Methemoglobin levels in malaria: a systematic review and meta-analysis of its association with Plasmodium falciparum and Plasmodium vivax infections and disease severity

Abstract

Reports indicate that Plasmodium infections influence methemoglobin levels. However, findings have been inconclusive or have varied across different geographic and demographic contexts. This systematic review and meta-analysis aimed to consolidate existing data regarding the association between Plasmodium infections and alterations in methemoglobin levels related to the severity of the infection. A comprehensive literature search of several databases, including Ovid, ProQuest, Embase, Scopus, MEDLINE, and PubMed, was conducted to identify relevant studies that examined methemoglobin levels in patients with malaria. Qualitative synthesis and meta-analysis of the pooled standardized mean difference were conducted to synthesize the differences in methemoglobin levels between: (1) patients with malaria and those without malaria and (2) patients with severe malaria and those with uncomplicated malaria based on various themes including publication year, study design, study area, Plasmodium species, age group, symptomatic status, severity status, and method of malaria detection. Of the 1846 studies that were initially identified from the main databases and additional searches on Google Scholar, 10 studies met the eligibility criteria and were selected for this review. The systematic review distinctly highlighted an association between malaria and elevated methemoglobin levels, an observation consistent across diverse geographical regions and various Plasmodium species. Furthermore, the meta-analysis confirmed this by demonstrating increased methemoglobin levels in patients with malaria compared to those without malaria (P < 0.001, Hedges' g 2.32, 95% CI 1.36-3.29, I² 97.27, 8 studies). Moreover, the meta-analysis found elevated methemoglobin levels in patients with severe malaria compared to those with uncomplicated malaria (P < 0.001, Hedges' g 2.20, 95% CI 0.82-3.58, I² 96.20, 5 studies). This systematic review and meta-analysis revealed increased methemoglobin levels in patients with P. falciparum and P. vivax infections, with a notable association between elevated methemoglobin levels and severe malaria. Future research should focus on elucidating the specific mechanisms by which changes in methemoglobin levels are related to infections by P. falciparum and P. vivax, particularly in terms of severity, and how these alterations could potentially impact patient management and treatment outcomes.

Keywords: Malaria; Meta-analysis; Methemoglobin; Oxidized hemoglobin; Plasmodium.

Figure 1

Study flow diagram.

Figure 2

The difference in methemoglobin levels between patients with and without malaria. Blue box effect estimate, green diamond pooled effect estimate, N number of participants, Mean mean methemoglobin level, SD standard deviation, CI confidence interval.

Figure 3

The difference in methemoglobin levels between patients with severe malaria and those with uncomplicated malaria. Blue box effect estimate, green diamond pooled effect estimate, N number of participants, Mean mean methemoglobin level, SD standard deviation, CI confidence interval.

Figure 4

The leave-one-out meta-analysis revealed the robustness of the meta-analysis results that showed significantly increased methemoglobin levels in patients with malaria compared to those without malaria. It confirmed that these significant findings remained consistent even when individual studies were excluded one by one from the analysis. Green dot pooled effect estimate, green line confidence interval, CI confidence interval.

Figure 5

The leave-one-out meta-analysis revealed the robustness of the meta-analysis results that showed significantly increased methemoglobin levels in patients with severe malaria compared to those with uncomplicated malaria. It confirmed that these significant findings remained consistent even when individual studies were excluded one by one from the analysis. Green dot pooled effect estimate, green line confidence interval, CI confidence interval.