The high risk of malarial recurrence in patients with Plasmodium-mixed infection after treatment with antimalarial drugs: a systematic review and meta-analysis

Abstract

Background: Malaria mixed infections are often unrecognized by microscopists in the hospitals, and a delay or failure to treat Plasmodium-mixed infection may lead to aggravated morbidity and increased mortality. The present study aimed to quantify the pooled proportion and risk of malarial recurrences after the treatment of Plasmodium-mixed infection. The results of the study may provide benefits in the management of Plasmodium-mixed infection in co-endemic regions.

Methods: This systematic review and meta-analysis searched the international Prospective Register of Systematic Reviews (PROSPERO; ID = CRD42020199709), MEDLINE, Web of Science, and Scopus for potentially relevant studies in any language published between January 1, 1936, and July 20, 2020, assessing drug efficacy in patients with Plasmodium-mixed infection. The primary outcome was the pooled prevalence of Plasmodium parasitemia after initiating antimalarial treatment for Plasmodium-mixed infection. The secondary outcome was the pooled risk ratio (RR) of malarial recurrence in Plasmodium-mixed infection compared with those in Plasmodium falciparum and Plasmodium vivax mono-infection. The pooled analyses were calculated by random-effects meta-analysis. After the initial treatment in different days of recurrences (≤ 28 days or > 28 days), the risk of Plasmodium parasitemia was compared in subgroup analysis.

Results: Out of 5217 screened studies, 11 were included in the meta-analysis, including 4390 patients from six countries. The pooled prevalence of all recurrences of Plasmodium-mixed parasitemia was 30% (95% confidence interval (CI) 16-43; I²: 99.2%; 11 studies). The RR of malarial recurrence within 28 days after the initial treatment (clinical treatment failure) of Plasmodium-mixed parasitemia compared with the treatment of P. falciparum was 1.22 (p: 0.029; 95% CI 1.02-1.47; Cochran Q: 0.93; I²: 0%; six studies), while there was no significant difference in the risk of recurrence 28 days after initial treatment compared with the treatment of P. falciparum (p: 0.696, RR: 1.14; 95% CI 0.59-2.18; Cochran Q < 0.05; I²: 98.2%; four studies). The subgroup analysis of antimalarial drugs showed that significant malarial recurrence within 28 days was observed in patients treated with artemisinin-based combination therapies (ACTs) with no significant heterogeneity (p: 0.028, RR: 1.31; 95% CI 1.03-1.66; Cochran Q: 0.834; I²: 0%).

Conclusions: The present findings showed a high prevalence of malarial recurrence after the initial treatment of Plasmodium-mixed infection. Moreover, significant malaria recurrence of mixed infection occurred within 28 days after treatment with ACTs.

Keywords: Artemisinin; Chloroquine; Malaria; Mosquito; Plasmodium; Relapse; Treatment failure.

Fig. 1

Flow chart for the study selection

Fig. 2

Pooled prevalence estimate of malarial recurrence

Fig. 3

Estimated risk of recurrence in patients after treatment of Plasmodium-mixed infection compared to those after treatment of P. falciparum

Fig. 4

Subgroup analysis of recurrence in patients after treatment of Plasmodium-mixed infection

Fig. 5

Subgroup analysis of antimalarial drugs used in patients with all recurrences. IV: intravenous

Fig. 6

Subgroup analysis of antimalarial drugs used in patients with recurrence within 28 days

Fig. 7

Subgroup analysis of clinical signs in patients with all recurrences

Fig. 8

Estimated risk of recurrence in patients after treatment of Plasmodium-mixed infection compared to those after treatment of P. vivax

Fig. 9

Funnel plot analysis