Risk Factors For Severe Malaria Research Articles

Establishing and applying an adaptive framework for imported malaria: a field practice in Anhui Province, China from 2012 to 2022

BackgroundAnhui Province is currently facing an increase in imported malaria cases as a result of globalization and international travel. In response, Anhui Province has implemented a comprehensive adaptive framework to effectively address this threat.MethodsThis study collected surveillance data from 2012 to 2022 in Anhui Province. Descriptive statistics were used to analyze the epidemiological characteristics of imported malaria cases. Additionally, multivariate logistic regression was employed to identify factors associated with severe malaria. Documents were reviewed to document the evolution of the adaptive framework designed to combat imported malaria. The effectiveness of the adaptive framework was evaluated based on the rates of timely medical visits, timely diagnosis, and species identification.ResultsDuring the study period, a total of 1008 imported malaria cases were reported across 77 out of 105 counties in Anhui Province, representing a coverage of 73.33%. It was found that 10.52% of imported cases went undiagnosed for more than seven days after onset. The multivariate analysis revealed several potential risk factors for severe malaria, including increasing age (OR = 1.049, 95%CI:1.015–1.083), occupation (waitperson vs. worker, OR = 2.698, 95%CI:1.054–6.906), a longer time interval between onset and the initial medical visit (OR = 1.061, 95%CI:1.011–1.114), and misdiagnosis during the first medical visit (OR = 5.167, 95%CI:2.535–10.533). Following the implementation of the adaptive framework, the rates of timely medical visits, timely diagnosis, and species identification reached 100.00%, 78.57%, and 100.00%, respectively.ConclusionsAnhui Province has successfully developed and implemented an adaptive framework for addressing imported malaria, focusing on robust surveillance, prompt diagnosis, and standardized treatment. The experiences gained from this initiative can serve as a valuable reference for other non-endemic areas.

Imported severe Plasmodium falciparum infection in the first trimester of pregnancy complicated by post-artemisinin delayed hemolysis and intrauterine fetal death, a case report

BackgroundPost-artemisinin delayed hemolysis (PADH) is a serious complication in patients who recover from severe malaria after receiving artemisinin-based combined therapy (ACT), including artemether-lumefantrine. In Japan, among the antimalarial drugs recommended by the World Health Organization (WHO) guideline for severe malaria, intravenous quinine gluconate is available only in 29 designated hospitals, and intravenous artesunate is unavailable. Therefore, oral artemether-lumefantrine is occasionally administered as an alternative, even though it may be a suboptimal treatment. In non-endemic settings like Japan, a lack of knowledge of malaria and the side effects, such as post-artemisinin delayed hemolysis caused by the ACT, can have critical consequences. Like our patient, being a primigravida in the early stages of pregnancy is a serious risk factor for severe malaria and must be carefully monitored.Case presentationThis report describes a severe case of imported Plasmodium falciparum malaria complicated by fetal loss and prolonged anemia, requiring frequent blood transfusions. The patient was a previously healthy pregnant Japanese female in her 30 s. She developed a high fever 2 days after returning from Nigeria. The patient fulfilled the severe malaria criteria by WHO. On arrival, an abdominal ultrasound incidentally revealed a fetus of 5 week gestational age with a heartbeat in the uterus. Given her pregnancy and the severity of the disease, she was administered intravenous quinine 16 mg/kg as a loading dose. However, the second dose of quinine was not administered due to frequent vomiting and QTc prolongation. We initiated treatment with oral artemether-lumefantrine, and clearance of parasitemia was confirmed by microscopic observation on day 4. Miscarriage was noted on day 6 after admission. Moreover, the patient became feverish again up to 39 °C, and from days 14 to 22, the patient required multiple blood transfusions due to PADH. On day 40, follow-up was discontinued as the hemoglobin level exceeded 10 g/dL.ConclusionsIn patients who recover from severe malaria after ACT treatment, monitoring the hemoglobin level for at least a month is strongly recommended for prompt identification of PADH. Travelers to malaria-endemic countries, especially primigravida women, should be provided with adequate information on the risk and prevention of infection.

Biochemical characteristics of patients with imported malaria.

This study aimed to investigate the clinical and biochemical profiles of patients with imported malaria infection between 1 January 2011 and 30 April 2022 and admitted to the Fourth People's Hospital of Nanning. This cohort study enrolled 170 patients with conformed imported malaria infection. The clinical and biochemical profiles of these participants were analyzed with malaria parasite clearance, and signs and symptoms related to malaria disappearance were defined as the primary outcome. A multivariable logistic regression model was used to evaluate the odds ratios (ORs) with 95% confidence intervals (CIs) for cerebral malaria. The Cox model was used to estimate the hazard ratios (HRs) with 95% CIs for parasite clearance. Adenosine deaminase and parasitemia were found to be independent risk factors for severe malaria in patients with imported malaria (OR = 1.0088, 95% CI: 1.0010-1.0167, p = 0.0272 and OR = 2.0700, 95% CI: 1.2584-3.4050, p = 0.0042, respectively). A 0.5-standard deviation (SD) increase of variation for urea (HR = 0.6714, 95% CI: 0.4911-0.9180), a 0.5-SD increase of variation for creatinine (HR = 0.4566, 95% CI: 0.2762-0.7548), a 0.25-SD increase of variation for albumin (HR = 0.4947, 95% CI: 0.3197-0.7653), a 0.25-SD increase of variation for hydroxybutyrate dehydrogenase (HR = 0.6129, 95% CI: 0.3995-0.9402), and a 1.0-SD increase of variation for ferritin (HR = 0.5887, 95% CI: 0.3799-0.9125) were associated with a higher risk for increased parasite clearance duration than a low-level change. Aspartate aminotransferase, urea, creatinine, albumin, hydroxybutyrate dehydrogenase, and ferritin are useful biochemical indicators in routine clinical practice to evaluate prognosis for imported malaria.

Investigating Differences in Nutritional Parameters in Ugandan Children with Plasmodium falciparum Severe Malaria

Background: In 2018, malaria produced an estimated 272,000 deaths in children <5 years of age, accounting for 67% of all malaria deaths worldwide, with a majority in the WHO African Region. Malnutrition is an important risk factor for malaria. Wasting, Stunting and Underweight are crucial indicators of malnutrition. Annually, 14 million children <5 are classified as wasted and 59 million children are classified as stunted.  
 Objective: The objective of this study is to determine the association between each of the major manifestations of severe malaria (SM) and nutritional parameters – weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ) – in children from the Ugandan cities Mulago and Jinja.  
 Methods: To assess differences in WAZ, HAZ, and WHZ by the five types of SM and community controls (CC), we evaluated Z-scores from children <5 years old enrolled in a prospective cohort study (NDI, Neurodevelopmental Impairment in Children with Severe Malaria) at enrollment and 12-month follow-up.  
 Results: WAZ and WHZ at baseline were significantly lower among SM groups than in CC (p<0.001), but there were no significant differences observed at 12-month follow-up. There were no major differences in HAZ between the SM and CC groups. WAZ and HAZ at baseline were significantly lower among High Mortality (HM) versus Low Mortality (LM) groups (p<0.01). At 12-month follow-up, HAZ remained significantly lower in HM versus LM (p<0.01). There were no major differences in WHZ between the HM and LM groups. Compared to those who survived, the 27 children who died had significantly lower WAZ (p<0.05), but no major differences in HAZ or WHZ. 
 Conclusion: Underweight, stunting, and wasting may be risk factors for SM. Overall, a more comprehensive understanding of how SM elicits adverse effects in children is necessary. Nutrition intervention programs must be implemented to prevent child stunting, wasting, underweight, and mortality. 

Epidemiology of Plasmodium falciparum Malaria and Risk Factors for Severe Disease in Hubei Province, China.

This study aimed to describe the epidemiology of Plasmodium falciparum malaria and identify risk factors for severe disease in Hubei Province, China, using a case-based survey of retrospective data from 2013 to 2018. From 2013 to 2018, a total of 763 imported malaria cases were reported in Hubei Province; 69.2% (528/763) cases were caused by P. falciparum species. The proportion of malaria caused by P. falciparum increased from 66.7% in 2013 to 74.0% in 2018 (χ2 = 21.378, P < 0.05). Plasmodium falciparum malaria was reported in 77 counties of Hubei Province. The majority of imported P. falciparum cases originated from Africa (98.9%, 522/528); 9.7% (51/528) of patients infected with P. falciparum developed severe malaria. Three deaths (case fatality rate: 0.6%) were related to imported P. falciparum malaria. Risk factors for severe malaria were being female (odds ratio [OR] = 3.593, 95% CI: 1.003-12.874), age ≥ 50 years (OR = 2.674, 95% CI: 1.269-5.634), > 3 days between symptom onset and diagnosis (OR = 2.383, 95% CI: 1.210-4.693), and the first-visit medical institution at the township level or lower (OR = 2.568, 95% CI: 1.344-4.908). Malaria prevention should be undertaken among high-risk groups, infection with P. falciparum should be detected early to prevent severe disease and death, and healthcare providers in health facilities at the township level should be trained on early recognition of malaria.

Prevalence of and risk factors for severe malaria caused by Plasmodium and dengue virus co-infection: a systematic review and meta-analysis

BackgroundCo-infection with both Plasmodium and dengue virus (DENV) infectious species could have serious and fatal outcomes if left undiagnosed and without timely treatment. The present study aimed to determine the pooled prevalence estimate of severe malaria among patients with co-infection, the risk of severe diseases due to co-infection, and to describe the complications of severe malaria and severe dengue among patients with co-infection.MethodsRelevant studies published between databases between 12 September 1970 and 22 May 2020 were identified and retrieved through a search of the ISI Web of Science, Scopus, and MEDLINE. The pooled prevalence and 95% confidence interval (CI) of severe malaria among patients with Plasmodium and DENV co-infection was estimated with a random-effects model to take into account the between-study heterogeneity of the included studies. The risks of severe malaria and severe diseases due to co-infection were estimated with the pooled odds ratio (OR) and 95% CI with a random-effects model.ResultsOf the 5653 articles screened, 13 studies were included in the systematic review and meta-analysis. The results demonstrated that the pooled prevalence estimate of severe malaria among patients with co-infection was 32% (95% CI: 18–47%, I2 = 92.3%). Patients with co-infection had a higher risk of severe diseases than those with DENV mono-infection (odds ratio [OR] = 3.94, 95% CI: 1.96–7.95, I2 = 72%). Patients with co-infection had a higher risk of severe dengue than those with DENV mono-infection (OR = 1.98, 95% CI: 1.08–3.63, I2 = 69%). The most severe complications found in severe dengue were bleeding (39.6%), jaundice (19.8%), and shock/hypotension (17.9%), while the most severe complications found in severe malaria were severe bleeding/bleeding (47.9%), jaundice (32.2%), and impaired consciousness (7.43%).ConclusionsThe present study found that there was a high prevalence of severe malaria among patients with Plasmodium and DENV co-infection. Physicians in endemic areas where these two diseases overlap should recognize that patients with this co-infection can develop either severe malaria or severe dengue with bleeding complications, but a greater risk of developing severe dengue than severe malaria was noted in patients with this co-infection.Trial registrationThe protocol of this study was registered at PROSPERO: CRD42020196792.

Malaria in HIV-infected patients in a nonendemic setting.

The impact of HIV infection on malaria is unclear in nonendemic areas. In endemic territories, HIV has been reported to be a risk factor for higher morbidity. Nowadays, as HIV-infected patients travel more, it is important to assess the impact of HIV at the individual level on imported malaria. This retrospective case-control study collected data on HIV-infected patients diagnosed with malaria (2000-2017) and matched them with two controls based on age, sex and ethnicity. Clinical and biological parameters were collected and compared. We identified 47 cases and matched them with 94 controls. Comparing each of the WHO 2014 severity criteria, hyperparasitemia above 10% (P = 0.006; 12.8 versus 1.1%), icterus (P = 0.042; 14.9 versus 4.3%), acute renal failure (P = 0.022; 25.5 versus 9.6%) and bacteraemia (P = 0.014; 6.4 versus 0%) were significantly more present in HIV-infected patients with a trend to more cerebral malaria (12.8 versus 6.4%). HIV- infected patients were hospitalized more frequently and for longer periods. We observed a higher number of severity criteria when CD4 T-cell count was lower, especially below 200 cells/μl. The difference in occurrence of severe malaria disappeared when patients with CD4 T-cell count more than 500 cells/μl and undetectable viral load (n = 9) were compared with controls. De-novo HIV diagnosis was made during the malaria episode in 17% of cases. HIV infection has an impact on the imported malaria profile, although it is unclear whether well controlled HIV-infected patients have a higher risk of severe malaria. HIV-infected patients should be particularly targeted for pretravel advice.

Risk factors of severe imported malaria in Anhui province, China

We aimed to determine risk factors for developing severe illness in patients infected with imported Plasmodium falciparum, and identify factors that can be implemented in preventive public health actions. Data of patients in Anhui province were collected from the China Information System for Disease Control and Prevention and Information System for Parasitic Disease Control and Prevention from 2012 to 2018. Epidemiological characteristics, clinical severity, and preventive measures were analyzed using descriptive statistics. Risk factors for severe malaria were identified by logistic regression. During the study period, 8.01% (53/662) of patients infected with P. falciparum developed severe malaria; the annual severe incidence rate varied from 5.93% to 10.77% and the fatality rate was 0.6%. Two models were built to analyze the delay from symptom onset to treatment; one analyzed data by stage, whereas the other analyzed data combined from all stages. In model 1, multivariate analysis identified misdiagnosis at first medical visit and patient delay as risk factors for severe malaria (odds ratio: 3.108 and 3.385, respectively, all p < 0.01). In model 2, overall delay was a significant factor of severe malaria onset (odds ratio: 4.719, p = 0.000). In both models, patients with a history of previous infection had a significantly reduced risk of developing severe malaria; high parasitemia (≥2.5%) was associated with an increased risk of severe infection. Delay between symptom onset and treatment was an important cause for development of severe disease in Anhui province. Measures to reduce delays should be used and implemented in preventive public health actions.

Risk factors for severe malaria among hospitalized patients in the United States, 2000-2014.

Factors associated with the development of severe malaria have not been well described for cases occurring in the United States (US). Severe malaria hospitalizations data from the 2000-2014 Nationwide Inpatient Sample were analyzed. Frequencies were reported by demographic, clinical, species, financial, geographic, and institutional characteristics, and trends and disparities were identified. Logistic regression models were used to identify potential predictors for severe disease among those with malaria. From 2000 to 2014, there were an estimated 4823 severe malaria cases, representing 21.9% of all malaria-related hospitalizations, including 182 severe malaria deaths. Severe malaria was most common among inpatients who were male, Black, aged 45-64 years, and hospitalized in the South Atlantic division of the US. Older age was associated with higher odds of severe malaria, cerebral malaria, ARDS, severe anemia, and renal failure. Males had higher odds of developing renal failure and jaundice, while females had higher odds of developing severe anemia. HIV infection was associated with increased odds of severe malaria, severe anemia, and renal failure. Primary and secondary prevention measures, such as pre-travel consultations, chemoprophylaxis, and early diagnosis and treatment, should be emphasized and improved among high-risk prospective travelers to malaria endemic countries.

Diagnostic challenges of prolonged post-treatment clearance of Plasmodium nucleic acids in a pre-transplant autosplenectomized patient with sickle cell disease

BackgroundAutosplenectomy, as a result of sickle cell disease, is an important risk factor for severe malaria. While molecular methods are helpful in providing rapid and accurate infection detection and species identification, the effect of hyposplenism on result interpretation during the course of infection should be carefully considered.Case presentationA 32-year old autosplenectomized Nigerian male with severe sickle cell disease was referred to the National Institutes of Health for allogenic hematopoietic stem cell transplant. Despite testing negative for malaria by both smear and PCR 2 weeks after arrival in the USA, the patient developed fever and diffuse bilateral lower rib cage and upper abdominal pain 2 weeks later and subsequently tested positive for Plasmodium falciparum. Parasitaemia was tracked over time by microscopy and nucleic acid tests to evaluate the therapeutic response in the setting of hyposplenism. The patient showed prompt resolution of patent infection by microscopy but remained positive by molecular methods for > 30 days after treatment initiation.ConclusionWhile molecular testing can provide sensitive Plasmodium nucleic acid detection, the persistence of Plasmodium nucleic acids following adequate treatment in functionally asplenic patients can lead to a diagnostic dilemma. In such patients, clinical response and peripheral blood smears should guide patient management following treatment. Nonetheless, in pre-transplant patients at high-risk for pre-existing Plasmodium infections, highly sensitive molecular assays can be useful to rule out infection prior to transplantation.

Demographic, Socioeconomic, and Geographic Factors Leading to Severe Malaria and Delayed Care Seeking in Ugandan Children: A Case-Control Study.

We studied associations between delayed care seeking, demographic, socioeconomic, and geographic factors and likelihood of severe malaria in Ugandan children. The study was based at Jinja Hospital, Uganda. We enrolled 325 severe malaria cases and 325 uncomplicated malaria controls matched by age and residence. Patient details, an itinerary of events in response to illness, household information, and location of participants' residences were captured. Conditional logistic regression was used to determine risk factors for severe malaria and delayed care seeking. Delayed care seeking (≥ 24 hours after fever onset; odds ratio [OR] 5.50; 95% confidence interval [CI] 2.70, 11.1), seeking care at a drug shop as the initial response to illness (OR 3.62; 95% CI 1.86, 7.03), and increasing distance from place of residence to the nearest health center (OR 1.45; 95% CI 1.17, 1.79) were independent risk factors for severe malaria. On subgroup analysis, delayed care seeking was a significant risk factor in children with severe malaria attributable to severe anemia (OR 15.6; 95% CI 3.02, 80.6), but not unconsciousness (OR 1.13; 95% CI 0.30, 4.28). Seeking care at a drug shop (OR 2.84; 95% CI 1.12, 7.21) and increasing distance to the nearest health center (OR 1.18; 95% CI 1.01, 1.37) were independent risk factors for delayed care seeking. Delayed care seeking and seeking care at a drug shop were risk factors for severe malaria. Seeking care at a drug shop was also a predictor of delayed care seeking. The role of drug shops in contributing to delayed care and risk of severe malaria requires further study.

Effects of Aging on Parasite Biomass, Inflammation, Endothelial Activation, Microvascular Dysfunction and Disease Severity in Plasmodium knowlesi and Plasmodium falciparum Malaria

In populations pauci-immune to malaria, risk of severe malaria increases with age. This is particularly apparent in Plasmodium knowlesi malaria. However, pathophysiological mechanisms underlying knowlesi malaria, and of the age-related increase in risk of severe malaria in general, are poorly understood. In Malaysian patients aged ≥12 years with severe (n = 47) and nonsevere (n = 99) knowlesi malaria, severe (n = 21) and nonsevere (n = 109) falciparum malaria, and healthy controls (n = 50), we measured parasite biomass, systemic inflammation (interleukin 6 [IL-6]), endothelial activation (angiopoietin-2), and microvascular function, and evaluated the effects of age. Plasmodium knowlesi parasitemia correlated with age (Spearman's correlation coefficient [rs] = 0.36; P < .0001). In knowlesi malaria, IL-6, angiopoietin-2, and microvascular dysfunction were increased in severe compared to nonsevere disease, and all correlated with age, independent of parasitemia. In falciparum malaria, angiopoietin-2 increased with age, independent of parasite biomass (histidine-rich protein 2 [HRP2]). Independent risk factors for severe malaria included parasitemia and angiopoietin-2 in knowlesi malaria, and HRP2, angiopoietin-2, and microvascular dysfunction in falciparum malaria. Parasite biomass, endothelial activation, and microvascular dysfunction are associated with severe disease in knowlesi malaria and likely contribute to pathogenesis. The association of each of these processes with aging may account for the greater severity of malaria observed in older adults in low-endemic regions.

Obesity and Diabetes as Risk Factors for Severe Plasmodium falciparum Malaria: Results From a Swedish Nationwide Study.

Noncommunicable diseases and obesity are increasing in prevalence globally, also in populations at risk of malaria. We sought to investigate if comorbidity, in terms of chronic diseases and obesity, is associated with severe Plasmodium falciparum malaria. We performed a retrospective observational study in adults (≥18 years of age) diagnosed with malaria in Sweden between January 1995 and May 2015. We identified cases through the surveillance database at the Public Health Agency of Sweden and reviewed clinical data from 18 hospitals. Multivariable logistic regression was used to assess associations between comorbidities and severe malaria. Among 937 adults (median age, 37 years; 66.5% were male), patients with severe malaria had higher prevalence of chronic diseases (28/92 [30.4%]) compared with nonsevere cases (151/845 [17.9%]) (P = .004). Charlson comorbidity score ≥1 was associated with severe malaria (adjusted odds ratio [aOR], 2.63 [95% confidence interval {CI}, 1.45-4.77), as was diabetes among individual diagnoses (aOR, 2.98 [95% CI, 1.25-7.09]). Median body mass index was higher among severe (29.3 kg/m2) than nonsevere cases (24.7 kg/m2) (P < .001). Obesity was strongly associated with severe malaria, both independently (aOR, 5.58 [95% CI, 2.03-15.36]) and in combination with an additional metabolic risk factor (hypertension, dyslipidemia, or diabetes) (aOR, 6.54 [95% CI, 1.87-22.88]). The associations were observed among nonimmune travelers as well as immigrants from endemic areas. Comorbidities, specifically obesity and diabetes, are previously unidentified risk factors for severe malaria in adults diagnosed with P. falciparum. Noncommunicable diseases should be considered in the acute management and prevention of malaria.

Factors associated with severe malaria among children below ten years in Mutasa and Nyanga districts, Zimbabwe, 2014-2015.

IntroductionSevere malaria is a rare life threatening illness. Only a small proportion of patients with clinical malaria progress to this medical emergency. On reviewing 61 malaria death investigation forms submitted to the provincial office in 2014, 22(36%) were children below ten years who succumbed to severe malaria. Mutasa and Nyanga Districts reported 73% of these deaths. This study was conducted to determine factors associated with severe malaria so as to come up with evidence based interventions to prevent severe malaria and associated mortality.MethodsA 1:2 unmatched case control study was conducted. A case was defined as a child 10 years and below, who was admitted at Hauna (Mutasa) or Nyanga District Hospitals between September 2014 and May 2015 with a primary diagnosis of severe malaria. Controls were children of similar age with uncomplicated malaria. Permission to conduct the study was sought and granted by the Medical Research Council of Zimbabwe (Approval number B/874), Joint Research Ethics Committee, Health Studies Office and the Manicaland Directorate Institutional Review Board. Written informed consent was sought from all caregivers of enrolled children. Interviewer administered questionnaires were used to ascertain exposures.ResultsA total of 52 cases and 104 controls were enrolled into the study. The median age of cases was 4 years (Q1=3, Q3=9) and 6 years for controls (Q1=3, Q3=8). The Case Fatality Rate among cases was 28.8%. The independent risk factors for severe malaria were; distance >10km to the nearest health facility [Adjusted Odds Ratio (aOR)=14.35, 95% CI=1.30, 158.81], duration of symptoms before seeking medical care >2 days [aOR=9.03, 95% CI=2.21, 36.93], having comorbidities [aOR=5.38, 95% CI=1.90, 15.19], staying in a house under construction [aOR=4.51, 95%CI=1.80, 11.32] and duration of illness before receiving antimalarial medicines >24 hours [aOR=3.82, 95% CI=1.44, 10.12]. Owning at least one ITN in the household [aOR=0.32, 95% CI=0.11, 0.95] and having a mother as a caregiver [aOR=0.23, 95% CI=0.09, 0.76] were independently protective of severe malaria. Being undernourished [Odds Ratio (OR)=10.13, 95% CI=1.04, 98.49] and being female [OR=0.27, 95% CI=0.08, 0.96] were associated with mortality owing to severe malaria.ConclusionFactors associated with severe malaria and mortality owing to severe malaria identified in this study are consistent with other studies. Caregiver healthcare seeking behaviours, patient related factors and health system related factors are important determinants of severe malaria among children. There is need for regular health education campaigns emphasizing on malaria prevention, signs and symptoms and benefits of seeking medical care immediately for sick children.

Composition of the gut microbiota modulates the severity of malaria

Plasmodium infections result in clinical presentations that range from asymptomatic to severe malaria, resulting in ∼1 million deaths annually. Despite this toll on humanity, the factors that determine disease severity remain poorly understood. Here, we show that the gut microbiota of mice influences the pathogenesis of malaria. Genetically similar mice from different commercial vendors, which exhibited differences in their gut bacterial community, had significant differences in parasite burden and mortality after infection with multiple Plasmodium species. Germfree mice that received cecal content transplants from "resistant" or "susceptible" mice had low and high parasite burdens, respectively, demonstrating the gut microbiota shaped the severity of malaria. Among differences in the gut flora were increased abundances of Lactobacillus and Bifidobacterium in resistant mice. Susceptible mice treated with antibiotics followed by yogurt made from these bacterial genera displayed a decreased parasite burden. Consistent with differences in parasite burden, resistant mice exhibited an elevated humoral immune response compared with susceptible mice. Collectively, these results identify the composition of the gut microbiota as a previously unidentified risk factor for severe malaria and modulation of the gut microbiota (e.g., probiotics) as a potential treatment to decrease parasite burden.

Influence of common variants of TLR4 and TLR9 on clinical outcomes of Plasmodium falciparum malaria in Odisha, India

BackgroundIn malaria, the toll-like receptors (TLRs) have recently emerged as major player of innate immunity. However, implication of TLR variants on clinical manifestations of malaria is conflicting. The present study aims to provide relevant information of growing interest in understanding the role of TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms on clinical outcomes of malaria. MethodsWe genotyped TLR4D299G, TLR9T-1237C and TLR9T-1486C polymorphisms by PCR-RFLP methods and subsequently analyzed in 200 uncomplicated patients and 200 severe patients. Further, the severe malaria categorized into sub-clinical groups such as cerebral malaria (CM), non-cerebral severe malaria (NCSM), single organ dysfunction (SOD) and multi-organ dysfunctions (MODS) are analyzed. ResultThe TLR9-1237CC genotype was observed at significantly low frequency in MODS (p=0.0008), while in heterozygous state (TC) it was proportionately more frequent in SOD (p=0.087) as compared to mild malaria. The TLR9T-1486C heterozygote was more common in all categories of severe malaria. However, pair wise LD analysis revealed significant linkage between T-1237C and T-1486C, whereas haplotype analysis showed significantly low frequency of C-T haplotype in CM (p=0.005, pc=0.02) and high frequency of T-C haplotype in NCSM as compared to mild malaria. ConclusionAlthough TLR9-1237C could be a risk factor for severe malaria in heterozygous state, negative association of CC genotype with MODS warrants caution of segregating severe malaria into its sub-clinical groups while interpreting data. Further, clinical outcome in malaria was observed to be apparently modulated by LD between TLR9 promoter variants.

Reducing the Delay in Initiation of Treatment Improved Clinical Outcomes in Patients with Imported Malaria

Although imported malaria poses a grave public health threat in Japan, diagnostic methods and disease management among patients and primary care providers has rarely been reported. Here, we retrospectively reviewed medical records of patients diagnosed with imported malaria in our hospital from 1991 to 2010. Thirty-four malaria cases were identified, corresponding to approximately 2% of the total number of cases in Japan. Falciparum malaria has become predominant in the last 2 decades, and compared with patients in the earlier decade (1991-2000), patients in the latter decade (2001-2010) showed significantly shorter delays in consulting medical facilities. The overall hospital delay also tended to be shorter in the latter decade, although delayed referral of patients by a week or more was still observed in more than one-third of the cases. The prevalence of risk factors for severe malaria among patients on the day of the referral visit was also lower in the latter decade. Further, the number of WHO-defined cases of severe malaria was smaller, and the length of the hospital stay was not prolonged during that decade. These findings indicated that a shorter delay in seeking medical treatment could reduce the risks of severe malaria.

Does a significant reduction in malaria risk make lopinavir/ritonavir-based ART cost-effective for children with HIV in co-endemic, low-resource settings?

HIV infection and malaria co-infection is not uncommon among children in co-endemic regions, and evidence suggests that HIV is a risk factor for severe malaria among children. HIV protease inhibitors (PIs) are highly effective in pediatric HIV treatment regimens, however, their effectiveness against malaria has been mixed, with some PIs demonstrating in vitro activity against Plasmodium falciparum. Recent findings suggest lopinavir/ritonavir (LPV/r)-based treatment regimens reduce the incidence of malaria infection by over 40% in pediatric HIV patients compared to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. We assessed whether a significant reduction in malaria risk makes LPV/r-based ART regimens cost-effective compared to NNRTI-based regimens in co-endemic, low-resource settings. We modeled the difference in unit cost per disability adjusted life year (DALY) gained among two theoretical groups of HIV+ children under 5 years old receiving ART in a resource-limited setting co-endemic for malaria. The first group received standard NNRTI-based antiretrovirals, the second group received a standard regimen containing LPV/r. We used recent cohort data for the incidence reduction for malaria. Drug costs were taken from the 2011 Clinton Health Access Initiative Antiretroviral (ARV) ceiling price list. DALYs for HIV and malaria were derived from WHO estimates. Our model suggests a unit cost of US$147 per DALY gained for the LPV/r-based group compared to US$37 per DALY gained for the NNRTI-based group. In HIV and malaria co-endemic settings, considerations of PI cost effectiveness incorporating known reductions in malaria mortality suggest a nominal increase in DALYs gained for PIs over NNRTI-based regimens for HIV positive children under five on ART. Our analysis was based on several assumptions due to lack of sound data on malaria and HIV DALY attribution among pediatric populations. Further study in this area is required.

Variations in ncRNA gene LOC284889 and MIF-794CATT repeats are associated with malaria susceptibility in Indian populations

BackgroundThere are increasing evidences on the role of non-coding RNA (ncRNA) as key regulator of cellular homeostasis. LOC284889 is an uncharacterized ncRNA gene on reverse strand to MIF mapped to 22q11.23. MIF, a lymphokine, regulates innate immune response by up-regulating the expression of TLR4, suppressing the p53 activity and has been shown to be involved in malaria pathogenesis.MethodsIn this study, the possible effect of MIF variations on malaria susceptibility was investigated by re-sequencing the complete MIF gene along with 1 kb each of 5′ and 3′ region in 425 individuals from malaria endemic regions of the Orissa and Chhattisgarh states of India. The subjects comprised of 160 cases of severe malaria, 101 of mild malaria and 164 ethnically matched asymptomatic controls. Data were statistically compared between cases and controls for their possible association with Plasmodium falciparum malarial outcome.ResultsIt is the first study, which shows that the allele A (rs34383331T > A) in ncRNA is significantly associated with increased risk to P. falciparum malaria [severe: OR = 2.08, p = 0.002 and mild: OR = 2.09, P = 0.005]. In addition, it has been observed that the higher MIF-794CATT repeats (>5) increases malaria risk (OR = 1.61, p = 0.01). Further, diplotype (MIF-794CATT and rs34383331T > A) 5 T confers protection to severe malaria (OR = 0.55, p = 0.002) while 6A (OR = 3.07, p = 0.001) increases malaria risk.ConclusionsThese findings support the involvement of ncRNA in malarial pathogenesis and further emphasize the complex genetic regulation of malaria outcome. In addition, the study shows that the higher MIF-794CATT repeats (>5) is a risk factor for severe malaria. The study would help in identifying people who are at higher risk to malaria and adapt strategies for prevention and treatment.

Imported malaria in children: incidence and risk factors for severity

To assess the incidence of imported malaria in children and to determine the frequency of delayed diagnosis and risk factors for severe malaria, we performed a retrospective multicenter cohort study in the northern region of France and included all children with a positive test for malaria from 2000 to 2006. The incidence of imported malaria in children <18 years, the frequency of a delayed diagnosis, and the risk factors for severe malaria were determined. The study identified 133 children with imported malaria. The mean incidence of this disease was 1.9/100 000 children <18 years (95% confidence interval [CI], 1.6–2.2). Detailed data were available for 120 children. Disease was considered severe in 19% of cases. The diagnosis was delayed (≥1 day after the first medical contact) in 31% of cases, and this delay was the only independent risk factor identified for severe imported malaria in children (adjusted odds ratio, 3.2; 95% CI, 1.2–8.8; P = 0.02).