Alteration of Blood Lactate Levels in Severe Falciparum Malaria: A Systematic Review and Meta-Analysis.
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ABSTRACT:
SUBMITTER: Wilairatana P
PROVIDER: S-EPMC8614809 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The understanding of platelet biology under physiological and pathological conditions like malaria infection is critical importance in the context of the disease outcome or model systems used. The importance of severe thrombocytopenia (platelet count < 50,000 cells (µL) and profound thrombocytopenia (platelet count < 20,000 cells/µL) in malaria patients remains unclear. This study aimed to synthesize evidence regarding the risks of severe and profound thrombocytopenia in patients with severe non-Plasmodium falciparum malaria. Our overall aim was to identify potential indicators of severe non-P. falciparum malaria and the Plasmodium species that cause severe outcomes. This systematic review was registered at the International Prospective Register of Systematic Reviews (PROSPERO) under registration ID CRD42020196541. Studies were identified from previous systematic reviews (n = 5) and the MEDLINE, Scopus, and Web of Science databases from 9 June 2019 to 9 June 2020. Studies were included if they reported the outcome of severe non-Plasmodium species infection, as defined by the World Health Organization (WHO) criteria, in patients with known platelet counts and/or severe and profound thrombocytopenia. The risk of bias was assessed using the Newcastle-Ottawa Scale (NOS). Data were pooled, and pooled prevalence (PP) and pooled odds ratios (ORs) were calculated using random effects models. Of the 118 studies identified from previous meta-nalyses, 21 met the inclusion criteria. Of the 4807 studies identified from the databases, three met the inclusion criteria. Nine studies identified from reference lists and other sources also met the inclusion criteria. The results of 33 studies reporting the outcomes of patients with severe P. vivax and P. knowlesi infection were pooled for meta-analysis. The PP of severe thrombocytopenia (reported in 21 studies) was estimated at 47% (95% confidence interval (CI): 33-61%, I2: 96.5%), while that of profound thrombocytopenia (reported in 13 studies) was estimated at 20% (95% CI: 14-27%, 85.2%). The pooled weighted mean difference (WMD) in platelet counts between severe uncomplicated Plasmodium infections (reported in 11 studies) was estimated at -28.51% (95% CI: -40.35-61%, I2: 97.7%), while the pooled WMD in platelet counts between severe non-Plasmodium and severe P. falciparum infections (reported in eight studies) was estimated at -3.83% (95% CI: -13.90-6.25%, I2: 85.2%). The pooled OR for severe/profound thrombocytopenia comparing severe to uncomplicated Plasmodium infection was 2.92 (95% CI: 2.24-3.81, I2: 39.9%). The PP of death from severe and profound thrombocytopenia was estimated at 11% (95% CI: 0-22%). These results suggest that individuals with severe non-P. falciparum infection (particularly P. vivax and P. knowlesi) who exhibit severe or profound thrombocytopenia should be regarded as high risk, and should be treated for severe malaria according to current WHO guidelines. In addition, severe or profound thrombocytopenia coupled with other clinical and microscopic parameters can significantly improve malaria diagnosis, enhance the timely treatment of malaria infections, and reduce the morbidity and mortality of severe non-P. falciparum malaria.
| S-EPMC8698983 | biostudies-literature
Project description:BACKGROUND:Plasmodium vivax is the most geographically widespread species among human malaria parasites. Immunopathological studies have shown that platelets are an important component of the host innate immune response against malaria infections. The objectives of this study were to quantify thrombocytopaenia in P. vivax malaria patients and to determine the associated risks of severe thrombocytopaenia in patients with vivax malaria compared to patients with P. falciparum malaria. MAIN BODY:A systematic review and meta-analysis of the available literature on thrombocytopaenia in P. vivax malaria patients was undertaken. Relevant studies in health-related electronic databases were identified and reviewed. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Fifty-eight observational studies (n?=?29?664) were included in the current review. Severe thrombocytopaenia (<?50?000/mm3) to very severe thrombocytopaenia (<?20?000/mm3) was observed in 10.1% of patients with P. vivax infection. A meta-analysis of 11 observational studies showed an equal risk of developing severe/very severe thrombocytopaenia between the patients with P. vivax malaria and those with P. falciparum malaria (OR: 1.98, 95% CI: 0.92-4.25). This indicates that thrombocytopaenia is as equally a common manifestation in P. vivax and P. falciparum malaria patients. One study showed a higher risk of developing very severe thrombocytopaenia in children with severe P. vivax malaria than with severe P. falciparum malaria (OR: 2.80, 95% CI: 1.48-5.29). However, a pooled analysis of two studies showed an equal risk among adult severe cases (OR: 1.19, 95% CI: 0.51-2.77). This indicates that the risk of developing thrombocytopaenia in P. vivax malaria can vary with immune status in both children and adults. One study reported higher levels of urea and serum bilirubin in patients with P. vivax malaria and severe thrombocytopaenia compared with patients mild thrombocytopaenia or no thrombocytopaenia, (P?<?0.001 in all comparisons). A pooled analysis of two other studies showed a similar proportion of bleeding episodes with thrombocytopaenia in severe P. vivax patients and severe P. falciparum patients (P?=?0.09). This implied that both P. vivax and P. falciparum infections could present with bleeding episodes, if there had been a change in platelet counts in the infected patients. A pooled analysis of another two studies showed an equal risk of mortality with severe thrombocytopaenia in both P. vivax and P. falciparum malaria patients (OR: 1.16, 95% CI: 0.30-4.60). However, due to the low number of studies with small sample sizes within the subset of studies that provided clinically relevant information, our confidence in the estimates is limited. CONCLUSION:The current review has provided some evidence of the clinical relevance of severe thrombocytopaenia in P. vivax malaria. To substantiate these findings, there is a need for well designed, large-scale, prospective studies among patients infected with P. vivax. These should include patients from different countries and epidemiological settings with various age and gender groups represented.
| S-EPMC5808388 | biostudies-literature
Project description:Although many studies have investigated the role of interleukin (IL)-12 cytokine in the pathogenesis of severe malaria, these studies were based on a limited number of participants, possibly affecting their outcomes. We analyzed the difference in IL-12 levels between patients with severe and uncomplicated malaria through a meta-analysis. A systematic review was conducted following the Cochrane Handbook for Systematic Reviews of Interventions and was reported according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses statement. Systematic literature searches were performed between 20 February and 2 March, 2022 in PubMed, Scopus, and Embase to identify studies reporting IL-12 levels in patients with severe and uncomplicated malaria. The quality of included studies was determined using the Strengthening the Reporting of Observational Studies in Epidemiology guidelines. The pooled mean difference (MD) in IL-12 between patients with severe and uncomplicated malaria was estimated using the DerSimonian-Laird method for the random-effects model. Altogether, 1885 potentially relevant articles were identified, and 10 studies enrolling 654 patients with severe malaria and 626 patients with uncomplicated malaria were included in the meta-analysis. Patients with severe malaria had lower mean IL-12 levels than those with uncomplicated malaria (p = 0.01, MD: -33.62, 95% confidence interval [CI]: -58.79 to -8.45, I2: 99.29%, 10 studies). In conclusion, decreased IL-12 levels might significantly contribute to the development of severe malaria. As most published literature demonstrated the role of IL-12 in animal models, human studies are required to understand the mechanisms involved in low IL-12 levels in patients with severe malaria.
| S-EPMC9368085 | biostudies-literature
Project description:Vitamin E has an antioxidant property and is associated with protection against malaria. The current study used systematic review and meta-analysis approaches examining the variance in blood levels of vitamin E in malaria patients as compared with uninfected individuals. The protocol for the systematic review was registered with PROSPERO (CRD4202341481). Searches for pertinent studies were carried out on Embase, MEDLINE, Ovid, PubMed, Scopus, ProQuest, and Google Scholar. The combined effect estimate (Cohen's d) of the difference in vitamin E levels in malaria patients as compared with uninfected individuals was estimated using the random effects model. The searches yielded 2009 records, and 23 studies were included in the systematic review. The majority of the studies (80%) found that vitamin E levels were significantly lower in malaria patients than those who were not infected. Overall, the results revealed a significant reduction in blood levels of vitamin E in malaria patients when compared with uninfected individuals (p < 0.01, Cohen's d: -2.74, 95% CI: -3.72-(-1.76), I2: 98.69%, 21 studies). There was a significant reduction in blood levels of vitamin E in patients suffering from severe malaria, in comparison with those experiencing less severe forms of the disease (p < 0.01, Cohen's d: -0.56, 95% CI: -0.85-(-0.26), I2: 0%, 2 studies), but no variation in blood levels of vitamin E among patients suffering from either P. falciparum or P. vivax malaria (p = 0.13, Cohen's d: -1.15, 95% CI: -2.62-0.33, I2: 93.22%, 3 studies). In summary, the present study strongly suggests that vitamin E levels are significantly reduced in malaria patients, with a more pronounced decrease observed in cases of severe malaria. However, the type of malaria parasite, specifically P. falciparum or P. vivax, did not appear to influence the levels of vitamin E. This study highlights the potential role of vitamin E in the pathogenesis of malaria and suggests that improved vitamin E status might be beneficial for improving disease outcomes.
| S-EPMC10421180 | biostudies-literature
Project description:BackgroundInterleukin (IL)-4 had been linked to malaria severity, but the findings are controversial, and the evidence is inconsistent and imprecise. In the current investigation, data on IL-4 levels in patients with severe and uncomplicated malaria were compiled.MethodsThe systematic review was registered at PROSPERO (CRD42022323387). Searches for relevant articles on IL-4 levels in patients with severe malaria and studies that examined IL-4 levels in both uncomplicated malaria and healthy controls were performed in PubMed, Embase, and Scopus using the search strategy without limitation to publication years or language. The quality of all included studies was evaluated using The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: standards for reporting observational studies. Qualitative and quantitative data syntheses were performed. The random-effects model, which weights each study according to its between- and within-study variance, was used to pool the mean difference (MD) of individual studies. The degree of heterogeneity was determined using Cochran's Q and I2 statistics. Additionally, meta-regression and subgroup analyses were perfomed to investigate possible sources of heterogeneity. The outliers were identified using the leave-one-out method and assessed publication bias using funnel plots, Egger's test, and a contour-enhanced funnel plot.ResultsA total of 2300 studies were identified through database searches, and 36 were included for analyses. The meta-analysis results showed lower mean IL-4 levels in severe malaria (434 cases) than in uncomplicated malaria (611 cases) (P = 0.01, pooled MD: -3.36 pg/mL, 95% confidence intervals CI -5.55 to -1.16 pg/mL, I2: 98.15%, 11 studies). The meta-analysis results showed no difference in mean IL-4 levels between cerebral malaria (96 cases) and noncerebral severe malaria (108 cases) (P = 0.71, pooled MD: 0.86 pg/mL, 95% CI -3.60 to 5.32 pg/mL, I2 92.13%, four studies). Finally, no difference was found in mean IL-4 levels between uncomplicated malaria (635 cases) and healthy controls (674 cases) (P = 0.57, pooled MD: 0.79 pg/mL, 95% CI -1.92 to 3.50 pg/mL, I2: 99.89%, 11 studies).ConclusionThe meta-analysis revealed lower IL-4 levels in patients with severe malaria than in those with uncomplicated malaria, though a trend toward comparable IL-4 levels between both groups was more likely because several sources of heterogeneities were observed. Based on the limited number of studies included in the meta-analysis, until additional investigations have been conducted, IL-4 consideration as an alternative prognostic factor for malaria severity is not warranted.
| S-EPMC9277793 | biostudies-literature
Project description:BackgroundPlasmodium vivax is one of the major species of malaria infecting humans. Although emphasis on P. falciparum is appropriate, the burden of vivax malaria should be given due attention. This study aimed to synthesize the evidence on severe malaria in P. vivax infection compared with that in P. falciparum infection.Methods/principal findingsWe searched relevant studies in electronic databases. The main outcomes required for inclusion in the review were mortality, severe malaria (SM) and severe anaemia (SA). The methodological quality of the included studies was assessed using the Newcastle-Ottawa Scale. Overall, 26 studies were included. The main meta-analysis was restricted to the high quality studies. Eight studies (n = 27490) compared the incidence of SM between P. vivax infection and P. falciparum mono-infection; a comparable incidence was found in infants (OR: 0.45, 95% CI:0.04-5.68, I2:98%), under 5 year age group (OR: 2.06, 95% CI: 0.83-5.1, I2:83%), the 5-15 year-age group (OR: 0.6, 95% CI: 0.31-1.16, I2:81%) and adults (OR: 0.83, 95% CI: 0.67-1.03, I2:25%). Six studies reported the incidences of SA in P. vivax infection and P. falciparum mono-infection; a comparable incidence of SA was found among infants (OR: 3.47, 95%:0.64-18.94, I2: 92%), the 5-15 year-age group (OR:0.71, 95% CI: 0.06-8.57, I2:82%). This was significantly lower in adults (OR:0.75, 95% CI: 0.62-0.92, I2:0%). Five studies (n = 71079) compared the mortality rate between vivax malaria and falciparum malaria. A lower rate of mortality was found in infants with vivax malaria (OR:0.61, 95% CI:0.5-0.76, I2:0%), while this was comparable in the 5-15 year- age group (OR: 0.43, 95% CI:0.06-2.91, I2:84%) and the children of unspecified-age group (OR: 0.77, 95% CI:0.59-1.01, I2:0%).ConclusionOverall, the present analysis identified that the incidence of SM in patients infected with P. vivax was considerable, indicating that P. vivax is a major cause of SM. Awareness of the clinical manifestations of vivax malaria should prompt early detection. Subsequent treatment and monitoring of complications can be life-saving.
| S-EPMC4133404 | biostudies-literature
Project description:Previous epidemiological studies showed that blood lead level (BLL) was associated with malaria infection and severity. Therefore, the present study aimed to qualitatively and quantitatively synthesize the evidence on the association between BLL and risk of malaria infection and severity using the systematic review and meta-analysis approach. Potentially relevant studies were identified from three databases using a combination of search terms. The quality of the included studies was assessed using the checklist for the cross-sectional studies developed by the Joanna Briggs Institute. The qualitative synthesis of the risk or odds of malaria infection in patients with BLL was performed as the outcome of each included study could not be pooled. The pooled mean BLL and prevalence of malaria infection of the included studies was estimated using a random-effect model. The heterogeneity of the outcomes among the included studies was assessed using the Cochran Q test and I2 statistics. The subgroup analysis of the study sites and participants was performed to explore the source(s) of heterogeneity of the outcomes. Publication bias was assessed in the case of more than 10 studies used for pooling of the same outcome. Among 114 potentially relevant studies identified from the databases, 6 eligible studies were included for qualitative and quantitative syntheses. The results showed that the pooled mean BLLs were 7.33 μg/dL in children (95% confidence interval (95%CI), 4.08-10.58; I2, 98.2%), 7.94 μg/dL in children with BLL > 45 mg/dL before chelation (95%CI, 7.87-8.01), 7.41 μg/dL in infants (95%CI, 7.34-7.48 μg/dL), 9.20 μg/dL in children with malaria (95%CI, 9.16-9.24 μg/ dL), and 36.37 μg/dL in pregnant women (95%CI, 34.43-38.31 μg/dL). The prevalence rates of malaria among participants (2381 participants, 803 malaria-positive patients) were 53% in children (95%CI, 50-57%; I2, 99.8%), 24% in children with BLL > 45 mg/dL before chelation (95%CI, 21-27%), 12% in infants (95%CI, 8-18%), and 21% in pregnant women (95%CI, 18-26%). The subgroup analysis of countries demonstrated that the prevalence rates of malaria among participants was 17% in Benin (95%CI, 13-21%; I2, 98.8%) and 36% in Nigeria (95%CI, 10-63%; I2, 99.4%). BLL associated with decreased risk of malaria was demonstrated by two studies conducted in Benin and Nigeria, while BLL associated with increased risk of malaria was demonstrated by a study conducted in Nigeria. BLL was associated with the risk of severe malaria, involving severe neurological features and severe anemia. In conclusion, the present systematic review and meta-analysis determined the current status of the studies on BLL and risk of malaria in African countries. Further studies are needed to investigate the impact of BLL on patients with malaria to help the clinician determine the risk of severity, such as the development of neurological features or severe anemia, among patients exposed to lead.
| S-EPMC8396233 | biostudies-literature
Project description:Despite several studies examining the relationship between calcium levels and malaria, inconsistencies and varied results remain in the literature. This study aimed to synthesize the evidence on the association between blood calcium levels and malaria severity. A systematic literature search was conducted in the Embase, Scopus, PubMed, Ovid, and Google Scholar databases. The studies that investigated calcium levels in participants with malaria were reviewed and included for synthesis. The quality of included studies was assessed based on a standardized checklist by the Joanna Briggs Institute (JBI) critical appraisal checklists. The thematic synthesis had been used for qualitative synthesis. For the quantitative synthesis, the meta-analysis was performed to estimate the pooled effect sizes for differences in calcium levels between groups of participants using a random effect model using Hedge's g as a measure of effect size. Out of the 4574 identified records, 14 studies were reviewed. The thematic synthesis across these studies noted a consistent theme: reduced calcium levels in malaria patients compared to uninfected controls. However, the meta-analysis encompassing three specific analyses-comparing calcium levels between malaria patients and controls, severe and non-severe malaria cases, and fatal cases versus survivors-showed no significant difference in calcium levels. The statistics were as follows: (1) p = 0.15, Hedge's g: -1.00, 95% CI: -2.37-0.38, I2: 98.97, 9 studies; (2) p = 0.35, Hedge's g: -0.33, 95% CI: -1.02-0.36, I2: 81.61, 3 studies; and (3) p = 0.71, Hedge's g: -0.14, 95% CI: -0.91-0.62, I2: 87.05, 3 studies. Subgroup analyses indicated that regional disparities, especially between Africa and Asia, and participant age groups may influence these outcomes. While a trend of decreased calcium levels in malaria patients was observed, the meta-analytical results suggest regional and age-related variations. Further investigations should emphasize these differences to better guide clinical management, prognostic applications, and the crafting of policies concerning malaria's metabolic effects.
| S-EPMC10650696 | biostudies-literature
Project description:BackgroundDelay in receiving treatment for uncomplicated malaria (UM) is often reported to increase the risk of developing severe malaria (SM), but access to treatment remains low in most high-burden areas. Understanding the contribution of treatment delay on progression to severe disease is critical to determine how quickly patients need to receive treatment and to quantify the impact of widely implemented treatment interventions, such as 'test-and-treat' policies administered by community health workers (CHWs). We conducted a pooled individual-participant meta-analysis to estimate the association between treatment delay and presenting with SM.Methods and findingsA search using Ovid MEDLINE and Embase was initially conducted to identify studies on severe Plasmodium falciparum malaria that included information on treatment delay, such as fever duration (inception to 22nd September 2017). Studies identified included 5 case-control and 8 other observational clinical studies of SM and UM cases. Risk of bias was assessed using the Newcastle-Ottawa scale, and all studies were ranked as 'Good', scoring ≥7/10. Individual-patient data (IPD) were pooled from 13 studies of 3,989 (94.1% aged <15 years) SM patients and 5,780 (79.6% aged <15 years) UM cases in Benin, Malaysia, Mozambique, Tanzania, The Gambia, Uganda, Yemen, and Zambia. Definitions of SM were standardised across studies to compare treatment delay in patients with UM and different SM phenotypes using age-adjusted mixed-effects regression. The odds of any SM phenotype were significantly higher in children with longer delays between initial symptoms and arrival at the health facility (odds ratio [OR] = 1.33, 95% CI: 1.07-1.64 for a delay of >24 hours versus ≤24 hours; p = 0.009). Reported illness duration was a strong predictor of presenting with severe malarial anaemia (SMA) in children, with an OR of 2.79 (95% CI:1.92-4.06; p < 0.001) for a delay of 2-3 days and 5.46 (95% CI: 3.49-8.53; p < 0.001) for a delay of >7 days, compared with receiving treatment within 24 hours from symptom onset. We estimate that 42.8% of childhood SMA cases and 48.5% of adult SMA cases in the study areas would have been averted if all individuals were able to access treatment within the first day of symptom onset, if the association is fully causal. In studies specifically recording onset of nonsevere symptoms, long treatment delay was moderately associated with other SM phenotypes (OR [95% CI] >3 to ≤4 days versus ≤24 hours: cerebral malaria [CM] = 2.42 [1.24-4.72], p = 0.01; respiratory distress syndrome [RDS] = 4.09 [1.70-9.82], p = 0.002). In addition to unmeasured confounding, which is commonly present in observational studies, a key limitation is that many severe cases and deaths occur outside healthcare facilities in endemic countries, where the effect of delayed or no treatment is difficult to quantify.ConclusionsOur results quantify the relationship between rapid access to treatment and reduced risk of severe disease, which was particularly strong for SMA. There was some evidence to suggest that progression to other severe phenotypes may also be prevented by prompt treatment, though the association was not as strong, which may be explained by potential selection bias, sample size issues, or a difference in underlying pathology. These findings may help assess the impact of interventions that improve access to treatment.
| S-EPMC7571702 | biostudies-literature
Project description:BackgroundMalaria, a severe health threat, significantly affects total antioxidant status (TAS) levels, leading to considerable oxidative stress. This systematic review and meta-analysis aimed to delineate differences in TAS levels between malaria patients and healthy controls, and assess correlations between disease severity and parasite density.MethodsThe systematic review was registered with the International Prospective Register of Systematic Reviews (PROSPERO) under registration number CRD42023448761. A comprehensive literature search was conducted in databases such as Embase, MEDLINE, Journals@Ovid, PubMed, Scopus, ProQuest, and Google Scholar to identify studies reporting data on TAS levels in malaria patients. Data from the included studies were analysed both qualitatively and quantitatively. Differences in TAS levels between malaria patients and controls were pooled using a random effects model, with Hedges' g as the effect size measure.ResultsOf 1796 identified records, 20 studies met the inclusion criteria. The qualitative synthesis of these studies revealed a marked decrease in TAS levels in patients with malaria compared to non-malaria cases. The meta-analysis results showed a significant decrease in TAS levels in patients with malaria compared to non-malaria cases (P < 0.01, Hedges' g: - 2.75, 95% CI - 3.72 to -1.78, I2: 98.16%, 13 studies), suggesting elevated oxidative stress in these patients. Subgroup analyses revealed that TAS level variations were significantly influenced by geographical region, age group, Plasmodium species, and method for measuring TAS. Notably, TAS levels were significantly lower in severe malaria cases and those with high parasite density, indicating a potential relationship between oxidative stress and disease severity.ConclusionThis study highlights the potential utility of TAS as a biomarker for disease risk and severity in malaria. The significant decrease in TAS levels in malaria patients compared to controls implies increased oxidative stress. Further well-designed, large-scale studies are warranted to validate these findings and elucidate the intricate mechanisms linking TAS and malaria.
| S-EPMC11210049 | biostudies-literature