals in Malawi was 30.5% (275/901) in 1995. The purpose of this study was to determine whether improved case management with intensive nursing care could lower this case fatality rate. A total of 75 children admitted with kwashiorkor in Blantyre, Malawi, received intensive nursing care. This included nursing in individual clean beds with blankets, a nurse:child ratio of 1:3, supervised feedings every 2 h, a paediatrician with expertise in treating kwashiorkor always available for consultation, laboratory evaluation for systemic infection and empiric use of ceftriaxone. Nineteen of these children died (25%). The causes of death were life threatening electrolyte abnormalities (hypokalaemia, hyponatraemia, hypophosphataemia) in nine cases, overwhelming infection in eight cases and congestive heart failure in two children. Children infected with the human immunodeficiency virus were more likely to die (9/20), as were children with life threatening electrolyte abnormalities (9/15) and children with more severe wasting. When compared with 225 children treated in the same year at the same institution, who were carefully matched for severity of kwashiorkor, intensive nursing did not improve overall survival.

Childhood infections in the tropical north of Australia.

In the tropical north of Australia there are high rates of infections in Aboriginal children living in remote communities. In addition to the burden of respiratory infections, diarrhoeal disease and skin sepsis, there are high rates of acute rheumatic fever, outbreaks of poststreptococcal glomerulonephritis and gonococcal conjunctivitis, endemic trachoma and various intestinal parasites. A number of infections generally restricted to the tropics are also present and can cause disease in both indigenous and non-indigenous children. These include melioidosis, Murray Valley encephalitis and dengue on the east coast. With global warming, these infections may become more common and more widespread within Australia and the potential for establishment of introduced infections such as Japanese encephalitis and malaria may increase.

Unique pattern of urinary tract calculi in Australian Aboriginal children.

Young Aboriginal children in remote regions of tropical and desert Australia are at risk of developing urate stones in their upper urinary tract from an early age. These radiolucent calculi were only recognized with the availability of ultrasound diagnosis and are not associated with anatomic anomalies or abnormal uric acid production/metabolism. Although these stones appear to resolve spontaneously after the weaning period, some result in ureteric obstruction and infection which may lead to renal damage. This pattern of urolithiasis differs from the usual global urolithiasis pattern of either endemic bladder stones in young children in developing countries or predominantly calcium-based stones in upper tracts of older children and adults in affluent industrialized countries, where upper tract urate stones account for only a minority of childhood urinary tract stones. Risk factors for urate stones are low urine output and acidic urine. An association between urolithiasis and carbohydrate intolerance leading to chronic acidosis has been suggested for Aboriginal children, but existing limited evidence does not support this as a major aetiological factor. Although further studies on the epidemiology, natural history and management of these urate stones are needed, we believe the focus should be on improving the known social and environmental risk factors of remote Aboriginal children during the weaning period which contribute to the unacceptably high prevalence of failure to thrive, diarrhoeal disease, environmental enteropathy, iron deficiency and urolithiasis.

Milk formulas in acute gastroenteritis and malnutrition: a randomized trial.

OBJECTIVE: To compare three low-lactose milk formulas differing in osmolality and degree of protein hydrolysis in the treatment of diarrhoea and malnutrition in subjects with high rates of lactose intolerance, osmotic diarrhoea and a tropical/environmental enteropathy. METHODS: A randomized double-blind trial of 180 Aboriginal children under 3 years of age admitted with acute diarrhoea and/or malnutrition was carried out. The intervention milk formulas were: (i) De-Lact, a low-osmolality lactose-free formula; (ii) O-Lac, a lactose-free formula; and (iii) Alfaré, a partially hydrolysed formula. Outcome measures were diarrhoeal severity, weight gain, formula palatability and changes in intestinal permeability (L/R ratios). RESULTS: The duration of diarrhoea in days (mean; 95% confidence interval) was significantly longer on Alfaré (8.5; 7.0-10.0) compared to De-Lact (6.1; 5.0-7.2) and O-Lac (6.9; 5.6-8.1; P = 0.04). There were no differences in mean intake between formulas, but palatability of Alfaré was significantly worse (P < 0.01) than the other formulas. Over the trial 5 days, improvement in L/R ratios was significantly greater (P = 0.05) for De-Lact (18.6; 10.6-26.6) than for Alfaré (8.5; 2.1-14.9). Weight gain was not significantly different between the three formulas, except in a malnourished subgroup who had better weight gain on De-Lact (P = 0.05). CONCLUSIONS: In these Aboriginal children with diarrhoea and growth failure, a low osmolality milk was associated with better outcomes and a partially hydrolysed formula with less improvement in mucosal recovery, suggesting that cow's milk protein intolerance is not contributing to greater diarrhoeal severity or enteropathy in Aboriginal children.

Soluble transferrin receptor in Aboriginal children with a high prevalence of iron deficiency and infection.

OBJECTIVES: Aboriginal children in tropical Australia have a high prevalence of both iron deficiency and acute infections, making it difficult to differentiate their relative contributions to anaemia. The aims of this study were to compare soluble transferrin receptor with ferritin in iron deficiency anaemia (IDA), and to examine how best to distinguish the effect of iron deficiency from infection on anaemia. METHODS: We conducted a prospective study of 228 admissions to Royal Darwin Hospital in children from 6 to 60 months of age. Transferrin receptor concentrations were measured by a particle-enhanced immunoturbidimetric assay and ferritin by a microparticle enzyme immunoassay. RESULTS: On multiple regression, the best explanatory variables for haemoglobin differences (r2=33.7%, P<0.001) were mean corpuscular volume (MCV), red cell distribution width (RDW) and C-reactive protein (CRP); whereas transferrin receptor and ferritin were not significant (P>0.4). Using > or =2 abnormal indices (MCV, RDW, blood film)+haemoglobin <110 g/l as the reference standard for IDA, transferrin receptor produced a higher area under the curve on receiver operating characteristic curve analysis than ferritin (0.79 vs. 0.64, P<0.001) or the transferrin receptor-ferritin index (0.77). On logistic regression, the effect of acute infection (CRP) on haemoglobin was significant (P<0.001) at cut-offs of 105 and 110 g/l, but not at 100 g/l when only iron deficiency indicators (MCV, RDW, blood film) were significant. CONCLUSIONS: Transferrin receptor does not significantly improve the diagnosis of anaemia (iron deficiency vs. infection) over full blood count and CRP, but in settings with a high burden of infectious diseases and iron deficiency, it is a more reliable adjunctive measure of iron status than ferritin.

Stereospecific receptors for substance P on cultured human IM-9 lymphoblasts.

The neuropeptide substance P (SP), which has been demonstrated to bind specifically to human blood T lymphocytes and to stimulate their uptake of [3H]thymidine and [3H]leucine, now is shown to bind stereospecifically to cultured human lymphoblasts of the IM-9 line. The specific binding of [3H]SP by IM-9 lymphoblasts increases linearly with the concentration of IM-9 lymphoblasts, achieves a plateau after approximately 15 to 20 min at 4 degrees C and 4 to 6 min at 37 degrees C, and is rapidly reversible at both 4 degrees C and 37 degrees C. The binding of [3H]SP at steady-state conditions demonstrates a dissociation constant (KD) of 0.65 +/- 0.19 nM (mean +/- SD, n = 5) and 22,641 +/- 6143 receptors per IM-9 lymphoblast. Maximal specific binding of [3H]SP to IM-9 lymphoblasts is observed at pH 7.4 and is dependent on the presence of Mg2+, but not Ca2+, in the medium. The peptide structural determinants of the inhibition of binding of [3H]SP to IM-9 lymphoblasts by substituent peptides and homologs of SP indicate that the receptors recognize predominantly the carboxy-terminal portion of SP. The characteristics of the interaction of SP with IM-9 lymphoblasts suggests a receptor-directed mechanism by which neuropeptides may modulate specifically the contributions of lymphocytes to immunity.

An iron treatment trial in an aboriginal community: improving non-adherence.

OBJECTIVE: To compare supervised vs unsupervised oral iron treatment in anaemic Aboriginal children living in a remote community with a 40% prevalence of iron deficiency anaemia. METHODOLOGY: A randomised unblinded clinical trial in children < 6 years presenting to a remote Health Centre with anaemia. Oral iron prescribed as a daily unsupervised dose (group A) was compared to twice weekly supervised administration (group B) over 12 weeks. Parenteral iron (group C) was reserved for failure of oral treatment. RESULTS: Only 3 of 25 children in group A responded to treatment compared to 23 of 26 children in group B (odds ratio = 7.7, 95% confidence interval 2.6-25.0). After six weeks of treatment, the mean haemoglobin rise was 0.96 g/L in group A compared to 10.9 g/L in group B and 12.4 g/L in group C. On entry to the study, 29.4% of subjects were underweight, 33.3% stunted and 35.3% microcephalic. The mean catch-up in weight/height on iron treatment over the study was only 0.28 (0.08, 0.48) Z-scores. CONCLUSIONS: Oral iron as directly observed twice weekly treatment is superior to unsupervised therapy. In view of the poor compliance with unsupervised treatment and the high prevalence of iron deficiency anaemia (along with stunting and microcephaly) in Aboriginal children in northern Australia, we propose to undertake in partnership with communities a nutritional intervention program with a high energy weaning food fortified with micronutrients (iron, vitamin A, zinc, folate) as the most effective strategy to address these nutritional problems in the weaning period.