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

There seems to be a particular emphasis on articles in the category of Epidemiology this past month, which is not to the exclusion of other topics, as the reader will see.  Given the high incidence of vivax malaria in certain areas of Africa (see several articles under Epidemiology), this report includes two articles on the treatment of patients suffering from this potentially recurrent form of malaria.  Also, in a separate section that traverses Prevention, Treatment, and Campaigns, we report on what might be controversial publications on the internet regarding artemisinin combination therapy, especially in the framework of mass drug administration. This section comes after Treatment in today’s report, because it flows naturally after the article on the use of herbal preparations.

Prevention:

Subtopic Vaccines 

Das J & al. explored the mechanism whereby the recently discovered enhanced effectiveness of the RTS,S/AS01 vaccine if the third dose is delayed and the amount is reduced in Delayed Fractional Dosing With RTS,S/AS01 Improves Humoral Immunity to Malaria Via a Balance of Polyfunctional NANP6- and Pf16-Specific Antibodies. Med. 2021 Nov 12 ; 2:1269-1286. www.cell.com/med/fulltext/S2666-6340(21)00343-3.  The article was recently cited by Duffy PE in Making a Good Malaria Vaccine Better, Trends Parasitol, 2022 Jan; 38(1):9-10. doi: 10.1016/j.pt.2021.11.006.

Vaccine ignorance and resistance is of recent importance the world over. The recently WHO-endorsed malaria vaccine is not an exception to this phenomenon. Immurana M& al., Determinants of Willingness to Accept Child Vaccination Against Malaria in Ghana, Int J Health Plann Manage, 2022 Jan 4, doi: 10.1002/hpm.3406 found “that religion, region of residence and awareness of the malaria vaccine, influence the willingness to uptake the vaccine for children. Moreover, younger mothers (15-26 years), households in the richest wealth quintile, male-headed households and the number of children aged five years and below in a household, are found to be associated with less willingness to uptake the vaccine for children.”

Vector control and protection from vectors

Fink G & al., Mosquito Net Use in Early Childhood and Survival to Adulthood in Tanzania, New Eng J Med 2022 Feb 3, 386:428-36. doj:10-1056/NEJMoa2112524 and the accompanying editorial, Eisele TP, Slutsker L, Insecticide-Treated Nets and the Persistence of Childhood Survival Gains to Adulthood, New Eng J Med, 2022 Feb 3, 386:490-91, doj: 10-1056/NEJMe2119317 address the question whether insecticide treated net (ITN) use in households with small children merely delay the onset of malaria to older age groups.  This longitudinal study over 20 years that focused on death rates found significant difference in death rates before age five between users and nonusers, but no such difference during later in life.

Resistance of mosquitoes to pyrethroid in ITNs has led to the addition of other chemicals.  Ngufor C & al., Comparative Efficacy of Two Pyrethroid-Piperonyl Butoxide Nets (Olyset Plus and Permanet 3.0) Against Pyrethroid Resistant Malaria Vectors: A Non-Inferiority Assessment, Malaria J, 2021 Jan 11, vol 21 art 20. malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04041-9 concludes that whereas Olyset Plus nets performed better in killing mosquitoes after 20 washes, both nets were superior to the standard pyrethroid containing nets, and using WHO statistical criteria, Permanet 3.0 was “non-inferior.” Furthermore, “[c]onsidering the low levels of mortality observed and increasing pyrethroid-resistance in West Africa, it is unclear whether either of these nets would demonstrate the same epidemiological impact observed in community trials in East Africa.”

In an extensive literature review, Pryce J & al. conclude that “in communities using ITNs, the addition of IRS {indoor residual spraying} with ‘non-pyrethroid-like’ insecticides was associated with reduced malaria prevalence. Malaria incidence may also be reduced on average, but there was unexplained qualitative heterogeneity, and the effect may therefore not be observed in all settings. When using ‘pyrethroid-like’ insecticides, there was no … additional benefit of IRS in communities using ITNs.” The article is Indoor Residual Spraying for Preventing Malaria in Communities Using Insecticide-Treated Nets, Cochrane Database Syst Rev, 2022 Jan 17;1(1):Cd012688. doi: 10.1002/14651858.Cd012688.Pub3.

Mmbando AS & al. constructed experimental huts and reported the outcome in The Effect of Light and Ventilation on House Entry by Anopheles arabiensis Sampled Using Light Traps in Tanzania: An Experimental Hut Study, Malaria J, 2022 Feb 5, vol 21 art 36, malariajournal.biomedcentral.com/ articles/10.1186/s12936-022-04063-3. They found that even though mosquitoes were attracted to light in the huts with open eaves, the improved ventilation created by the openings more than counter-balanced this effect.

“Insecticide-treated livestock (ITL) is a potential novel strategy by which zoophagic mosquitos are killed after feeding upon animals treated with an insecticide. Although there are several insecticide candidates in the pipeline with a wide efficacy range against mosquitos, additional field studies with epidemiological outcomes are required to test the impact of this intervention on malaria transmission. Insecticides under consideration have long been used in livestock to improve animal health and productivity, but each has food and environmental safety considerations,” conclude Ruiz-Castillo P & al. in Insecticide-Treated Livestock: A Potential One Health Approach to Malaria Control in Africa, Trends Parasitol, 2022 Feb;38(2):112-123.  doi: 10.1016/j.pt.2021.09.006.

Chemoprophylaxis

“Tafenoquine is a long-acting 8-aminoquinoline approved for antimalarial prophylaxis for ≤6 months. Additional data is needed to establish the drug’s longer-term safety profile, including potential ophthalmic or neuropsychiatric effects.” Novitt-Moreno A & al., Long-Term Safety of the Tafenoquine Antimalarial Chemoprophylaxis Regimen: A 12-Month, Randomized, Double-Blind, Placebo-Controlled Trial, Travel Med Inf Dis, 2022 Jan-Feb, 45:102211, doi: 10.1016/j.tmaid.2021.102211 find that the drug is safe for prophylaxis up to 52 weeks.  Another article to be published in the same journal, Schlagenhauf P & al., Tafenoquine for Malaria Chemoprophylaxis – Status Quo 2022, Travel Med Inf Dis, 2022 Mar-Apr, 46:102268. https://doi.org/10.1016/j.tmaid.2022.102268 unfortunately has no abstract available.

“Mefloquine has been around from the 1970s, and was developed in the United States keeping in mind the soldiers that were being deployed to areas where chloroquine resistant strains of Plasmodium were discovered. Mefloquine was preferred for its once a week dosage. Within a decade of its introduction, reports of the side effects associated with its long-term use surfaced. Mefloquine is now reported to cause a myriad of neuropsychiatric side effects including anxiety, sleep disturbance, depression, dizziness and frank psychosis, especially in patients with pre-existing psychiatric disorders.” Ahmad SS & al., Mefloquine as a Prophylaxis for Malaria Needs to Be Revisited, Int J Parasitol Drugs Drug Resist, 2021 Dec;17:23-26.  doi: 10.1016/j.ijpddr.2021.06.003 reviews the side effects.  {Parenthetically, this reviewer started using Mefloquine during his tour as a US Army public health officer in Vietnam in 1969-70 and has continued to use it multiple times virtually every year since then during travel in Africa and South and Southeast Asia, without any side effects, as has his wife.}

Chemoprevention during pregnancy is the topic of Antonescu LR & al., The Effect of Intermittent Preventive Treatment of Malaria During Pregnancy and Placental Malaria on Infant Risk of Malaria, J Infect Dis, 2022 Jan 18;225(2):248-256.  doi: 10.1093/infdis/jiab351. They compared two preventive regimens, dihydroartemisinin-piperaquine (DP) and sulfadoxine-pyrimethamine (SP). Whereas it has been known that DP provides greater protection from placental malaria than SP, there was no difference on the infant’s risk of malaria.  In fact, even known exposure to placental malaria caused no increase in malaria in the infants studied.

Diagnosis:

Several articles deal with Rapid Diagnostic Tests (RDTs).

Wittenauer R & al. acknowledge that there is variability among RDTs in terms of reliability.  Their analysis is designed to answer the following questions: “(1) Has the market share by quality of RDTs in the Global Fund’s procurement orders changed over time? (2) What is the relationship between unit price and RDT quality? (3) Has the market for RDTs financed by the Global Fund become more concentrated over time?”  Published as Price, Quality, and Market Dynamics of Malaria Rapid Diagnostic Tests: Analysis of Global Fund 2009–2018 Data, Malaria J, 2022 Jan 12, vol 21, art 21 malariajournal.biomedcentral.com/articles/10.1186/s12936-021-04008-2, they conclude that “[l]ower-quality RDTs have lost market share between 2009 and 2018, as have the highest-quality RDTs. No statistically significant relationship between price per test and PDS was found when adjusting for order volume, product type, and year of purchase.”

On Bioko Island, Equatorial Guinea Hosch S & al. examined RDT results compared to more reliable qPCR tests and found 4.7% false negatives, while among the positives, 28.4% were negative on qPCR testing.  In their report, Analysis of Nucleic Acids Extracted from Rapid Diagnostic Tests Reveals a Significant Proportion of False Positive Test Results Associated with Recent Malaria Treatment, Malaria J, 2022 Jan 24, vol 21 art 23. https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04043-7,  they state that “this high proportion of false-positive RDTs could be explained by P. falciparum histidine rich protein 2 (PfHRP2) antigen persistence after recent malaria treatment.” Therefore they conclude that “[m]alaria surveillance depending solely on RDTs needs well-integrated quality control procedures to assess the extent and impact of reduced sensitivity and specificity of RDTs on malaria control programmes.”

Slater H & al., Performance and Utility of More Highly Sensitive Malaria Rapid Diagnostic Tests, BMC Infect Dis, 2022 Feb 4;22(1):121. doi: 10.1186/S12879-021-07023-5 is a study of “all published and available unpublished studies that use {a particular brand of Highly Sensitive RPD} HS-RPD and assess its performance…” They found “that across 18 studies, in prevalence surveys, the mean sensitivity of the HS-RDT is estimated to be 56.1% … compared to 44.3% … for a conventional RDT (co-RDT) when using nucleic acid amplification techniques as the reference standard. In studies where prevalence was estimated using both the HS-RDT and a co-RDT, we found that prevalence was on average 46% higher using a HS-RDT compared to a co-RDT. For use in clinical diagnosis and screening pregnant women, the HS-RDT was not significantly more sensitive than a co-RDT.”

“Rapid diagnostic tests (RDTs) for Plasmodium falciparum commonly detect histidine-rich protein 2 (HRP-2), but HRP-2 deletions are increasingly recognized.” Bachman CM & al., A Novel Malaria Lateral Flow Assay for Detecting Plasmodium falciparum Lactose Dehydrogenase in Busia, Uganda, Am J Trop Med Hyg, 2022 Jan 17;tpmd210956. doi: 10.4269/ajtmh.21-0956 report on a “prototype test detecting parasite lactate dehydrogenase (pLDH) and {in comparison to} to commercially available RDTs at a health facility in Uganda, using quantitative polymerase chain reaction as a gold standard. The prototype pLDH test had a high sensitivity for infections with at least 100 parasites/µL (98%), comparable to HRP-2, and greater than an existing pLDH RDT (89%). Specificity for the prototype test was 99.5%, which is greater than the HRP-2 tests (93-95%). Therefore, the prototype pLDH test may be an attractive alternative malaria diagnostic.”

Zeleke AJ & al., Plasmodium falciparum Histidine-Rich Protein 2 and 3 Genes Deletion in Global Settings (2010–2021): A Systematic Review and Meta-Analysis, Malaria J, 2022 Jan 29, vol 21 art 26, malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04051-7 also report that “[t]he usefulness of histidine-rich protein-2/3 (HRP2/3)-based rapid diagnostic tests of malaria due to Plasmodium falciparum has been threatened by the appearance of mutant PfHRP2/3 genes.” As a result of their review of 27 publications on the subject, they “showed that there is a high pooled prevalence of PfHRP2/3 gene deletions in Plasmodium falciparum confirmed isolates and also a high proportion of their deletions among false-negative malaria cases using PfHRP2-based RDT results. Hence, malaria diagnosis based on PfHRP2-based rapid tests seems to be less sensitive and warrants further evaluation of PfHRP2/3 gene deletions.”

In DR Congo, Stan MH & al. advocate for a “pediatric malaria assessment tool incorporating socio-demographics, symptoms and physical exam findings {that} may guide investigations to reduce unnecessary testing and provide better patient-centered care” in their paper, Malaria Amongst Febrile Children: Call for a Pediatric Malaria Assessment Tool, Pan Afr Med J, 2021 Oct 7;40:84 doi: 10.11604/pamj.2021.40.84.21165.

Okiring J & al. found that “[f]emales disproportionately contribute to the burden of malaria diagnosed at public health facilities in Uganda, especially once they reach childbearing age.” The results published as Gender Difference in the Incidence of Malaria Diagnosed at Public Health Facilities in Uganda, Malaria J, 2022 Jan 21, vol 21 art 22. malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04046-4 disclosed that the “incidence of malaria diagnosed per 1000 person years was 735 among females and 449 among males …, with larger differences among those 15–39 years … and over 39 years … compared to those under 15 years…”

A paper that could be cited under Epidemiology as Diagnosis, Amoah LE & al., Nationwide Molecular Surveillance of Three Plasmodium Species Harboured by Symptomatic Malaria Patients Living in Ghana, Parasit Vect, 2022 Jan 28, vol 15 art 40,  parasitesandvectors.biomedcentral.com/articles/ 10.1186/s13071-022-05153-6 discloses that in Ghana, the “frequency of P. falciparum, P. malariae and P. ovale detected by PCR was 74.9, 1.4 and 0.9%, respectively. Of the suspected symptomatic P. falciparum malaria cases, 33.5% contained submicroscopic densities of parasites. For all regions, molecular diagnosis of P. falciparum, P. malariae and P. ovale was significantly higher than diagnosis using microscopy: up to 98.7% … of P. malariae and 97.8% … of P. ovale infections detected by PCR were missed by microscopy.”

Treatment:

Mpimbaza A & al. conducted health facility assessments, health care worker, and patient exit surveys at government and private health facilities. They reported their findings in Adherence to Malaria Management Guidelines by Health Care Workers in the Busoga Sub-Region, Eastern Uganda, Malaria J, 2022 Jan 15, vol 21 art 25, accessible at malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04048-2r.  Malaria testing services were available at > 85% of facilities. Artemether-lumefantrine (AL) was in stock at 76.5% of facilities. Of those with a positive result, nearly all were prescribed an anti-malarial, with AL (95.1%) accounting for most prescriptions. … Overall, 86.9% of all enrolled patients received appropriate malaria case management. However, only 50.7% of patients seen at primary care physicians received appropriate malaria management.

Dabira ED & al., Efficacy, Safety and Tolerability of Pyronaridine-artesunate (PA) in Asymptomatic Malaria-infected Individuals: A Randomized Controlled Trial, Clin Infect Dis, 2022 Jan 29; 74(2):180-188.  doi: 10.1093/cid/ciab425. “This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. … A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen.” Side effects were minimal.

Fluid therapy is an important supportive measure for patients with severe malaria. Kallman LC & al., Fluid Therapy in Severe Malaria, Lancet Inf Dis, 2022 Jan 17, https://doi.org/10-1016/S1473-3099(21)00471-0 focuses on this aspect of treatment with particular attention to what can be done in low-resource areas, particularly, since physical examination and physiological indices have limited reliability in guiding fluid therapy. Invasive measures can be more accurate than physical examination and physiological indices but are often unavailable in endemic areas, and non-invasive measures, such as ultrasound, are mostly unexplored.

Hanboonkunupakarn B, White NJ, Advances and Roadblocks in the Treatment of Malaria, Br J Clin Pharmacol, 2022 Feb; 88(2):374-382.  doi: 10.1111/Bcp.14474 focuses on how to deal with the emerging resistance to artemisinin regimens; however, the abstract is unrevealing as to the details.

“World Health Organization recommends quinine plus clindamycin as first-line treatment of malaria in the first trimester of pregnancy and as a second-line treatment for uncomplicated falciparum malaria when artemisinin-based drug combinations are not available.” Obonyo CO & al. compared this regimen with that of artemether-lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria in children below 5 years of age.  Their report, Efficacy of 3-Day Low Dose Quinine Plus Clindamycin Versus Artemether-Lumefantrine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in Kenyan Children (CLINDAQUINE): An Open-Label Randomized Trial, Malaria J, 2022 Feb 2, vol 21 art 30, https://malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04050-8 does not support the “use of a 3-day low dose course of quinine plus clindamycin in the treatment of uncomplicated falciparum malaria in children under 5 years of age in Kenya, where artemether-lumefantrine is still effective.”

“WHO has recommended that a single low dose of primaquine could be added to artemisinin-based combination therapies to reduce Plasmodium falciparum transmission in areas aiming for elimination of malaria or areas facing artemisinin resistance.” Stone W & al., Pyronaridine-Artesunate or Dihydroartemisinin-Piperaquine Combined with Single Low-Dose Primaquine to Prevent Plasmodium falciparum Malaria Transmission in Ouélessébougou, Mali: A Four-Arm, Single-Blind, Phase 2/3, Randomised Trial, Lancet Microbe, 2022 Jan; 3(1):E41-E51. doi: 10.1016/S2666-5247(21)00192-0 reports that “[i]n individuals who were infectious before treatment, the median percentage reduction in mosquito infection rate 48 h after treatment was 100·0% … for individuals treated with {both regimens} plus primaquine,”  compared with much lesser success if primaquine was not added. There were no serious adverse events. Therefore they “support the use of single low-dose primaquine as an effective supplement to {these ACT regimens} for blocking P falciparum transmission.”

“Decoquinate (DQ) displays strong activity against multistage infection by Plasmodium parasites.” However, the oral use of DQ for the treatment of malaria at the blood stage has not been successful. Zeng S & al., created liposome formulations of the drug. Decoquinate Liposomes: Highly Effective Clearance of Plasmodium Parasites Causing Severe Malaria, Malaria J, 2022 Jan 24 vol 21 art 24 malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04042-8 reports that these formulations in vitro inhibited P. falciparum within freshly isolated human red blood cells.  Also, they injected the formulations into mice infected P. berghei and found “impressive efficacy.”

Two articles deal with the treatment of vivax malaria.

Woon S-A & al., Antimalarials for Children with Plasmodium vivax infection: Current Status, Challenges, and Research Priorities, Parasitol Int, 2022 Apr; 87:102512. doi:10.1016/.parint.2021. 102512 summarizes “efficacy and pharmacokinetic data for Plasmodium vivax in children…. Relapse after re-activation of dormant liver-stage hypnozoites poses additional challenges for treatment, elimination, and control strategies for P. vivax.”  In view of the latter fact, Vélez ID & al. turned to tafenoquine.  Their article, Tafenoquine Exposure Assessment, Safety, and Relapse Prevention Efficacy in Children With Plasmodium vivax Malaria: Open-Label, Single-Arm, Non-Comparative, Multicentre, Pharmacokinetic Bridging, Phase 2 Trial, Lancet Child Adolesc Health, 2022 Feb, 6(2):86-95, doi: 10.1016/S2352-4642(21)00328-X, concludes that “single-dose tafenoquine, including a dispersible formulation, had exposure, safety, and efficacy consistent with observations in adolescents and adults, notwithstanding post-dose vomiting.”

The continuing quest for new effective antimalarial therapy is the subject of Happi GM & al., Contribution of Meliaceous Plants in Furnishing Lead Compounds for Antiplasmodial and Insecticidal Drug Development, J Ethnopharmacol, 2022 Mar 1; 285:114906. doi: 10.1016/j.jep.2021.114906.  This article reports on a literature review and concludes that “[s]tudies performed so far on Meliaceae plants have reported compounds with significant antiplasmodial and insecticidal activity, lending support to the use of species of this family in folk medicine, for the treatment of malaria. Moreover, results qualified several of these species as important sources of compounds for the development of eco-friendly pesticides to control mosquito vectors.”

The Controversy

An interesting set of articles were recently brought to the attention of this reviewer about a preparation called Artavol.  In December 2012, BJG Knols published a blog entitled A “vaccine” against malaria from Africa: ARTAVOL® in which he quoted a Dr. P. Lutgen {Ph D. in Chemistry} that Artavol, which is “composed of ground kernels of avocado, extracts of lemon grass and extracts of  dried artemisia herb which does not contain artemisinin, … demonstrated that if taken regularly during one year it renders a person immune against malaria. It also reduced the asymptomatic malaria cases in an adult population by 60%.” Then, on 21 April 2020, (no author) Health Ministry Asks UCC to Withdraw Antimalarial Beverage Adverts, The Independent, reported that “during an interview with Uganda Radio Network (URN) this morning, Dr Jimmy Opigo who heads the Malaria Control Programme at the Ministry of Health said promoting Artavol as prevention for malaria is wrong. He adds that the properties from which Artavol is made can only stay in the blood for a very short time something that puts its users at risk of resistance to artemisinin-based combination therapy (ACT). www.independent.co.ug/health-ministry-asks-ucc-to-withdraw-antimalarial-beverage-adverts/.  Yet, one year later,  Amanya M & al., Prophylactic Effect of ARTAVOL® on Plasmodium berghei Infected Mice, East Africa Science, 2021 Mar 15, 3(1) doi.org/10.24248/EASci-D-20-00010 report on evidence that in mice, the substance does have anti-plasmodial effects.

Additional literature received or reviewed in this context includes a lengthy untitled commentary obviously composed again by Dr. Lutgen (it gives his email address), which castigates the WHO for allegedly conspiring with major pharmaceutical firms to foster the use of ACT to the exclusion of herbal preparations, including Artavol.  This document, apparently published by malariaworld newsletter,  https://malariaworld.org/page/malariaworld-newsletter, also makes the allegation that artemisinin resistance has now been reported in ten African countries.  Since this reviewer could not find the original of this document at the website mentioned, he searched the website of IFBV-BELHERB, of which Dr. Lutgen is Secretary.  On that website appeared Malaria: The Dramatic Failure of Mass Drug Administration with the French subtitle “Échec des ACT contre malaria,” which translates to “failure of ACTs against malaria.”  Dated 21 January 2022, it also appeared unchanged on the malariaworld newsletter.  This article is a compendium of references from the scientific literature that is said to chronicle failed mass drug administration campaigns in multiple African countries and asserts that “numerous clinical trials, small and large, demonstrated that Artemisia annua and Artemisia afra infusions or powdered leaves reduce parasitemia much more efficiently than ACTs, that they inhibit spororoites [sic] and eliminate all gametocytes. With Artemisia afra infusions malaria eradication becomes possible.”

IFBV-BELHERB is an organization in Luxembourg that considers the promotion of herbal remedies for parasitic diseases as its main mission.  It promotes the publication of articles on the subject in the scientific and electronic media.  PubMed cites four articles co-authored by Dr. Lutgen over the past 12 years; two of them, dealing with herbal anti-malarials, had to be retracted in 2020.

Campaigns:

Nalinya S & al., Malaria Prevention Interventions Beyond Long-Lasting Insecticidal Nets and Indoor Residual Spraying in Low- And Middle-Income Countries: A Scoping Review, Malaria J, 2022 Feb 2, vol 21 art 31, malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04052-6. The authors reviewed the relevant literature from 1994 to 2020 and found 31 articles that met their criteria.  The three main themes included housing design, mosquito repellents, and integrated vector control (i.e. larvae source management).  It is of interest that this article cites closure of eaves as beneficial, whereas Mmbando & al. argue that improved ventilation is more important (see Prevention above)

Marathe A & al., Potential Impact of 5 Years of Ivermectin Mass Drug Administration on Malaria Outcomes in High Burden Countries, BMJ Glob Health, 2021 Nov; 6(11):e006424. doi: 10.1136/bmjgh-2021-006424. This is a calculation of possible outcomes, concluding that there is a potential of significantly reducing both infections and deaths, if Ivermectin mass administration is introduced in the nine countries studied.

“In 2021, the World Health Organization (WHO) published the 2nd edition of its guidance for testing genetically modified mosquitoes {WHO. Guidance framework for testing genetically modified mosquitoes, Second edition, Geneva, World Health Organization, 2021. Available from https://www.who.int/publications/i/item/9789240025233}. A major portion of that report was dedicated to ethical considerations, stressing and the importance of responsible community engagement.” Roberts RJ and Thyzi D discuss the application of this guidance in Articulating Ethical Principles Guiding Target Malaria’s Engagement Strategy, Malaria J, 2022 Feb 5, vol 21 art 35, malariajournal.biomedcentral.com/articles/10.1186/s12936-022-04062-4.

Agins B & al., Effective Management of District-Level Malaria Control and Elimination: Implementing Quality and Participative Process Improvements, BMC Public Health, 2022 Jan 20; vol 22 art 140. doi: 10.1186/s12889-021-12322-2 is an article calling for the application of quality improvement principles to malaria control and elimination campaigns.

Epidemiology:

During the past month nineteen (19) published articles dealt with the epidemiology of malaria in Africa.  Given this volume, this section will contain a description of those of greatest relevance to the work of MPI; the others will be mentioned.  The abstracts of all of them are available on demand.

A descriptive ecological study was conducted by Haileselassie W & al., reviewing health service records at Abobo district health office in Ethiopia. The records were reviewed to extract data on malaria morbidity, mortality, and prevention and control methods. They report in Burden of Malaria, Impact of Interventions and Climate Variability in Western Ethiopia: An Area with Large Irrigation Based Farming, BMC Public Health, 2022 Jan 29; vol 22 art 196, doi: 10.1186/s12889-022-12571-9 that P. falciparum was annually the infectious agent in up to 90% of the cases and “[t]here was no statistically significant association between season and total malaria case number” However, three months’ “lagged humidity had significant positive effect on total malaria cases.”

The ratio among various Plasmodium species infecting patients was very different from the above, as reported in Mulugeta A & al., Six-Year Trend Analysis of Malaria Prevalence at University of Gondar Specialized Referral Hospital, Northwest Ethiopia, from 2014 to 2019, Sci Rep, 2022 Jan 26; 12(1):1411. doi: 10.1038/s41598-022-05530-2. Here P. ovale was most frequent with 47.2%, with P. falciparum making up 45.6% of case, the remainder being mixed infections.  However, in the latter three years of the study, P. falciparum became more frequent.  Also in contrast with the above report, there was high seasonal fluctuation from year to year.  Children and young adults were infected more often than older adults and young males were more prone to be affected than young females.

Seasonal variations were also reported in Nigussie TZ & al., Distribution of Malaria Incidence in The Amhara National Regional State, Ethiopia, Spat Spatiotemporal Epidemiol, 2022 Feb;40:100475. doi: 10.1016/j.sste.2021.100475. “The risk of malaria incidence was decreased by 24% per 100 m increase in altitude. Monthly minimum temperature decreases the risk of malaria by 2.2% per a 1°C increment. The risk of malaria transmission was increased by 8% per 100 mm rise in the total monthly rainfall of districts.”

Abdulraheem MA & al., High Prevalence of Plasmodium malariae and Plasmodium ovale in Co-Infections with Plasmodium falciparum in Asymptomatic Malaria Parasite Carriers in Southwestern Nigeria, Int J Parasitol, 2022 Jan; 52(1):23-33 doi: 10.1016/j.ijpara.2021.06.003 is a “cross-sectional survey of 1032 adolescents (ages 10-19 years) from eight schools located in Ibadan, southwestern Nigeria in 2016… The prevalence of asymptomatic malaria was determined using microscopy, rapid diagnostic tests and PCR for 658 randomly selected samples. Of these, we found that 80% of asymptomatic schoolchildren were positive for malaria parasites by PCR, compared with 47% and 9%, determined by rapid diagnostic tests and microscopy, respectively. Malaria parasite species typing … revealed high rates of carriage of Plasmodium malariae (53%) and Plasmodium ovale (24%). Most asymptomatic infections were co-infections of two or more species (62%)

Quaye IK, & al. state that “several countries in sub-Saharan Africa have reported cases of Plasmodium vivax (Pv) …. The burden of Pv and Plasmodium ovale (Po) appear to be more than acknowledged.” Their article is The Pan African Vivax and Ovale Network (PAVON): Refocusing on Plasmodium vivax, ovale and Asymptomatic Malaria in Sub-Saharan Africa, Parasitol Int, 2021 Oct; 84:102415. doi: 10.1016/j.parint.2021.102415.

Manirakiza G & al., Molecular Identification and Anti-Malarial Drug Resistance Profile of Plasmodium falciparum from Patients Attending Kisoro Hospital, Southwestern Uganda, Malaria J, 2022 Jan 15 vol 21 art 21.  https://malariajournal.biomedcentral.com/articles/10.1186/s12936-021-04023-3 reports that over 90% of the 134 malaria patients in this hospital were infected by P. falciparum, the rest by P. ovale and P. malariae.  The drug resistance mentioned in the title of the article refers to resistance to chloroquine, which at less than 30% is said to show evidence of waning resistance to chloroquine.

Krezanoski PJ & al. found Marked Reduction in Antibiotic Usage Following Intensive Malaria Control in a Cohort of Ugandan Children, BMC Med, 2021 Nov 30;19(1):294.  doi: 10.1186/S12916-021-02167-2. They state that “[t]his added benefit of malaria control could have important implications for antibiotic prescribing practices, efforts to curtail antimicrobial resistance, and health system costs.”

Kamau A & al. focus on demographics and clinical presentation as reported in Malaria Hospitalisation in East Africa: Age, Phenotype and Transmission Intensity, BMC Med, 2022 Jan 27 vol 20 art28.  Doi: 10.1186/S12916-021-02224-W. Clinical data from 21 surveillance hospitals in East Africa were reviewed. 52,684 malaria admissions aged 1 month to 14 years were described … The majority of malaria admissions were below 5 years of age (69-85%) and rare among children aged 10-14 years (0.7-5.4%) … The mean age of all-cause malaria hospitalisation was 49.5 months … under low transmission compared with 34.1 months at high transmission … Cerebral malaria presented … at a mean of 48.7 months …”

Bationo CS & al., Spatio-Temporal Analysis and Prediction of Malaria Cases Using Remote Sensing Meteorological Data in Diébougou Health District, Burkina Faso, 2016-2017, Sci Rep, 2021 Oct 8;11(1):20027.  doi: 10.1038/s41598-021-99457-9. This study “aimed to identify the spatial distribution of malaria hotspots at the village level in Diébougou health district, Burkina Faso, and to model the temporal dynamics of malaria cases as a function of meteorological conditions and of the distance between villages and health centres (HCs). Case data for 27 villages were collected in 13 HCs. Four spatial hotspots, involving 7 of the 27 villages, were detected, … The multivariate analysis found greater variability in incidence between HCs than between villages linked to the same HC.” The authors also report meteorological variables related to precipitation and temperature.

Band G & al., Malaria Protection Due to Sickle Haemoglobin Depends on Parasite Genotype, Nature, 2022 Feb;602(7895):106-111, doi: 10.1038/S41586-021-04288-3.

Chen J & al., Progress in the Study of Epidemiologic Characteristics and Influencing Factors of Asymptomatic Malaria Infection in Africa, Altern Ther Health Med, 2021 Nov;27(6):52-56. https://pubmed.ncbi.nlm.nih.gov/33620333/

Ebel E & al., Revisiting the Malaria Hypothesis: Accounting for Polygenicity and Pleiotropy, Trends Parasitol, 2022 Jan 19;S1471-4922(21)00337-8. doi: 10.1016/j.pt.2021.12.007.

Gumbo A & al., Occurrence and Distribution of Nonfalciparum Malaria Parasite Species Among Adolescents and Adults in Malawi, J Infect Dis, 2022 Jan 18;225(2):257-268. doi: 10.1093/infdis/jiab353

Monahan P & al., Malaria and Covid-19: A Double Battle for Burundi, Afr J Emerg Med, 2022 Mar; 12(1):27-29. doi: 10.1016/j.afjem.2021.10.006.

Muhoza P & al., A Data Quality Assessment of the First Four Years of Malaria Reporting in the Senegal DHIS2, 2014-2017, BMC Health Serv Res, 2022 Jan 2;22(1):18. doi: 10.1186/S12913-021-07364-6.

Obasohan PE & al., Individual and Contextual Factors Associated with Malaria among Children 6-59 Months in Nigeria: A Multilevel Mixed Effect Logistic Model Approach, Int J Environ Res Public Health, 2021 Oct 26; 18(21):11234. doi: 10.3390/ijerph182111234.

Osei SA & al., Low Incidence of COVID-19 Case Severity and Mortality in Africa; Could Malaria Co-Infection Provide the Missing Link? BMC Infect Dis, 2022 Jan 22; 22(1):78.  doi: 10.1186/S12879-022-07064-4.

Phyo AP & al., Clinical Impact of Vivax Malaria: A Collection Review, PLoS Med, 2022 Jan 18; 19(1):e1003890. doi: 10.1371/journal.pmed.1003890.

Reiker T & al., Emulator-Based Bayesian Optimization for Efficient Multi-Objective Calibration of an Individual-Based Model of Malaria, Nat Commun, 2021 Dec 10; 12(1):7212. doi: 10.1038/S41467-021-27486-Z.