HYPOGLYCAEMIA IN AFRICAN CHILDREN WITH SEVERE MALARIA
Abstract
Hypoglycaemia, defined as a plasma glucose concentration below 2·2 mmol/l, developed in 15 of 47 prospectively studied Gambian children with severe chloroquine-sensitive falciparum malaria. 5 of these hypoglycaemic children died compared with 1 in the normoglycaemic group (p = 0·02). In contrast to previous observations in quinine-treated adults, in whom hypoglycaemia was associated with hyperinsulinaemia, plasma concentrations of insulin were appropriately low and plasma ketones were high. Raised plasma concentrations of lactate and alanine suggested impairment of hepatic gluconeogenesis. In African children, hypoglycaemia is an important and treatable manifestation of severe malaria and is unrelated to antimalarial treatment.
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Cited by (205)
The effect of blood transfusion on outcomes among African children admitted to hospital with Plasmodium falciparum malaria: a prospective, multicentre observational study
2020, The Lancet HaematologyInfection with Plasmodium falciparum leads to severe malaria and death in approximately 400 000 children each year in sub-Saharan Africa. Blood transfusion might benefit some patients with malaria but could potentially harm others. The aim of this study was to estimate the association between transfusion and death among children admitted to hospital with P falciparum malaria.
In this prospective, multicentre observational study, we analysed admissions to six tertiary care hospitals in The Gambia, Malawi, Gabon, Kenya, and Ghana that participated in the Severe Malaria in African Children network. Patients were enrolled if they were younger than 180 months and had a Giemsa-stained thick blood smear that was positive for P falciparum. Blood transfusion (whole blood at a target volume of 20 mL per kg) was administered at the discretion of the responsible physicians who were aware of local and international transfusion guidelines. The primary endpoint was death associated with transfusion, which was estimated using models adjusted for site and disease severity. We also aimed to identify factors associated with the decision to transfuse. The exploratory objective was to estimate optimal haemoglobin transfusion thresholds using generalised additive models.
Between Dec 19, 2000, and March 8, 2005, 26 106 patients were enrolled in the study, 25 893 of whom had their transfusion status recorded and were included in the primary analysis. 8513 (32·8%) patients received a blood transfusion. Patients were followed-up until discharge from hospital for a median of 2 days (IQR 1–4). 405 (4·8%) of 8513 patients who received a transfusion died compared with 689 (4·0%) of 17 380 patients who did not receive a transfusion. Transfusion was associated with decreased odds of death in site-adjusted analysis (odds ratio [OR] 0·82 [95% CI 0·71–0·94]) and after adjusting for the increased disease severity of patients who received a transfusion (0·50 [0·42–0·60]). Severe anaemia, elevated lactate concentration, respiratory distress, and parasite density were associated with greater odds of receiving a transfusion. Among all study participants, transfusion was associated with improved survival when the admission haemoglobin concentration was up to 77 g/L (95% CI 65–110). Among those with impaired consciousness (Blantyre Coma Score ≤4), transfusion was associated with improved survival at haemoglobin concentrations up to 105 g/L (95% CI 71–115). Among those with hyperlactataemia (blood lactate ≥5·0 mmol/L), transfusion was not significantly associated with harm at any haemoglobin concentration—ie, the OR of death comparing transfused versus not transfused was less than 1 at all haemoglobin concentrations (lower bound of the 95% CI for the haemoglobin concentration at which the OR of death equals 1: 90 g/L; no upper bound).
Our findings suggest that whole blood transfusion was associated with improved survival among children hospitalised with P falciparum malaria. Among those with impaired consciousness or hyperlactataemia, transfusion was associated with improved survival at haemoglobin concentrations above the currently recommended transfusion threshold. These findings highlight the need to do randomised controlled trials to test higher transfusion thresholds among African children with severe malaria complicated by these factors.
US National Institute of Allergy and Infectious Diseases.
Hypoglycemia in the Toddler and Child
2020, Sperling Pediatric Endocrinology: Expert Consult - Online and PrintGlucose is an obligate fuel for the brain. Profound and prolonged hypoglycemia causes permanent brain injury. At plasma glucose concentrations less than 54 mg/dL, the cerebral metabolic rate of glucose decreases; at even lower plasma glucose concentrations functional brain failure occurs. Systemic glucose balance is maintained by physiologic endocrine and metabolic processes that ensure normoglycemia and a continuous supply of glucose to the brain. Hypoglycemia is uncommon beyond the newborn period and early infancy, and is usually caused by disturbances in fasting adaptation: an acquired disorder of the endocrine system; prolonged fasting in susceptible individuals (e.g., an intercurrent gastrointestinal illness); congenital abnormalities, such as hyperinsulinism or inborn errors of metabolism; or accidental exposure to medication or toxins. During fasting, the brain initially uses glucose provided from a combination of glycogenolysis and gluconeogenesis in the liver. As liver glycogen stores diminish, adipose tissue lipolysis is activated to increase availability of free fatty acids as fuel for peripheral tissues, such as muscle and for ketogenesis in the liver, which makes ketones available as a brain fuel and partly replaces glucose utilization. Because of their larger ratio of brain relative to muscle mass, the time to reach the fasting hyperketonemia stage is markedly shorter in younger infants and children than in adults. This chapter describes an approach to diagnosis of fasting hypoglycemia, based on identifying the specific cause of failure to maintain normal glucose homeostasis. Key diagnostic information is often best derived from blood and urine specimens (referred to as critical samples) obtained at the time of hypoglycemia and immediately before reversing hypoglycemia.
Critical Roles of Endogenous Glucocorticoids for Disease Tolerance in Malaria
2019, Trends in ParasitologyCitation Excerpt :Important to note is that, in both trials, all patients were treated with the antimalarial drug quinine. Quinine is known to induce hypoglycemia by insulin secretion, which may have masked the potential positive metabolic effects of dexamethasone [97,98]. Despite the apparent failure of dexamethasone to help patients with CM, one of the most fulminant complications, the therapeutic impact on larger patient numbers and other complications that have a broader therapeutic window remains unknown.
During malaria, the hypothalamic–pituitary–adrenal (HPA) axis is activated and glucocorticoid (GC) levels are increased, but their essential roles have been largely overlooked. GCs are decisive for systemic regulation of vital processes such as immune responses, vascular function, and metabolism, which are crucial in malaria. Here, we introduce GCs in general, followed by their versatile roles for disease tolerance in malaria. A complementary comparison is provided with their role in sepsis. Finally, potential translational implications are considered. The failed clinical trials of dexamethasone against cerebral malaria in the past have diminished the interest in GCs in malaria. However, the issue of relative corticosteroid insufficiency has barely been explored in malaria patients, but may hold promise for a better understanding and treatment of specific malaria complications.
Host Energy Source Is Important for Disease Tolerance to Malaria
2018, Current BiologyCitation Excerpt :Metabolic analysis of malaria-infected patients showed increases in free fatty acids, ketone bodies, and components of the glycolytic pathway during infection, suggesting patient anorexia and substantial metabolic remodeling similar to our mice [30]. Furthermore, hypoglycemia is also clinically associated with worse outcomes and has been correlated specifically with cases of severe malarial anemia [31–36]. Targeting diet and nutrition to combat infection is an exciting area of research; however, our work here and that of others highlight that these interventions are complex and pathogen specific [7–9, 37–39].
Pathologic infections are accompanied by a collection of short-term behavioral perturbations collectively termed sickness behaviors [1, 2]. These include changes in body temperature, reduced eating and drinking, and lethargy and mimic behaviors of animals in torpor and hibernation [1, 3, 4, 5, 6]. Sickness behaviors are important, pathogen-specific components of the host response to infection [1, 3, 7, 8, 9]. In particular, host anorexia has been shown to be beneficial or detrimental depending on the infection [7, 8]. While these studies have illuminated the effects of anorexia on infection, they consider this behavior in isolation from other behaviors and from its effects on host metabolism and energy. Here, we explored the temporal dynamics of multiple sickness behaviors and their effect on host energy and metabolism throughout infection. We used the Plasmodium chabaudi AJ murine model of malaria as it causes severe pathology from which most animals recover. We found that infected animals did become anorexic, skewing their metabolism toward fatty acid oxidation and ketosis. Metabolism of fats requires oxygen for the production of ATP. In this model, animals also suffer severe anemia, limiting their ability to carry oxygen concurrent with their switch toward fatty acid metabolism. We reasoned that the combination of anorexia and anemia would increase pressure on glycolysis as a critical energy pathway because it does not require oxygen. Treating infected mice when anorexic with the glycolytic inhibitor 2-deoxyglucose (2DG) reduced survival; treating animals with glucose improved survival. Peak parasite loads were unchanged, demonstrating changes in disease tolerance. Parasite clearance was reduced with 2DG treatment, suggesting altered resistance.
UK malaria treatment guidelines 2016
2016, Journal of Infection1.Malaria is the tropical disease most commonly imported into the UK, with 1300–1800 cases reported each year, and 2–11 deaths.
2. Approximately three quarters of reported malaria cases in the UK are caused by Plasmodium falciparum, which is capable of invading a high proportion of red blood cells and rapidly leading to severe or life-threatening multi-organ disease.
3. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other species of plasmodium: Plasmodium ovale, Plasmodium malariae or Plasmodium knowlesi.
4. Mixed infections with more than one species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria.
5. There are no typical clinical features of malaria; even fever is not invariably present. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints.
6. A diagnosis of malaria must always be sought in a feverish or sick child or adult who has visited malaria-endemic areas. Specific country information on malaria can be found at http://travelhealthpro.org.uk/. P. falciparum infection rarely presents more than six months after exposure but presentation of other species can occur more than a year after exposure.
7. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until more than one blood specimen has been examined. Other travel related infections, especially viral haemorrhagic fevers, should also be considered.
8. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites. P. falciparum and P. vivax (depending upon the product) malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens. RDTs for other Plasmodium species are not as reliable.
9. Most patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h as patients can deteriorate suddenly, especially early in the course of treatment. In specialised units seeing large numbers of patients, outpatient treatment may be considered if specific protocols for patient selection and follow up are in place.
10. Uncomplicated P. falciparum malaria should be treated with an artemisinin combination therapy (Grade 1A). Artemether–lumefantrine (Riamet®) is the drug of choice (Grade 2C) and dihydroartemisinin-piperaquine (Eurartesim®) is an alternative. Quinine or atovaquone–proguanil (Malarone®) can be used if an ACT is not available. Quinine is highly effective but poorly-tolerated in prolonged treatment and should be used in combination with an additional drug, usually oral doxycycline.
11. Severe falciparum malaria, or infections complicated by a relatively high parasite count (more than 2% of red blood cells parasitized) should be treated with intravenous therapy until the patient is well enough to continue with oral treatment. Severe malaria is a rare complication of P. vivax or P. knowlesi infection and also requires parenteral therapy.
12. The treatment of choice for severe or complicated malaria in adults and children is intravenous artesunate (Grade 1A). Intravenous artesunate is unlicensed in the EU but is available in many centres. The alternative is intravenous quinine, which should be started immediately if artesunate is not available (Grade 1A). Patients treated with intravenous quinine require careful monitoring for hypoglycemia.
13. Patients with severe or complicated malaria should be managed in a high-dependency or intensive care environment. They may require haemodynamic support and management of: acute respiratory distress syndrome, disseminated intravascular coagulation, acute kidney injury, seizures, and severe intercurrent infections including Gram-negative bacteraemia/septicaemia.
14. Children with severe malaria should also be treated with empirical broad spectrum antibiotics until bacterial infection can be excluded (Grade 1B).
15. Haemolysis occurs in approximately 10–15% patients following intravenous artesunate treatment. Haemoglobin concentrations should be checked approximately 14 days following treatment in those treated with IV artemisinins (Grade 2C).
16. Falciparum malaria in pregnancy is more likely to be complicated: the placenta contains high levels of parasites, stillbirth or early delivery may occur and diagnosis can be difficult if parasites are concentrated in the placenta and scanty in the blood.
17. Uncomplicated falciparum malaria in the second and third trimester of pregnancy should be treated with artemether–lumefantrine (Grade 2B). Uncomplicated falciparum malaria in the first trimester of pregnancy should usually be treated with quinine and clindamycin but specialist advice should be sought. Severe malaria in any trimester of pregnancy should be treated as for any other patient with artesunate preferred over quinine (Grade 1C).
18. Children with uncomplicated malaria should be treated with an ACT (artemether–lumefantrine or dihydroartemisinin-piperaquine) as first line treatment (Grade 1A). Quinine with doxycycline or clindamycin, or atovaquone–proguanil at appropriate doses for weight can also be used. Doxycycline should not be given to children under 12 years.
19. Either an oral ACT or chloroquine can be used for the treatment of non-falciparum malaria. An oral ACT is preferred for a mixed infection, if there is uncertainty about the infecting species, or for P. vivax infection from areas where chloroquine resistance is common (Grade 1B).
20. Dormant parasites (hypnozoites) persist in the liver after treatment of P. vivax or P. ovale infection: the only currently effective drug for eradication of hypnozoites is primaquine (1A). Primaquine is more effective at preventing relapse if taken at the same time as chloroquine (Grade 1C).
21. Primaquine should be avoided or given with caution under expert supervision in patients with Glucose-6-phosphate dehydrogenase deficiency (G6PD), in whom it may cause severe haemolysis.
22. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy and when breastfeeding (until the G6PD status of child is known); after initial treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery or cessation of breastfeeding when hypnozoite eradication can be considered.
23. An acute attack of malaria does not confer protection from future attacks: individuals who have had malaria should take effective anti-mosquito precautions and chemoprophylaxis during future visits to endemic areas.
Severe malaria
2022, Malaria Journal