Risk factors for UK Plasmodium falciparum cases

Background An increasing proportion of malaria cases diagnosed in UK residents with a history of travel to malaria endemic areas are due to Plasmodium falciparum. Methods In order to identify travellers at most risk of acquiring malaria a proportional hazards model was used to estimate the risk of acquiring malaria stratified by purpose of travel and age whilst adjusting for entomological inoculation rate (EIR) and duration of stay in endemic countries. Results Travellers visiting friends and relatives and business travellers were found to have significantly higher hazard of acquiring malaria (adjusted hazard ratio (HR) relative to that of holiday makers 7.4, 95% CI 6. 4-8. 5, p < 0. 0001 and HR 3.4, 95% CI 2.9-3.8, p < 0. 0001, respectively). All age-groups were at lower risk than children aged 0-15 years. Conclusions These estimates of the increased risk for these groups accounting for exposure should be used to inform programmes to improve awareness of the risks of malaria when travelling

Defining childhood severe falciparum malaria for intervention studies.

Background Clinical trials of interventions designed to prevent severe falciparum malaria in children require a clear endpoint. The internationally accepted definition of severe malaria is sensitive, and appropriate for clinical purposes. However, this definition includes individuals with severe nonmalarial disease and coincident parasitaemia, so may lack specificity in vaccine trials. Although there is no “gold standard” individual test for severe malaria, malaria-attributable fractions (MAFs) can be estimated among groups of children using a logistic model, which we use to test the suitability of various case definitions as trial endpoints. Methods and Findings A total of 4,583 blood samples were taken from well children in cross-sectional surveys and from 1,361 children admitted to a Kenyan District hospital with severe disease. Among children under 2 y old with severe disease and over 2,500 parasites per microliter of blood, the MAFs were above 85% in moderate- and low-transmission areas, but only 61% in a high-transmission area. HIV and malnutrition were not associated with reduced MAFs, but gastroenteritis with severe dehydration (defined by reduced skin turgor), lower respiratory tract infection (clinician's final diagnosis), meningitis (on cerebrospinal fluid [CSF] examination), and bacteraemia were associated with reduced MAFs. The overall MAF was 85% (95% confidence interval [CI] 83.8%–86.1%) without excluding these conditions, 89% (95% CI 88.4%–90.2%) after exclusions, and 95% (95% CI 94.0%–95.5%) when a threshold of 2,500 parasites/μl was also applied. Applying a threshold and exclusion criteria reduced sensitivity to 80% (95% CI 77%–83%). Conclusions The specificity of a case definition for severe malaria is improved by applying a parasite density threshold and by excluding children with meningitis, lower respiratory tract infection (clinician's diagnosis), bacteraemia, and gastroenteritis with severe dehydration, but not by excluding children with HIV or malnutrition

Likely Health Outcomes for Untreated Acute Febrile Illness in the Tropics in Decision and Economic Models; A Delphi Survey

BACKGROUND: Modelling is widely used to inform decisions about management of malaria and acute febrile illnesses. Most models depend on estimates of the probability that untreated patients with malaria or bacterial illnesses will progress to severe disease or death. However, data on these key parameters are lacking and assumptions are frequently made based on expert opinion. Widely diverse opinions can lead to conflicting outcomes in models they inform. METHODS AND FINDINGS: A Delphi survey was conducted with malaria experts aiming to reach consensus on key parameters for public health and economic models, relating to the outcome of untreated febrile illnesses. Survey questions were stratified by malaria transmission intensity, patient age, and HIV prevalence. The impact of the variability in opinion on decision models is illustrated with a model previously used to assess the cost-effectiveness of malaria rapid diagnostic tests. Some consensus was reached around the probability that patients from higher transmission settings with untreated malaria would progress to severe disease (median 3%, inter-quartile range (IQR) 1-5%), and the probability that a non-malaria illness required antibiotics in areas of low HIV prevalence (median 20%). Children living in low transmission areas were considered to be at higher risk of progressing to severe malaria (median 30%, IQR 10-58%) than those from higher transmission areas (median 13%, IQR 7-30%). Estimates of the probability of dying from severe malaria were high in all settings (medians 60-73%). However, opinions varied widely for most parameters, and did not converge on resurveying. CONCLUSIONS: This study highlights the uncertainty around potential consequences of untreated malaria and bacterial illnesses. The lack of consensus on most parameters, the wide range of estimates, and the impact of variability in estimates on model outputs, demonstrate the importance of sensitivity analysis for decision models employing expert opinion. Results of such models should be interpreted cautiously. The diversity of expert opinion should be recognised when policy options are debated

Multidrug resistant pulmonary tuberculosis treatment regimens and patient outcomes: an individual patient data meta-analysis of 9,153 patients.

Treatment of multidrug resistant tuberculosis (MDR-TB) is lengthy, toxic, expensive, and has generally poor outcomes. We undertook an individual patient data meta-analysis to assess the impact on outcomes of the type, number, and duration of drugs used to treat MDR-TB

Fetal haemoglobin and malaria

The inherited disorders of human haemoglobin are very common in some populations. Relative protection afforded to heterozygous carriers of these conditions against P. falciparum malaria is a likely cause for these high gene frequencies. However, very little is known at the cellular level of how this protective effect works. As an approach to this problem, an in vitro culture technique was developed in order to examine the factors which might modify the interaction of P. falciparum with human red cells. Fetal haemoglobin was of particular interest as a means of protection, since young infants, who are known to have high levels of this haemoglobin, are relatively resistant to P. falciparum. Furthermore, there is increasing evidence that infants heterozygous for thalassaemia and other haemoglobinopathies have higher levels of fetal haemoglobin than expected during the first year of life. A paucity of parasites was observed in the fetal haemoglobin-containing cells in young infants but this was shown to be due to the predilection of the parasite for metabolically young cells. Fetal haemoglobin was shown to have no effect on the rates of invasion of parasites into cells from a variety of conditions. However fetal haemoglobin caused significant retardation of growth once the parasite had entered the cell. This effect was independent of cell age. Further findings indicated that in the sickling disorders and glucose-6-phosphate dehydrogenase deficiency the red cell provided an unfavourable environment for the development of P. falciparum. This was not the case in thalassaemia and haemoglobin C and E traits. It was therefore suggested that these latter disorders have maintained their high frequencies due to the relatively high level of fetal haemoglobin which occurs in heterozygous carriers at an early stage in life, and protects them at an age when mortality from falciparum malaria is at its highest.</p

UK malaria treatment guidelines.

Malaria is the tropical disease most commonly imported into the UK, with 1500-2000 cases reported each year, and 10-20 deaths. 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. Most non-falciparum malaria cases are caused by Plasmodium vivax; a few cases are caused by the other two species of Plasmodium: Plasmodium ovale or Plasmodium malariae. Mixed infections with more than 1 species of parasite can occur; they commonly involve P. falciparum with the attendant risks of severe malaria. Management of malaria depends on awareness of the diagnosis and on performing the correct diagnostic tests: the diagnosis cannot be excluded until 3 blood specimens have been examined by an experienced microscopist. There are no typical clinical features of malaria, even fever is not invariably present. The optimum diagnostic procedure is examination of thick and thin blood films by an expert to detect and speciate the malarial parasites; P. falciparum malaria can be diagnosed almost as accurately using rapid diagnostic tests (RDTs) which detect plasmodial antigens or enzymes, although RDTs for other Plasmodium species are not as reliable. The treatment of choice for non-falciparum malaria is a 3-day course of oral chloroquine, to which only a limited proportion of P. vivax strains have gained resistance. 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. This must 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. Uncomplicated P. falciparum malaria can be treated orally with quinine, atovaquone plus proguanil (Malarone) or co-artemether (Riamet); quinine is highly effective but poorly tolerated in prolonged dosage and is always supplemented by additional treatment, usually with oral doxycycline. ALL patients treated for P. falciparum malaria should be admitted to hospital for at least 24 h, since patients can deteriorate suddenly, especially early in the course of treatment. 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. In the UK, the treatment of choice for severe or complicated malaria is currently an infusion of intravenous quinine. This may exacerbate hypoglycaemia that can occur in malaria; patients treated with intravenous quinine therefore require careful monitoring. Intravenous artesunate reduces high parasite loads more rapidly than quinine and is more effective in treating severe malaria in selected situations. It can also be used in patients with contra-indications to quinine. Intravenous artesunate is unlicensed in the EU. Assistance in obtaining artesunate may be sought from specialist tropical medicine centres, on consultation, for named patients. 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, renal impairment/failure, seizures, and severe intercurrent infections including gram-negative bacteraemia/septicaemia. Falciparum malaria in pregnancy is more likely to be severe and 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. The treatment of choice for falciparum malaria in pregnancy is quinine; doxycycline is contraindicated in pregnancy but clindamycin can be substituted for it, and is equally effective. Primaquine (for eradication of P. vivax or P. ovale hypnozoites) is contraindicated in pregnancy; after treatment for these infections a pregnant woman should take weekly chloroquine prophylaxis until after delivery when hypnozoite eradication can be considered. Children are over-represented in the incidence of malaria in the UK, probably because completely susceptible UK-born children accompany their overseas-born parents on visits to family and friends in endemic areas. Malaria in children (and sometimes in adults) may present with misleading symptoms such as gastrointestinal features, sore throat or lower respiratory complaints; the diagnosis must always be sought in a feverish or very sick child who has visited malaria-endemic areas. Children can be treated with most of the antimalarial regimens which are effective in adults, with appropriate dosage adjustment. Doxycycline plus quinine should not be given to children under 12 years as doxycycline is contraindicated in this age group, but clindamycin can be substituted for doxycycline, and pyrimethamine-sulfadoxine (Fansidar) may also be an effective substitute. 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

Effect of previous treatment on association of number of likely effective drugs with treatment success—during different phases of treatment.

<p>Likely effective, drugs to which isolate susceptible in laboratory testing. <i>n</i>, number of patients in subgroup of interest. aOR, adjustment described in footnotes for <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001300#pmed-1001300-t003" target="_blank">Table 3</a>. Success, defined as cure or treatment completion; see Methods for definitions. Initial intensive phase, period when injectable given. Continuation phase, period when no injectable given. Only 18 studies provided information regarding drug susceptibility testing and the number of drugs in the initial phase, while only 15 of these described the number of drugs in the continuation phase. Bold, estimates are significantly different from the reference group.</p

Association of treatment success with duration (adjusted odds and upper bound of CI shown).

<p>(A) Duration of initial intensive phase in all patients (reference group 1.0–2.5 mo). (B) Duration of initial intensive phase—restricted to patients not previously treated with second-line drugs (reference group 1.0–2.5 mo). (C) Total duration of therapy in all patients (reference group is 6.0–12.5 mo). Patients receiving therapy for less than 6 or more than 36 mo excluded from analysis. Note: For duration of 24.6–27.5 mo the upper limit of the CI was 30.2. This is truncated at 21. (D) Total duration of therapy—analysis restricted to patients not previously treated with second-line drugs (reference group is 6.0–12.5 mo. Patients receiving therapy for less than 6 or more than 36 mo excluded from analysis). Note: For duration of 24.6–27.5 mo, the upper limit of the CI was 56.5. This is truncated at 21.</p

Association of number of likely effective drugs with treatment success—during different phases of treatment.

<p>Likely effective, drugs to which isolate susceptible in laboratory testing. <i>n</i>, number of patients in subgroup of interest. aOR, adjusted for age, sex, HIV, past TB treatment, past MDR treatment (treatment for more than 1 mo with two or more second-line drugs), and extent of disease. Missing information was imputed for the following parameters in the following number of patients: Sex was missing in three, age was missing in 27, HIV was missing in 1,271(14%), history of past TB treatment missing in 443 (5%), history of past second-line drug use 758 (8%), and extent of disease information missing in 174 (2%). Success, defined as cure or treatment completion; see <a href="http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.1001300#s2" target="_blank">Methods</a> for definitions. Initial intensive phase, period when injectable given. Continuation phase, period when no injectable given. Only 18 studies provided information regarding drug susceptibility testing and the number of drugs in the initial phase, while only 15 of these described the number of drugs in the continuation phase. Bold, estimates are significantly different from the reference group.</p>a<p>Variance of the random intercepts and slopes was low—so heterogeneity not likely to be important.</p>b<p>Variance of the random intercepts and slopes could not be estimated.</p