Monthly Science & Research Report for June 2021

By Dr. Derick Pasternak, Malaria Science & Research Coordinator, Malaria Partners International 

 After the news last month from West Africa about a remarkably effective malaria vaccine, this month’s collection of articles is much more heavily weighted toward the epidemiology of the infection.  No doubt work continues both on the vaccine and on therapeutic alternatives for use in patients with artemisinin resistant organisms and we shall see reports about progress in these spheres soon. 

Prevention:

Malaria can be easily prevented through individual and societal combined efforts by keeping the environment safe, effective utilization of long lasting insecticide nets and early treatment. Notwithstanding, infections remain prevalent in many parts of Africa.  Fikrie A & al. report on Malaria Prevention Practices and Associated Factors Among Households of Hawassa City Administration, Southern Ethiopia, 2020,  PLoS One. 2021 May 13;16(5):e0250981. doi: 10.1371/journal.pone.0250981.  Their result show that 54.3% of households investigated practiced good measure of malaria prevention and control measures. Urban residence, secondary school completed  and other factors  were significantly associated with malaria prevention practices. Nonetheless, almost half of households practiced poor prevention and control measures.

Schapira A & Kondrashin A, Prevention of Re-Establishment of Malaria, Malar J. 2021 May 31; 20(1):243. doi: 10.1186/s12936-021-03781-4 state that “[t]he current consensus on prevention of re-establishment of malaria is based on the following principles: (1) Fundamental role of general health services; (2) Surveillance; (3) Vector control; (4) Border actions; (5) Intersectoral collaboration.” They also point out that alertness of the general health services to suspected malaria (vigilance) needs to be maintained everywhere, while health education is rational only if targeting high-risk sub-populations.

Mwin PK & al. report on experience in a single regional hospital in Predictors of Placental Malaria in Upper West Regional Hospital-Ghana, BMC Pregnancy Childbirth. 2021 May 26;21(1):403. doi: 10.1186/s12884-021-03861-y.  Rates of placental malaria were low (7%) and were primarily found in primigravidae and women who had fewer than four antenatal visits.  They conclude that more antenatal visits would result in  fewer cases of placental malaria. 

Diagnosis:

Two articles deal with possible overdiagnosis of malaria in areas where the disease is endemic:

Oboh MA & al. studied four diagnostic tools in diagnosing 436 individuals suspected of having malaria in SW Nigeria.  As the report in  Comparative Analysis of Four Malaria Diagnostic Tools and Implications for Malaria Treatment in South Western Nigeria, Int J Infect Dis. 2021 May 24;S1201-9712(21)00451-3. doi: 10.1016/j.ijid.2021.05.049, they used nested polymerase chain reactions (nPCR) as the definitive standard. By comparison, rapid diagnostic testing gave 42.2%, quantitative polymerase chain reactions gave 57.8% and microscopy 8.9% gave false positive results.  On the other hand, microscopy gave 62.5% false negative results. Although the abstract doesn’t specifically mention this, the authors seem to imply that decentralized testing suffers from inadequate training on the part of those performing the tests.

In Peterson I & al., Overdiagnosis of Malaria Illness in an Endemic Setting: A Facility-Based Surveillance Study in Malawi, Am J Trop Med Hyg. 2021 May 3;tpmd201209. doi: 10.4269/ajtmh.20-1209, the authors conclude that “malaria infection accounted for about 50% of fevers in children younger than 5 years old with microscopy-confirmed Plasmodium falciparum infection, and less than 20% of such fevers in school-age children.”  They state that “[o]utpatient settings in Malawi had a high burden of malaria illness, but also possible overdiagnosis of malaria illness. Interventions to reduce malaria transmission and rapid testing for other common febrile illness may improve diagnostic clarity among outpatients in malaria endemic settings.”

Treatment:

Al Khaya KAJ and Sequeira RP reviewed 35 updated national guidelines and the President’s Malaria Initiative for adherence to the WHO recommendations on drug treatment and prevention of chloroquine-resistant falciparum malaria in pregnant women. Their article, Drug Treatment and Prevention of Malaria in Pregnancy: a Critical Review of the Guidelines, Malar J. 2021 Jan 23;20(1):62. doi: 10.1186/s12936-020-03565-2 goes into detail about the details in which these guidelines need further updating in order to come into compliance with WHO recommendation.

HIV-infection, tuberculosis and malaria are the big three communicable diseases that plague sub-Saharan Africa. If these diseases occur as co-morbidities they require polypharmacy, which may lead to severe drug-drug-gene interactions and variation in adverse drug reactions, but also in treatment outcomes. Findings of Pallaerla SR & al., Pharmacogenetic Considerations in the Treatment of Co-infections with HIV/AIDS, Tuberculosis and Malaria in Congolese Populations of Central Africa, Int J Infect Dis. 2021 Mar;104:207-213. doi: 10.1016/j.ijid.2020.12.009. Epub 2020 Dec 9 contribute to the understanding of pharmacogenetic variants involved in the metabolism of drugs used to treat HIV-infection, TB and malaria in ROC and their diversity in different populations. Such knowledge helps to predict drug efficacy, toxicity and ADRs and to inform individual and population-based decisions.

Imran IZ, Elusiyan CA, Agbedahunsi JM & al., Bioactivity-Directed Evaluation of Fruit of Kigelia africana (Lam.) benth. Used in Treatment of Malaria in Iwo, Nigeria, J Ethnopharmacol 2021 Mar 25; 268:113680.  doi: 10.1016/j.jep.2020.113680. Epub 2020 Dec 8 is another study of locally used plant-based remedies for malaria.  Of 31 plants used in the area, the authors conclude that only Kigelia africana has significant “antiplasmodial activity in the order of fruit > root > leaf > stem bark.” Even the most efficacious source required chemopreparation, however.

Cassiano GC & al. advocate exploring protein kinases as a therapeutic approach in Targeting Malaria Protein Kinases, Adv Protein Chem Struct Biol. 2021;124:225-274. doi: 10.1016/bs.apcsb.2020.10.004. Epub 2020 Nov 1. “These enzymes catalyze the phosphorylation of several proteins, thereby regulating a variety of cellular processes and playing crucial roles in the development of all stages of the malaria parasite life cycle. Moreover, the large phylogenetic distance between Plasmodium species and its human host is reflected in marked differences in structure and function of malaria protein kinases between the homologs of both species, indicating that selectivity can be attained. In this review, [they] describe the functions of the different types of Plasmodium kinases and highlight the main recent advances in the discovery of kinase inhibitors as potential new antimalarial drug candidates.

Campaigns:

Many sources dealt with the news that genetically modified male Aedes aegypti mosquitoes were released in the Florida Keys.  See Milius S, The US’s First Open-Air Genetically Modified Mosquitoes Have Taken Flight, Science News, 14 May 2021, https://www.sciencenews.org/article/mosquito-genetically-modified-us-florida-keys-pest-control-zika-dengue?utm_source=Editors_Picks&utm_medium=email&utm_campaign =editorspicks051621.  Although there is no direct relevance of this event to the vectors of malaria, the approach may be promising for future control of Anopheles mosquitoes as well.

Yet another study of the general population’s understating of how to prevent malaria is Otomayo AI & al., Community Knowledge, Attitude and Practices on Malaria Vector Control Strategies in Lagos State, South-West Nigeria,  J Med Entomol. 2021 May 15;58(3):1280-1286. doi: 10.1093/jme/tjaa278. . Structured questionnaires were employed for the survey of 520 households. “Respondents’ [local government areas had] no significant impact on attitude and practice to malaria vector control methods. However, ‘level of education’ as well as ‘type of dwelling structure’ impacted significantly on some practices and attitude. [Indoor residual spraying] is the major tool employed in malaria vector control, but sometimes it is used in combination with other methods. A good number of residents also use [long lasting insecticide nettings].

Epidemiology:

One of a number of studies exploring the effect of comorbidity and COVID-19 is Achan J & al., Impact of Current Malaria Infection and Previous Malaria Exposure on the Clinical Profiles and Outcome of COVID-19 in a High Malaria Transmission Setting: A Prospective Cohort Study, Lancet, 2021 May 12, https://dx.doi.org/10.2139/ssrn.3844848.  They “determined the prevalence of malaria and describe the consequences of SARS-CoV-2 and malaria co-infection in a high burden malaria setting… Of 597 PCR confirmed Covid-19 cases enrolled between 16th April and 30th October 2020, …[o]verall prevalence of P. falciparum infection was 11.7%…Patients with low previous P. falciparum exposure had a higher frequency of severe/critical Covid-19 cases.”

The focus of Gavi S & al., Malaria Incidence and Mortality in Zimbabwe During the COVID-19 Pandemic: Analysis of Routine Surveillance Data, Malar J. 2021 May 24;20(1):233. doi: 10.1186/s12936-021-03770-7 is reversed, in that it examined the impact of the pandemic on the incidence of malaria. “Compared to the same period in 2017, 2018 and 2019, there was an excess of over 30,000 malaria cases from January to June 2020. The number of malaria deaths recorded in January to June 2020 exceeded the annual totals for 2018 and 2019. District level maps indicated that areas outside high malaria burden provinces experienced higher than expected malaria incidence and mortality, suggesting potential outbreaks.”

Two articles report more general epidemiologic analysis of malaria prevalence.   Nyasa RB & al., Trends in Malaria Prevalence and Risk Factors Associated with the Disease in Nkongho-Mbeng; A Typical Rural Setting in the Equatorial Rainforest of the South West Region of Cameroon,  PLoS One 2021 May 18;16(5):e0251380. doi: 10.1371/ journal.pone.0251380 examines “a typical rural setting in the equatorial rain forest region of Cameroon, with no existing knowledge of the epidemiology of malaria in this locality… A cross-sectional survey was conducted, during which blood samples were collected from 500 participants and examined by microscopy. Risk factors such as, age, sex, duration of stay in the locality, housing type, environmental sanitation and intervention strategies including use of, LLINs and drugs were investigated. Trends in malaria morbidity were also determined. Of the 500 samples studied, 60 were positive, giving an overall prevalence of 12.0% with the prevalence of asymptomatic infection (10.8%), more than quadruple the prevalence of symptomatic infections (1.2%)…” Long lasting insecticide netting was used in most cases, but did not significantly influence prevalence (non-significant increase among users!); risk factors included being male, living in certain localities and having bushes near the homes. 

Every year, thousands of seasonal farm workers travel to farm corridors in Northwest Ethiopia. Tilaye T & al. studied malaria in this population and reported in  Malaria Infection is High at Transit and Destination Phases Among Seasonal Migrant Workers in Development Corridors of Northwest Ethiopia: A Repeated Cross-Sectional Study, Res Rep Trop Med. 2021 May 26;12:107-121. doi: 10.2147/RRTM.S306001. The results showed that the “odds of malaria infection among migrant workers at the destination phase was 1.5 … times higher compared to the transit phase. The significance of this and the comparison with non-migrant populations is not mentioned in the abstract.

Lubinda J & al., Climate Change and the Dynamics of Age-Related Malaria Incidence in Southern Africa, Environ Res. 2021 Mar 22;197:111017. doi: 10.1016/j.envres.2021.111017 states that “changing climatic and environmental factors are among those suspectedly behind high malaria incidence” in parts of Zambia. They conclude that “[c]limate variables influenced malaria substantially more than mosquito nets and indoor residual spraying interventions.. as well as “that climate parameters negatively impact malaria control efforts by exacerbating the transmission conditions via more conducive temperature and rainfall environments, which are augmented by cultural and socioeconomic exposure mechanisms.”

Two articles report on malaria and anemia:

Gaston RT & al. Joint Modelling of Malaria and Anaemia in Children Less Than Five Years of Age in Malawi, Heliyon. 2021 May 4;7(5):e06899. doi: 10.1016/j.heliyon.2021.e06899 examines a group of 2724 children with extremely high rate of malaria (37.2%). At the same time, 59.6% of these children tested were anemic.  Using statistical modeling, they conclude that there is “a positive association between anaemia and malaria. Furthermore, the same results showed that mother’s education level, child’s age, the altitude of the place of residence, place of residence, toilet facility, access to electricity and children who slept under a mosquito bed net the night before the survey had a significant effect on malaria and anaemia.”

Muriuki JM & al., Malaria Is a Cause of Iron Deficiency in African Children, Nat Med. 2021 Apr; 27(4):653-658. doi: 10.1038/s41591-021-01238-4. Epub 2021 Feb 22. “To test the hypothesis that malaria might cause [iron deficiency (ID), they] used sickle cell trait (HbAS, rs334), a genetic variant that confers specific protection against malaria2, …. HbAS was associated with a 30% reduction in ID among children living in malaria-endemic countries in Africa (n = 7,453), but not among individuals living in malaria-free areas (n = 3,818). Genetically predicted malaria risk was associated with an odds ratio of 2.65 for ID per unit increase in the log incidence rate of malaria. This suggests that an intervention that halves the risk of malaria episodes would reduce the prevalence of ID in African children by 49%.”

Related to the above is Mann DM & al., Undernutrition and Malaria Among Under-Five Children: Findings from the 2018 Nigeria Demographic and Health Survey, Pathog Glob Health. 2021 May 4;1-11. doi: 10.1080/20477724.2021.1916729. “Cross-sectional data … included a study population of 12,996 children aged 0-59 months. Stunting …, underweight …, wasting …, malaria test results, and socio-demographic factors were obtained and examined. … The prevalence of stunting was 37.0%, with 22.0% underweight, 6.9% wasting, and 22.6% tested positive for malaria… Undernutrition and malaria frequently occurred among males, residents of rural areas, the poorest wealth quintile, and children of mothers with no formal education. The odds of having malaria was 89% higher among under-five stunted children … However, underweight … and wasting … were not significantly associated with malaria.“

Tazebew B, Munshea A, Nibret E, Prevalence and Association of Malaria with ABO Blood Group and Hemoglobin Level in Individuals Visiting Mekaneeyesus Primary Hospital, Estie District, Northwest Ethiopia: A Cross-Sectional Study, Parasitol Res. 2021 May;120(5):1821-1835. doi: 10.1007/s00436-021-07093-z. Epub 2021 Mar 3. In this study, “[s]ociodemographic variables and relevant data were collected from 390 randomly selected individuals through structured questionnaire. Then, thick and thin smears were prepared from finger pricked blood samples, stained, and examined microscopically for detection and identification of malaria parasites. ABO blood group and hemoglobin levels of the same subjects were also determined… Most (14.6%) of malaria-positive cases were among individuals with blood group A, while the least numbers of cases were among subjects with blood group O… The prevalence of anemia was 23.1% and significantly associated with malaria.”

Malaria infection is reportedly linked to endemic Burkitt lymphoma (eBL) in malaria-endemic areas. Kotepui PU, Kotepui M, Malaria Infection and Risk for Endemic Burkitt Lymphoma: A Systematic Review and Meta-Analysis, Int J Environ Res Public Health. 2021 May 30;18(11):5886. doi: 10.3390/ijerph18115886 aimed to pool the overall risk (or odds) of eBL among children with previous or concurrent malaria infection. “Ten studies were included, reporting the number of malaria cases in eBL and non-eBL (5 studied malaria infection and the odds of eBL; five studied the burden of IgGs to malarial antigens and the odds of eBL). According to the meta-analysis results, the odds of eBL was not increased by malaria infection… However, the included studies, which are only few, do not generally agree on this point. Therefore, the risk for eBL in children diagnosed with malaria should be investigated further by longitudinal studies to confirm our evidence-based approach.”

Hawadak J & al. report in Global Trend of Plasmodium malariae and Plasmodium ovale spp. Malaria Infections in the Last Two Decades (2000-2020): A Systematic Review and Meta-Analysis , Parasit Vectors. 2021 Jun 3;14(1):297.  doi: 10.1186/s13071-021-04797-0 that 113 studies were included in their analysis, among which 51.33% were from the African Region. “The P. malariae and P. ovale spp. pooled prevalence were 2.01% (95% CI 1.31-2.85%) and 0.77% (95% CI 0.50-1.10%) respectively, with the highest prevalence in the African Region… In this review, data analysis revealed that P. malariae and P. ovale spp. have decreased in the last 20 years, but not significantly, and these species were more commonly present with other Plasmodium species as co-infections. No difference in prevalence between symptomatic and asymptomatic patients was observed for either P. malariae or P. ovale spp.”

Basic Research:

Altable M & de la Serna JM, Protection Against COVID-19 in African Population: Immunology, Genetics, and Malaria Clues for Therapeutic Targets, Virus Res, . 2021 Jul 2;299:198347. doi: 10.1016/j.virusres.2021.198347. Epub 2021 Feb 22.

Junqueira C & al., γδ T cells Suppress Plasmodium falciparum Blood-Stage Infection by Direct Killing and Phagocytosis, Nat Immunol. 2021 Mar;22(3):347-357. doi: 10.1038/s41590-020-00847-4. Epub 2021 Jan 11.

Katsoulis O & al., Immunopathology of Acute Kidney Injury in Severe Malaria,. Front Immunol, 2021 Apr 23;12:651739. doi: 10.3389/fimmu.2021.651739.

Ma F & al., Structural Basis for Placental Malaria Mediated by Plasmodium falciparum VAR2CSA, Nat Microbiol. 2021 Mar;6(3):380-391. doi: 10.1038/s41564-020-00858-9. Epub 2021 Jan 15.