losartan-potassium and Malaria--Falciparum

Despite optimal antimalarial treatment and advances in malaria eradication, the mortality rate associated with severe malaria due to Plasmodium falciparum infection, including cerebral malaria (CM), remains unacceptably high. This suggests that strategies directed solely at parasite eradication may be insufficient to prevent neurological complications and death in all cases of CM. Therefore, there is an urgent need to develop innovative adjunctive therapeutic strategies to effectively reduce CM-associated mortality. CM pathogenesis is believed to be due, in part, to an aberrant host immune response to P. falciparum, resulting in deleterious consequences, including vascular activation and dysfunction. Development of effective and affordable therapeutic strategies that act to modulate the underlying host-mediated immunopathology should be explored to improve outcome. In this article, we summarize immunomodulatory therapies that have been assessed in clinical trials to date, and highlight novel and promising treatment strategies currently being investigated to address this major global health challenge.

Topics: Africa; Antimalarials; Arginine; Clinical Trials as Topic; Dexamethasone; Epidemiologic Studies; Erythropoietin; Humans; Immunomodulation; Inflammation; Levamisole; Malaria, Cerebral; Malaria, Falciparum; Nitric Oxide; Plasmodium falciparum; PPAR gamma; Rosiglitazone; Thiazolidinediones

Severe malaria due to Plasmodium falciparum causes more than 800,000 deaths every year. Primary therapy with quinine or artesunate is generally effective in controlling P. falciparum parasitemia, but mortality from cerebral malaria and other forms of severe malaria remains unacceptably high. Long-term cognitive impairment is also common in children with cerebral malaria. Of the numerous adjunctive therapies for cerebral malaria and severe malaria studied over the past five decades, only one (albumin) was associated with a reduction in mortality. In this article, we review past and ongoing studies of adjunctive therapy, and examine the evidence of efficacy for newer therapies, including inhibitors of cytoadherence (e.g., levamisole), immune modulators (e.g., rosiglitazone), agents that increase nitric oxide levels (e.g., arginine) and neuroprotective agents (e.g., erythropoietin).

Topics: Antimalarials; Arginine; Erythropoietin; Humans; Levamisole; Malaria, Cerebral; Malaria, Falciparum; Plasmodium falciparum; Randomized Controlled Trials as Topic; Rosiglitazone; Thiazolidinediones

Anemia is a common and serious complication of malaria due to Plasmodium falciparum infection, a major health problem in tropical areas. Herein, the relation was investigated between the levels of circulating erythropoietin (EPO) and immunomodulatory cytokines in response to chloroquine treatment. Thirty-seven healthy control subjects and 40 patients with acute P. falciparum infection were included in the study. All subjects were adult male Sudanese. Blood samples were collected before chloroquine administration (25 mg/kg body weight, orally on three consecutive days) and 3 and 30 days after start of the therapy. Measurements included routine hematological parameters and the concentrations of immunoreactive EPO, tumor necrosis factor-alpha (TNF-alpha), interleukin 1alpha (IL-1), IL-6, and interferon gamma (INF-gamma). Chloroquine treatment led to a decrease in EPO levels in the control subjects but an increase in malaria patients at day 30. The latter was likely due to the anti-inflammatory action of the drug because INF-gamma, IL-1, and IL-6 concentrations declined on chloroquine treatment. Based on these findings, we propose that an impaired EPO production in association with a prolonged elevation of certain inflammatory cytokines can contribute to the anemia in some malaria patients which can be reversed by chloroquine therapy.

Topics: Adult; Case-Control Studies; Chloroquine; Cytokines; Erythropoietin; Humans; Immunologic Factors; Interferon-gamma; Interleukin-1; Interleukin-6; Malaria, Falciparum; Male; Sudan

Malarial anemia is associated with a shift in iron distribution from functional to storage compartments. This suggests a relative deficit in erythropoietin production or action similar to that observed in other infections. Our study in Kenyan children with asymptomatic malaria aimed at investigating whether malaria causes increased erythropoiesis, and whether the erythropoietic response appeared appropriate for the degree of resulting anemia. Longitudinal and baseline data were used from a trial with a 2 x 2 factorial design, in which 328 anemic Kenyan children were randomly assigned to receive either iron or placebo, and sulfadoxine-pyrimethamine or placebo. Erythropoiesis was evaluated by serum concentrations of erythropoietin and soluble transferrin receptor. Prospectively collected data showed that malarial infection resulted in decreased hemoglobin concentrations, and increased serum concentrations of erythropoietin and transferrin receptor. Conversely, disappearance of malarial antigenemia resulted in increased hemoglobin concentrations, and decreased concentrations of these serum indicators. Additionally, our baseline data showed that current or recent malarial infection is associated with increased serum concentrations of erythropoietin and transferrin receptor, and that these were as high as or perhaps even higher than values of children without malarial infection and without inflammation. Our findings indicate that in asymptomatic malaria, the erythropoietic response is adequate for the degree of anemia, and that inflammation probably plays no or only a minor role in the pathogenesis of the resulting anemia. Further research is needed to demonstrate the role of deficient erythropoietin production or action in the pathogenesis of the anemia of symptomatic malaria.

Topics: Adaptation, Physiological; Anemia, Iron-Deficiency; Child, Preschool; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Iron; Kenya; Longitudinal Studies; Malaria, Falciparum; Receptors, Transferrin

Anaemia in pregnancy is common in underdeveloped countries, and malaria remains the predominant cause of the condition in Ghana. Anti-erythropoietin (anti-EPO) antibody production may be implicated in the pathogenesis of Plasmodium falciparum malaria-related anaemia in pregnancy. This study ascertained the prevalence of anti-EPO antibody production and evaluated the antibodies' relationship with Plasmodium falciparum malaria and malaria-related anaemia in pregnancy.. This hospital-based case-control study recruited a total of 85 pregnant women (55 with Plasmodium falciparum malaria and 30 controls without malaria). Venous blood was taken from participants for thick and thin blood films for malaria parasite microscopy. Complete blood count (CBC) analyses were done using an automated haematology analyzer. Sandwich enzyme-linked immunosorbent assay (ELISA) was used to assess serum erythropoietin (EPO) levels and anti-EPO antibodies. Data were analyzed using IBM SPSS version 22.0.. Haemoglobin (p<0.001), RBC (p<0.001), HCT (p = 0.006) and platelet (p<0.001) were significantly lower among pregnant women infected with Plasmodium falciparum. Of the 85 participants, five (5.9%) had anti-EPO antibodies in their sera, and the prevalence of anti-EPO antibody production among the Plasmodium falciparum-infected pregnant women was 9.1%. Plasmodium falciparum-infected pregnant women with anti-EPO antibodies had lower Hb (p<0.001), RBC (p<0.001), and HCT (p<0.001), but higher EPO levels (p<0.001). Younger age (p = 0.013) and high parasite density (p = 0.004) were significantly associated with Plasmodium falciparum-related anti-EPO antibodies production in pregnancy. Also, younger age (p = 0.039) and anti-EPO antibody production (p = 0.012) related to the development of Plasmodium falciparum malaria anaemia in pregnancy.. The prevalence of anti-EPO antibodies among pregnant women with Plasmodium falciparum malaria was high. Plasmodium falciparum parasite density and younger age could stimulate the production of anti-EPO antibodies, and the antibodies may contribute to the development of malarial anaemia in pregnancy. Screening for anti-EPO antibodies should be considered in pregnant women with P. falciparum malaria.

Topics: Anemia; Case-Control Studies; Erythropoietin; Female; Ghana; Humans; Malaria; Malaria, Falciparum; Plasmodium falciparum; Pregnancy; Pregnant Women

Among the severe malaria syndromes, severe malarial anemia (SMA) is the most common, whereas cerebral malaria (CM) is the most lethal. However, the mechanisms that lead to CM and SMA are unclear.. We compared transcriptomic profiles of whole blood obtained from Ugandan children with acute CM (n = 17) or SMA (n = 17) and community children without Plasmodium falciparum infection (n = 12) and determined the relationships among gene expression, hematological indices, and relevant plasma biomarkers.. Both CM and SMA demonstrated predominantly upregulated enrichment of dendritic cell activation, inflammatory/Toll-like receptor/chemokines, and monocyte modules, but downregulated enrichment of lymphocyte modules. Nuclear factor, erythroid 2 like 2 (Nrf2)-regulated genes were overexpressed in children with SMA relative to CM, with the highest expression in children with both SMA and sickle cell disease (HbSS), corresponding with elevated plasma heme oxygenase-1 in this group. Erythroid and reticulocyte-specific signatures were markedly decreased in CM relative to SMA despite higher hemoglobin levels and appropriate increases in erythropoietin. Viral sensing/interferon-regulatory factor 2 module expression and plasma interferon-inducible protein-10/CXCL10 negatively correlated with reticulocyte-specific signatures.. Compared with SMA, CM is associated with downregulation of Nrf2-related and erythropoiesis signatures by whole-blood transcriptomics. Future studies are needed to confirm these findings and assess pathways that may be amenable to interventions to ameliorate CM and SMA.

Topics: Anemia; Anemia, Sickle Cell; Biomarkers; Chemokine CXCL10; Chemokines; Child; Child, Preschool; Dendritic Cells; Down-Regulation; Erythroid Cells; Erythropoiesis; Erythropoietin; Female; Gene Expression Profiling; Gene Expression Regulation; Heme Oxygenase-1; Hemoglobins; Humans; Infant; Interferon Regulatory Factor-2; Malaria, Cerebral; Malaria, Falciparum; Male; Monocytes; NF-E2-Related Factor 2; Plasmodium falciparum; Reticulocytes; Toll-Like Receptors; Transcriptome; Uganda

One of the commonest complications of Plasmodium falciparum malaria is the development of severe malarial anemia (SMA), which is, at least in part, due to malaria-induced suppression of erythropoiesis. Factors associated with suppression of erythropoiesis and development of SMA include accumulation of malarial pigment (hemozoin, PfHz) in bone marrow and altered production of inflammatory mediators, such as tumor necrosis factor (TNF)-α, and nitric oxide (NO). However, studies investigating the specific mechanisms responsible for inhibition of red blood cell development have been hampered by difficulties in obtaining bone marrow aspirates from infants and young children, and the lack of reliable models for examining erythroid development. As such, an in vitro model of erythropoiesis was developed using CD34+ stem cells derived from peripheral blood to examine the effects of PfHz, PfHz-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media (CM-PfHz), TNF-α, and NO on erythroid cell development. PfHz only slightly suppressed erythroid cell proliferation and maturation marked by decreased expression of glycophorin A (GPA). On the other hand, CM-PfHz, TNF-α, and NO significantly inhibited erythroid cell proliferation. Furthermore, decreased proliferation in cells treated with CM-PfHz and NO was accompanied by increased apoptosis of erythropoietin-stimulated CD34+ cells. In addition, NO significantly inhibited erythroid cell maturation, whereas TNF-α did not appear to be detrimental to maturation. Collectively, our results demonstrate that PfHz suppresses erythropoiesis by acting both directly on erythroid cells, and indirectly via inflammatory mediators produced from PfHz-stimulated PBMC, including TNF-α and NO.

Topics: Anemia; Antigens, CD34; Apoptosis; Cell Proliferation; Cells, Cultured; Culture Media, Conditioned; Erythropoiesis; Erythropoietin; Glycophorins; Hematopoietic Stem Cells; Hemeproteins; Humans; Inflammation Mediators; Leukocytes, Mononuclear; Malaria; Malaria, Falciparum; Nitric Oxide; Nitric Oxide Donors; Pigments, Biological; Recombinant Proteins; Tumor Necrosis Factor-alpha

Topics: Adult; Anemia, Iron-Deficiency; Antimalarials; Erythropoietin; Female; Hematocrit; Humans; Malaria, Falciparum; Male; Plasmodium falciparum

Iron deficiency anemia (IDA) affects many young women in sub-Saharan Africa. Its etiology is multifactorial, but the major cause is low dietary iron bioavailability exacerbated by parasitic infections such as malaria.. We investigated whether asymptomatic Plasmodium falciparum parasitemia in Beninese women would impair absorption of dietary iron or utilization of circulating iron.. Iron absorption and utilization from an iron-fortified sorghum-based meal were estimated by using oral and intravenous isotope labels in 23 afebrile women with a positive malaria smear (asexual P. falciparum parasitemia; > 500 parasites/μL blood). The women were studied while infected, treated, and then restudied 10 d after treatment. Iron status, hepcidin, and inflammation indexes were measured before and after treatment.. Treatment reduced low-grade inflammation, as reflected by decreases in serum ferritin, C-reactive protein, interleukin-6, interleukin-8, and interleukin-10 (P < 0.05); this was accompanied by a reduction in median serum hepcidin of ≈ 50%, from 2.7 to 1.4 nmol/L (P < 0.005). Treatment decreased serum erythropoietin and growth differentiation factor 15 (P < 0.05). Clearance of parasitemia increased geometric mean dietary iron absorption (from 10.2% to 17.6%; P = 0.008) but did not affect systemic iron utilization (85.0% compared with 83.1%; NS).. Dietary iron absorption is reduced by ≈ 40% in asymptomatic P. falciparum parasitemia, likely because of low-grade inflammation and its modulation of circulating hepcidin. Because asymptomatic parasitemia has a protracted course and is very common in malarial areas, this effect may contribute to IDA and blunt the efficacy of iron supplementation and fortification programs. This trial was registered at clinicaltrials.gov as NCT01108939.

Topics: Adolescent; Adult; Anemia, Iron-Deficiency; Antimicrobial Cationic Peptides; Benin; Erythropoietin; Female; Ferritins; Food, Fortified; Growth Differentiation Factor 15; Hepcidins; Humans; Inflammation; Inflammation Mediators; Intestinal Absorption; Iron, Dietary; Isotope Labeling; Malaria, Falciparum; Parasitemia; Plasmodium falciparum; Sorghum; Young Adult

Facilitation of endogenous neuroprotective pathways, such as the erythropoietin (Epo) pathway, has been proposed as adjuvant treatment strategies in cerebral malaria. Whether different endogenous protein expression levels of Epo or differences in the abundance of its receptor components could account for the extent of structural neuropathological changes or neurological complications in adults with severe malaria was investigated.. High sensitivity immunohistochemistry was used to assess the frequency, distribution and concordance of Epo and components of its homodimeric and heteromeric receptors, Epo receptor and CD131, within the brainstem of adults who died of severe malaria. The following relationships with Epo and its receptor components were also defined: (i) sequestration and indicators of hypoxia; (ii) vascular damage in the form of plasma protein leakage and haemorrhage; (iii) clinical complications and neuropathological features of severe malaria disease. Brainstems of patients dying in the UK from unrelated non-infectious causes were examined for comparison.. The incidence of endogenous Epo in parenchymal brain cells did not greatly differ between severe malaria and non-neurological UK controls at the time of death. However, EpoR and CD131 labelling of neurons was greater in severe malaria compared with non-neurological controls (P = .009). EpoR labelling of vessels was positively correlated with admission peripheral parasite count (P = .01) and cerebral sequestration (P < .0001). There was a strong negative correlation between arterial oxygen saturation and EpoR labelling of glia (P = .001). There were no significant correlations with indicators of vascular damage, neuronal chromatolysis, axonal swelling or vital organ failure.. Cells within the brainstem of severe malaria patients showed protein expression of Epo and its receptor components. However, the incidence of endogeneous expression did not reflect protection from vascular or neuronal injury, and/or clinical manifestations, such as coma. These findings do not provide support for Epo as an adjuvant neuroprotective agent in adults with severe malaria.

Topics: Adult; Aged; Aged, 80 and over; Brain Ischemia; Brain Stem; Case-Control Studies; Cytokine Receptor Common beta Subunit; Erythropoietin; Female; Humans; Immunohistochemistry; Malaria, Falciparum; Male; Middle Aged; Plasmodium falciparum; Receptors, Erythropoietin; United Kingdom; Vietnam; Young Adult

To gain insight into potential relationships between tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), erythropoietin (EPO), and anemia in acute malaria, 90 children 3 to 11 years with acute malaria were studied. According to parasitemia and hemoglobin levels, they were divided into 3 groups: G1 (mild): asexual low-density Plasmodium falciparum parasitemia <8000 parasites/ul and hemoglobin levels >8g/dl. G2 (high-density uncomplicated): asexual high-density parasitemia (>8000 parasites/ul, with hemoglobin levels >8 g/dl. G3 (anemia): with severe malaria symptoms and parasitemia with anemia (hemoglobin levels <8 g/dl). Hospital controls included 10 children with matching age group who required inpatient management but had no malaria parasitemia. Good marrow response was in G1 & G2 showed by elevation of serum EPO and soluble transferring receptors (sTfR) and increased red cell distribution width (RDW). In G3, bone marrow suppression was in spite of increased EPO level in response to anemia. TNF-alpha level was significantly higher G2 and G3 (P.05). IL-10 levels in G1 were significantly higher than in hospital control group (P<0.05). The highest level of IL-10 was in G2. The mean IL-10 to TNF-alpha ratio in G2 (4.64) was significantly higher (P<.005) than in G3 (mean ratio, 1.77).

Topics: Anemia; Animals; Case-Control Studies; Child; Child, Preschool; Erythropoietin; Female; Hemoglobins; Humans; Interleukin-10; Malaria, Falciparum; Male; Parasitemia; Plasmodium falciparum; Saudi Arabia; Tumor Necrosis Factor-alpha

To elucidate the relationship between falciparum malaria-associated anemia and serum erythropoietin (Epo) levels and reticulocyte response during acute malaria infection, 87 adults aged 18-65 years presenting with acute, uncomplicated malaria were examined on enrollment and for 28 days of follow-up. The 87 patients were divided into 2 groups: those with anemia (n = 45) and those without (n = 42). Serum samples were taken on admission (Day 0), then on Days 7, 21, and 28, to measure the reticulocyte count, absolute reticulocyte count, reticulocyte hemoglobin content, and erythropoietin level (Epo). The absolute reticulocyte counts for the anemic patients were significantly higher than for those without anemia on Days 0, 7, 21, and 28. The serum Epo levels for the anemic patients were significantly higher than the non-anemic group only on Day 0 (44.39 +/- 4.06 vs 25.91 +/- 4.86 mlU/ml, p < 0.001). Inadequate Epo production was found in 31.03% (27/87) of patients on Day 0, 37.93% (33/87) on Day 7, 43.67% (38/87) on Day 21, and 39.08% (34/87) on Day 28. These results indicate defective Epo production and reticulocyte response in adult patients suffering from acute P. falciparum malaria, which differs from pediatric patients. Our findings may provide the basis for further study into the choice of therapeutic strategies to treat acute P. falciparum malaria-associated anemia with recombinant human Epo to correct refractory anemia due to malaria.

Topics: Acute Disease; Adolescent; Adult; Aged; Anemia; Erythropoietin; Female; Hematocrit; Humans; Longitudinal Studies; Malaria, Falciparum; Male; Middle Aged; Reticulocyte Count; Reticulocytes; Young Adult

Severe forms of anemia in children in the developing countries may be characterized by different clinical manifestations at particular stages of development. Whether this reflects developmental changes in adaptation to anemia or other mechanisms is not clear. The pattern of adaptation to anemia has been assessed in 110 individuals with hemoglobin (Hb) E beta-thalassemia, one of the commonest forms of inherited anemia in Asia. It has been found that age and Hb levels are independent variables with respect to erythropoietin response and that there is a decline in the latter at a similar degree of anemia during development. To determine whether this finding is applicable to anemia due to other causes, a similar study has been carried out on 279 children with severe anemia due to Plasmodium falciparum malaria; the results were similar to those in the patients with thalassemia. These observations may have important implications both for the better understanding of the pathophysiology of profound anemia in early life and for its more logical and cost-effective management.

Topics: Adaptation, Physiological; Adolescent; Adult; Age Distribution; Aging; Anemia; Animals; beta-Thalassemia; Child; Child, Preschool; Developing Countries; Erythropoietin; Humans; Infant; Malaria, Falciparum; Middle Aged

Severe anaemia can develop in the aftermath of Plasmodium falciparum malaria because of protracted bone marrow suppression, possibly due to residual subpatent parasites.. Blood was collected from patients with recent malaria and negative malaria microscopy. Detection of the Plasmodium antigens, lactate dehydrogenase (Optimal), aldolase and histidine rich protein 2 (Now malaria) were used to differentiate between patients with (1) no malaria, (2) recent cleared malaria, (3) persistent P. falciparum infection. Red cell distribution width (RDW), plasma levels of soluble transferrin receptor (sTfR) and erythropoietin (EPO) were measured as markers of erythropoiesis. Interleukin (IL) 10 and tumour necrosis factor (TNF)alpha were used as inflammation markers.. EPO was correlated with haemoglobin, irrespective of malaria (R = -0.36, P < 0.001). Persistent P. falciparum infection, but not recent malaria without residual parasites, was associated with bone marrow suppression i.e., low RDW (P < 0.001 vs. P = 0.56) and sTfR (P = 0.02 vs. P = 0.36). TNF-alpha and IL-10 levels were not associated with bone marrow suppression.. In the treatment of malaria, complete eradication of parasites may prevent subsequent development of anaemia. Severely anaemic children may benefit from antimalarial treatment if antigen tests are positive, even when no parasites can be demonstrated by microscopy.

Topics: Anemia; Animals; Bone Marrow Diseases; Child; Child, Preschool; Erythropoiesis; Erythropoietin; Female; Hemoglobins; Humans; Infant; Interleukin-10; L-Lactate Dehydrogenase; Malaria, Falciparum; Male; Parasitemia; Proteins; Receptors, Transferrin; Tumor Necrosis Factor-alpha

Topics: Anemia; Animals; Erythropoietin; Female; Humans; Malaria, Falciparum; Nitric Oxide; Pregnancy; Pregnancy Complications, Parasitic; Prolactin; Tumor Necrosis Factor-alpha

Anemia is an important complication of malaria, and its pathogenesis is not well understood. To gain insight into potential age-related relationships between tumor necrosis factor alpha (TNF-alpha), interleukin 10 (IL-10), erythropoietin, and anemia during acute malaria, 273 children of ages 12 to 120 months presenting with acute, uncomplicated malaria in Kampala, Uganda, were monitored at enrollment and 3 and 7 days later. Younger children had higher geometric mean erythropoietin, TNF-alpha, and alpha(1)-acid glycoprotein (AGP) concentrations than older children. Univariate regression analysis revealed that age, log(10) erythropoietin levels, IL-10/TNF-alpha ratio, and AGP levels were each significantly associated with hemoglobin levels at baseline. Hemoglobin concentrations were inversely correlated with the log(10) erythropoietin level at all three visits. For the older age groups, higher levels of TNF-alpha were significantly associated with higher IL-10 levels at all three visits, but this relationship was significant only at baseline for younger children. These data suggest that younger children do not maintain IL-10 production in response to the inflammatory process, and this mechanism may contribute to the more severe anemia found in younger children. Acute malaria is an illness whose incidence and severity are largely age dependent. Further studies are needed to understand the relationships between age-related immune responses to malaria and their role in the pathogenesis of malarial anemia.

Topics: Acute Disease; Age Factors; Anemia; Child; Child, Preschool; Erythropoietin; Humans; Infant; Interleukin-10; Longitudinal Studies; Malaria, Falciparum; Regression Analysis; Severity of Illness Index; Tumor Necrosis Factor-alpha; Uganda

Involvement of neutrophils in the control of blood parasites in malaria has been reported. Both, mononuclear phagocytes and neutrophils are known to be stimulated by cytokines such as TNF-alpha in order to augment the defence potency against the parasites. Previously, it has been shown that serum-G-CSF concentrations are increased in patients with bacterial sepsis. In vitro studies have shown that P. falciparum - infected erythrocytes induce the release of G-CSF by several cells such as endothelial cells and monocytes, however, nothing is known about G-CSF serum concentrations during the clinical course of severe P. falciparum malaria. Thus, it was the aim of the present study to investigate the time course for G-CSF serum concentrations in patients with complicated P. falciparum malaria, and to correlate these values with other mediators of inflammation and hematopoesis. Twenty-six patients suffering from complicated P. falciparum malaria were included in the study, and 20, age and sex matched, healthy volunteers were used as the negative control group. Serum samples for determination of G-CSF were taken on day 0, 7 and 14, and measured by ELISA. We found significantly increased serum concentrations of G-CSF in patients with complicated P. falciparum malaria on day 0, values decreasing to within the normal range by day 7. A significant correlation was found between G-CSF (d0) and procalcitonin, the parasite count, erythropoietin and macrophage inflammatory protein, however no correlation could be shown for the neutrophil count. In conclusion, on the day of hospital admission, elevated serum concentrations of G-CSF were detected in patients with complicated P. falciparum malaria, which might indicate a role of G-CSF in the acute defence mechanism against the parasites.

Topics: Adolescent; Adult; Animals; Antimalarials; Artemisinins; Artesunate; Calcitonin; Calcitonin Gene-Related Peptide; Chemokine CCL4; Child; Enzyme-Linked Immunosorbent Assay; Erythrocytes; Erythropoietin; Female; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Macrophage Inflammatory Proteins; Malaria, Falciparum; Male; Mefloquine; Middle Aged; Nitrates; Plasmodium falciparum; Protein Precursors; Reference Values; Sesquiterpenes; Stem Cell Factor

Topics: Adolescent; Adult; Anemia; Child; Child, Preschool; Erythropoietin; Female; Humans; Infant; Malaria, Falciparum; Male

To study the importance of bone marrow inhibition in the pathogenesis of malarial anaemia, haematological and parasitological parameters were followed in patients with acute malaria. Three patient categories were studied, severe malarial anaemia (SA), cerebral malaria (CM) and uncomplicated malaria (UM). Red cell distribution width (RDW) was used as a surrogate marker of release of young erythrocytes and reticulocytes. Initially RDW was low in all patients in spite of markedly increased concentrations of erythropoietin (EPO). 3 d after institution of treatment and coinciding with parasite clearance RDW increased dramatically, reaching the highest levels 1-2 weeks later. Although severe anaemia was corrected by blood transfusion during the first 3 d of treatment, the peak RDW correlated significantly with the initial EPO levels. This suggests that Plasmodium falciparum infection causes a rapidly reversible suppression of the bone marrow response to EPO. Furthermore, the inhibition of bone marrow response was a general finding irrespective of initial haemoglobin levels suggesting that the severity of anaemia depends upon the degree of peripheral erythrocyte destruction in patients with suppressed bone marrow response to EPO.

Topics: Antimalarials; Bone Marrow; Bone Marrow Diseases; Child; Child, Preschool; Chloroquine; Erythropoiesis; Erythropoietin; Hemoglobins; Humans; Malaria, Falciparum

One of the most serious manifestations of Plasmodium falciparum malaria is anaemia. Its established causes are increased red cell destruction and ineffective erythropoiesis. Since proinflammatory cytokines have been shown to suppress the in vitro synthesis of erythropoietin (Epo), we measured serum immunoreactive Epo in 90 Sudanese patients suffering from malaria. Even in severe cases of anaemia (blood haemoglobin < 80 g/l), serum Epo levels rarely exceeded 300 U/l. For comparison, serum Epo was increased up to 12,000 U/l in a reference group of Caucasian patients with anaemia not associated with infection. Moreover, the slope of the log Epo/haemoglobin regression line was less steep in malarial anaemia. Thus, as documented for other chronic inflammatory disorders, there is a relative lack of Epo in malaria-associated anaemia. Treatment with the antimalarial drug chloroquine may aggravate the defect in Epo production, because chloroquine inhibited Epo synthesis when tested in cell culture.

Topics: Adolescent; Adult; Anemia; Cell Line; Chloroquine; Erythropoietin; Ferritins; Humans; Interleukin-6; Iron; Malaria, Falciparum; Male; Reticulocyte Count; Sudan

The pathophysiologic backgrounds of anemia in malaria are complex and multifactorial. The purpose of the present study was to measure serum concentrations of erythropoietin (EPO) and to evaluate the adequacy of EPO production in patients suffering from acute Plasmodium falciparum malaria. Fifteen patients with complicated malaria were included in the study. Serum samples were taken on the day of admission, and days 7, 14, 21 and 28. Serum EPO concentrations were measured using an enzyme-linked immunosorbent assay. The median serum EPO concentration was 15.6 mU/ml on the day of admission (range 0.5-567) mU/ml, 10.6 mU/ml (1.2-863) on day 7, 11.8 mU/ml (0.5-72.8) on day 14, 10 mU/ml (0.5-74.6) on day 21, and 8.3 mU/ml (2.2-61.6) on day 28. Inadequate EPO production was found in 46.6% of the patients on the day of admission, which increased to 67% and 68% on days 7 and 14, and reached a maximum of 80% on day 21. Almost 54% of patients had inadequate EPO production on day 28. Our data indicate inadequate EPO production in patients suffering from acute P. falciparum malaria, which might contribute to the prolonged anemia observed in these patients.

Topics: Acute Disease; Adolescent; Adult; Anemia; Erythropoietin; Hematocrit; Humans; Malaria, Falciparum; Middle Aged

Plasma immunoreactive erythropoietin concentrations were determined in 84 children with Plasmodium falciparum malaria in Gabon. There was an inverse log/linear relationship between hemoglobin or hematocrit and plasma erythropoietin, indicating that erythropoietin levels increased exponentially as circulating hemoglobin decreased. These result show that P. falciparum malaria does not lead to decreased erythropoietin production, and in turn reduced erythropoietin production does not contribute to the pathogenesis of malarial anemia. There is an adequate response of erythropoietin to anemia in children with P. falciparum malaria.

Topics: Age Factors; Anemia; Blood Transfusion; Child; Child, Preschool; Erythropoietin; Female; Hematocrit; Hemoglobins; Humans; Infant; Malaria, Falciparum; Male; Parasitemia; Regression Analysis; Severity of Illness Index