Abstract
Background
Although, several studies have reported abnormal Mean Corpuscular Volume (MCV) values and anaemia associated with malaria infections with a focus on Plasmodium falciparum among patients with complicated and uncomplicated malaria, none has looked at the association with asymptomatic malaria. This study aimed to assess this association.
Methods
We conducted a cross-sectional study using 3 mL of blood samples from 549 children aged 5–17 years attending 5 schools selected in the Volta Region. Semi-structured questionnaires were administered to the children to obtain demographic data. Blood samples were collected to estimate the children's full blood count (FBC) and malaria status. Data obtained were analysed using STATA 15 software. P-values of less than 0.05 were considered statistically significant.
Results
Most of the children in this study (49.9%) had normal MCV (81.3–91.3 fL) with an overall malaria prevalence of 55.6 % (95% CI: 51.3–59.8) and anaemia prevalence of 48.6% (95% CI 44.4–52.9). Most anaemic children had normal MCV (81.3–91.3 fL) (49.8, 95% CI 43.7–56.0). The predicted probability of malaria was highly likely among children with normal MCV (81.3–91.3 fL) but with high variability and uncertainty among those with low MCV (<81.3 fL) and high MCV (>91.3 fL).
Conclusion
This study shows a reduced predicted probability of malaria among children with low and high MCV, playing a protective function against malaria. Further studies are required to elucidate the interaction.
Introduction
Plasmodium falciparum (P. falciparum) malaria is a serious public health problem that affects millions of people living in endemic areas [1]. The condition is responsible for significant malaria morbidity and mortality, especially among children [1]. In 2020, P. falciparum was responsible for approximately 98% of all the 241 million global malaria cases and 627 thousand malaria deaths, with children under 5 years of age constituting 80% of mortality [2]. P. falciparum is the main species of malaria reported in Ghana. Ghana recorded more than 5 million cases of malaria in 2020, with an estimated 12 thousand deaths with children under 5 years of age constituting a significant proportion of these deaths [3].
Infections with P. falciparum among children often progress to severe or complicated diseases, especially in young children if not promptly and adequately treated [4]. Despite the capacity of P. falciparum to cause severe disease, asymptomatic infections are possible, especially among older children and adults [4]. P. falciparum infection has been associated with various abnormalities in haematological indices, as reported by several studies [5–7]. These haematological indices include white blood cell (WBC) related indices such as total WBC count and its differentials such as neutrophil count and others [5–7]. Red blood cell (RBC)-related indices include haemoglobin (HB) level, mean corpuscular HB (MCH), the mean corpuscular HB concentration (MCHC), the width of red cell distribution (RDW), and mean corpuscular volume (MCV) [5–7].
The MCV is an erythrocyte-related haematological parameter that measures average volume and size of a RBC [8]. It is an important component of the complete blood count (CBC) haematological analysis that aids the clinician to interpret anaemia as a function of RBC size in a patient [8]. Consequently, MCV categorises anaemia into three categories, namely, microcytic anaemia when the MCV value is below normal, normocytic anaemia when the MCV value is normal, and macrocytic anaemia when the MCV value is above the normal range [8]. Although iron deficiency anaemia from whatever condition is the most common reason for low MCV [9], others, such as anaemia of chronic disease [10], sideroblastic anaemia [11], thalassemia [12], and other conditions have been reported to result in low MCV. High MCV, on the other hand, has been found to be caused by or associated with folate and vitamin B12 deficiency, as well as hepatic insufficiency, chronic alcoholism, and others [13]. Infections such as malaria have been associated with an abnormal MCV [8].
Although anaemia with normal MCV has been associated with infections such as malaria [8], many studies have reported abnormal MCV values associated with malaria infections [5, 6]. While many of these studies focused on P. falciparum malaria, many reported on patients with complicated and uncomplicated malaria and none on asymptomatic individuals. It is imperative therefore, to determine if there is a host-parasite relationship in asymptomatic malaria infection and anaemia in infected individuals. Hence, we carried out this study aimed to assess the association between asymptomatic P. falciparum malaria infection, anaemia and the MCV values of school children in Ghana.
Methods
Study site and population
This study was carried out in the Volta Region of Ghana, one of the 16 regions located in the southern part of the country. It is bounded by the Volta Lake and the Eastern Region in the west, Togo on the east, and the Gulf of Guinea to the south. It has 18 districts, with most of its population living in rural areas. The study was carried out in 2 districts and a municipality, namely the predominantly rural districts of Adaklu and Agotime-Ziope and the urban Ho municipality. The study involved 549 children aged 5–17 years in 5 primary schools in these districts and municipalities.
Study design and procedure
The study was a cross-sectional study that involved the administration of questionnaires and the collection of blood samples from the children. The 5 schools were purposefully selected from the urban, peri-urban, and rural areas of the districts. These included Freetown primary selected from the urban Ho municipality, Evangelical Presbyterian primary schools in Afegame and Kpetoe, in the Agotime-Ziope district, and Davanu primary schools in the Adaklu district representing the rural areas as well as Dave primary school in the peri-urban area of Adaklu districts close to Ho municipality. Questionnaire administration and blood sample collections took place from 14 March to 14 April 2016, between 9:30 am and 3 pm each day.
Sample size calculation
In this study, a minimum sample size of 335 was calculated using the Cochrane formula for sample size at a 95% confidence level and a 5% margin of error, with an existing malaria prevalence of 67.8% among school children in Adaklu and Agotime-Ziope districts in Volta Region [14].
Sample collection and laboratory procedure
Details of data collection for this study have previously been reported elsewhere [15, 16]. Briefly, 3 mL of blood was obtained from the median cubital vein into an appropriately labelled dipotassium ethylenediaminetetraacetic acid anticoagulant (K2EDTA) tube and transported to a designated laboratory for analysis on the same day of collection. Before sample collection, questionnaires were administered to the children to obtain information on their age, sex, location, and with whom the child stayed. Blood samples were tested for malaria as well as automated estimation of participants' full blood count (FBC). For the detection of malaria parasites, a thick blood film for malaria parasites was prepared, fixed in absolute methanol, air-dried, and then subsequently stained with Romanowsky Giemsa for microscopy. A slide with asexual forms of the malaria parasite was considered positive, whereas the absence of malaria parasites after 200 high-power fields were examined was considered negative. Two microscopists independently examined the slides for the presence of the malaria parasite. A third microscopist with malaria microscopy competency level one (defined as the scientist ability to detect 90% of malaria parasitaemia in 40 positive slides, identify 90% of malaria species in 20 positive slides and quantify parasites within 25% of true counts in 15 slides) [17], was called for a review to give a final opinion. FBC estimation was performed using an automated haematology analyser (Sysmex, Kakogawa, Japan). The normal reference range for MCV from the FBC was 80–100 fL. However, for the purpose of this study, because of the age and sex variation of the children studied, the reference range of the MCV values was re-classified into quartiles, where low MCV was defined, as values below the lower quartile (MCV <81.3 fL), normal as values between the lower and upper quartile (MCV between 81.3 and 91.3 fL), and high as values above upper quartile (>91.3 fL).
Anaemia was classified, according to the WHO classification for diagnosing and classifying anaemia as HB < 11.5 g dL−1 for children aged 5–11 years, HB < 12 g dL−1 for 12–14 years and nonpregnant females ≥15 years, and HB < 13 g dL−1 for males ≥15 years [18].
Quality control measures
Thorough quality control checks to ensure the accuracy and precision of the haematology analyser (Sysmex, Kakogawa, Japan) before running the samples of the study participants were carried out, strictly adhering to the manufacturer's instruction by running the manufacturer's provided quality-controlled samples. Also, malaria-positive, and negative blood films from known malaria-positive and negative blood samples were prepared and used for quality control of the 10% Giemsa stain. Two qualified parasitologists independently examined 15% of both positive and negative well-prepared randomly selected slides. A third and final opinion from a third senior parasitologist with malaria microscopy competency level one, was sought in the instance of any discrepancy in the two initial examinations. It was adjudged that the Giemsa stain was good following consistency in the microscopic outcomes.
Statistical analysis
The data obtained from this study were entered into Microsoft Excel 2016 for cleaning and consistency checks. Data was then coded and transported to STATA 15 software for statistical analysis. Simple cross-tabulation was performed to produce frequencies and percentages of variables of interest. Pearson Chi-square test was used to determine the sociodemographic differences in the sex distribution of the study participants. The Clopper-Pearson test statistic was used to determine the 95% confidence interval of relevant variables of interest. Pearson correlation coefficient analysis was performed to assess the strength and direction of the association between the participants' malaria status and MCV, haemoglobin, age, sex, and location. Using the post-estimation analysis margins plot, the predicted probability of malaria with increasing MCV was assessed and presented graphically. All analytical outcomes with P-values less than 0.05 were considered statistically significant.
Ethical clearance
Ethical approval for this study was obtained from the Ghana Health Service Ethics Committee (GHS-ERC: 29/11/15). Before enrolment into the study, written informed consent was also obtained from the parents of the children, as well as signed assent forms by the children.
Results
This study recruited 549 children comprising 300 (54.6%) females. Most of the children were 9–11 years (37.9%) and in lower primary (51.2%) at the time of this study. Most of the males were aged 9–11 years (41.4%), whereas most of the females were between 12 and 14 years old (35.7%). However, almost equal proportions of children lived in urban (38.1%) and rural (36.6%) communities, whereas most of the males (41.1%) lived in rural communities, and most females (40.7%) lived in urban settings. In this study, both male (59.0%) and female (58.3%) children generally lived with both parents (Table 1).
Sex distribution of study participants stratified by sociodemographic characteristics
| Parameters | Total n (%) | Sex of school child n (%) | P-value | |
| Male | Female | |||
| Overall | 549 (100%) | 249 (45.4) | 300 (54.6) | |
| Age, years | ||||
| 15–17 | 55 (10.0) | 30 (12.0) | 25 (8.3) | |
| 12–14 | 174 (31.7) | 67 (26.9) | 107 (35.7) | |
| 9–11 | 208 (37.9) | 103 (41.4) | 105 (35.0) | |
| 6–8 | 110 (20.0) | 48 (19.3) | 62 (20.7) | |
| 1–5 | 2 (0.4) | 1 (0.4) | 1 (0.3) | 0.15 |
| Location | ||||
| Urban | 209 (38.1) | 87 (34.9) | 122 (40.7) | |
| Peri-urban | 139 (25.3) | 59 (23.7) | 80 (26.7) | |
| Rural | 201 (36.6) | 103 (41.1) | 98 (32.7) | 0.11 |
| Child stays with | ||||
| Father | 24 (4.4) | 15 (6.0) | 9 (3.0) | |
| Mother | 79 (14.4) | 38 (15.3) | 41 (13.7) | |
| Both parents | 322 (58.7) | 147 (59.0) | 175 (58.3) | |
| Grandparents | 69 (12.6) | 30 (12.0) | 39 (13.0) | |
| Others | 55 (10.0) | 19 (7.6) | 36 (12.0) | 0.22 |
This study recorded an overall malaria prevalence of 55.6% (95% CI: 51.3–59.8), higher among males, 61.5% (95% CI: 55.1–67.5) than observed among their female counterparts. Most of the children (49.9%) had their MCV falling between the first and third quartile (81.3–91.3 fL). The prevalence of malaria was higher among both males (56.2%, 95% CI: 48.0–64.2) and females (50.0%, 95% CI: 41.8–58.2) whose MCV fell within 81.3–91.3 fL. The prevalence of malaria also predominated among children who lived in rural communities (74.1%) than among those in urban and peri-urban communities. Although malaria prevalence was high among females from the urban communities (57.1%), a higher prevalence of malaria was observed among males in the rural communities (45.0%). Overall anaemia prevalence in this study was 48.6% while anaemia among malaria-positive children was 47.9%. The results show a consistently higher prevalence of malaria in children with MCV falling between the first and third quartile (Table 2).
Haemoglobin and sex distribution of malaria prevalence stratified by quartiles of MCV
| Parameters | Total | Quartile of MCV | ||
| LQ ≤81.2 fL | LQ-UQ 81.3–91.3 fL | UQ ≥91.4 fL | ||
| Overall, n (%) | 549 | 138 (25.1) | 274 (49.9) | 137 (25.0) |
| n (%) (95% CI) | n (%) (95% CI) | n (%) (95% CI) | n (%) (95% CI) | |
| Haemoglobin (total population) | ||||
| Low | 267 (48.6) (44.4–52.9) | 69 (25.8) (20.7–31.5) | 133 (49.8) (43.7–56.0) | 65 (24.3) (19.3–29.9) |
| Normal | 282 (51.4) (47.1–55.6) | 69 (24.5) (19.6–29.9) | 141 (50.0) (44.0–56.0) | 72 (25.5) (20.5–31.0) |
| Malaria cases | ||||
| Overall | 305 (55.6) (51.3–59.8) | 73 (23.9) (19.3–29.1) | 162 (53.1) (47.3–58.8) | 70 (23.0) (18.4–28.1) |
| Sex | ||||
| Males | 249 | 62 (24.9) (19.7–30.8) | 134 (53.8) (47.4–60.1) | 53 (21.3) (16.4–26.9) |
| Malaria Positive | 153 (61.5) (55.1–67.5) | 38 (24.8) (18.2–32.5) | 86 (56.2) (48.0–64.2) | 29 (19.0) (13.1–26.1) |
| Females | 300 | 76 (25.3) (20.5–30.7) | 140 (46.7) (40.9–52.5) | 84 (28.0) (23.0–33.4) |
| Malaria Positive | 152 (50.7) (44.9–56.5) | 35 (23.0) (16.6–30.5) | 76 (50.0) (41.8–58.2) | 41 (27.0) (20.1–34.8) |
| Malaria positive by residence and sex | ||||
| Urban | 98 (46.9) (40.1–53.9) | 33 (33.7) (24.4–43.9) | 51 (52.0) (41.7–62.2) | 14 (14.3) (8.0–22.8) |
| Male | 42 (42.9) (32.9–53.3) | 13 (31.0) (17.6–47.1) | 25 (59.5) (43.3–74.4) | 4 (9.5) (2.7–22.6) |
| Female | 56 (57.1) (46.7–67.1) | 20 (35.7) (23.4–49.6) | 26 (46.4) (33.0–60.3) | 10 (17.9) (8.9–30.4) |
| Peri-urban | 58 (41.7) (33.4–50.4) | 12 (20.7) (11.2–33.4) | 30 (51.7) (38.2–65.0) | 16 (27.6) (16.7–40.9) |
| Male | 29 (50.0) (36.6–63.4) | 5 (17.2) (5.8–35.8) | 18 (62.1) (42.3–79.3) | 6 (20.7) (8.0–39.7) |
| Female | 29 (50.0) (36.6–63.4) | 7 (24.1) (10.3–43.5) | 12 (41.4) (23.5–61.1) | 10 (34.5) (17.9–54.3) |
| Rural | 149 (74.1) (67.5–80.0) | 28 (18.8) (12.9–26.0) | 81 (54.4) (46.0–62.5) | 40 (26.8) (19.9–34.7) |
| Male | 82 (55.0) (46.7–63.2) | 20 (24.4) (15.6–35.1) | 43 (52.4) (41.1–63.6) | 19 (23.2) (14.6–33.8) |
| Female | 67 (45.0) (36.8–53.3) | 8 (11.9) (5.3–22.2) | 38 (56.7) (44.0–68.8) | 21 (31.3) (20.6–43.8) |
| Haemoglobin (Malaria case) | ||||
| Low | 146 (47.9) (42.1–53.6) | 33 (22.6) (16.1–30.3) | 79 (54.1) (45.7–62.4) | 34 (23.3) (16.7–31.0) |
| Normal | 159 (52.1) (46.4–57.9) | 40 (25.2) (18.6–32.6) | 83 (52.2) (44.1–60.2) | 36 (22.6) (16.4–29.9) |
LQ-Lower quartile, UQ-Upper quartile.
As shown in Table 3, malaria exhibited a very weak, reverse, and non-significant association with MCV (r = −0.030; P-value = 0.477) and age including a significant weak and negative association with the sex of the child. Malaria, however, showed a very weak but positive association with haemoglobin (r = 0.015; P-value = 0.720) but this association was not statistically significant. However, the location of the children significantly correlated positively with their MCV (r = 0.116; P-value = 0.006) and malaria (r = 0.235; P-value = <0.001).
Pearson correlation between malaria and MCV and sociodemographic characteristics
| Parameters | Mean corpuscular volume (fL) | Haemoglobin | Age | Sex of school child | Location |
| Malaria | −0.030 | 0.015 | −0.045 | −0.108* | 0.235** |
| P-value | 0.477 | 0.720 | 0.290 | 0.011 | <0.001 |
| Location | 0.116** | 0.064 | −0.038 | −0.083 | 1 |
| P-value | 0.006 | 0.133 | 0.368 | 0.052 |
**Correlation is significant at P < 0.01.
*Correlation is significant at P < 0.05.
Figure 1 below presents the predicted probability of malaria with increase in MCV. Generally, the probability of malaria infection as a function of MCV was consistently higher among females than males. The results show that the predicted probability of malaria was highly likely, around 0.28 for males and 0.45 for females whose MCV fell within the first and third quartile. The large confidence intervals for the predicted probability of malaria in MCVs below the lower quartile (81.3 fL) and above the upper quartile (91.3 fL) suggest a reduction in the predicted probability of malaria at these MCVs.
Predicted probability of malaria with advancement in MCV
Citation: European Journal of Microbiology and Immunology 14, 2; 10.1556/1886.2024.00007
Discussion
Most of the children (50%) in this study had their MCV values within the normal reference range, some manifesting low (25%) and high (25%) MCV values. Anaemic children in this study were in the minority (49%), and they mainly had normocytic anaemia (50%), with 26% and 24% of the children showing microcytic and macrocytic anaemia respectively. Although microcytic anaemia is a common finding among children, especially in Africa [19–21], it was not the most prevalent type of anaemia in this study since most of the children had normocytic anaemia. Retrospective hospital-based studies in the Volta Region Ghana, and Hawassa Ethiopia reported microcytic anaemia as the most prevalent anaemia seen in children visiting the hospital [22, 23]. The contrasting findings might be due to differences in study populations, with hospital-based studies dealing with sick children under the age of 5 years, while our study was focused on apparently healthy older children in the community. The most common cause of microcytic anaemia in children, especially those in Africa, is nutritional iron deficiency [19, 24], a finding that has been earlier reported in a study conducted among children in the same district as our study [14]. Our present study did not assess nutritional anaemia in the study population, however nutritional iron deficiency anaemia is reportedly common among children in the district [14]. Macrocytic anaemia, although it had the same prevalence as microcytic anaemia in this study, is a relatively rare occurrence among children [21]. Ghana and Ethiopian studies reported zero and less than 6% prevalence, respectively, for macrocytic anaemia [22, 23].
In this study, there was a high prevalence (56%) of asymptomatic P. falciparum, which is not an uncommon finding in malaria-endemic areas [25, 26]. Most of these children (53%) with asymptomatic malaria had MCV values within the normal reference range (81.3–91.3 fL). This contrasts with some other studies that have reported high MCV [5] and low MCV with malaria [6, 27]. These studies were carried out among adults with clinical malaria compared to our study that focused on asymptomatic school-going children. This might be one of the reasons for the contrasting findings between the studies. However, malaria has been reported to be often associated with a normal reference range of MCV [8] and normocytic anaemia, although some instances of microcytic anaemia may be seen in areas where alpha and beta thalassemia traits with iron deficiency are prevalent [28].
This study revealed a very weak association between asymptomatic malaria and MCV (r = −0.030; P-value = 0.477). However, we noticed a reduced predicted probability of malaria with an MCV below 81 fL but an increased predicted probability of malaria as MCV goes high beyond 91 fL. Although evidence from our analysis indicates a general increase in the predicted probability of malaria with advancement in MCV, we noticed increased variation and uncertainty in the estimates below and above the normal range of MCV evidenced by the increased confidence intervals of the estimates. Consequently, malaria appears more predictable in the normocytic range of MCV (81.3–91.3 fL) due to the much smaller confidence intervals (Fig. 1). These findings might suggest that normal MCV may favour or increase the risk of malaria infection. In contrast, low and high MCV appears to proffer a protective function against malaria.
The conventional knowledge that iron deficiency, which often manifests as low MCV, is somewhat protective against malaria infection [29–31] supports the finding of this study. Iron deficiency anaemia, low MCV, and sickle cell disease, have been found to be evolutionary protective mechanisms against malaria, seen mostly in people of African descent where malaria is endemic [30]. A study in Ghana discovered lower MCV values among children in areas of low malaria transmission intensity compared to areas of higher transmission intensity [32]. The Plasmodium parasite requires iron for its asexual proliferation in humans, and it can get this from RBCs with adequate HB, as seen in normal MCV [29–31]. Iron supplementation has also been reported, to worsen the severity of malaria [29, 31].
In the case of macrocytosis, there is limited report on its protective role against malaria, however, the increase in the size of the RBCs might interfere with the integrity of the cytoskeleton of the red cell membrane, a mechanism that has been reported to impede RBC invasion of the Plasmodium parasite [30]. Malaria has also been reported, to cause macrocytosis or megaloblastic anaemia [33, 34], with a case report showing asymptomatic P. falciparum infection causing megaloblastic anaemia in a 7-year-old boy with pancytopenia [34].
Although our findings did not point to an appreciable association between MCV and asymptomatic P. falciparum infection among the children studied, the dynamism observed as regards the variability in the predicted probability of malaria, normocytosis and abnormal MCV values is worthy of note and warrants consideration in the discussion of the complex interaction between MCV/anaemia, and asymptomatic malaria.
In this study, we assumed conditional independence of our variables that may not hold for our dataset, as there may be some hidden factors or dependencies which affect the relationship between our variables that are not accounted for by the conditioning variable. Therefore, our calculations may be biased or inaccurate due to the influence of potential confounding factors. This is a limitation of our study that should be considered when interpreting our results. Further studies should employ more rigorous tests and analyses to verify the conditional independence assumption and to account for possible sources of dependence.
Conclusion
In this study, majority (49.9%) of the children had their MCV value within the normal reference value. Children with anaemia were the minority (48.6%), and they were majorly normocytic anaemia (49.8%). Most of the children (55.6%) had asymptomatic P. falciparum infection, with most of them (53.1%) having MCV values in the normocytic range. Whereas there was a notable variation and uncertainty in the predicted probability estimates of malaria among children with MCV values below and above the normal range of MCV, the estimates were more consistent and predictable in the normocytic range of MCV (81.3–91.3 fL), suggestive of a higher likelihood of malaria with normal MCV values. A more robust longitudinal study is required to elucidate further the intricacies in the interaction between MCV and asymptomatic P. falciparum infection.
Funding
This study was not funded.
Authors contribution
Conceptualization: VN. Orish.
Writing-Original draft: VN. Orish PK Kwadzokpui, SY Lokpo, R Safianu.
Writing-Reviewing and Editing: R Izurieta, R Pandit, A Marinkovic, S Prakash.
Data analysis: PK Kwadzokpui, C Okorie, A Sanyaolu.
Conflict of interest
The authors declare no conflict of interest.
Data sharing
Available upon request.
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