Background
Malaria is a public health problem, with an estimated 219 million cases in 87 countries, and 435,000 malaria-related deaths were estimated in 2017 [
1]. The highest prevalence is in the World Health Organization (WHO) African Region [
1]. There are five major
Plasmodium species which can infect human beings, including
Plasmodium falciparum,
Plasmodium vivax,
Plasmodium malariae,
Plasmodium ovale, and
Plasmodium knowlesi [
2]. The transmission of malaria in humans occurs through the bite of a female
Anopheles mosquito [
2]. In addition, blood transfusion and maternal transmission have been demonstrated as other routes of malaria infection with less frequent occurrences [
3].
Most malaria diseases in humans are caused by
P. falciparum and
P. vivax [
4]. Both species were geographically present in the southeastern and western Pacific regions, with a higher distribution of
P. falciparum than
P. vivax in Africa, while
P. vivax is more prevalent than
P. falciparum in South America [
5].
P. ovale infection is widespread principally in tropical Africa, whereas
P. knowlesi infection occurs only in certain forested areas of Southeast Asian countries [
5].
P. malariae is frequently co-endemic with
P. falciparum in sub-Saharan Africa, South America, Indonesia, Southeast Asia, and the western Pacific [
6]. A previous study found that 7.4% of
P. malariae infections were mixed infections with
P. falciparum [
7].
Severe malaria is any complication of
Plasmodium species infection that develops rapidly and leads to death within hours or days [
8], and these complications were listed by the WHO [
9]. Most severe malaria-related deaths are caused by
P. falciparum, while
P. vivax or
P. ovale can also induce severe complications resulting in death but less frequently than
P. falciparum [
10]. Severe malaria is a rare complication that occurs in patients with
P. malariae infection [
11], including acute kidney injury [
12‐
15], cerebral malaria [
16], and prostrated and multiple convulsions [
17]. This is the first systematic review and meta-analysis to demonstrate the prevalence of severe
P. malariae infection among patients using articles published in three research databases.
Discussion
This is the first systematic review and meta-analysis demonstrating the pooled prevalence estimate of severe
P. malariae infection. The results demonstrated that the pooled prevalence estimate of severe
P. malariae malaria was low (3%). These results were in accordance with a previous study indicating that severe
P. malariae infection was a rare complication with less frequent occurrence in malarial patients [
11]. The mechanism of severe malaria among
P. malariae infections is unknown.
P. malariae is a slow-growing parasite infecting mature red blood cells [
28]. It can result in a lower number of merozoites produced per 72-h erythrocytic cycle, called quartan or tertian malaria, inducing the earlier development of human immunity [
6].
P. malariae is not the cause of malarial relapse from persistent liver-stage parasites, but the recrudescence of blood-stage parasites can persist for long periods without signs or symptoms. Even with appropriate treatment, chronic subclinical
P. malariae infection can occur because of its extended prepatent period when the inadequate drug in the blood cannot eliminate newly emerging merozoites [
28,
29]. As most patients infected with
P. malariae infections have no sign or symptoms of malaria, they have no need for health services during their asymptomatic infection [
30]. Even though patients suspected of having
P. malariae infections visit the health service,
P. malariae parasites are missed by light microscopy due to their low parasite density compared to that of
P. falciparum parasites [
31,
32]. It is also difficult to distinguish
P. malariae from other
Plasmodium species using a microscopic method, and its prevalence may be underestimated, resulting in late disease presenting severe complications [
17,
33]. In addition,
P. malariae infection can easily be misdiagnosed when microscopy is used for detection and is often treated as a bacterial infection [
12]. The detection of
P. malariae by microscopy in patients with mixed infection with
P. falciparum in endemic areas where
P. falciparum predominates is also difficult, as, in the area of malaria endemicity in Africa, infections of
P. malariae can frequently be mixed with
P. falciparum infections [
6]. Another possible cause of severe malaria in patients with
P. malariae infection is rosette formation, i.e., the binding of two or more infected red cells to an uninfected red cell, which is associated with microcirculatory blood flow obstruction in
P. falciparum infection and has been reported in patients with
P. malariae infection [
17].
The present systematic review and meta-analysis demonstrated that severe anaemia was the most common complication in patients with
P. malariae infection, as reported by the included studies. The included study by Douglas et al. [
21], demonstrated that the proportion of severe anaemia in
P. malariae infection was lower than that in non-
P. malariae infection. They indicated that
P. malariae infection was associated a lower mean haemoglobin level than infection with other
Plasmodium spp., [
21]. The included study by Langford et al., 2015, enrolled 5097 patients with
P. malariae infections and demonstrated that the mean haemoglobin concentration was lower (9.0 g/dl) in patients with
P. malariae infection than in those with infection with all other
Plasmodium species [
22]. Nevertheless, the lower haemoglobin concentrations associated with a greater risk of death were reported in patients with
P. falciparum infection [
21]. This causation of anaemia in malarial patients might be due to the higher parasitaemia level of
P. falciparum and potentially cause a rapid drop in haemoglobin [
21]. Previous studies suggested that the severe anaemia during
P. malariae infection might be due to prolonged erythrocyte destruction and bone marrow suppression with a minimal reduction of erythrocyte lifespan by a low parasitaemia level [
21,
22,
34]. It should be noted that most patients with
P. malariae infection in the included studies were Highland Papuans, who are the ethnic group with the highest risk of severe anaemia caused by nutritional and haematological factors [
22]. These factors can potentially contribute to the lower mean haemoglobin level in these patients, as the risk of severe anaemia in
P. malariae infections was similar to that for
P. falciparum and
P. vivax infections after adjusting for ethnicity in the multivariable model [
22].
Regarding the age distribution of patients with
P. malariae infection, the included study by Langford et al., clarified that most patients with
P. malariae infections were aged more than 15 years, which was older than those with
P. falciparum,
P. vivax, and mixed infections, reflecting the low transmission intensity in Indonesia [
22]. A low number of patients with
P. malariae infections were aged less than 5 years (10.9%), the most vulnerable group affected by malaria [
35]. This systematic review and meta-analysis indicated that pulmonary complications and renal impairment were frequently found in patients with
P. malariae infection. The mechanism of pulmonary complications in patients with severe
P. malariae infection is unknown. Lung injury in
P. malariae malaria might be caused by microvascular sequestration, similar to
P. falciparum infection, which can increase vascular permeability, resulting in fluid loading and progression to pulmonary oedema [
36]. Nevertheless, further study is needed to investigate whether red blood cells parasitized with
P. malariae cytoadhere to endothelial cells of humans.
Renal impairment and nephrotic syndrome were commonly present in patients with
P. malariae infection, with a mixed IgM and IgG immune complex located at the renal basement membrane [
37].
P. malariae infection has long been recognized as the causative agent of nephrotic syndrome among untreated
P. malariae infections [
29,
38‐
40]. In addition, albuminuria was commonly seen in patients treated with
P. malariae for neurosyphilis in the 1930s [
41]. Nevertheless, the included study by Langford et al. demonstrated a very low prevalence of nephrotic syndrome (0.1%) among 5097 enrolled patients with
P. malariae infections [
22]. Although a lower prevalence of nephrotic syndrome occurred in
P. malariae infections, the proportion of nephrotic syndrome was higher in
P. malariae infection than in infections with the other
Plasmodium species [
22]. Previous studies demonstrated that
P. malariae-induced nephrotic syndrome can lead to progressive renal failure, particularly in young adults [
42,
43].
P. malariae-induced acute renal failure after treatment with quinine was reported previously. In this case, treatment with intravenous quinine and four rounds of renal dialysis improved the renal function of the patient [
12]. An unusual case of transfusion-transmitted
P. malariae infection in an individual with thalassemia major remained undiagnosed for several months, and the individual eventually developed acute renal failure [
15].
Severe malaria caused by
P. malariae infection is infrequent and is caused by multiple susceptibility genes: genes related to inflammation, including tumour necrosis factor (TNF), interleukin-6 (IL-6) and IL-10, macrophage migration inhibitory factor (MIF), angiotensin-converting enzyme (ACE), and catalase; genes for coagulation factors, including plasminogen activator inhibitor (PAI)-1; fibrinogen; coagulation factors II, V, VII, and XIII; and genes related to innate immunity, including toll-like receptor (TLR)-2, TLR-4, TLR-5, mannose-binding lectin (MBL), interleukin 1 receptor associated kinase 1 (IRAK-1), cluster of differentiation-14 (CD-14), toll interleukin-1 receptor-associated protein (TIRAP), and Nf-κB inhibitor (IκB) [
13]. In addition, a previous study indicated that five important genes, including IRAK-1 rs1059703, CD-14 rs2569190, TNF-beta rs909253, IL-6 rs1800795, and MIF rs755622, were associated with the increased severity of multiple organ dysfunction syndrome in a case of
P. malariae infection [
44].
The present systematic review and meta-analysis had several limitations. First, the number of included studies was limited, which might affect the pooled estimate of severe
P. vivax malaria prevalence globally. Second, although severe
P. malariae infection was associated with a high burden of severe anaemia, the quantitative analysis of haemoglobin concentrations in
P. malariae infection could not be performed, as it was reported quantitatively only in the included study by Douglas et al. [
21]. Third, nephrotic syndrome and albuminuria could not be analysed, as only the included study by Langford et al. [
22] reported the number of
P. malariae infections with nephrotic syndrome. Fourth, the age distribution of patients with
P. malariae infections could not be analysed, as only the included study by Langford et al. reported the age distribution of patients with
P. malariae infections. Fifth, the parasitaemia level related to severe
P. malariae infection could not be analysed, as only the included study by Bottieau et al. [
26] reported the parasitaemia level. In view of all results, although the present study reported a low prevalence of severe
P. malariae infection, those with
P. malariae infection need to be investigated for anaemia and, if present, treated aggressively to prevent anaemia-related death.
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