Chronic Malaria Is Associated With Trauma-related Splenic Rupture Requiring Splenectomy.

Plasmodium falciparum and Plasmodium vivax are co-endemic in the Asia-Pacific region. Their capacity to induce and sustain diverse T-cell responses underpins protective immunity. We compared T-cell responses to the largely conserved merozoite surface protein-5 (PfMSP5) during acute and convalescent falciparum and vivax malaria. Lymphoproliferation and IFN--γ secretion to PfMSP5 and purified protein derivate were quantified in adults with falciparum (n=34), and vivax malaria (n=12) or asymptomatic residents (n=10) of Papua, Indonesia. Responses were reassessed 7-28 days following treatment. The frequency of IFN-γ responders to PfMSP5 was similar in acute falciparum (63%) or vivax (67%) malaria. However, significantly more IFN-γ-secreting cells were detectable during vivax compared with falciparum infection. Purified protein derivative responses showed a similarly enhanced pattern. While rapidly lost in vivax patients, PfMSP5-specific responses in falciparum malaria remained to day 28. By contrast, frequency and magnitude of lymphoproliferation to PfMSP5 were similar for falciparum and vivax infections. Cellular PfMSP5-specific responses are most frequent during either acute falciparum or vivax malaria, indicating functional T-cell responses to conserved antigens. Both effector and central memory T-cell functions are increased. Greater IFN-γ responses in acute P. vivax, suggest enhancement of pre-existing effector T-cells during acute vivax infection.

BackgroundOxylipins and endocannabinoids are low molecular weight bioactive lipids that are crucial for initiation and resolution of inflammation during microbial infections. Metabolic complications in malaria are recognized contributors to severe and fatal malaria, but the impact of malaria infection on the production of small lipid derived signalling molecules is unknown. Knowledge of immunoregulatory patterns of these molecules in malaria is of great value for better understanding of the disease and improvement of treatment regimes, since the action of these classes of molecules is directly connected to the inflammatory response of the organism.MethodsDetection of oxylipins and endocannabinoids from plasma samples from forty children with uncomplicated and severe malaria as well as twenty controls was done after solid phase extraction followed by chromatography mass spectrometry analysis. The stable isotope dilution method was used for compound quantification. Data analysis was done with multivariate (principal component analysis (PCA), orthogonal partial least squares discriminant analysis (OPLS-DA®) and univariate approaches (receiver operating characteristic (ROC) curves, t tests, correlation analysis).ResultsForty different oxylipin and thirteen endocannabinoid metabolites were detected in the studied samples, with one oxylipin (thromboxane B2, TXB2) in significantly lower levels and four endocannabinoids (OEA, PEA, DEA and EPEA) at significantly higher levels in infected individuals as compared to controls according to t test analysis with Bonferroni correction. Three oxylipins (13-HODE, 9-HODE and 13-oxo-ODE) were higher in severe compared to uncomplicated malaria cases according to the results from multivariate analysis. Observed changes in oxylipin levels can be connected to activation of cytochrome P450 (CYP) and 5-lipoxygenase (5-LOX) metabolic pathways in malaria infected individuals compared to controls, and related to increased levels of all linoleic acid oxylipins in severe patients compared to uncomplicated ones. The endocannabinoids were extremely responsive to malaria infection with majority of this class of molecules found at higher levels in infected individuals compared to controls.ConclusionsIt was possible to detect oxylipin and endocannabinoid molecules that can be potential biomarkers for differentiation between malaria infected individuals and controls and between different classes of malaria. Metabolic pathways that could be targeted towards an adjunctive therapy in the treatment of malaria were also pinpointed.

Two black African immigrants, with no history of recent travel outside France, received a diagnosis of a malignant lymphoproliferative disorder and splenomegaly, and they subsequently underwent splenectomy. A few weeks after surgery, both patients experienced an acute episode of Plasmodium falciparum malaria, so the initial diagnosis was corrected retrospectively and changed to hyperreactive malarial splenomegaly. These cases illustrate the difficulty in distinguishing hyperreactive malarial splenomegaly from malignant lymphoproliferative disorders and therefore underline the role of the spleen in the immune system's defense against malaria.

An open-label, randomized controlled trial was carried out in 2011–2012 in the Democratic Republic of the Congo to test the efficacy, safety, and tolerability of the artemisinin-based combination treatments dihydroartemisinin-piperaquine, amodiaquine-artesunate, and artemether-lumefantrine. Six hundred eighty-four children aged 3 to 59 months with uncomplicated Plasmodium falciparum malaria were randomly allocated to each study arm. Children were hospitalized for 3 days, given supervised treatment, and followed up weekly for 42 days. All regimens were well tolerated and rapidly effective. The median parasitemia clearance half-life was 2.2 h, and half-lives were similar between arms (P = 0.19). The PCR-uncorrected cure rates by day 42 were 73.0% for amodiaquine-artesunate, 70.2% for artemether-lumefantrine, and 86.3% for dihydroartemisinin-piperaquine (P = 0.001). Early treatment failure occurred in three patients (0.5%), one in each arm. The PCR-corrected cure rates were 93.4% for amodiaquine-artesunate, 92.7% for artemether-lumefantrine, and 94.3% for dihydroartemisinin-piperaquine (P = 0.78). The last provided a longer posttreatment prophylactic effect than did the other two treatments. The day 7 plasma concentration of piperaquine was below 30 ng/ml in 47% of the children treated with dihydroartemisinin-piperaquine, and the day 7 lumefantrine concentration was below 280 ng/ml in 37.0% of children who received artemether-lumefantrine. Thus, although cure rates were all satisfactory, they could be improved by increasing the dose. (This study has been registered with the International Standard Randomized Controlled Trial Number Register [www.isrctn.org] under registration no. ISRCTN20984426.)

Background: The high prevalence of uncomplicated malaria as seen in this study suggests the importance of timely diagnosis and effective treatment and encourages new activities to further decrease complicated malaria cases.Methods: In this study, malaria was diagnosed by conventional thick and thin peripheral smear stained with Leishman stain, examined under oil immersion. The slide was considered negative when there were no parasites in 100 HPF. Rapid diagnostic tests were based on detection of specific plasmodium antigen, LDH (optimal test) for Vivax and HRP2 for falciparum. The mode of presentations like fever, splenomegaly, vomiting, abdominal pain, laboratory investigations and complications were noted. Simple malaria was defined as Plasmodium vivax or Plasmodium falciparum malaria without any complications. All the statistical analysis was done by using SPSS 16 version and in MS Excel. Qualitative variables were expressed as frequencies and percentages. Chi-square was used for examining the categorical data.Results: A total 100 cases of malaria diagnosed by rapid diagnostic test and/or peripheral smear were studied. 69% of the cases were falciparum malaria and 31% of the cases were vivax malaria. Males were more commonly affected than females. Vivax malaria was most common between 5-10 years of age and falciparum malaria was more common in 0-5 years of age. Uncomplicated malaria was seen in 73% of the cases and complicated malaria was seen in 27% of the cases. Incidence of complicated malaria was more common in case of falciparum malaria. Fever, pallor, hepatomegaly and splenomegaly were significant for clinical diagnosis of malaria. Severe anaemia was the most common presentation of complicated malaria followed by jaundice. Cerebral malaria was more common in case of falciparum malaria. Metabolic acidosis and renal failure were more common in falciparum malaria. Hypoglycemia, significant bleeding and shock were more common in falciparum malaria. ARDS was most common in vivax malaria.Conclusions: This study emphasizes the importance of severity of P. Vivax malaria and recommends further studies to establish mortality and severity predictors specific to it.

Inflammation and monocytes are thought to be important to human malaria pathogenesis. However, the relationship of inflammation and various monocyte functions to acute malaria, recovery from acute malaria, and asymptomatic parasitemia in endemic populations is poorly understood. We evaluated plasma cytokine levels, monocyte subsets, monocyte functional responses, and monocyte inflammatory transcriptional profiles of 1- to 10-year-old Kenyan children at the time of presentation with acute uncomplicated malaria and at recovery 6 weeks later; these results were compared with analogous data from asymptomatic children and adults in the same community. Acute malaria was marked by elevated levels of proinflammatory and regulatory cytokines and expansion of the inflammatory "intermediate" monocyte subset that returned to levels of healthy asymptomatic children 6 weeks later. Monocytes displayed activated phenotypes during acute malaria, with changes in surface expression of markers important to innate and adaptive immunity. Functionally, acute malaria monocytes and monocytes from asymptomatic infected children had impaired phagocytosis of P. falciparum-infected erythrocytes relative to asymptomatic children with no blood-stage infection. Monocytes from both acute malaria and recovery time points displayed strong and equivalent cytokine responsiveness to innate immune agonists that were independent of infection status. Monocyte transcriptional profiles revealed regulated and balanced proinflammatory and antiinflammatory and altered phagocytosis gene expression patterns distinct from malaria-naive monocytes. These observations provide insights into monocyte functions and the innate immune response during uncomplicated malaria and suggest that asymptomatic parasitemia in children is not clinically benign. Support for this work was provided by NIH/National Institute of Allergy and Infectious Diseases (R01AI095192-05), the Burroughs Wellcome Fund/American Society of Tropical Medicine and Hygiene, and the Rainbow Babies & Children's Foundation.

Presence of pro-oxidants in plasma of patients suffering from falciparum malaria

Systems analysis shows a role of cytophilic antibodies in shaping innate tolerance to malaria

The relationship between glucose production and plasma glucose concentration in children with falciparum malaria

The splenic complications of acute malaria include two different prognostic and treatment entities: splenic infarction and splenic rupture. This is the first case of splenic infarction during an acute malaria due to Plasmodium ovale in a 34-year-old man. As in the majority other described cases of splenic infarction, the course was spontaneously favourable, suggesting that this complication was relatively benign compared to splenic rupture, which is life-threatening and usually necessitating surgery.

In vivo and in vitro gametocyte production of Plasmodium falciparum isolates from Northern Thailand

CEREBRAL ring hemorrhages are seen in a variety of diseases, such as fat embolism, laceration of the brain, acute Plasmodium falciparum malaria, postvaccinial and parainfectious encephalitides, pernicious anemia, aplastic anemia and leukemia, and intoxications (barbiturates, neoarsphenamine, arsphenamine), as reviewed by Kirschbaum,1Dietrich,2Weimann,3Lindau,4Durck,5Wolff,6Winblad,7Sjovall,8and others. These hemorrhages may occur in such large numbers throughout the white matter that the hemorrhagic tendency is considered one of the important features of the disease process. This justifies the use of the term brain purpura (Schmidt9), acute hemorrhagic leucoencephalitis (Alexander and Putnam,10Hurst,11Henson and Russell12), and acute necrotizing hemorrhagic encephalopathy (Adams, Cammermeyer, and Denny-Brown13). The effusions of blood are thought to take place in diseases in which the nerves to the vessels have been paralyzed and stasis has thereby been furthered, with diapedesis hemorrhages, as

Objective: To evaluate the comparative efficacy of amodiaquine (AMQ) alone and the combination of AMQ and chlorpheniramine (CP) in the treatment of acute uncomplicated malaria in children. Subjects: Of the 110 children enrolled in the study, 103 with acute uncomplicated malaria, aged 6 months to 12 years, were evaluated using the 14-day modification of the WHO field test. The patients were randomized to 2 groups. Group 1 received supervised treatment with AMQ alone (10 mg AMQ base/kg daily for 3 days), while group 2 received supervised treatment with AMQ (same dose as group 1) plus CP (AMQCP) for 7 days. Results: Both treatment regimens were well tolerated and no patient was withdrawn as a result of recurrent vomiting or drug-related adverse events. There was no significant difference in mean fever and parasite clearance times. The cure rates at day 7 were 90.2 versus 100% (ρ = 0.027) for AMQ versus AMQCP, while the day 14 cure rates were 85.9 versus 98.1% for AMQ versus AMQCP, respectively (ρ = 0.016). Conclusion: The combination of AMQ plus CP proved significantly more effective than AMQ alone in the treatment of acute uncomplicated falciparum malaria, most probably due to the enhancement of the antimalarial effect of AMQ by CP. The combination of AMQCP could be a better alternative to AMQ alone as a companion drug in artemisinin-based combination therapies.

Granulocyte colony-stimulating factor (G-CSF)-mobilized blood stem cells may become the preferable source of hematopoietic stem cells (HSCs) for gene therapy because of the higher yield of cells compared with conventional bone marrow harvesting. A G-CSF-associated risk of splenic rupture has been recognized in normal donors of HSCs, but limited information is available about the G-CSF effect in the presence of splenomegaly and extramedullary hematopoiesis. We investigated the G-CSF effect in a thalassemic mouse model (HBB(th-3)) as compared with a normal strain (C57BL/6), in terms of safety, mobilization efficacy, and distribution of stem cells among hematopoietic compartments. There was no death or clinical sequelae of splenic rupture in G-CSF-treated animals of either strain; however, hemorrhagic infarcts in the spleen were detected with low frequency in G-CSF-treated HBB(th-3) mice (12.5%). HBB(th-3) mice mobilized less effectively than C57BL/6 mice (Lin(-)Sca-1(+)c-Kit(+) cells/microl of peripheral blood mononuclear cells [PBMCs]: 90 +/- 55 vs. 255 +/- 174, respectively, p = 0.01; CFU-GM/ml PBMCs: 390 +/- 262 vs. 1131 +/- 875, p = 0.01) because of increased splenic trapping of hematopoietic stem and progenitor cells (Lin(-)Sca-1(+)c-Kit(+) cells per spleen (x10(5)): 487 +/- 35 vs. 109 +/- 19.6, p = 0.01; CFU-GM per spleen (x10(2)): 1470 +/- 347 vs. 530 +/- 425, p = 0.0006). Splenectomy restored the mobilization proficiency of thalassemic mice at comparable levels to normal mice and resulted in the development of a hematopoietic compensatory mechanism in the thalassemic liver that protected splenectomized mice from severe anemia. Our data imply that, in view of human gene therapy for thalassemia, either multiple cycles or alternative ways of mobilization may be required for a sufficient yield of transplantable HSCs. In addition, strategies to minimize the risk of G-CSF-induced splenic infarcts should be explored in a clinical setting.

Forty splenic infarcts in 23 patients were examined with ultrasound (US). At clinical presentation, splenic infarction was associated with severe left upper quadrant pain (n = 10) or diffuse abdominal pain (n = 4) or was asymptomatic (n = 9). In this retrospective study, predominantly wedge-shaped (n = 17) or round (n = 23), irregularly delineated (n = 33) or smooth (n = 7), hypoechoic (n = 40) and anechoic (n = 5) lesions were found at first examination. During follow-up observation, four patients died because of complications unrelated to infarct, and five patients underwent splenectomy as a consequence of US findings. Expanding intralienal liquefaction, increasing subcapsular hemorrhage, free peritoneal blood (even in spleens shown to have an intact surface at sonography), and flow phenomena in the area of infarction demonstrated at B-mode pulsed Doppler US were identified as infarct-related complications associated with the risk of splenic rupture. Despite the high self-healing tendency in splenic infarction, short-term follow-up with US is recommended for early recognition of these possible complications.