No abstract

Co-infection with malaria and chikungunya (CHIKV) could exert a significant public health impact with infection misdiagnosis. Therefore, this study aimed to collect qualitative and quantitative evidence of malaria and CHIKV co-infection among febrile patients. Methods: Potentially relevant studies were identified using PubMed, Web of Science, and Scopus. The bias risk of the included studies was assessed using the checklist for analytical cross-sectional studies developed by the Joanna Briggs Institute. The pooled prevalence of malaria and CHIKV co-infection among febrile patients and the pooled prevalence of CHIKV infection among malaria patients were estimated with the random effect model. The odds of malaria and CHIKV co-infection among febrile patients were also estimated using a random effect model that presumed the heterogeneity of the outcomes of the included studies. The heterogeneity among the included studies was assessed using the Cochran Q test and I2 statistics. Publication bias was assessed using the funnel plot and Egger’s test. Results: Of the 1924 studies that were identified from the three databases, 10 fulfilled the eligibility criteria and were included in our study. The pooled prevalence of malaria and CHIKV co-infection (182 cases) among febrile patients (16,787 cases), stratified by diagnostic tests for CHIKV, was 10% (95% confidence interval (CI): 8–11%, I2: 99.5%) using RDT (IgM), 7% (95% CI: 4–10%) using the plaque reduction neutralization test (PRNT), 1% (95% CI: 0–2%, I2: 41.5%) using IgM and IgG ELISA, and 4% (95% CI: 2–6%) using real-time RT-PCR. When the prevalence was stratified by country, the prevalence of co-infection was 7% (95% CI: 5–10%, I2: 99.5%) in Nigeria, 1% (95% CI: 0–2%, I2: 99.5%) in Tanzania, 10% (95% CI: 8–11%) in Sierra Leone, 1% (95% CI: 0–4%) in Mozambique, and 4% (95% CI: 2–6%) in Kenya. The pooled prevalence of CHIKV infection (182 cases) among malaria patients (8317 cases), stratified by diagnostic tests for CHIKV, was 39% (95% CI: 34–44%, I2: 99.7%) using RDT (IgM), 43% (95% CI: 30–57%) using PRNT, 5% (95% CI: 3–7%, I2: 5.18%) using IgM and IgG ELISA, and 9% (95% CI: 6–15%) using real-time RT-PCR. The meta-analysis showed that malaria and CHIKV co-infection occurred by chance (p: 0.59, OR: 0.32, 95% CI: 0.6–1.07, I2: 78.5%). Conclusions: The prevalence of malaria and CHIKV co-infection varied from 0% to 10% as per the diagnostic test for CHIKV infection or the country where the co-infection was reported. Hence, the clinicians who diagnose patients with malaria infections in areas where two diseases are endemic should further investigate for CHIKV co-infection to prevent misdiagnosis or delayed treatment of concurrent infection.

Interleukin-6 (IL-6) is generated by immune cells during infection with malaria parasites and they are associated with the immunopathogenesis of malaria. The present systematic review and meta-analysis aimed to compare the differences in IL-6 levels between several groups of patients with malaria and healthy control groups. The systematic review was registered at PROSPERO with a registration number: CRD42021290753. Systematic literature searches were conducted in PubMed, Web of Science, and Scopus until November 7, 2021 to obtain studies that documented IL-6 levels in patients with malaria. The quality of the included studies was assessed using critical appraisal tools from the Joanna Briggs Institute. Differences in the mean IL-6 levels among patients with: (1) severe and non-severe malaria, (2) uncomplicated malaria and controls, (3) uncomplicated and asymptomatic malaria, (4) asymptomatic malaria and healthy controls, and (5) those that died or survived were estimated using a random-effects model. Forty-three of 1,969 studies were included in the systematic review. Results of the meta-analysis showed that patients with severe malaria had higher mean IL-6 levels than those with non-severe malaria [P = 0.04, weight mean difference (WMD) = 96.63 pg/mL, 95% confidence interval (CI) = 0.88 − 19.38 pg/mL, I2 = 99.9%, 13 studies]. Patients with uncomplicated malaria had higher mean IL-6 levels than the controls (P < 0.001, WMD = 42.86 pg/mL, 95% CI = 30.17 − 55.56 pg/mL, I2 = 100%, 17 studies). No differences in the mean levels of IL-6 were found between patients with uncomplicated malaria and those with asymptomatic malaria (P = 0.063, WMD = 42.07 pg/mL, 95% CI =  − 2.23 pg/mL to − 86.37 pg/mL, I2 = 99.1%, 8 studies), or between patients with asymptomatic malaria and healthy controls (P = 0.45, WMD = 1.67 pg/mL, 95% CI =  − 2.73 pg/mL to − 6.07 pg/mL, I2 = 98.1%, 2 studies). A higher mean level of IL-6 was observed in patients who died compared with the levels of those who survived (P = 0.007, WMD = 1,399.19 pg/mL, 95% CI = 384.16 − 2,414.2 pg/mL, I2 = 93.1%, 4 studies). Our meta-analysis of the pooled evidence can be used to guide future studies in which IL-6 levels are measured during malaria outbreaks to monitor malaria severity. Heterogeneity of the effect estimate among the included studies was the main limitation of this analysis. In conclusion, significantly increased levels of IL-6 were observed in patients with severe malaria compared with those in patients with non-severe malaria, which indicates that IL-6 is a candidate marker for severe malaria. Future studies should investigate the sensitivity and specificity of increased IL-6 levels to determine the effectiveness of assessments of IL-6 levels monitoring of malaria infection and severity.

Background Tumour necrosis factor-alpha (TNF-α) levels are reportedly altered during malaria. In this systematic review and meta-analysis, we aimed to collect and compare data on TNF-α levels between patients with malaria of varying severity and healthy asymptomatic positive controls. Methods We searched PubMed, Scopus and Web of Science for studies that reported TNF-α levels in malaria cases of different severity and healthy asymptomatic positive controls using a combination of search terms. The quality of the included studies was assessed using the Strengthening the Reporting of Observational Studies in Epidemiology checklist. To compare the TNF-α levels among fatal cases, severe cases, uncomplicated cases and healthy asymptomatic positive controls, we applied the random-effects model that assumed the existence of variations between studies. The effect estimate was pooled mean difference (MD) with a 95% confidence interval (CI). Results From 1694 studies, we included 31 studies that met our eligibility criteria for systematic review and meta-analysis. Patients with severe malaria showed higher mean TNF-α levels than those with uncomplicated malaria (P &lt; 0.001, pooled MD = 79.02 pg/ml, 95% CI: 63.68–94.35 pg/ml, I2: 99.5%, n = 26 studies). Furthermore, fatal cases had no difference in the mean TNF-α levels in comparison with survived cases (P = 0.055, pooled MD = 82.38 pg/ml, 95% CI: −1.93 to 166.69 pg/ml, I2: 99.54%, n = 5 studies). Finally, patients with uncomplicated malaria showed higher mean TNF-α levels than those with asymptomatic malaria (P &lt; 0.001, pooled MD = 45.10 pg/ml, 95% CI: 18.45–71.76 pg/ml, I2: 97.09%, n = 5 studies). Conclusion This systematic review and meta-analysis confirmed the increase of TNF-α levels in patients with severe malaria. Therefore, TNF-α may be alternatively used as a prognostic biomarker of severe malaria. Trial registration Not applicable.

This study investigated whether C-reactive protein (CRP) can be used as a marker for the early detection and monitoring of malaria severity. Potentially relevant studies were searched in Medline (PubMed), Scopus, and Web of Science. Differences in CRP between (1) severe malaria and uncomplicated malaria, (2) uncomplicated malaria and asymptomatic malaria, (3) uncomplicated malaria and febrile/healthy controls, and (4) asymptomatic malaria and febrile/healthy controls were estimated using random-effects models. Twenty-nine studies were included for meta-analysis. The results of meta-analysis demonstrated higher mean CRP levels in (1) patients with severe malaria compared with uncomplicated malaria (p < 0.001, standard mean difference [SMD]: 1.52, 95% confidence interval [CI]: 0.91–2.12, I2: 95.1%), (2) patients with uncomplicated malaria than in those with asymptomatic malaria (p: 0.001, SMD: 1.65, 95% CI: 0.67–2.62, I2: 96.7%), (3) patients with uncomplicated malaria compared with febrile/healthy controls (p < 0.001, SMD: 2.38, 95% CI: 1.37–3.40, I2: 98.5%), and (4) patients with asymptomatic malaria compared with febrile/healthy controls (p < 0.001, SMD: 2.55, 95% CI: 1.60–3.50, I2: 99.2%). This study demonstrated CRP levels are a biomarker for the early detection and monitoring of malaria severity.