Malaria is a parasitic infection that is caused by the Plasmodium species which is transmitted through a bite of the female Anopheles mosquito [1] . The five common species of the Plasmodium spp that cause malaria in humans are Plasmodium falciparum, Plasmodium ovale, Plasmodium vivax, Plasmodium malariae, and Plasmodium knowlesi [2] . Among these, Plasmodium falciparum and Plasmodium vivax are associated with severe forms of malaria, the former being the most lethal [2] . P. falciparum accounts for 80% - 90% of cases of malaria in Africa while the remaining 8% and 2% - 3% are caused by P. ovale and P. malariae respectively [3] .

Malaria affects over 55% of the world’s population which cuts across 124 countries, 90% - 95% of which are in Sub-Saharan Africa [4] [5] . Recent World Health Organisation (WHO) data in 2020 estimated 241 million cases of malaria worldwide with Africa accounting for about 96% of all the cases and over 627,000 deaths occurring annually from malaria worldwide of which about 95% were from the African region [4] [5] . About one out of every five deaths of under-five children worldwide is due to malaria [4] . In Nigeria, malaria affects up to 97% of the population with 100 million cases and up to 300,000 deaths annually [4] [6] . The majority of these deaths occur in under-five children [7] . Malaria also accounts for up to 60% of outpatient visits and 30% of hospitalizations among under-five children [5] . The Southwestern region of Nigeria accounts for the highest number of malaria cases among under-five children in Nigeria with a prevalence of 50.3% compared to Southeastern Nigeria which has the lowest prevalence of 27.6% [5] .

Malaria could either be uncomplicated when an individual presents with symptoms suggestive of malaria and a positive parasitologic test or severe when it is accompanied by or leads to complications that are life-threatening [8] . The complications include severe anaemia, cerebral malaria, hypoglycaemia, acute kidney injury, pulmonary oedema, haemoglobinuria, metabolic acidosis, algid malaria, and hyperparasitemia [9] [10] [11] . Severe anaemia and cerebral malaria are however the most common severe forms of malaria among children with cerebral malaria being responsible for the highest proportion of malaria mortality [12] [13] .

Studies have consistently documented some ophthalmologic findings in cerebral malaria which include absence of corneal reflex, pupillary constriction, poor reaction to light, and retinal changes [14] [15] . These retinal changes were found to be of prognostic value in children with severe malaria. Some of these retinal changes include whitening of the retina and macula, orange discolouration of retinal vessels, papilloedema, and retinal haemorrhages [16] [17] . Oluwayemi et al. [18] in a study in Nigeria reported that retinal haemorrhage was significantly associated with higher mortality in cerebral malaria subjects. Similarly, Essuman et al. [19] in a study in Ghana concluded that the severity of retinal haemorrhages and papilloedema may be useful in predicting the likelihood of death in cerebral malaria. Singh et al. [17] in a study in India observed that papilloedema and retinal haemorrhages were predictors of mortality. Maude et al. [20] believed that the retinopathy seen in cerebral malaria and other forms of severe malaria are manifestations of the same pathophysiological mechanisms occurring at different anatomical sites. Therefore, it is possible that these retinal changes could also be occurring in other forms of severe malaria apart from cerebral malaria and could probably precede the clinical manifestations of severe malaria [20] [21] .

Identification of the ophthalmoscopic changes in severe malaria as well as uncomplicated malaria could heighten the alertness of clinicians in children and therefore the need for early and appropriate interventions to prevent mortality. There is a dearth of studies on ophthalmoscopic changes in severe malaria and uncomplicated malaria in this environment which is an endemic region for malaria. This study was, therefore, carried out to identify and compare the ophthalmoscopic changes between severe malaria and uncomplicated malaria and also to determine the factors associated with the ophthalmoscopic changes. This study will, therefore, help to determine the importance of fundoscopy in all patients with severe and uncomplicated malaria to engender early treatment and better outcomes. Findings from this study will provide additional information on the ophthalmoscopic features of a wider range of malaria which may then inform the need for the inclusion of ophthalmoscopy in the assessment of all cases of malaria.

Study design: This was a hospital-based comparative cross-sectional study.

Study site: This study was carried out at the Children Emergency Room (CHER) and Children Out-patient (CHOP) units of the Paediatrics Department, Federal Medical Centre (FMC), Owo, Ondo state. The FMC, Owo is a tertiary hospital that serves as the referral centre for Ondo state as well as some adjoining states of Edo, Osun, Ekiti, and Kogi. Owo is a semi-urban town with a population of about 300,000 people according to the National Population Commission [22] . Owo town is located within the south-west geo-political zone of Nigeria and lies within latitude 7.1833˚N and longitude 5.5833˚E which is within the malaria endemic belt of the world [22] [23] . The people of the town are mostly traders, farmers, and civil servants.

Study population: The case group was children between the ages of six months and five years that were admitted to the CHER with features of severe malaria including palor, convulsions, loss of consciousness, the passage of coke-coloured urine, prostration, jaundice, shock, abnormal bleeding caused by asexual forms of P. falciparum while the control group were age and sex-matched children with uncomplicated malaria caused by asexual forms of P. falciparum seen at the CHOP. Children with chronic illnesses like sickle cell disease, diabetes, and hypertension that affect the eyes were excluded from the study.

Study duration: November 2020 to August 2021.

Ethical consideration: Approval for the study was obtained from the Federal Medical Centre, Owo Ethics and Research Committee with number FMC/OW/380/VOL.CXXXVL/98. Written informed consent was obtained from the caregiver of each of the subjects that were recruited for the study

Sample size estimation

The sample size for this study was determined using the formula by Charan and Biswas [24] .

N = ( Z α + Z β ) 2 { p 1 ( 1 − p 1 ) + p 2 ( 1 − p 2 ) } ( p 1 − p 2 ) 2

N = Minimum sample size.

P₁ = Proportion with malaria retinopathy in severe malaria group is 0.70.

P₂ = Proportion of malaria retinopathy in uncomplicated malaria is 0.50.

Z_α = Standard normal deviate corresponding to level of significance (usually 5%) i.e. 1.96.

Z_β = Standard normal variate for power of 90% is 1.28.

N = ( 1.96 + 1.28 ) 2 { 0.7 ( 1 − 0.7 ) + 0.5 ( 1 − 0.5 ) } ( 0.7 − 0.5 ) 2

N = 120.7.

Applying an attrition rate of 5%, the minimum sample size was 130 for each of the severe and uncomplicated malaria groups.

Sampling technique: All consecutive admissions into the children’s emergency room and visits to the children’s outpatient clinics were noted. Those whose ages were between six months to five years and who met the inclusion criteria for severe malaria were recruited into the severe malaria group. They were tested for the presence of an asexual form of Plasmodium falciparum using the microscopy method. Those that tested positive for the asexual form of Plasmodium falciparum and whose parents had given consent were recruited into the study until the sample size was completed.

For the uncomplicated malaria group, all children between the ages of six months and five years presenting at the Children’s outpatient with fever and any other symptoms related to malaria were tested for the asexual form of Plasmodium falciparum using the microscopy method. Only those in whom the parasite was detected on microscopy were recruited.

Two hundred and six patients were admitted for different forms of severe malaria during the study period out of which one hundred and thirty (63.1%) that met the inclusion criteria were recruited into the severe malaria group. The demographic distribution and nutritional status of the study participants is as shown in Table 1. The predominant age group was age 13 - 24 months (26.9%) while only 12.3% were age group 37 - 48 months. The overall mean age of all participants was 30.1 (±18.1) months. About two-thirds (66.1%) of subjects in the severe malaria group were below 36 months. The mean ages of uncomplicated and severe malaria groups were 29.5 (±18.0) months and 30.8 (±18.4) months respectively. There was no statistically significant difference in the mean ages of the two groups (t = 0.556, p = 0.578). The male to female ratio was 1.2:1 for the study participants, but slightly higher (1.3:1) for the severe malaria group. Majority of the study participants have normal weight (72.7%) and height (79.2%). There were no statistically significant differences in the age, gender and nutritional status of the subjects in the two study groups.

*Fischer’s Exact test was used; **Figures in parenthesis are percentages of column total.

Three (2.3%) subjects died among the severe malaria group during the course of the study of which one (0.8%) had cerebral malaria while two (1.5%) had severe anaemia. One of the severe anaemia subjects had retinal whitening (0.8%) while the remaining two had no retinopathy. All three subjects died within 24 hours of hospital presentation.

None of the twenty three subjects with malaria retinopathy had resolution at 24 hours of treatment while eighteen (78.3%) had resolution at 48 hours of admission. The remaining five (21.7%) were discharged home with retinopathy but were lost to follow-up.

This study was undertaken to identify and compare malaria retinopathy in different forms of severe malaria and uncomplicated malaria as well as to determine the factors associated with the occurrence of malaria retinopathy.

None of the children with uncomplicated malaria in this study had malaria retinopathy. While studies on malaria retinopathy in severe malaria abound, there are only a few available studies of the phenomenon in uncomplicated malaria. Maude et al. [27] in a study in Bangladesh reported a prevalence of 12% among uncomplicated malaria and the forms of malaria retinopathy were retinal whitenings and vessel changes [27] . The reason for the difference in the prevalence of retinopathy in uncomplicated malaria in the present study could be due to the age differences of the subjects of the studies. The current study focused on children below five years while the other study was done among adults. Similarly, the utilization of the indirect ophthalmoscopy method supplemented by a fundus camera that was used by Maude et al. [27] which has a better sensitivity in identifying the mildest form of retinopathy could also have accounted for the very high prevalence that was reported in that study. Nevertheless, this current study has further demonstrated that malaria retinopathy is almost exclusive to severe malaria hence; its presence should heighten the alertness of the clinician for early and appropriate interventions.

The prevalence of malaria retinopathy among children with severe malaria in this study was 17.7%. This prevalence was lower than the 37% reported by Mohammed et al. [28] in Kano, Nigeria; and 73% reported by Essuman et al. [19] in Ghana. The lower prevalence observed in the current study could be attributed to the diversity in the forms of severe malaria that constituted the study population. While the three earlier studies focused predominantly on cerebral malaria and severe anaemia which have been more consistently associated with malaria retinopathy the current study included other forms of severe malaria which were less associated with retinopathy. This may thus have a dilutional effect on the observed prevalence. In addition, the use of direct ophthalmoscopy in this study as against indirect ophthalmoscopy or a combination of both (which has a higher sensitivity) used in the earlier studies could also have contributed to the reported lower prevalence. Although indirect ophthalmoscopy would be more desirable for better accuracy it is not practicable for routine bedside clinical practice and also not readily available in resource-poor settings including the site of the current study.

Retinal whitening was the most common form of retinopathy observed in the current study while retinal haemorrhage was the least common. This pattern is similar to what has been observed previously by Beare et al. [16] and Essuman et al. [19] who documented that retinal whitening was the most frequent form of retinopathy. This was further corroborated by the finding of cytoadherence erythrocytes within the retinal vessels of subjects who had retinal whitening as well as the predominance of receptors within the retina which allows for attachment of the parasite [29] . It is important to note that the prevalence of retinal whitening though, the highest among the other forms of retinopathy in the current study is much lower compared to those earlier reported by Essuman et al. [19] and Beare et al. [16] in studies where fundoscopy was done by the ophthalmologist using indirect ophthalmoscopy method which are factors that could independently or jointly increase the sensitivity of the fundoscopy.

The current study has been able to identify that malaria retinopathy does not only occur in cerebral malaria as it was observed in children with other forms of severe malaria. It was however observed that malaria retinopathy was more significantly associated with cerebral malaria, metabolic acidosis, multiple convulsions, and haemoglobinuria. Being the most lethal form of severe malaria, cerebral malaria retinopathy has received the greatest attention. Studies on cerebral malaria have observed a high prevalence of retinopathy ranging between 44% - 73%. Oluwayemi et al. [18] reported a prevalence of 44.0% in Ekiti, Essuman et al. [19] reported 73% in Ghana, while Beare et al. [26] and Burton et al. [30] reported 61% and 66.7% respectively. In the same vein, cerebral malaria retinopathy prevalence in the current study was 43.8%, half of whom had retinal haemorrhages. Examination of the fundus should therefore be considered important when cerebral malaria is being suspected in a child as the presence of retinopathy could support the diagnosis. In this study, the prevalence of malaria retinopathy was significantly high among subjects with cerebral malaria, similar to what has been observed in other studies [19] [26] [30] . The pathogenesis and pathologic changes of retinopathy although, not completely understood have been said to be similar to those that occur in the brain in cerebral malaria while receptors responsible for attachment and cytoadherence of the Plasmodium species are said to be equally predominant in the brain and retina [14] . It is therefore not unexpected that cerebral malaria will be more associated with retinopathy than other non-cerebral forms of severe malaria.

While the overall prevalence of retinal haemorrhage in this study was 5.4%, it was significantly more common among those with cerebral malaria, multiple convulsions, and heamoglobinuria. The 21.9% prevalence of retinal haemorrhages in cerebral malaria was similar to the 23.3% that was reported by Olumese et al. [31] in Ibadan. Both studies were carried out among children of similar age groups within the same geographical location and using a similar method of fundoscopy. Mohammed et al. [28] and Oluwayemi et al. [18] however, documented a very low prevalence of retinal haemorrhage in children with cerebral malaria in Ekiti and Kano states of Nigeria respectively, while the prevalences reported by Beare et al. [16] and Essuman et al. [19] were almost double that of the current study. Rather than just attributing this difference to geographical location or method of fundoscopy, a more detailed multicentre study involving ophthalmologists might be useful to further highlight the relationship of retinal haemorrhage to cerebral malaria.

In keeping with previous studies [19] [26] , it was noted in the current study that all the observed types of malaria retinopathy were significantly associated with the two forms of severe malaria that affect the brain (cerebral malaria and multiple convulsions). This further provides evidence that retinopathy is more associated with certain forms of severe malaria especially those with pathologic changes within the brain. Some authors have further documented the usefulness of malaria retinopathy in prognosticating cerebral malaria [16] [17] . Beyond this, however, this study documented an association between retinal whitening and metabolic acidosis similar to the findings of Maude et al. [27] between vessel changes and hypoglycaemia as well as between retinal haemorrhage and haemoglobinuria. This indicates that retinopathy is not limited to cerebral malaria.

To the best of our knowledge, the association of haemoglobinuria and hypoglycaemia with malaria retinopathy has not been reported previously. Metabolic acidosis causes endothelial dysfunction and hence affects vascular integrity [32] . This may increase the risk for ischaemia, localised tissue hypoxia, and haemorrhage leading to retinopathy [27] . With increased intravascular haemolysis resulting in haemoglobinuria, the free serum haemoglobin scavenges nitric oxide which is a potent vasodilator [33] . This decreased nitric oxide may predispose to ischaemia of the retina. Also, free haemoglobin has been shown to cause oxidative damage by lipid peroxidation and loss of vascular integrity. This predisposes to vasoconstriction, and thus possibly contributes to retinopathy [34] . Therefore, it is prudent that all children with severe malaria be examined for retinopathy. A longitudinal study of patients with these other forms of severe malaria who have retinopathy may be desirable. This will assist in determining the prognostic values of retinopathy in them just as has been severally done for cerebral malaria.

It is noteworthy that despite being the most common form of severe malaria in this study, there was no significant association between severe anaemia and any form of malaria retinopathy. This was contrary to the observation of Beare et al. [16] in Malawi and Essuman et al. [19] in Ghana who found a significant association between malaria retinopathy and severe anaemia. The exact reason for the difference is unknown. However, the retinopathy associated with severe anaemia in malaria has been described as being mild, which is best detected by the more sensitive indirect ophthalmoscopy used by the authors compared to the direct ophthalmoscopy used in the present study [16] [19] . Although, there was no direct significant association between retinal haemorrhage and severe anaemia on one hand, the importance of the presence of retinal haemorrhage in severe anemia as a possible indicator of severe haemolysis could be observed in this study. The only four subjects who had retinal haemorrhage among a large number of subjects with severe anaemia were the same as the only four who had retinal haemorrhage among the few with haemoglobinuria which showed significant association. This suggests that the presence of retinal haemorrhages could serve as an indicator of massive haemolysis with subsequent haemoglobinuria (and the possibility of kidney injuries from the toxic effects of haemoglobin contact with the renal tubules) which therefore calls for closer attention when found. A longitudinal study to further document the presence of such a relationship is however advocated.

The limitation of this study was the inability to perform post-mortems for patients that died because of the refusal to give consent and aversion by the pathologists to conduct post-mortems due to the Corona Virus pandemic. Post-mortem is the confirmatory test to diagnose cerebral malaria.

In conclusion, the current study showed the presence of retinopathy in all forms of severe malaria and was not limited to cerebral malaria as speculated by other studies; it also revealed that cerebral malaria and haemoglobinuria were predictors of retinopathy. This, therefore, calls for routine fundoscopic examination in all children with severe malaria and the need for ophthalmoscopic examination training for all health care workers.

The authors declare no conflicts of interest regarding the publication of this paper.

Olayinka, O.O., Abiodun, P.O., Jegede, T.O., Fasoranti, I.O., Salau, Q.O., Kareem, A.J., Olayinka, J.N., Obasohan, E.S., Babalola, B.D., Ademuyiwa, A.A., Ekogiawe, F.T., Abazu I.S. and Babalola, E.O. (2023) Malaria Retinopathy among Under-Five Children with Severe and Uncomplicated Malaria in a Tertiary Health Institution in Southwest Nigeria: A Comparative Study. Advances in Infectious Diseases, 13, 355-374. https://doi.org/10.4236/aid.2023.133031