Background
Malaria is a febrile illness caused by protozoans of the genus
Plasmodium. Globally, an estimated 3.3 billion people in 97 countries and territories are at risk of being infected with malaria parasite and developing disease [
1]. Majority of patients present with fever, but fever alone remains a poor discriminator of malaria infection hence the need to confirm or refute the role of malaria in febrile presentation [
2].
Malaria transmission from an infected human host to a female anopheline mosquito is mediated through highly specialized sexual-stage parasites, i.e., gametocytes. The gametocytes of
P. falciparum hold a prominent place in the history of malaria [
3]. Several factors including age, host immune response (including co-infection with other pathogens), host anaemia, insecticide spraying, and mass drug administration are likely to influence the appearance of gametocytes at presentation [
3]. However, clinically immune infections often have lower gametocytemia as a result of having anti-parasite immunity, conferring protection against high-density parasitaemia [
4].
Splenomegaly has been reported as one of the common pathologies among children with multiple parasitic aetiologies [
5]. Splenomegaly which occurs in all forms of malaria with repeated attacks is the main clinical marker of endemicity in
P. falciparum transmission areas [
6]. A palpable spleen has been reported as an independent risk factor for anaemia [
7,
8]. Individuals with either gametocytes or splenomegaly have a reduced mean haemoglobin (Hb) concentration when compared to those without [
3,
9]. Though anaemia is generally used as a measure of the impact of malaria in patients [
10], repeated infections with malaria might not only impair the level of Hb, but also other parameters of the blood and even the whole of the cardiovascular system [
11]. Impairment of cardiovascular parameters as shown by tachycardia and hypotension [
12‐
14] represents a major step towards malaria caused death. There is a paucity of knowledge on the malaria related alteration of cardiovascular indices in children in an endemic setting such as the Mount Cameroon area.
As an intraerythrocytic parasite of the fluid component of the cardiovascular system,
Plasmodium induces haematological alterations involving major cell lines such as RBCs, leucocytes and thrombocytes which may lead to complications in malaria pathology characterised by splenomegaly, anaemia, thrombocytopenia and disseminated intravascular coagulation [
13,
15]. This has been supported by Sumbele
et al. [
8,
16] who reported anaemia among children with malaria as a common haematological state in the Mount Cameroon area. Several studies [
16‐
18] have been conducted on malaria in the Mount Cameroon area, but none on the impact on cardiovascular parameters. Furthermore, most of the cardiovascular findings reported so far are on severe/complicated malaria [
11,
19‐
21]. The aim of this study was to investigate the additive effect of gametocyte carriage in children with malaria parasitaemia on the prevalence of fever and splenomegaly, on blood pressure, heart rate and haematological indices in children living in the Mount Cameroon area.
Discussion
Infection with
P. falciparum is very likely to result in symptoms that include fever and splenomegaly. Even though splenomegaly is one of the main clinical markers of endemicity of malaria in
P. falciparum transmission areas [
19], it is frequently absent during acute infection in non-immune subjects [
7,
30]. The proportion of fever and splenomegaly in communities in malaria endemic regions requires investigation as the proportion of individuals with these conditions who report to health facilities harbouring infection may be higher. This paper in addition investigates the influence of gametocyte carriage on blood pressure, heart rate and haematological indices in children with malaria parasitaemia, living in a
meso endemic community in the Mount Cameroon area.
The overall prevalence of fever (21.6 %) is significantly lower than that reported by Sumbele
et al. [
23] in the same community (28.2 %) in 2006 and comparable to the report of Songue
et al. [
31] during the rainy season in children in communities along the Chad Cameroon pipeline. The decrease in prevalence has been attributed to the intensification of malaria control measures. However, consistent with other findings [
32], the prevalence of fever was higher in children with malaria parasitaemia. The relationship between fever and
P. falciparum parasitaemia depends strongly on season which may thus affect the malaria-attributable fraction of fever cases [
33]. Never the less, fever per se occurred less often in children who were aparasitaemic and malaria parasitaemic children who in addition carried gametocytes recorded the highest prevalence of fever.
Parasite prevalence and level of exposure are closely related and clinically immune infections have been reported to have lower gametocytemia as a result of having anti-parasite immunity, conferring protection against high-density parasitaemia [
4]. The lack of anti-parasite immunity is evident in children of the ≤ 5 years age group who had the highest geometric mean gametocytes/μL of blood than their counterparts. The overall prevalence of gametocytes in the study population was lower (7.3 %) than the 17.49 % reported by Kimbi
et al. [
34] in children in the same area. On the other hand, the gametocyte density was higher (56/μL of blood) than that (23/μL of blood) reported by Kimbi
et al. [
34]. The higher gametocyte density is unusual in an era where amodiaquine-atesunate, an artemisin combination therapy which is gametocidal and significantly lowers gametocyte prevalence and density following treatment [
35] is used as the first line treatment of non severe malaria in Cameroon. This probably brings to light the persistence of low grade malaria parasitaemia in some of the children resulting in the development of gametocytes. The fact that a number of the children with asexual parasites concurrently harboured gametocytes has direct implications for transmissibility. These children probably did not seek treatment and were thus able to carry malaria parasites for longer duration resulting in the development of gametocytes and the ensuing consequences.
The lowered WBC and lymphocyte counts noticed in children harbouring gametocytes and asexual parasite is unusual as the aparasitaemic and those harbouring asexual parasite only had similar mean WBC and lymphocyte counts. However, the observed malaria associated decrease in WBC and lymphocyte counts is in line with the decrease in lymphocyte count in untreated malaria reported by Sumbele
et al. [
16]. Furthermore, the temperature of the child significantly influenced the lymphocyte counts as revealed in the multivariate analysis. At the first look, this is unexpected as lymphocytes, particularly T cells, play a major role in immunity against
P. falciparum malaria by releasing pro- and anti-inflammatory cytokines such as TNF-α, interferon-γ and other cytokines, and activating other inflammatory cells. However, excessive secretion of the pro-inflammatory cytokines contributes to disease severity [
12,
36].
Findings from the multiple linear regression analysis revealed that the presence of gametocytes significantly influenced the Hb, Hct, RBC and systolic pressure. In like manner, a comparison of haematological variables revealed these variables to be significantly lowest in children harbouring both gametocytes and asexual parasites. The reduction in these red cell indices in gametocyte positive children is not unusual as Sumbele
et al. [
8] and Nacher
et al. [
37] reported a strong link between anaemia and gametocyte carriage. The destruction of the oxygen transporter (Hb) and tissue hypoxia leading invariably to erythrocyte destruction is conducive for gametogenesis [
3].
One of the additive significant influences of gametocyte carriage is the lowered systolic blood pressure observed in children who had both asexual parasites and gametocytes when compared with those aparasitaemic and those harbouring only asexual parasites. This may be associated to the fever observed in this group of children. Fever and excessive sweating, accompanied with lack of rehydration, lead to continuous dehydration. During hyperthermia, one of the mechanisms involved in regulating the temperature by the body is vasodilation. This is caused by inhibition of the sympathetic centres in the hypothalamus [
38]. More also, the host immune reaction against malaria parasites involves pro- and anti-inflammatory cytokines as well as mediators like nitric oxide [
12], a major down-regulator of vascular tone [
39‐
41]. The loss of water and the decrease of peripheral resistance (vasodilation) lead to a reduction of blood pressure. Furthermore,
P. falciparum infection is known to cause low platelet levels and disseminated intravascular coagulation with bleeding [
13], resulting in low blood pressure. The significantly low mean platelet count observed in children harbouring gametocytes in comparison with the aparasitaemic and those with asexual parasitaemia only in the univariate analysis was of no consequence in the multivariate analysis.
Observation from the study revealed the presence of mild and very enlarged spleens in the study population. Splenic enlargement has been highlighted as a consequence of malaria parasitaemia [
42] and multiple parasitic aetiologies [
5]. A palpable spleen may arise due to congestion of RBCs, increase in the relative number of macrophages in the spleen, hence leading to an increase in spleen weight associated with expansion of both the red and white pulp [
43]. Splenomegaly was significantly highest in children harbouring both asexual parasite and gametocytes than their counterparts, especially those in the ≤5 years and 6–10 years age groups. In fact, mild and very enlarged spleens were significantly highest in children with ASP + Gam than their AP and ASP Pos counterparts. Further observation from the study revealed the significantly highest prevalence of anaemia to occur in children with splenomegaly concurrently harbouring both asexual parasites and gametocytes. In Cameroon, anaemia remains a major public health problem [
8,
32] and malaria has been frequently associated with haemolysis, anaemia, decreased erythropoiesis and splenomegaly [
8,
44]. The contribution of splenic enlargement to early anaemia of acute malaria through sequestering RBCs in the spleen have been highlighted [
38,
45]. Additionally, findings from another study by Crookston
et al. [
46] reported children who experience anaemia and have splenomegaly are more likely to present asymptomatic malaria. This probably accounts for the prevalence of splenomegaly and anaemia observed in the community where a large proportion of the children with malaria parasitaemia were asymptomatic.
Findings from the study demonstrated a significant influence of the spleen size on red cell indices such as the Hb level, Hct, and RBC while, temperature in addition to the Hb and Hct significantly influenced the MCH. The effects may be attributed to the role of the spleen in clearing infected [
38,
47] and non-infected red blood cells from the circulation [
38] while fever and the inflammatory reaction may shorten RBC survival [
48]. In line with previous studies [
3,
4], a palpable spleen was revealed to be an independent risk factor of anaemia and anaemia is more pronounced in patients with malaria than in other systemic infections [
48]. As anaemia progressively worsens, platelet counts decrease with accompanying splenomegaly suggesting hypersplenism may, at least in part, contribute to thrombocytopenia [
49]. This is in line with the findings of this study as children with splenomegaly were 1.1 (CI = 0.93–1.30) times at odds of having thrombocytopaenia than those with normal spleen.
Although not significant, the heart rate was higher in gametocyte positive children than those aparasitaemic and those having asexual parasites only. As well, the temperature of the child was significantly associated with the heart rate. The significant association of temperature with the heart rate is not unexpected as an increase of only 1 °C raises the heart rate by about 10 beats per minute. This explains the faster heart beats observed in cases with fever [
50]. The higher heart rate in children infected with both asexual and sexual stages of malaria parasites may be a feedback of the heart to the decrease of the cardiac output (CO). In effect, in patients with malaria, the pre-load may decrease or the after-load increases and this might contribute to a decreased CO [
11,
12]. Also, sequestered parasitized RBCs obstruct the microvasculature causing tissue hypoxia [
51], secondary to cytoadhesion of parasite infected red blood cells (RBCs) to vascular endothelium [
11,
52]. In addition, contact of platelet membrane damages endothelial lining of vessels [
53] and the sequestered RBCs undergo haemolysis, increasing anaemia and reduced tissue oxygen provision. Resting heart rate is higher in people with anaemia due to the decreased number of RBCs present in circulation [
54]. Tachycardia is one of the most common symptoms of iron-deficiency anaemia. These results are in line with other findings [
13,
14] showing that impairment of cardiovascular parameters is common in
P. falciparum malaria as the disease gets toward complication. The observed increase of the heart rate could help balance the provision of oxygen to the tissues.
In addition to the gametocytaemia, increased spleen size, the trophozoite count also had significant influence on haematological indices such as MCV and MCH and cardiovascular indices like the heart beats/min. It is worth noting that despite all variations in the hemodynamic parameters, majority of the values remained within normal ranges. However, our findings can serve as a relevant warning signal, highlighting the hidden danger of the impact of gametocyte carriage, asymptomatic malaria parasitaemia and uncomplicated malaria on the cardiovascular system. The fact that some children did not even display signs of malaria infection is a strong proof that regular investigations are invaluable in malaria endemic areas. The more infections are persistent in an area of transmission, the more risky the population will be, irrespective of whether the patient has asymptomatic or uncomplicated malaria.
Competing interests
We the authors declare that we have no competing interests.
Authors’ contributions
IUNS was involved in all phases of the study, including study design, data collection, data analysis, interpretation, and write-up of the manuscript; OSMB was involved in study design, data collection, and write-up of the manuscript; HKK was involved in supervision and revised the manuscript; TRN was involved in the collection and laboratory examination of samples; TNA supervised the study and revised the manuscript. All authors read and approved the final manuscript.
IUNS: PhD and Lecturer of Parasitology, Department of Zoology and Animal Physiology.
OSMB: PhD and Lecturer of Physiology, Department of Zoology and Animal Physiology.
HKK: PhD and Associate Professor of Medical Parasitology, Department of Zoology and Animal Physiology.
TRN: MSc Zoology and PhD candiadate, Department of Zoology and Animal Physiology.
TNA: PhD and Professor of Medical Parasitology, Department of Microbiology and Parasitology.