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L'anémie sévère est la seule anomalie à l'hémogramme définie comme critère de gravité du paludisme. Cependant, il existe d'autres perturbations à l'hémogramme non encore décrites au CHU de Bouaké. L'objectif était d'étudier les anomalies observées à l'hémogramme au cours du paludisme grave de l'enfant pour l'amélioration du pronostic. Étude transversale menée dans le service de pédiatrie du CHU de Bouaké de janvier à mars 2021. Les cas de paludisme grave avec bilan paraclinique comportant au moins un hémogramme ont été inclus. Les paramètres d'étude étaient sociodémographiques, cliniques et biologiques. La comparaison des variables était faite avec le test de Chi2 ou le test exact de Fisher au seuil de significativité p < 0,05. Deux cent huit cas de paludisme grave dont 203 avec une anomalie à l'hémogramme sur au moins une lignée sanguine soit une fréquence des anomalies de 97,60 %. Le sex-ratio était de 1,74 avec un âge médian de 29 mois [6–144 mois]. Les motifs d'admission étaient dominés par : fièvre (83,17 %), vomissements (50,48 %) et anémie (49,04 %). La parasitémie moyenne était de 13 321,92 trophozoïtes/μL [800–150 000]. Les formes de gravité étaient : anémie sévère (79,81 %), formes neurologiques (10,10 %), formes neuro-anémiques (5,29 %), hyperparasitémie (4,80 %). Les principales anomalies à l'hémogramme étaient l'anémie (97,6 %), la thrombopénie (82,69 %), la lymphopénie (68,75 %) et l'hyperleucocytose (63,94 %). La létalité était de 4,81 %. Les facteurs significativement associés au décès étaient la thrombopénie profonde < 25 000/μL (p < 0,000001), l'anémie sévère < 5 g/dL (p < 0,001) et la densité parasitaire ≥ 50 000 trophozoïtes/μL (p < 0,006). La thrombopénie et la lymphopénie sont aussi fréquentes au cours du paludisme grave de l'enfant. La thrombopénie profonde est un facteur de mauvais pronostic d'où l'intérêt d'études complémentaires afin de la retenir éventuellement comme critère de gravité. Severe anemia is the only blood count abnormality defined as a criterion of malaria severity. However, there are other blood count abnormalities that have not yet been described at Bouaké University Hospital. The aim of this study was to investigate the blood count abnormalities observed in severe malaria in children with a view to improving the prognosis. Cross-sectional study conducted in the Paediatrics Department of the Bouaké University Hospital from January to March 2021. Cases of severe malaria with a paraclinical work-up including at least one blood count were included. The study parameters were sociodemographic, clinical and biological. Variables were compared using the Chi2 test or Fisher's exact test at a significance level of p < 0.05. Two hundred and eight cases of severe malaria, including 203 with a blood count abnormality in at least one blood line, i.e. a frequency of abnormalities of 97.60%. The sex ratio was 1.74 with a median age of 29 months [6–144 months]. Reasons for admission were dominated by fever (83.17%), vomiting (50.48%) and anemia (49.04%). Mean parasitaemia was 13,321.92 trophozoites/μL [800–15,000]. The forms of severity were: severe anemia (79.81%), neurological forms (10.10%), neuro-anemic forms (5.29%), hyperparasitemia (4.80%). The main blood count abnormalities were anemia (97.6%), thrombocytopenia (82.69%), lymphopenia (68.75 %) and hyperleukocytosis (63.94%). Case fatality was 4.81%. Factors significantly associated with death were profound thrombocytopenia < 25,000/μL (p < 0.000001), severe anemia < 5 g/dL (p < 0.001) and parasite density ≥ 50,000 trophozoites/μL (p < 0.006). Thrombocytopenia and lymphopenia are also common in severe malaria in children. Profound thrombocytopenia is a poor prognostic factor, hence the need for further studies to determine whether it should be included as a criterion of severity. [ABSTRACT FROM AUTHOR]

• Prostration is associated with death from malaria in sub-Saharan African children. • Consideration of prostration increases predictive model performance. • Risk factors of mortality due to malaria show pronounced inter-study variations. • Simple risk scores are important tools for rapid clinical risk stratification. Malaria is still one of the main reasons for hospitalization in children living in sub-Saharan Africa. Rapid risk stratification at admission is essential for optimal medical care and improved prognosis. Whereas coma, deep breathing, and, to a lesser degree, severe anemia are established predictors of malaria-related death, the value of assessing prostration for risk stratification is less certain. Here we used a retrospective multi-center analysis comprising over 33,000 hospitalized children from four large studies, including two observational studies from the Severe Malaria in African Children network, a randomized controlled treatment study, and the phase-3-clinical RTS,S-malaria vaccine trial, to evaluate known risk factors of mortality and with a specific emphasis on the role of prostration. Despite comparable age profiles of the participants, we found significant inter- and intra-study variation in the incidence of fatal malaria as well as in the derived risk ratios associated with the four risk factors: coma, deep breathing, anemia, and prostration. Despite pronounced variations, prostration was significantly associated with an increased risk of mortality (P <0.001) and its consideration resulted in improved predictive performance, both in a multivariate model and a univariate model based on the Lambaréné Organ Dysfunction Score. Prostration is an important clinical criterion to determine severe pediatric malaria with possible fatal outcomes. [ABSTRACT FROM AUTHOR]

• Animal data suggest interleukin-6 (IL-6) signaling has a role in malaria. • Genetic analyses have identified benefit of IL-6 inhibition in other infections. • In malaria, the genetic analyses do not support therapeutic IL-6 inhibition. Severe malaria remains a deadly disease for many young children in low- and middle-income countries. Levels of interleukin (IL)-6 have been shown to identify cases of severe malaria and associate with severity, but it is unknown if this association is causal. A single nucleotide polymorphism (SNP; rs2228145) in the IL-6 receptor was chosen as a genetic variant that is known to alter IL-6 signaling. We tested this, then took this forward as an instrument to perform Mendelian randomization (MR) in MalariaGEN, a large cohort study of patients with severe malaria at 11 worldwide sites. In MR analyses using rs2228145, we did not identify an effect of decreased IL-6 signaling on severe malaria (odds ratio 1.14, 95% confidence interval 0.56-2.34, P = 0.713). The estimates of the association with any severe malaria subphenotype were similarly null, although with some imprecision. Further analyses using other MR approaches had similar results. These analyses do not support a causal role for IL-6 signaling in the development of severe malaria. This result suggests IL-6 may not be causal for severe outcomes in malaria, and that therapeutic manipulation of IL-6 is unlikely to be a suitable treatment for severe malaria. [ABSTRACT FROM AUTHOR]

New evidence highlights a potential role for kidney injury in the development of neurocognitive sequelae in children with severe falciparum malaria. In parallel, neuroimaging studies have demonstrated that adults with severe malaria and acute kidney injury have brain changes identical to the ones seen in cerebral malaria. This emerging kidney–brain pathogenic axis is novel in the context of severe malaria and, to investigate its long-term effects rigorously, the definitions of acute kidney injury and cerebral malaria need to be reconsidered. The use of biomarkers may be pivotal to identify patients with altered kidney and brain function, thereby informing their clinical management and rehabilitation. In the meanwhile, kidney protective therapies and malaria chemoprevention may help to decrease malaria-associated neurodisabilities. Severe falciparum malaria is a medical emergency and a leading cause of death and neurodisability in endemic areas. Common complications include acute kidney injury (AKI) and cerebral malaria, and recent studies have suggested links between kidney and brain dysfunction in Plasmodium falciparum infection. Here, we review these new findings and present the hypothesis of a pivotal pathogenic crosstalk between the kidneys and the brain in severe falciparum malaria. We highlight the evidence of a role for distant organ involvement in the development of cerebral malaria and subsequent neurocognitive impairment post-recovery, describe the challenges associated with current diagnostic shortcomings for both AKI and brain involvement in severe falciparum malaria, and explore novel potential therapeutic strategies. [ABSTRACT FROM AUTHOR]

The current definition of severe malaria in non-endemic areas follows WHO criteria, which mainly target children in malaria-endemic areas, potentially misclassifying cases in non-endemic regions. We assessed the performance of a modified severe malaria classification criteria within our patient cohort. A cohort study of patients managed for malaria in a non-endemic setting (2005–2023) was analyzed. We classified patients into severe malaria (SM) using WHO 2013 criteria except for hyperparasitemia, where 2 % threshold was applied. Patients with SM were distinguished as very severe malaria (VSM) when presenting at least one of the following conditions: parasitemia >10 %, pulmonary edema, impaired consciousness, seizures, renal failure, metabolic acidosis or hyperlactatemia, shock or hypoglycemia. In patients with SM and no criteria for VSM, less severe malaria (LSM) was defined by: 2–10 % parasitemia, hyperbilirubinemia, prostration, anemia or minor bleeding. The primary composite outcome was death or the need for a life-saving intervention, as analyzed in the three comparative groups. Secondary outcome was the prevalence of co-infections. Among 506 patients with malaria, 176 (34.8 %) presented with SM. A total of 37 (7.3 %) patients developed a life-threatening condition, namely death (n = 4) and/or the need for life-saving interventions (n = 34). All fatalities and 33 out of the 34 life-saving interventions occurred in the VSM group. Patients in LSM group did not develop any life-threatening conditions. As to co-infections, 28 (5.5 %) patients had a community-acquired co-infection, with no differences between groups (p = 0.763). Severity criteria definitions would benefit from a review when assessing patients with malaria in non-endemic areas. Within the spectrum of SM, patients reclassified as LSM have a low risk of developing a life-threatening condition and present low co-infection incidence and could benefit from management out of intensive care units and a restrictive use of empirical antibiotics. [ABSTRACT FROM AUTHOR]

• Plasmodium falciparum infection established from a retuning traveler from Kazakhstan. • Kazakhstan was declared malaria-free in 2012. • Patient had no travel history outside Europe, other than Kazakhstan. • Molecular tests done in Germany confirmed parasites belong to a NF54 type of African origin. • The possibility of airport malaria cannot be ruled out. Following a 2-week trip to Kazakhstan, a 42-year-old woman presented at the emergency department in Germany with fever, headache, nausea, and neurological symptoms. An infection with Plasmodium falciparum was rapidly diagnosed. The patient was immediately treated with intravenous artesunate and transferred to an intensive care unit. The initial parasite density was as high as 30% infected erythrocytes with 845,880 parasites/µL. Since Kazakhstan was declared malaria-free in 2012, molecular testing for Plasmodium has been initiated to identify a possible origin. Genotyping of the msp-1 gene and microsatellite markers showed that the parasites are of African origin, with two different alleles indicating a polyclonal infection. After a hospitalization of 10 days, the patient was discharged in good health. Overall, our results emphasize that malaria must be on the list of differential diagnoses for patients with fever of unknown origin, even if they come from countries where malaria does not commonly occur. [ABSTRACT FROM AUTHOR]

Early treatment with parenteral antimalarials is key in preventing deaths and complications associated with severe and cerebral malaria. This can be challenging in 'hard-to-reach' areas in Africa where transit time to hospitals with facilities to administer drugs parenterally can be more than 6 h. Consequently, the World Health Organization has recommended the use of artesunate (ATS) suppositories for emergency treatment of patients, however, this treatment is only for children under 6 years. The intranasal route (INR) can provide a safe and effective alternative to parenteral and rectal routes for patients of all ages; thus, reducing delays to the initiation of treatment. Hence, we designed ATS-loaded nanostructured lipid carriers (NLCs) for intranasal administration. ATS-NLCs were formulated using varying concentrations of lipid matrices made up of solidified reverse micellar solutions (SRMS) comprising a 1:2 ratio of Phospholipon ® 90H and lipids (Softisan ® 154 or Compritol ®). ATS-NLCs were spherical, and the small sizes of ATS-NLCs obtained for some formulations (76.56 ± 1.04 nm) is an indication that ATS-NLCs can pass through the nasal mucosa and reach the brain or systemic circulation. Encapsulation efficiency of ATS in NLCs was ≥70% for all formulations. ATS-NLCs achieved up to 40% in vitro drug release in 1 h, while ex vivo permeation studies revealed that formulating ATS as NLCs enhanced permeation through pig nasal mucosa better than drug solution. Most importantly, the activity and reduction in parasitaemia [in mice infected with P lasmodium berghei ANKA in a murine cerebral malaria model] by ATS-NLCs administered through the INR (54.70%, 33.28%) was comparable to intramuscular administration (58.80%, 42.18%), respectively. Therefore, intranasal administration of NLCs of ATS has great potentials to serve as a satisfactory alternative to parenteral administration for the treatment of severe and cerebral malaria in both adults and children in remote areas of sub-Saharan Africa. [Display omitted] • High encapsulation of a hydrophilic drug (artesunate (ATS) in nanostructured lipid carriers (NLCs) can be achieved by using solidified reverse micellar solutions as solid lipid. • Encapsulating ATS in NLCs improved ex vivo permeation better than simple drug solution. • Intranasal administration of ATS-NLCs had comparable outcomes as intramuscular administration in the treatment of severe malaria in mice. [ABSTRACT FROM AUTHOR]

Objectives: A systematic review and meta-analysis (SR-MA) of the available Indian literature on severe vivax malaria (SVM) was undertaken.Methods: Relevant studies in eight electronic databases were retrieved and reviewed. The preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines were followed. The methodological quality of the studies included in the MA was assessed.Results: Overall, 162 studies were included in the work. The pooled proportion of SVM was 29.3%. The main severity signs/symptoms seen in SVM were jaundice, severe thrombocytopenia (ST), multi-organ dysfunction, and severe anaemia with pooled proportion of 37.4%, 37.2%, 24.2% and 20.4%, respectively. P. falciparum was inducing 6% less ST (RR = 0.94, 95% CI 0.5-1.5, I2 = 77.87%), 10% less thrombocytopenia (RR = 0.9, 95% CI 0.7-1.1, I2 = 91.68%) and 20% less DIC (RR = 0.8, 95% CI 0.3-1.9, I2 = 0%) than P. vivax. An atypical condition like myocarditis, was most commonly observed among the studied SVM cases. The mortality rate in SVM cases ranged from 0 to 12.9% among hospital patients with P. vivax mono-infections.Conclusions: The present SR-MA provides evidence for P. vivax as the etiologic agent of severe malaria leading to deaths in few cases as seen recently in India. However, research gaps outlined here emphasise the need for further studies on SVM in pregnancy, SVM in drug resistance and correlations with cytoadherence in disease severity due to P. vivax. [ABSTRACT FROM AUTHOR]

Imported malaria is often misdiagnosed due to the aspecific symptoms and lack of familiarity among clinicians. This study aims to evaluate a decade-long trend of imported malaria cases in a Belgian teaching hospital by analyzing demographics, clinical characteristics, and outcomes. Medical records of 223 patients with confirmed malaria diagnoses between 2010 and 2019 were analyzed. Most patients were male (63.2%), aged 18-65 years (77.1%), and visiting friends or relatives (40.8%). Central Africa was the most common travel destination (54.3%), and 63.7% did not take prophylaxis. Symptoms were flu-like, with fever (91.9%) being most prevalent. P. falciparum was identified in 88.3% of cases. A high proportion of severe cases (41.7%) and a low mortality rate (0.9%) were recorded. A severe form of the disease is associated with a more extended hospital stay than uncomplicated form (median of 5 vs. 4 days, p < 0.001). Thirty-five-point five percent [33/93] of patients with severe malaria have had a previous malaria infection compared to 50.8% [66/130] of uncomplicated patients (p = 0.013) wich was statistically significant. Malaria disproportionately affects VFRs traveling to Central Africa, and flu-like symptoms should raise suspicion. Prophylaxis is essential to prevent the disease, and early diagnosis is critical for effective management. A severe form of the disease is associated with a more extended hospital stay than uncomplicated form and people with a previous history of malaria have a less severe disease [ABSTRACT FROM AUTHOR]

[Display omitted] • A patient with severe malaria suffered a severe recrudescent episode. • Artesunate monotherapy is associated with a higher risk of recrudescence. • Hyperparasitaemia is associated with a higher risk of recrudescence. • Parasite clearance time is an indicator of recrudescence risk. • Antimalarial stewardship programs are needed to promote good clinical practices. A patient presenting with severe malaria, with hyperparasitaemia, received 7-day artesunate monotherapy. A severe recrudescence was detected and attributed to hyperparasitaemia, monotherapy and a polyclonal infection without Kelch 13 gene mutation. A second treatment with artesunate, then quinine, followed by artemether-lumefantrine, was successful. [ABSTRACT FROM AUTHOR]

• "cys2/MFK*/*REY" motif with short length were restricted to cerebral and severe malaria. • Higher expression level of var group A was associated with malaria severity. • Peptide VAR P5 (DIGDIVRGKDLY) appeared to be a good marker for severity. Plasmodium falciparum erythrocyte membrane protein is encoded by a highly variable multicopy var gene family known to play a key role in malaria pathogenicity. Therefore, we investigated sequence variation, expression profile and immune response of the Duffy binding-like domain (DBLα) region of the var gene. Blood samples were collected from patients with cerebral, severe and mild malaria in Chhattisgarh, India, a region with endemic malaria. Polymerase chain reaction amplicons were cloned and sequenced to determine sequence variation. The expression level was analyzed targeting the upstream region of var gene using the Delta-Delta-Ct method. Immunoglobulin G (IgG) level was determined against the 6 synthetic peptides of the DBLα region. The study identified that group 1 and group 5 sequences (cysteine/position of limited variability (cys/PoLV) classification) along with cys2/cys4 and MFK*/REY motifs and short amino acid length were significantly associated with malaria severity. The specific PoLV (MFKS, LREA, PTNL) were restricted to cerebral malaria. The expression level of var group A was higher than var groups B and C, demonstrating its prognostic characteristic. All peptides showed high-quality IgG response, while VAR P5 appeared to be a good marker for severity. The present study illustrates the presence of specific sequences of DBLα tags involved in severe malaria that could be targeted in future interventions for malaria control and elimination. [ABSTRACT FROM AUTHOR]

Malaria is the most widely spread parasitic disease in the world, especially in the tropics affecting mostly children and pregnant women. In children, mostly under-fives carry the heaviest burden in terms of morbidity and mortality. The aim of this study was to determine the epidemiological and clinical aspects, and outcome of children 3 months to 15 years old with severe malaria at the Yaounde Gynaeco-Obstetric and Pediatric Hospital (YGOPH), a referral hospital in Yaounde, Cameroon. It was a descriptive study at the general pediatric unit of the YGOPH. We enrolled all children aged 3 months to 15 years admitted for severe malaria, with one or more signs of severity and confirmed by a Rapid Diagnostic Test (RDT) and/or thick blood smear (TBS). Over six months, 1782 children were admitted in the unit and 466 had severe malaria giving a frequency of 26.10%. The mean age was 51 ± 42 months, and the sex ratio was 1.2. The highest transmission rate was during the rainy season, within the months of April and May. The main symptoms on admission were prostration, fever with body temperature ≥40 °C and convulsions (61.90%, 58.00%, and 30.30% respectively). RDT was positive in 98.90% of cases and TBS was positive in 60.00%. The outcome was favourable in 93.30% of the patients and 16 died giving a mortality rate of 3.80%. Severe malaria is a public health problem affecting mostly children under five years. Proper management consists of prompt diagnosis and early appropriate treatment. Prevention is by information, education and communication on environmental cleanliness and the use of insecticide-treated mosquito nets. [ABSTRACT FROM AUTHOR]

• The safety profile of artemisinin derivatives must be monitored. • Parenteral artesunate has been associated with hemolytic events in non-immune travelers. • In malaria-endemic areas post artesunate hemolytic anemia seems not to be such an important problem as in non-endemic areas. • However, in malaria-endemic areas, there is a high prevalence of anemia in children. • Anemia must be followed-up in children with severe malaria irrespective of treatment. This retrospective analysis performed in Manhiça, Southern Mozambique, aimed to describe the frequency of post-malarial anemia (measured as a decrease of hematocrit ≥10%) and the need for blood transfusions in children with severe malaria treated with intravenous quinine or parenteral artesunate. All children <15 years admitted with a parasitologically-confirmed diagnosis of malaria from 1st January 2003 to 31st December 2017, alive at hospital discharge, and with at least one measurement of hematocrit within 28 days after hospital discharge, detected by passive case detection, were included. The overall prevalence of post-malarial anemia observed in the study was 23.13%, with an estimated incidence rate of 288.84 episodes/1,000 children-month at risk in the follow-up period (28 days after discharge). There were no differences between treatment groups, although the study showed a higher association between blood transfusions and artesunate treatment. In this setting, children with severe malaria frequently present a meaningful decrease of hematocrit (>=10%) in the first weeks after their episode, sometimes requiring blood transfusions. Because of the high underlying prevalence of anemia in malaria-endemic settings, all children with severe malaria need to be actively followed up, irrespective of the treatment received. [ABSTRACT FROM AUTHOR]

The major growth in point-of-care malaria diagnosis over the past decade has been based on immunochromatographic malaria rapid diagnostic tests (mRDTs), which generally detect Plasmodium falciparum via its abundant histidine-rich protein 2 (HRP2). Here, we review the discovery and biology of HRP2, as well as the strengths and weaknesses of HRP2-based diagnosis compared with alternative antigens. We highlight recent studies describing HRP2 deletion in Latin America, Eritrea, and possibly other regions, and the methodological challenges of confirming deletion of the pfhrp2 gene. We also discuss the mechanism of persistent HRP2 positivity after effective antimalarial treatment, along with other emerging HRP2-based applications, including detection of submicroscopic malaria and diagnosis of severe malaria. HRP2 detection forms the basis of the most sensitive mRDTs currently available, and HRP2-based mRDTs have been the central element in the scale-up of mRDTs over the last decade, allowing malaria diagnosis even in remote areas in sub-Saharan African. Over 1 billion mRDTs have been sold so far. Parasites with HRP2 deletion were first reported from the Amazon region (Peru and neighbouring countries) in 2010 and, more recently, at high prevalence in Eritrea. Persistence of HRP2 in the circulation for several weeks following successful antimalarial treatment is now understood to be due to splenic pitting, and HRP2 measurement can be used to predict postartesunate-delayed haemolysis. The concentration of HRP2 can be used to define severe malaria (plasma) and quantify in vitro growth (laboratory culture). There is increasing interest in ultrasensitive HRP2 detection to detect asymptomatic malaria in low-transmission areas, potentially allowing public health-level interventions. [ABSTRACT FROM AUTHOR]

There has been a marked increase in the reporting of confirmed vivax malaria cases in certain geographical areas. This study investigated cases of severe vivax malaria in the Republic of Korea. We retrospectively reviewed the medical records of adult patients diagnosed with vivax malaria in the Republic of Korea during the period 2000 to 2016. Diagnosis was made using the World Health Organization criteria, with the exception of parasite density. Among 1366 malaria cases, 255 (18.7%) were classified as severe vivax malaria, and 46 (3.4%) required intensive care. None of patients died of malaria. Patients with severe vivax malaria were older and had more comorbidity. The enrollment periods were classified into three groups, 2000 to 2005 (506 cases), 2006 to 2010 (696 cases), and 2011 to 2016 (304 cases). Malaria cases decreased from 2011 to 2016, but severe malaria cases increased significantly over time (14.3%, 20.1%, and 22.8%, p = 0.003). Common severe manifestations were shock (45.6%) and jaundice (43.1%). Cases of severe malaria increased, and shock and jaundice were the predominant findings of severe vivax malaria in the Republic of Korea. [ABSTRACT FROM AUTHOR]

Malaria is a parasitic disease of which Plasmodium falciparum causes the most severe form of the disease. The immune response against Plasmodium spp. is complex and remains unclear. The present report aimed to better understand the humoral immune response in severe malaria and analyse new immunodominant antigen candidates as possible serological marker in severe malaria in children. This study included children aged 0–16 years from Guinea-Bissau with clinical signs of severe malaria. Serological and immunochemical characterisation of different anti- P. falciparum antibodies were made by ELISA and immunoblotting using a crude protein extract of P. falciparum . Sera from 12 children with severe malaria were analysed. Nine samples were positive for total anti- P. falciparum antibodies, seven for IgM and eight for total IgG anti- P. falciparum . There was a predominance of IgG1 response, suggesting a cytophilic action in severe malaria and a major role of IgG1 over other immunoglobulins. The antigenic profile of P. falciparum showed a consistent immunoblotting pattern of approximately 180 kDa, 100 kDa and around 50–40 kDa. The serological reactivity found in protein bands makes them as immunodominant antigens and promising candidates for serological markers in the context of severe malaria. [ABSTRACT FROM AUTHOR]

Background Sickle-cell-gene has a high frequency in malaria endemic regions. In India, though the prevalence of both sickle-cell-gene and malaria are high, no study has been carried out. This study aims to find out the possible differences in hematological and clinical parameters in severe falciparum malaria with respect to sickle cell genotypes. Methods Five hundred fourteen adults with severe falciparum malaria hospitalized in Department of Medicine, Veer Surendra Sai Institute of Medical Sciences and Research, Burla, between August, 2010 to December, 2014 were included and categorized on the basis of sickle cell genotypes. The hematological parameters were compared by one-way-analysis-of-variance and incidence of sub-phenotypes of severe malaria was compared by χ2 test across the groups. Results Patients with sickle cell anemia (HbSS) and severe falciparum malaria had lower hemoglobin level compared to patients with normal β-globin genotype (HbAA) and sickle cell trait (HbAS). Most of the hematological parameters were homogeneous in patients with HbAA and HbAS and different from patients with HbSS. Incidence of acute renal failure was low (χ2, 9.91; p , 0.002) and jaundice was high (χ2, 5.20; p , 0.022) in patients with HbSS. No clinical difference was observed in patients with HbAA and HbAS. The mortality was low (χ2, 4.33; p , 0.037) and high (χ2, 10.48; p , 0.001) in patients with HbAS and HbSS respectively compared to patients with HbAA. Conclusion Though sickle-cell-gene protects against falciparum infections, the hematological parameters and sub-phenotypes of severe malaria remain unchanged when the infection progresses to a severe form in patients with HbAA and HbAS. Presence of hemolytic anemia in patients with HbSS shows diverse hematological and clinical phenotypes as compared to others. High mortality in patients with HbSS emphasizes the need for a better preventive approach to save valuable lives. [ABSTRACT FROM AUTHOR]

Severe malaria is potentially life-threatening and requires the parenteral administration of the artemisinin-based formulation for short duration of action. Intravenous artemether formulation has shown potentially better therapeutic efficacy but its poor aqueous dissolution constitutes a challenge. This work produced human serum albumin (HSA)-bound artemether nanoparticles by emulsification and desolvation approach using nanoparticle albumin bound (nab) technology for intravenous (IV) administration. The prepared nanoparticles had a size below 50 nm. It was observed that higher HSA concentration; lower drug concentration and longer ultrasonication time (up to 60 s) favoured the production of smaller particles. Comparatively, the emulsification method allowed for higher drug entrapment per the same concentration of HSA and required less organic solvent, less water and less energy and is therefore the preferred method. HSA-bound artemether nanoparticles displayed significantly enhanced dissolution properties over raw artemether. In-vitro haemolysis studies demonstrated a significant decrease in haemolysis caused by artemether from 101% to 7% in the emulsification product and to 4% by the desolvation product. [ABSTRACT FROM AUTHOR]

Severe imported P. falciparum malaria is a source of morbi-mortality in non-endemic regions. WHO criteria don't accurately classify patients at risk of complications. There is a need to evaluate new tools such as biomarkers to better identify patients with severe imported malaria. A case-control study was conducted in Barcelona, from January 2011–January 2021. Adult patients with microbiologically confirmed P. falciparum malaria were classified according to WHO criteria. Patients with imported non-malarial fevers were included as controls. In each group, angiopoietin-1 (Ang-1), angiopoietin-2 (Ang-2), soluble triggering receptor expressed on myeloid cells (sTREM-1), C-reactive protein (CRP) and platelets were measured and their concentrations were compared between groups. New groups were made with a modified WHO severity classification and biomarkers' performance was evaluated using multiple imputation models. 131 participants were included: 52 severe malaria, 30 uncomplicated malaria and 49 non-malarial fever cases. All biomarkers except sTREM-1 showed significant differences between groups. Using the modified WHO severity classification, Ang-2 and CRP presented the best AUROC; 0.79 (95%CI 0.64–0.94) and 0.80(95%CI 0.67–0.93). A model combining CRP and Ang-2 showed the best AUROC, of 0.84(95%CI 0.68–0.99), with the highest sensitivity and specificity: 84.6%(95%CI 58.9–98.1) and 77.4% (95%CI 65.9–87.7), respectively. The combination of Ang-2 and CRP may be a reliable tool for the early identification of severe imported malaria. The use of a rapid prognostic test including the mentioned biomarkers could optimize imported malaria management, with the potential to decrease the rate of complications and hospitalizations in patients with imported malaria. • A model combining Angiopoietin-2 and C-reactive protein could be a valuable tool to improve the identification of severe imported malaria cases. [ABSTRACT FROM AUTHOR]

Background Severe imported Plasmodium falciparum malaria is a potentially life-threatening disease with a reported mortality rate of 5–10% when patients are admitted to the Intensive Care Unit. Methods To retrospectively review the clinical aspects, the value of severity predictive scores and the management of patients with severe P. falciparum malaria admitted to an ICU in Milano, Italy between January 2010 and December 2015. Results Twelve patients were included: seven were male and five female with a median age of 43 years. All were initially treated with intravenous quinine. Median parasitaemia upon admission was 14,5% (range 1–20%). At the time of ICU admission, 3 patients (25%) had 5 or more World Health Organization criteria for severe malaria while another 6 of them developed one or more of the latter during their stay in ICU. Five required mechanical ventilation because of respiratory failure due to ARDS. Four patients required renal replacement therapy. Three patients underwent blood exchange transfusion. All patients survived. Conclusions Our retrospective evaluation of adults patients admitted to the ICU with severe imported P. falciparum malaria demonstrated a favourable outcome. Severity predictive scores currently in use probably overestimate the risk of malaria mortality in patients treated in health care systems of high income countries. [ABSTRACT FROM AUTHOR]

Background Malaria is not endemic in Italy, but it still represents an important threat to the travelers' health. With this study we wanted to compare the characteristics of imported malaria between adults and children. Method This retrospective observational study includes all patients admitted to the Infectious Diseases Unit and in the Pediatric Department of Padua (Italy), and discharged with a diagnosis of malaria from 2005 to 2015. The variables considered are epidemiological and clinical. Results 172 cases of imported malaria were studied (124 adults and 48 children), P. falciparum was responsible for 90,7% of the cases, and was contracted mostly in Africa (96,5%), especially by foreigners visiting friends and relatives (VFR). Chemoprophylaxis was adopted only by few patients. 93% of all the patients developed the uncomplicated malaria, but pediatric patients had severe malaria significantly more often than adults (OR = 4,06, p = 0,015). Children also had significantly lower hemoglobin levels and higher parasitemia. The drugs used to treat the two groups were substantially different, but both had a good overall outcome. Conclusions In order to reduce the risk of imported malaria, educational actions should target potential VFR travelers, and they should underline the different risk of severe malaria in adults and children. A further implementation of the recommended therapies could improve the patients' outcome. [ABSTRACT FROM AUTHOR]

Young infants are less susceptible to severe episodes of malaria but the targets and mechanisms of protection are not clear. Cord blood antibodies may play an important role in mediating protection but many studies have examined their association with the outcome of infection or non-severe malaria. Here, we investigated whether cord blood IgG to Plasmodium falciparum merozoite antigens and antibody-mediated effector functions were associated with reduced odds of developing severe malaria at different time points during the first year of life. We conducted a case-control study of well-defined severe falciparum malaria nested within a longitudinal birth cohort of Kenyan children. We measured cord blood total IgG levels against five recombinant merozoite antigens and antibody function in the growth inhibition activity and neutrophil antibody-dependent respiratory burst assays. We also assessed the decay of maternal antibodies during the first 6 months of life. The mean antibody half-life range was 2.51 months (95% confidence interval (CI): 2.19–2.92) to 4.91 months (95% CI: 4.47–6.07). The rate of decline of maternal antibodies was inversely proportional to the starting concentration. The functional assay of antibody-dependent respiratory burst activity predicted significantly reduced odds of developing severe malaria during the first 6 months of life (Odds ratio (OR) 0.07, 95% CI: 0.007–0.74, P = 0.007). Identification of the targets of antibodies mediating antibody-dependent respiratory burst activity could contribute to the development of malaria vaccines that protect against severe episodes of malaria in early infancy. [ABSTRACT FROM AUTHOR]

Résumé Le paludisme grave, problème majeur de santé publique en Afrique a été étudié dans le but de préciser sa fréquence, d’identifier les formes cliniques et les signes prédictifs de la mortalité. Une étude transversale, descriptive et analytique a été réalisée entre janvier et août 2015 dans les services de pédiatrie du Centre Hospitalier et Universitaire de Brazzaville. Les enfants de 3 mois à 15 ans qui avaient une goutte épaisse positive pour le Plasmodium falciparum associé à au moins un des critères de gravité de l’OMS ont été inclus. Sur 4762 enfants hospitalisés, 382 l’étaient pour un paludisme grave. Il s’agissait de 232 garçons (60,7 %) et de 150 filles (39,3 %), âgés en moyenne de 5,5 ans. Ils avaient moins de 5 ans n = 174 (45,6 %). Les critères de gravité les plus observés étaient l’anémie n = 235 (61,5 %), les convulsions répétées n = 104 (27,2 %), le coma n = 70 (18,3 %), l’hémoglobinurie n = 67 (17,5 %), la prostration n = 66 (17,2 %) et les troubles de la conscience n = 59 (15,4 %). Les formes cliniques étaient isolées n = 217 (56,8 %) et associées n = 165 (43,2 %), dominées par les formes anémiques et neurologiques. L’évolution était favorable pour 357 enfants (93,5 %), elle s’est faite vers un décès pour 25 enfants (6,5 %). Les signes prédictifs du décès étaient les convulsions répétées, le coma, la détresse respiratoire, l’hépatomégalie, l’hypoglycémie et la thrombopénie. La fréquence élevée et la sévérité du paludisme grave incitent fortement l’usage de la moustiquaire imprégnée, l’assainissement du milieu, le traitement correct du paludisme simple et la prise en charge correcte des cas de paludisme grave. Summary Severe malaria, a major public health problem in Africa was studied in order to clarify its frequency to identify the clinical forms and signs predictive of mortality. A transversal, descriptive and analytical study was carried out between January and August 2015 in the pediatric services of the University Hospital of Brazzaville. Children from 3 months to 15 years who had a thick smear positive for Plasmodium falciparum associated with the at least one of the WHO severity criteria were included. About 4762 children hospitalized, 382 were for severe malaria. There were 232 boys (60.7 %) and 150 girls (39.3 %), mean age of 5.5 years. They had less than 5 years n = 174 (45.6%). The most observed severity criteria were anemia n = 235 (61.5%), repeated convulsions n = 104 (27.2%), coma n = 70 (18.3%), hemoglobinuria n = 67 (17.5 %), prostration n = 66 (17.2%) and impaired consciousness n = 59 (15.4%). The clinical forms were isolated n = 217 (56.8%) and related n = 165 (43.2%), dominated by anemia and neurological forms. The outcome was favorable in 357 children (93.5 %), it was done to death in 25 children (6.5 %). Predictive signs of death were repeated convulsions, coma, respiratory distress, hepatomegaly, hypoglycemia and thrombocytopenia. The high frequency and severity of severe malaria strongly encourage the use of treated mosquito nets, environmental sanitation, proper treatment of uncomplicated malaria and the proper management of severe malaria. [ABSTRACT FROM AUTHOR]

The molecular arms race between humans and Plasmodium falciparum in Africa resulted in selection of sickle-cell disease, which, on balance, protects heterozygote carriers against severe malaria. Band et al. discovered that parasites counter-adapt and can overcome disease resistance by identifying parasite genome signatures, termed P. falciparum sickle-associated (Pfsa) variants. [ABSTRACT FROM AUTHOR]

Tumour necrosis factor (TNF) – α has been shown to play an important role in the pathogenesis of falciparum malaria. Two TNF promoter polymorphisms, TNF-308 and TNF-238 have been associated with differential activity and production of TNF. In order to investigate the association between TNF-308 and TNF-238 and the clinical outcome of malaria in a Nigerian population, the two TNF polymorphisms were analysed using Sequenom iPLEX Platform. A total of 782 children; 283 children with uncomplicated malaria, 255 children with severe malaria and 244 children with asymptomatic infection (controls) were studied. The distribution of TNF-308 and TNF-238 genotypes were consistent with the Hardy-Weinberg equilibrium. Distribution of both TNF polymorphisms differed significantly across all clinical groups (TNF-308: p = 0.007; TNF-238: p = 0.001). Further tests for association with severe malaria using genotype models controlling for age, parasitaemia and HbAS showed a significant association of the TNF-238 polymorphism with susceptibility to severe malaria (95% CI = 1.43–6.02, OR = 2.94, p = 0.003237) The GG genotype of TNF-238 significantly increased the risk of developing cerebral malaria from asymptomatic malaria and uncomplicated malaria (95% CI = 1.99–18.17, OR = 6.02, p < 0.001 and 95% CI = 1.78–8.23, OR = 3.84, p < 0.001 respectively). No significant association was found between TNF-308 and malaria outcome. These results show thegenetic association of TNF-238 in the clinical outcome of malaria in Ibadan, southwest Nigeria. These findings add support to the role of TNF in the outcome of malaria infection. Further large scale studies across multiple malaria endemic populations will be required to determine the specific roles of TNF-308 and TNF-238 in the outcome of falciparum malaria infection. [ABSTRACT FROM AUTHOR]

Background Plasmodium vivax once considered benign is now being increasingly associated with complicated malaria where the spectrum of complications is vast and like Plasmodium falciparum . The clinical data is important with respect to the immunopathological status of the patient. Several genes like the vir genes and pvcrt-o are speculated to be attributing to the severity of P. vivax malaria. Methods In the present study we carried out the transcription analysis of five vir genes ( vir 14-related , vir 12 , vir 17-like , putative vir 14 and vir 10-related ) and pvcrt-o gene in severe (n=12) and non-severe (n=7) P. vivax clinical infections and studied the correlation of these genes with clinical disease severity. Results This study revealed multiorgan involvement in severe vivax cases with severe thrombocytopenia and anemia, the predominantly occurring symptoms. Four out of five vir genes and pvcrt-o showed a significant increase in expression levels of severe infections compared to the non-severe infections indicating their possible role in the changing pathogenesis of P. vivax . Conclusions The increased virulence in vivax malaria seems to be the result of multifactorial parameters changing it phenotypically as well as genotypically. However more studies are needed to understand the still nascent severity of P. vivax malaria. [ABSTRACT FROM AUTHOR]

There are limited data regarding prevalence, anti-malarial chemoprophylaxis, and causes of death for severe imported malaria. Thus, we conducted a systematic review and meta-analysis to characterise these variables. We searched studies reporting deaths attributable to severe imported malaria. The following pooled prevalence rates were determined: 1) the pooled prevalence of severe malaria among patients with imported malaria, 2) the pooled prevalence of deaths among patients with severe imported malaria, 3) the pooled prevalence of anti-malarial chemoprophylaxis among patients with severe imported malaria, and 4) the causes of death among patients with severe imported malaria. The search identified 52 studies that were mainly conducted in Europe (25, 48.1%), North America (16, 30.8%) and Asia (7, 13.5%). The pooled prevalence of severe imported malaria was 12.5% (95% confidence interval [CI] = 10.3%–14.6%, I 2 = 99.32%, 12393 severe cases/118325 imported cases). The pooled prevalence of deaths attributable to severe imported malaria was 5.1% (95% CI = 4.0%–6.2%, I 2 = 91.72%, 721 deaths/16310 severe cases). The pooled prevalence of adequate anti-malarial chemoprophylaxis among patients with severe imported malaria was 9.7% (95% CI = 6.5%–13.0%, I 2 = 89.9%, 203/2049 cases). The most common cause of death was multi-organ failure (12.3%). The results highlighted the need for education and preventative measures for travellers, immigrants, or workers who plan to visit malaria-endemic areas to minimize the risk of severe disease or death. [ABSTRACT FROM AUTHOR]

Plasmodium knowlesi malaria is a newly described zoonosis in Southeast Asia. Similarly to Plasmodium falciparum, P. knowlesi can reach high parasitaemia in the human host and both species cause severe and fatal illness. Interpretation of host–parasite interactions in studies of P. knowlesi malaria adds a counterpoint to studies on P. falciparum . However, there is no model system for testing the resulting hypotheses on malaria pathophysiology or for developing new interventions. Plasmodium knowlesi is amenable to genetic manipulation in vitro and several nonhuman primate species are susceptible to experimental infection. Here, we make a case for drawing on P. knowlesi as both a human pathogen and an experimental model to lift the roadblock between malaria research and its translation into human health benefits. [ABSTRACT FROM AUTHOR]

Artesunate has replaced quinine as the recommended first-line treatment of severe malaria as it clears parasites faster and lowers mortality. After artesunate's introduction, however, reports of delayed haemolysis have emerged. Typically, this adverse haemolytic event peaks two to three weeks after the acute phase of malaria, and can be severe enough to make blood transfusions necessary in the management of some patients. Delayed haemolysis has been detected in prospective studies in 7-21% of patients treated with artesunate. A confirmed risk factor in travellers is hyperparasitaemia, while additional in malaria-endemic countries young age has been shown to increase risk. The pathophysiology of this phenomenon has not yet been fully elucidated, but may include various combinations of delayed destruction of "pitted" erythrocytes and autoimmune aetiology. All patients treated with parenteral artesunate should be followed up for at least four weeks to detect signs of haemolysis and to allow appropriate symptomatic treatment. [ABSTRACT FROM AUTHOR]

Summary This study aimed to estimate the incidence of catastrophic health expenditures faced by households in Kinshasa with children affected by severe malaria. A total of 1350 children below the age of 15 year who were hospitalized due to severe malaria were included in the study. We analyzed the incidence of households facing catastrophic expenditures according to two thresholds: 40% of the household's capacity to pay and 10% of the household's total consumption. Based on the ‘40% of the capacity to pay’ threshold, the incidence of catastrophic health expenditures reached 81.1%, and this estimate reached 46.4% for the ‘10% above total consumption’ threshold. Regarding the ≥40% capacity to pay threshold, the incidences of catastrophic expenditures was higher among households with children who were admitted to state hospitals (adjusted odds ratio [aOR] 3.7) and private hospitals (aOR 59.1), for poor households (aOR 13), for households with medium socioeconomic statuses (aOR 3.2), for female-headed households (aOR 2.9), for households with children affected by the neurological form (aOR 4.8) and respiratory distress (aOR 3.6), and for households who opted for a pre-hospital resort (aOR 2.7). Similar results were obtained when the 10% above the total consumption threshold was applied. Greater government financing of medical attention would lead to a reduction in the catastrophic health expenditures faced by the poorest households. [ABSTRACT FROM AUTHOR]

Summary Severe malaria kills more than a half million people each year. Based on high-quality evidence of the efficacy superiority of artesunate over quinine in adults and children with severe malaria, the World Health Organization guidelines have been revised. The WHO currently recommends injectable artesunate as the first-line treatment for severe malaria. Since this revision in April 2011, only a small number of countries affected by malaria have adopted and implemented the new policy. If this policy is implemented, an additional 195,000 lives would be saved each year in Africa. Thus, there is an urgent need to speed up access to injectable artesunate in malaria-endemic countries. This review presents a background for recommending artesunate as the first-line treatment of severe malaria in children and adults, and interventions that are recommended to accelerate access to injectable artesunate. [ABSTRACT FROM AUTHOR]

Killer-cell immunoglobulin-like receptors (KIRs) are a group of natural killer cell receptors (NKRs) that regulate NK-cell-mediated production of interferon gamma (IFN-γ) in response to infection. These receptors have recently been suggested to influence the severity of clinical Plasmodium falciparum malaria infection. We examined the KIR locus in relation to malaria in children from southwest Nigeria. Sequence specific priming (SSP)-PCR was used to detect the KIR genes. The presence or absence of fifteen different KIR genes was determined in each individual and the proportions compared across 3 clinical groups; asymptomatic malaria, uncomplicated clinical malaria and severe clinical malaria. The genes KIR2DL5, KIR2DS3 and KIR2DS5 were present in a significantly higher proportion of individuals in the asymptomatic control group than in the malaria cases. Furthermore, KIR2DS3 and KIR2DS5 were present in a higher proportion of uncomplicated malaria cases than severe malaria cases. Carriage c-AB2 genotype (which comprises all centromeric KIR genes including KIR2DL5, KIR2DS3 and KIR2DS5) decreases with severity of the disease suggesting that the KIR AB profile might be associated with protection from severe malaria infection in this population in Nigeria. [ABSTRACT FROM AUTHOR]

Highlights: [•] Acidosis is an important contributor to mortality in patients with severe malaria. [•] A novel LC–MS method for simultaneous determination of 8 potential small organic acids contributing to acidosis. [•] Anion exchange SPE coupled with HILIC and ion trap LC–MS was utilized for separation and detection. [•] This new method demonstrated clinical applicability in plasma and urine of severe malaria patient. [Copyright &y& Elsevier]

Highlights: [•] The concept that parasite sequestration per se initiates severe malaria is challenged. [•] We contend that high parasite biomass is the main determinant of severe malaria. [•] Explanations for different severe malaria syndromes are suggested. [•] Understanding severe malaria pathogenesis is proposed as key to better treatment. [ABSTRACT FROM AUTHOR]

Sequestration of Plasmodium falciparum-infected erythrocytes ( Pf IE) in the capillaries of the central nervous system ( CNS) is the pathognomonic feature of cerebral malaria, a condition frequently leading to death. Sequestration of Pf IE in the placental intervillous spaces is the characteristic feature of malaria in pregnancy and is associated with low birthweight and prematurity. Although both patterns of sequestration are thought to result from the expression of different parasite proteins involved in cytoadhesion to human receptors, scant information exists on whether both conditions can coexist and whether this can lead to death. We conducted a prospective autopsy study including all consecutive pregnancy-related deaths in a tertiary-level referral hospital in Maputo, Mozambique, between October 2002 and December 2006. Extensive sampling of all major viscera was performed. All cases showing parasites in any of the viscera were included in the analysis. From 317 complete autopsies Pf IEs were identified in ten women (3.2%). All cases showed massive accumulation of Pf IE in small capillaries of the CNS but also in most visceral capillaries (heart, lung, kidney, uterus). Placental tissue, available in four cases, showed a massive accumulation of maternal Pf IE in the intervillous space. Coma (six women) and dyspnoea (five women) were the most frequent presenting clinical symptoms. In conclusion, massive visceral sequestration of Pf IE with significant involvement of the CNS is an infrequent but definite direct cause of maternal death in endemic areas of Africa. The Pf IE sequestered in cerebral capillaries and the placenta coexist in these fatal cases. [ABSTRACT FROM AUTHOR]

Background/Purpose: Malaria remains one of the most devastating parasitic diseases in the world. Its pathogenesis is still not clearly understood, although there are indications that several factors between the parasites, the host, and the environment may be involved. In malaria-endemic regions, Plasmodium falciparum infection is characterized by extensive genetic diversity. Describing this diversity provides important information about the local epidemiology of malaria and is crucial for understanding the parasite population structure and virulence, and for evaluating the impact of malaria control measures. The objective of this study was to characterize the genetic diversity of P. falciparum isolates in children with severe malaria by using polymerase chain reaction (PCR) genotyping of the highly polymorphic merozoite surface protein 2 (MSP-2) gene as a molecular marker. Methods: One hundred and sixteen children who presented with symptoms of severe malaria and who had microscopically confirmed P. falciparum monoinfection were enrolled in the study after they satisfied the inclusion criteria. Parasite DNA was extracted from the blood spot on to filter paper and analyzed by genotyping the MSP-2 gene using allele-specific nested PCR. Results: Twenty-six distinct MSP-2 alleles (13 FC27 alleles and 13 3D7 alleles) were detected in the study population. However, isolates of the 3D7 alleles were predominant in the population (55%), compared to isolates of the FC27 alleles (45%). However, this difference was not statistically significant. The multiplicity of infection (MOI) by P. falciparum was 1.3. Most isolates (66%) were monoclonal infections with one distinguishable clone per infected child. Conclusion: The present data suggest a low complexity of P. falciparum infection in isolates of individuals with severe malaria in the study population. The data also show that most infections were monoclonal. Furthermore, no specific genotype was associated with severe malaria in this study. [Copyright &y& Elsevier]

Abstract: Objective: The authors had for aim to evaluate diagnosis and treatment practices applied to children with clinically suspected severe malaria, in two referral hospitals of Kisangani. Patients and methods: A prospective study was carried out between January 1, 2010 and February 28, 2011 including all children admitted for clinically suspected severe malaria, with at least one of the WHO severity criteria. Results: One thousand one hundred and fifty-four children were admitted in the two hospitals, 427 (37.0%, n =1.154) for clinically suspected severe malaria: 155 (36.3%, n =427) had a positive thick drop examination (TDE), 198 (46.4%, n =427) a negative one, and 74 (17.3%, n =427) without thick blood smear examination. Prostration (48.0%) and anemia (40.3%) were the most common severity criteria, while 14.5% and 9.8% presented with convulsions and impaired consciousness respectively. The etiological treatment was quinine infusion. The case specific fatality rate was 19.4% (n =427), 7.7% (n =155) in confirmed cases, 9.6% (n =198) in patients with negative thick blood smear, and 70.3% (n =74) in patients without any TDE (P <0.001). Conclusion: Poor technical support and inadequate organization of the patient circuit can result in underestimating the metabolic complications of severe malaria and of other severe infections of early childhood. This is detrimental to the patients, even when effective drugs are available. [Copyright &y& Elsevier]

Abstract: Objectives: To identify independent risk factors of severe falciparum malaria among travelers to endemic regions. Materials and methods: A retrospective study on imported malaria into metropolitan France. The World''s Health Organization severity criteria were used to classify malarial episodes. Results: Nine hundred and twenty-one malarial cases were studied; 81 were severe. Independent risk factors of severe malaria were aged above 40 years, high level of parasitized erythrocytes (more than 4%), parasite acquisition in the south-eastern asian region, infection with a chloroquine resistant Plasmodium falciparum (P. falciparum) phenotype and a self administered antimalarial treatment. Conclusion: This study points out two particularly interesting results: severe malaria is significantly associated with the infection by a chloroquine resistant P. falciparum phenotype and with the parasite''s acquisition in the south-eastern asian region. [Copyright &y& Elsevier]

Summary: Plasmodium vivax (Pv) malaria is being increasingly recognized as a cause of severe malaria in children. Objectives: To describe the various severe manifestations associated with vivax malaria by retrospective analysis of records. Methods: Children between the ages of 0 and 18 years with a confirmed diagnosis of Pv malaria monoinfection done by peripheral blood film (PBF) and/or rapid diagnostic test (RDT) admitted between June and September 2009 were included. Their clinical, hematological and biochemical manifestations were analyzed. Results: Twenty-three patients of Pv malaria were retrospectively analyzed. Thrombocytopenia was present in 22 (96%) patients with counts less than 50,000/μL in 9 patients. Severe anemia (hgb<5mg/dl) was present in 8 (34%) patients. Cerebral malaria was present in 3 patients. Liver enzymes were elevated (>3 times normal) in 4 (17.3%) patients while jaundice (bilirubin>2.5mg/dl) was present in 2 patients (total bilirubin 5.2mg/dl and 14.3mg/dl). Renal dysfunction (creatinine>3mg/dl) was present in 6 (26%) patients with 2 patients showing severely deranged renal functions (blood urea 168mg/dl, 222mg/dl and serum creatinine 5.0mg/dl, 5.6mg/dl, respectively). Hypernatremia was present in one patient. One patient expired within 12h of presentation because of severely deranged hepatic and renal dysfunction. Conclusion: Pv malaria can lead to unusual and fatal complications. All new guidelines should include “Severe Vivax malaria” as a clinical entity. Further research into the etiopathogenesis and treatment would be important. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Despite the high prevalence of Plasmodium vivax (P vivax) malaria, research into its complications has lagged disproportionately as compared to Plasmodium falciparum (P falciparum) malaria. Material and methods: The present retrospective observational study was conducted on cases with P vivax mono-infection presenting with severe malaria on the basis of one or more criteria as per the World Health Organization guidelines being used for severe falciparum malaria in children, as well as other manifestations been classified as complicated malaria, during an outbreak of malaria in a single tertiary referral hospital of north India. Results: Seventy-four patients of acute malaria presented during the outbreak, of which 50 cases with P vivax mono-infection were included for the study. Complicated malaria was diagnosed in 41/50 cases, with thrombocytopenia being the commonest manifestation. Other presentations of severe malaria in our patients were liver dysfunction (with or without jaundice) 31/50 cases, respiratory involvement 14/50 cases, renal impairment 11/50 cases, circulatory collapse (Shock) 8/50 cases, severe anaemia 3/50 cases and central nervous system (CNS) involvement 2/50 cases. Conclusion: The term “benign tertian malaria” no longer holds true for P vivax mono-infection. The authors wish to open a new front for researches on the possible genotypic abnormalities that the parasite or its carrier might have acquired over decades and has transformed into a species with the malignant potential of P falciparum. [ABSTRACT FROM AUTHOR]

Severe malaria is a major cause of mortality in children, but comprises only a small proportion of Plasmodium falciparum infections in naturally exposed populations. The evaluation of vaccines that prevent severe falciparum disease will require clinical trials whose primary efficacy endpoint will be severe malaria risk during follow-up. Here, we show that such trials are feasible with fewer than 1000 participants in areas with intense malaria transmission during the age interval when severe malaria incidence peaks. [ABSTRACT FROM AUTHOR]

Abstract: Objective: To investigate the possible impact of soil-transmitted helminth (STH) infection on malaria severity, level of parasitaemia and clearance/reduction of Plasmodium parasites following treatment with anti-malarial drugs. Methods: 458 voluntary malaria patients who visited the Alaba Kulito Health Center, southern Ethiopia, for medical treatment in November and December 2007 were included in this study. Giemsa-stained thick and thin blood films were used for the determination of parasitaemia and identification of Plasmodium species, respectively. Stool sample was collected from these patients and diagnosed for intestinal helminths using Kato-Katz technique. Haemoglobin concentration was measured using a portable spectrophotometer (HemoCue HB 201). Malaria parasite clearance was checked on day 3 post-treatment. Findings: The prevalence of co-infection of malaria with the major soil-transmitted helminths (STHs), i.e., with hookworm species, Ascaris lumbricoides and Trichuris trichiura was 9.6%, 6.3% and 2.1%, respectively. About 8.1% of the study subjects had severe malaria. Intensity of hookworm infection showed positive association with malaria parasite densities (F =3.510, P =0.033). STHs infection in general was negatively correlated with the symptoms of severe malaria (OR=0.317, 95% CI=0.315–0.86, P =0.01), but a small proportion (4.5%) of malaria patients who were concurrently harboring one or more intestinal helminths had severe malaria. Only few malaria patients (2.3%) co-infected with STHs were found positive for Plasmodium parasites on day 3 post-treatment. Conclusion: The present findings indicate that soil-transmitted helminths have very little contribution to malaria severity in co-infected individuals. The findings also indicate that STHs do not have significant impact on clearance rate of Plasmodium falciparum and Plasmodium vivax when treated with anti-malarial drugs. [Copyright &y& Elsevier]

Abstract: The capacity of Plasmodium falciparum-infected red blood cells to bind uninfected red blood cells (“rosetting”) has been associated with high parasite density in numerous geographic areas and with severe malaria in African children. We summarize here the associations that have emerged from field studies and describe the various experimental models of rosetting that have been developed. A variety of erythrocyte receptors, several serum factors and a number of rosette-mediating PfEMP1 adhesins have been identified. Several var genes code for rosette-forming PfEMP1 adhesins in each P. falciparum genome, so that each clonal line has the capacity to generate distinct types of rosettes. To clarify their respective role in malaria pathogenesis, each of the multiple ligand/receptor interactions should be further studied for fine specificity, binding affinity and the impact of the large population polymorphism of the parasite variant repertoires should be assessed. Interestingly, some major human erythrocyte surface polymorphisms have been identified as affecting rosette formation, consistent with a role for rosetting in life-threatening falciparum malaria. [Copyright &y& Elsevier]

Abstract: T cells are thought to play a critical role in cerebral malaria pathogenesis. However, available evidences are restricted to rodent models in which Vβ specific T cell expansion has been associated with neurological syndrome suggesting involvement of superantigens or dominant antigens. Using flow cytometry, we studied the peripheral VβT cell repertoire of Ghanaian children with cerebral malaria, uncomplicated malaria and asymptomatic control children, to look for either expansion or deletion of specific Vβ associated with cerebral malaria. At admission, the general pattern of the repertoire of the patients was very similar, with no major distortion compared to the control group a part a significant increase of the frequency of the Vβ21.3 subset correlating with disease severity and attributed to the CD4 subset. During convalescence very limited fluctuations were observed including a significant decrease of the Vβ21.3 subset and increase of the Vβ20 subset, a subset not detected at admission. The remarkable stability of the Vβ repertoire observed in acute malaria either cerebral or uncomplicated argues against the idea that cerebral malaria would result from a T cell-mediated inflammatory shock syndrome driven by some dominant super-antigenic activity(ies). The significance of the reproducible increase of the CD4+Vβ21.3T cell subset deserves further investigations. [Copyright &y& Elsevier]

Abstract: Severe malaria is associated with sequestration of Plasmodium falciparum-infected red blood cells (PRBC) in the microvasculature and elevation of intercellular adhesion molecule-1 (ICAM-1) and TNF. In vitro co-culture of human umbilical vein endothelial cells (HUVEC), with either PRBC or uninfected RBC, required the presence of low level TNF (5pg/ml) for significant up-regulation of ICAM-1, which may contribute to increased cytoadhesion in vivo. These effects were independent of P. falciparum erythrocyte membrane protein-1 (PfEMP-1)-mediated adhesion but critically dependent on cell–cell contact. Further changes included increases in IL8 release and soluble TNF receptor shedding. Microarray analysis of HUVEC transcriptome following co-culture, using a human Affymetrix microarray chip, showed significant differential regulation of genes which defined gene ontologies such as cell communication, cell adhesion, signal transduction and immune response. Our data demonstrate that endothelial cells have the ability to mobilise immune and pro-adhesive responses when exposed to both PRBC and TNF. In addition, there is also a previously un-described positive regulation by RBC and TNF and a concurrent negative regulation of a range of genes involved in inflammation and cell-death, by PRBC and TNF. We propose that the balance between positive and negative regulation demonstrated in our study will determine endothelial pathology during a malaria infection. [Copyright &y& Elsevier]

Abstract: Plasma levels of three soluble inducible adhesion molecules, namely: intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and endothelial leucocyte adhesion molecule-1 (sELAM-1) or sE-selectin and the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNF-α) were measured in well-defined clinical groups of children with severe and uncomplicated malaria. The goal of the study was to investigate the role of these molecules in immunopathogenic processes associated with severe malaria in Cameroonian children. Results showed significantly increased plasma concentrations of sICAM-1, sVCAM-1 and sE-selectin in children with severe malaria compared to those with uncomplicated malaria and healthy children (P <0.001). TNF-α levels increased significantly in children with severe malaria, approximately 2-folds compared to those with uncomplicated malaria and about 3-folds compared to healthy children (P <0.001). More importantly, levels of TNF-α strongly correlated with those of the three adhesion molecules and were significantly associated with increased risk of death (P =0.03). In addition, children who died from severe malaria showed higher mean levels of all measured factors compared to those who recovered, with significant differences observed with sICAM-1 (P <0.001) and sE-selectin (P =0.002). Furthermore, children with severe malarial anemia relative to those without, showed significantly elevated levels of the three soluble molecules; and sICAM-1 was significantly associated with increased risk of severe anemia. Taken together, these results confirm the role of TNF-α and the three adhesion molecules in pathogenic processes associated with severe malaria in children, and suggest an association between sICAM-1 and severe malarial anemia. [Copyright &y& Elsevier]

Abstract: Introduction: We report a retrospective study in the medical intensive care unit of the Casablanca Ibn-Rochd University hospital. Material and methods: All patients over 14 years of age with falciparum malaria, who were admitted to ICUs between 1996 and 2001, were included. The main epidemiological features, criteria of admission, treatment, and outcome were investigated. Results: Ten patients were included for severe imported malaria. The mean age was 32±4 years. All patients had acquired falciparum malaria in sub-Saharan Africa. Chemoprophylaxis was inadequate in all patients. The mean time from symptom onset to treatment initiation was 9±2 days. Criteria of admission were impaired consciousness (7), acute renal failure (4), and respiratory distress (3). The most worrying factors were the severity of consciousness disorders, the acute respiratory distress syndrome, the metabolic acidosis, and the refractory shock. All patients presented with nosocomial respiratory infection related to Gram-negative bacilli, in the evolution. All patients received quinine therapy with loading dose and symptomatic treatment. Five patients died. Conclusion: The lethality of severe imported malaria is still high despite optimal management in ICUs. Improving chemoprophylaxis and an earlier diagnosis may reduce significantly the mortality rate. [Copyright &y& Elsevier]

Summary: 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 24h, 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. [Copyright &y& Elsevier]

Abstract: Severe malaria is characterized by the presence of asexual forms of Plasmodium falciparum in the blood and the presence of one or more OMS 2000 criterion. Imported malaria is defined as malarial infection acquired in an endemic country (often in sub-Saharan Africa) and treated in France. The largest patient group includes African patients, long-term residents in France, coming back from a vacation in their native country. In non-immunized adults, severe malaria causes multiple organe failure such as severe Gram-negative sepsis, with variable degrees of altered mental status. Severe sepsis is treated in an intensive care unit (mechanically assisted ventilation, kidney dialysis, vasoconstrictors…). Intravenous quinine is the reference treatment, but artemisinin derivatives (arthemeter and artesunate) are the most rapidly acting antmalarial drugs. [Copyright &y& Elsevier]