First Observations of Plasmodium malariae on the Long-Term Malaria Vector Control Program on Villages of the Balombo Region of Angola

Sylvie Manguin^{*, 1}, Vincent Foumane², Jean-Claude Toto², Franck Martineaud³, Maria Adelaide Dos Santos³, Filomeno Fortes⁴, Pierre Carnevale⁵

¹HSM, University of Montpellier, CNRS, IRD, Montpellier, France.

²Organization of Cooperation and Coordination for Endemic Diseases Control in Central Africa (OCEAC), PO 288 Yaoundé Cameroon.

³Clinic and Malaria Control Programme, Sonamet, Lobito, Angola.

⁴Institute of Hygiene and Tropical Medicine, Lisbon, Portugal.

⁵Le Majoral Building, 34420 Portiragnes Plage, France.

*Corresponding author: Sylvie Manguin, HSM, University of Montpellier, CNRS, IRD, Montpellier, France.

Received: 24 January 2024; Accepted: 30 January 2024; Published: 13 February 2024

1. Introduction

A great amount of work has been devoted to Plasmodium malariae since its first description by Laveran as Oscillaria malariae in 1881, then by Grassi and Feletti in 1890 under the name Haemamoeba malariae [1-10], until recent studies included genome sequencing [11- 19]. P. malariae is a particular species, especially at the clinical and parasitological levels, with a 72-hr erythrocyte cycle inducing a quartan fever with a slow development (15 days in both liver and Anopheles mosquito) [20, 21]. The parasite density is always low compared to Plasmodium falciparum and it produces clinical relapses, considered now as recrudescence, due to the asexual forms that persist in the host’s blood [20]. Considered benign, this Plasmodium species was used in the 40’s in experimental infections for the treatment of neurosyphilis [10]. Though, symptoms include nephropathies [22-26], long asymptomatic persistence of several years before access to recrudescence [27] that may induce transfusional malaria [28]. Cases of glomerulonephropathy associated with P. malariae infections were also reported with a disease that may persist and evolve despite the apparent elimination of parasites and with detectable chronic renal disease observed even 3-5 years after the so-called primary infection [29].

This species presents genetic polymorphism [30-34], it can be transmitted by palearctic or tropical vectors [35, 36], and due to its possibility to infect human and simian subjects [37, 38], it was considered as an anthropozoonotic species. This plasmodial species has a scattered world-wide distribution in malarious regions of Africa [39, 40], South America [41], Asia and Pacific [42] with a variable frequency in time and space according to the technique of investigations and biological analysis. With the recent acceleration of malaria control operations, the frequency of P. falciparum is decreasing [17, 43, 44] and a special interest has to be given to other plasmodial species, including P. malariae, which could persist for many years [45], or even the whole life of infected persons [19]. The genome of P. malariae has recently been decrypted [18, 46], which explains a case of resistance with a clinical recrudescence after treatment with the combination of artemether-lumefantrine (a full course of 6 doses over 3 days, equivalent to a total dosage of 6.2 mg/kg of artemether and 37.4 mg/kg of lumefantrine). The explanation given was that the primary infection would have been polyclonal, but the recrudescence was due to a resistant clone [46]. In 1937, the death of a 27-years old man in India was reported following what appeared to be the third malaria crisis access, with no particularly high fever, but parasitological examination revealed a high density of P. malariae. Despite treatment with quinine (injection and oral), resulting in the disappearance of microscopically observed Plasmodium, the subject died possibly from heart problems [47]. Overall, P. malariae is still a neglected human malaria parasite, not well understood that still contributes up to 10% of malaria infections in sub-Saharan Africa [34]. The objective of the study was to evaluate the prevalence of both P. malariae and P. falciparum in a mesoendemic malaria region of Angola where our study has been ongoing since 2007 [48-50]. In addition, it seemed important to pay a particular attention to these Plasmodium species in the framework of the study aiming at comparing the efficacy of four vector control methods, including long- asting deltamethrin-impregnated mosquito nets (LLIN), deltamethrin insecticide-treated plastic sheeting (ITPS), association LLIN and ITPS, and lambdacyhalothrin indoor residual spraying (IRS), in the Balombo region of Angola and to monitor its possible evolution with the implementation of different vector control operations.

2. Methodology

2.1 Study area

The Balombo study area in the Benguela Province of Angola was already described [48]. This study was made between February 2007 and December 2011, with sampling collections made every 2 months, in eight villages around the town of Balombo (12°21'S, 14°46’E) located at an altitude of 1,220 meters in a mountainous area of ancient volcanoes with a thermal spring at the west entrance to the city (Fig. 1). The vegetation is a tropical savannah with shrub prairie, the original forest has been severely degraded for crop development and domestic use. There is a well-marked dry and cold season in June to August and abundant rains from November to April. Temperatures vary between a minimum of 10°-15°C in June-August and a maximum of 30-35°C in March and April.

Figure 1: Map of collections sites in the 8 villages around the Balombo town, Benguela Province, Angola

2.2 Parasitological surveys

Parasitological surveys were carried out as part of a multidisciplinary evaluation of a vector control operation aiming at comparing four vector control methods in paired villages. The complete protocol of vector control method implementation is detailed in Brosseau et al. [48] and it included the following steps: (1) PermaNet 2.0 Long lasting deltamethrin-impregnated mosquito nets (LLIN) provided in Cahata and Caala; (2) association of LLIN with Zero Fly®, deltamethrin insecticide-treated plastic sheeting (ITPS) that were pinned on the hut walls in Capango and Canjala; (3) deltamethrin-treated ITPS Wall Lining (WL) model alone and also pinned on the walls in Chissequele and Barragem; and (4) conventional lambdacyhalothrin indoor Residual Spraying (IRS) with two rounds/year (every six months), followed by the installation of ITPS in Libata and Candiero in order to increase the long lasting efficacy of the treatment. Cross-sectional parasitological surveys were conducted on a regular basis every two months focusing on random samples of the population under 15 years of age. At the time of the field investigations, part of the population present in the village usually came to the team to have a blood test and, for obvious ethical reasons, a thick blood film (TBF) was prepared from each one of these volunteers and these TBF were coloured in the field with Giemsa. Then, microscopic observations were done at the medical department of the Angolese Sonamet Company located in Lobito, which supported the study through their Malaria Control Program (MCP).

To compare the efficacy of each vector control method, a subsample of children ≤ 15 years old was extracted from the original list to standardize the samples to be compared, but in the present study dealing with P. malariae the whole samples were considered with no age limits. Then, the number of blood smears done per village varied between 1,856 TBF in Capango to 3,387 TBF in Caala during the five years of the study (Table 1) and were constituted of people from all age groups, from 2 to 75 years old. Young children were accompanied by their volunteer mother. During the surveys a supplementary drop of blood was also obtained on filter paper for further immunological analysis at IRD in Montpellier, France for estimating the Anopheles biting pressure on the population before and after implementation of the four vector control methods [48]. Ethical approval was obtained from the National Malaria Control Program of the Ministry of Health of Angola, the Ethical authority in charge of approving studies on malaria research in Angola. In addition, written consent signed by the head of each household was obtained for all individuals enrolled in the study by Malaria Control Program (MCP) of the Sonamet Company. Microscopic parasitological examinations were done by the same team throughout the study with a regular double-checking by V. Foumane, parasitologist at OCEAC (Organisation de coordination pour la lutte contre les endémies en Afrique Centrale), Yaoundé, Cameroon, of 10% random sample slides. Results of these analyses were provided to the village health worker for further action to be taken by the National Malaria Control Program (NMCP) of Angola.

2.3 Statistical analysis

Data were analyzed and graphs constructed with GraphPad Prism6® software (San Diego, CA, USA). Distribution of parasitemia were analyzed with the non-parametric Mann-Whitney statistical test.

3. Results

3.1 Prevalence of Plasmodium malariae

From February 2007 to December 2011, 190 field surveys were done and 21,804 thick blood smears were prepared from which 5,431 were positive for Plasmodium (24.9%), 5,365 with P. falciparum (98.8%), 22 (0.4%) with P. malariae, and 44 (0.8%) with a mix of P. falciparum and P. malariae (Table 1).

Table 1: Parasitological surveys done from 2007 to 2011 in 8 villages of the Balombo region

No, number; TBF, thick blood film; TBF+, positive thick blood film; P.f., P. falciparum; P.m., P. malariae

3.2 Parasitemia of P. malariae alone or coinfections P. malariae and P. falciparum

1. malariae parasitemia, alone or associated with P. falciparum, were significantly not different with p-value = 0.1127. For single or mixed infections, the geometric means were of 466 and 787, and the medians of 450 and 746 respectively (Table 2).

Table 2: Parasitemia of P. malariae alone or associated to P. falciparum

3.3 Influence of vector control methods

The presence of P. malariae, alone or associated with P. falciparum, according to the vector control method is reported in Table 3. Similar percentages of infections were found when considering P. malariae and mixed P. malariae + P. falciparum with values ranging from 1% in villages with LLIN alone and IRS, 1.4% in villages with LLIN and Zero Fly, and 1.7% in villages with ITPS, while P. falciparum percentages vary between 98.3% and 99%. Besides, the number of infections with P. malariae alone or mixed with P. falciparum decreased drastically, by a factor of 4.5 after vector control operations with values of 54 out of 66 infections (82%) before to 12 (18%) after vector control implementation (Table 4). However, the parasitemia of P. malariae infections alone or in coinfection with P. falciparum did not change with vector control implementation as shown by p-values of 0.0778 for P. malariae infections alone (median = 480 before and 233 after VC) and p-value= 0.923 for coinfections (median = 804 before and 853 after VC) (Fig. 2).

Table 3: Presence of Plasmodium malariae according to vector control method implemented (TBF= thick blood film; LLIN= Long lasting insecticide treated net; ITPS= insecticide treated plastic sheeting; ZF= Zero Fly model of ITPS; IRS= Inside residual spraying)

Table 4: Prevalence and number of cases in parentheses of P. malariae alone (P.m.) or associated to P. falciparum (P.m. + P.f.) in surveys done before and after vector control (VC) implementation

LLIN= Long lasting insecticide treated net; ITPS= insecticide treated plastic sheeting; ZF= Zero Fly model of ITPS; IRS= Inside residual spraying.

Figure 2: Evolution of the parasitemia of P. malariae (Pm) alone or associated with P. falciparum (Pfm) with median (red line) before and after vector control implementation

3.4 Influence of the season

The analysis of P. malariae infections observed during the dry and rainy season surveys shows a similar overall number with respectively 30 and 36 infections, with twice less P. malariae alone infections in the rainy (32%) than the dry season (68%) (Table 5).

Table 5: Number of positive slides and prevalence of P. malariae (P.m.) alone or associated to P. falciparum (P.f.+P.m.) according to season

3.5 Influence of gender

The 66 infections of P. malariae alone or associated with P. falciparum included 28 men and 38 women. The parasite load of P. malariae were similar in men and women (p-value= 0.14; respective median 480 and 299) and the parasitemia of mixed infections P. malariae + P. falciparum were also similar in men and women (p-value= 0.93; respective median = 804 and 1,040) (Fig. 3).

Figure 3: Parasitemia due to P. malariae alone (Pm) or associated with P. falciparum (Pfm) with median (red line) according to the gender. M, men; W, women

3.6 Influence of age

Our sample was not prepared to be representative of the village populations since it was intended to mainly evaluate the impact of vector control operations on P. falciparum infections in children (≤ 15 years). However, for P. malariae evaluation, 2 age groups were considered such as <5 years old, considered as at-risk group, and > 5 years old. The results showed a similar number of infections in both groups with 11 carriers <5 years old and 11 carriers > 5 years old for infections with P. malariae alone, and 20 carriers <5 years old and 24 carriers > 5 years old for mixed infections P. malariae + P. falciparum.

4. Discussion

According to the last WHO malaria report [44], Angola is the fifth country with the highest number of malaria cases and deaths in the world, accounting respectively for 3.4% and 3.2% of the global cases and deaths in 2022, ranking 5^th and 7^th among the African countries. For the past 10 years, malaria figures in Angola have been steadily increasing with an incidence that jumped from 3.5 million confirmed cases in 2011 to 9.2 million in 2022, and a mortality that nearly doubled from 6,909 to 12,474 deaths respectively out of a total population of 35.6 million, all living in malaria-risk regions. In the Balombo region of Angola (Benguela Province), malaria is mesoendemic and all reported cases are due to P. falciparum with no report of the occurrence of P. malariae or P. ovale, due to their rarity, although records have shown the presence of these Plasmodium species in other parts of Angola [51- 55]. For instance in northern Angola, on a total of 3,316 blood samples collected, 541 (16.3%) were Plasmodium infected, out of them 477 (88.2%) were due to P. falciparum alone and 35 (6.5%) were coinfections P. falciparum and P. malariae [53]. In this study by Fancony et al. [53], P. malariae infections were reported by molecular methods and not observed with usual optical microscopy such as our study.

The five years longitudinal surveys in the eight villages around Balombo (Angola) confirmed the presence of P. malariae in the Balombo region of west-central Angola and its very low prevalence, with 22 cases out of 21,804 thick blood smears observed (0.1%), and this could explain why this species is rarely reported in single sectional surveys, deserving continuous training of microscopic technicians [56]. For example, during continuous training operations for microscopists from health centers in Bengo, Benguela and Luanda Provinces in Angola, there was an increase in the sensitivity and specificity of examinations after training, while noting false positive P. vivax case in Bengo and P. malariae infection on a slide considered as negative [57]. Using combined techniques such as microscopy and PCR assays, the prevalence of P. malariae mono-infections at 1% was found in the Democratic Republic of Congo, country neighbouring Angola [58], while it was at 2.5% in Cameroon and coinfections P. falciparum/P. malariae at 17% using the same two techniques and RDTs [59].

In Angola, a cross-sectional survey conducted in 733 Chinese and Southeast Asian migrants showed that most infections were due to P. falciparum, although infection and/or exposure to P. vivax and P. malariae was also detected [54]. Based on these very few reports, more attention should be given to the detection of non-falciparum infections in order to know what and where plasmodial species are circulating in Angola, and more widely in the south of the Saharan region for a more precise diagnosis of patients in order to provide them an appropriate malaria prophylaxis [60]. In addition, it is important to know where this plasmodial species is circulating for the diagnosis of patients being examined in non-endemic areas, to avoid kidney failure or any other complications due to P. malariae. Plasmodium infections with non-falciparum species, also referred to Non-Falciparum Malaria (NFM), are responsible for 25% of cases imported into Europe [55] and a retrospective analysis of the records from January 2006 to August 2016, recorded in a hospital in Portugal, revealed 19 cases of NFM among the 225 malaria cases including 12 cases from Angola. Out of these 19 NFM cases, 7 (37%) were due to P. malariae. The most frequent symptom was fever and the biological analysis showed thrombocytopenia. Treatments provided to these 19 NFM cases were quinine-doxycycline (11 patients), chloroquine (six patients) or artemether-lumefanthrin (two patients) with cure in all cases. In Henan Province of China, three patients, including two returning from Angola and one from Equatorial Guinea, had symptoms such as irregular fever, headache, chills. Two cases had elevated total bilirubin and splenomegaly and were confirmed as P. malariae infection by microscopic examination. Both were cured with artemisinin-based combination therapy (ACT) [52], while the usual drug can have crucial side effect of G6PD deficiency and must be given only with strict medical care in main hospital. In Jiangsu Province of China, an observational study of imported malaria cases was carried out for the period of 2011-2014 [51]. Out of 1,268 imported malaria cases, P. falciparum cases accounted for 83.4% (n = 1,058), and it was noticed that the proportions of P. ovale and P. malariae increased during these four year-period. Therefore, this increase in rare Plasmodium species originating from south-Saharan Africa and Southeast Asia needs to be better monitored at all levels of health providers focusing on diagnosis and treatment of malaria. In addition, due to long latency periods and misdiagnosis of P. malariae and P. ovale, there is an increased risk of re-introduction of malaria in China, declared malaria-free by WHO in 2021 [51, 61, 62]. A recent meta-analysis of the occurrence of P. malariae and P. ovale in the world revealed that 51% of these species were reported from the African region and each species was accounting for 3.16% and 1.69% respectively on this continent [17]. This prevalence of P. malariae is 10 times higher than the one found in this study (0.3% including mixed infections), which may be due to the fact that this species is often misidentified as P. falciparum or totally missed under microscopic examination due to the low parasite density compared to P. falciparum [63]. Then, the use of optical microscopy to search for Plasmodium parasites must be, in future studied, accompanied by PCR assays to confirm, and eventually increase the number of positive samples. This is particularly important as P. malariae shows a lower parasitemia compared to P. falciparum, therefore more difficult to detect under a microscope [21, 64].

To improve the diagnosis of certain fevers, anaemia [65] and nephropathies, it is important to be aware of the presence of P. malariae and thus avoiding misdiagnosis [66] in endemic and non-endemic areas [64, 67, 68] with the critical issues of mistreatment [60, 69-74]. The persistence of P. malariae even after ACT treatment is of great concern [75, 76], as well as its well-known long chronicity [3] with an amazing persistence for several years, such as a P. malariae case reported 32 years after the initial infection of stay in malaria-endemic areas [77]. It was reported that infections have been transmitted by blood transfusion twelve years, twenty years, and thirty years after infection of the donors [3]. In addition, it is important to highlight the fact P. malariae is a parasite of both man and African apes (chimpanzee and gorilla) [38, 78] and with current and foreseen environmental changes and forest destruction, the risk of human infections could greatly increase as it was recently seen with P. knowlesi in Indonesia and even more Malaysia [79-89].

5. Conclusion

Angola belongs to the Malaria Elimination Eight Regional Initiative (E8), as one of the 8 countries of southern Africa aiming to eliminate malaria by 2030 [90]. The expansion of malaria interventions in Angola in the 20 past years aimed to consolidate malaria control and move towards pre-elimination [91]. However, the case of residual malaria is of great concern and may jeopardize malaria elimination [92-94], especially if all efforts are concentrated on P. falciparum only. Non-falciparum species, such as P. malariae, are largely forgotten, although this species showed a prevalence of 3.16% in Africa, based on 50 studies, and 17% of coinfections with P. falciparum were recently reported from Cameroon [17, 59]. Better knowledge on the prevalence and burden of non-falciparum species is crucial in the aim of achieving malaria elimination in Angola and in the concerned countries of the E8 initiative. To accomplish this task, well-trained microscopists in the identification of non-falciparum species are needed; molecular techniques for the diagnosis of Plasmodium species must be popularized; and less expensive diagnostic techniques (such as hypersensitive RTDs) need to be developed.

Résumé

A la demande du Programme National de Lutte contre le Paludisme (PNLP), un programme de lutte antivectorielle a été mis en œuvre dès 2007 dans huit villages autour de Balombo (Angola) pour comparer l’efficacité de quatre méthodes de lutte antivectorielle dans les habitations. Ces méthodes comprenaient (1) des moustiquaires à imprégnation durable (MID) traitée à la deltaméthrine (PermaNet© 2.0 ou P.2.0); (2) l’association de MID P.2.0 et de bâches en plastique traitées avec un insecticide (BPTI), la deltaméthrine (delta-BPTI) - Zero Fly©; (3) delta-BPTI seul; et (4) 2 cycles de pulvérisation de lambdacyhalothrine à effet rémanent suivis de l’installation de delta-BPTI. Des enquêtes parasitologiques transversales (EPT) ont été effectuées tous les deux mois. L’identification des espèces de Plasmodium, la parasitémie, la présence de gamétocytes, et l’évolution dans le temps de ces paramètres ont été analysées. Un total de 190 EPT a été fait entre 2007 et 2011, Plasmodium spp. ont été observés dans 5.431 des 21.804 gouttes épaisses (GE) effectuées (24.9%). Plasmodium malariae seul a été observé dans 22 GE (0,4%) et des infections mixtes P. falciparum et P. malariae dans 44 GE (0,8%). Notre étude confirme la présence de P. malariae en Angola, qui doit être suivie en raison de son impact clinique, fièvre quarte, insuffisance rénale, chronicité, porteurs asymptomatiques, persistance pendant plusieurs années avec recrudescence à long terme et cas signalés de résistance aux ACT classiques. La prévalence de P. malariae a diminué après la mise en œuvre des méthodes de lutte antivectorielle. Le fardeau que représente P. malariae doit être étudié afin d’atteindre l’objectif d’élimination du paludisme d’ici 2030.

Acknowledgments

We are grateful to the Angolese Sonamet Company based at Lobito and its Medical Department in the framework of the Malaria Control Program (MCP), as well as the Subsea7 Company, which supported this study. We thank National and Provincial Public Health authorities, which allowed and supported the surveys. All the data were collected by the intense work of the MCP, Sonamet. We gratefully acknowledge Dr F. Fortes, chief of the National Malaria Control Programme of Angola during the study and now Director of the Institute of Hygiene & Tropical Medicine of the University Nova in Portugal, for his important and permanent support before and during this study.

Author Contributions

PC designed the study protocol; participated to field surveys, analyzed data and drafted the manuscript. FF supported the study and participated to field surveys. MADS, VF, JCT carried out the field surveys. MADS read all blood slides. VF did initial and ongoing training, participated in laboratory analysis and double-checked part of the blood slides. SM did data analysis and was fully involved in drafting and writing the manuscript. FM participated in data analysis and revised the manuscript. All authors read and approved the final manuscript.

Funding

The Angolese Sonamet Company based at Lobito and the Subsea7 Company funded this study.

Availability of data and materials

All data are fully available without restriction.

Declarations

Ethical Approval and consent to participate

This study was conducted in accordance with the Edinburgh revision of the Helsinki Declaration and was approved by the National Malaria Control Program of the Ministry of Health of Angola, the Ethical authority in charge of approving studies on malaria research in Angola. Written consent (signed by the head of each household) was obtained for all individuals enrolled in the study by the SONAMET Company - Malaria Control Program (MCP).

Conflicts of Interest

The authors declare that they have no conflicts of interest in relation to this article.

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