Malaria-endemic Regions Research Articles

Bayesian spatio-temporal distributed lag modeling for delayed climatic effects on sparse malaria incidence data

BackgroundIn many areas of the Greater Mekong Subregion (GMS), malaria endemic regions have shrunk to patches of predominantly low-transmission. With a regional goal of elimination by 2030, it is important to use appropriate methods to analyze and predict trends in incidence in these remaining transmission foci to inform planning efforts. Climatic variables have been associated with malaria incidence to varying degrees across the globe but the relationship is less clear in the GMS and standard methodologies may not be appropriate to account for the lag between climate and incidence and for locations with low numbers of cases.MethodsIn this study, a methodology was developed to estimate the spatio-temporal lag effect of climatic factors on malaria incidence in Thailand within a Bayesian framework. A simulation was conducted based on ground truth of lagged effect curves representing the delayed relation with sparse malaria cases as seen in our study population. A case study to estimate the delayed effect of environmental variables was used with malaria incidence at a fine geographic scale of sub-districts in a western province of Thailand.ResultsFrom the simulation study, the model assumptions which accommodated both delayed effects and excessive zeros appeared to have the best overall performance across evaluation metrics and scenarios. The case study demonstrated lagged climatic effect estimation of the proposed modeling with real data. The models appeared to be useful to estimate the shape of association with malaria incidence.ConclusionsA new method to estimate the spatiotemporal effect of climate on malaria trends in low transmission settings is presented. The developed methodology has potential to improve understanding and estimation of past and future trends in malaria incidence. With further development, this could assist policy makers with decisions on how to more effectively distribute resources and plan strategies for malaria elimination.

Genetic diversity and population structure of the human malaria parasite Plasmodium falciparum surface protein Pfs47 in isolates from the lowlands in Western Kenya.

Plasmodium falciparum parasites have evolved genetic adaptations to overcome immune responses mounted by diverse Anopheles vectors hindering malaria control efforts. Plasmodium falciparum surface protein Pfs47 is critical in the parasite’s survival by manipulating the vector’s immune system hence a promising target for blocking transmission in the mosquito. This study aimed to examine the genetic diversity, haplotype distribution, and population structure of Pfs47 and its implications on malaria infections in endemic lowlands in Western Kenya. Cross-sectional mass blood screening was conducted in malaria endemic regions in the lowlands of Western Kenya: Homa Bay, Kombewa, and Chulaimbo. Dried blood spots and slide smears were simultaneously collected in 2018 and 2019. DNA was extracted using Chelex method from microscopic Plasmodium falciparum positive samples and used to genotype Pfs47 using polymerase chain reaction (PCR) and DNA sequencing. Thirteen observed haplotypes of the Pfs47 gene were circulating in Western Kenya. Population-wise, haplotype diversity ranged from 0.69 to 0.77 and the nucleotide diversity 0.10 to 0.12 across all sites. All the study sites displayed negative Tajima’s D values although not significant. However, the negative and significant Fu’s Fs statistical values were observed across all the study sites, suggesting population expansion or positive selection. Overall genetic differentiation index was not significant (FST = -0.00891, P > 0.05) among parasite populations. All Nm values revealed a considerable gene flow in these populations. These results could have important implications for the persistence of high levels of malaria transmission and should be considered when designing potential targeted control interventions.

Insilico Functional Analysis of Genome-Wide Dataset From 17,000 Individuals Identifies Candidate Malaria Resistance Genes Enriched in Malaria Pathogenic Pathways.

Recent genome-wide association studies (GWASs) of severe malaria have identified several association variants. However, much about the underlying biological functions are yet to be discovered. Here, we systematically predicted plausible candidate genes and pathways from functional analysis of severe malaria resistance GWAS summary statistics (N = 17,000) meta-analysed across 11 populations in malaria endemic regions. We applied positional mapping, expression quantitative trait locus (eQTL), chromatin interaction mapping, and gene-based association analyses to identify candidate severe malaria resistance genes. We further applied rare variant analysis to raw GWAS datasets (N = 11,000) of three malaria endemic populations including Kenya, Malawi, and Gambia and performed various population genetic structures of the identified genes in the three populations and global populations. We performed network and pathway analyses to investigate their shared biological functions. Our functional mapping analysis identified 57 genes located in the known malaria genomic loci, while our gene-based GWAS analysis identified additional 125 genes across the genome. The identified genes were significantly enriched in malaria pathogenic pathways including multiple overlapping pathways in erythrocyte-related functions, blood coagulations, ion channels, adhesion molecules, membrane signalling elements, and neuronal systems. Our population genetic analysis revealed that the minor allele frequencies (MAF) of the single nucleotide polymorphisms (SNPs) residing in the identified genes are generally higher in the three malaria endemic populations compared to global populations. Overall, our results suggest that severe malaria resistance trait is attributed to multiple genes, highlighting the possibility of harnessing new malaria therapeutics that can simultaneously target multiple malaria protective host molecular pathways.

Genetic Diversity of Polymorphic Marker Merozoite Surface Protein 1 (Msp-1) and 2 (Msp-2) Genes of Plasmodium falciparum Isolates From Malaria Endemic Region of Pakistan.

Background: Understanding the genetic diversity of Plasmodium species through polymorphic studies can assist in designing more effective control strategies of malaria like new drug formulation and development of a vaccine. Pakistan is moderate endemic for Plasmodium falciparum, but little is known about the genetic diversity of this parasite. This study aimed to investigate the molecular diversity of P. falciparum based on msp-1 and msp-2 genes in the malaria-endemic regions of Khyber Pakhtunkhwa, Pakistan. Methods: A total of 199/723 blood samples, tested positive by microscopy for falciparum malaria, were collected from four districts (Dera Ismail Khan, Karak, Mardan, and Peshawar) of Khyber Pakhtunkhwa. Nested PCR amplification technique was employed to target block 2 of msp-1 and the central domain of msp-2 genes, including their respective allelic families K1, MAD20, RO33, FC27, and 3D7/IC, and to detect the extent of genetic diversity of P. falciparum clinical isolates. Results: Among the 199 microscopy-positive P. falciparum samples, a total of 192 were confirmed using PCR. Ninety-seven amplicons were observed for msp-1 and 95 for msp-2. A total of 33 genotypes, 17 for msp-1 (eight K1, six MAD20, and three RO33) and 16 for msp-2 (nine FC27 and seven 3D7/IC), were identified. The specific allelic frequency of the K1 family was higher (44.3%) than that of MAD20 (33.0%) and RO33 (23.0%) for msp-1, while the FC27 allelic family was dominant (60.0%) compared with 3D7/IC (40.0%) for msp-2. No polyclonal infection was observed in msp-1 and msp-2. The expected heterozygosity was 0.98 and 0.97 for msp-1 and msp-2, respectively. Conclusion: It was concluded that the P. falciparum populations are highly polymorphic, and diverse allelic variants of msp-1 and msp-2 are present in Khyber Pakhtunkhwa, Pakistan.

A nowcasting framework for correcting for reporting delays in malaria surveillance.

Time lags in reporting to national surveillance systems represent a major barrier for the control of infectious diseases, preventing timely decision making and resource allocation. This issue is particularly acute for infectious diseases like malaria, which often impact rural and remote communities the hardest. In Guyana, a country located in South America, poor connectivity among remote malaria-endemic regions hampers surveillance efforts, making reporting delays a key challenge for elimination. Here, we analyze 13 years of malaria surveillance data, identifying key correlates of time lags between clinical cases occurring and being added to the central data system. We develop nowcasting methods that use historical patterns of reporting delays to estimate occurred-but-not-reported monthly malaria cases. To assess their performance, we implemented them retrospectively, using only information that would have been available at the time of estimation, and found that they substantially enhanced the estimates of malaria cases. Specifically, we found that the best performing models achieved up to two-fold improvements in accuracy (or error reduction) over known cases in selected regions. Our approach provides a simple, generalizable tool to improve malaria surveillance in endemic countries and is currently being implemented to help guide existing resource allocation and elimination efforts.

Population-specific adaptation in malaria-endemic regions of asia.

Evolutionary mechanisms of adaptation to malaria are understudied in Asian endemic regions despite a high prevalence of malaria in the region. In our research, we performed a genome-wide screening for footprints of natural selection against malaria by comparing eight Asian population groups from malaria-endemic regions with two non-endemic population groups from Europe and Mongolia. We identified 285 adaptive genes showing robust selection signals across three statistical methods, iHS, XP-EHH, and PBS. Interestingly, most of the identified genes (82%) were found to be under selection in a single population group, while adaptive genes shared across populations were rare. This is likely due to the independent adaptation history in different endemic populations. The gene ontology (GO) analysis for the 285 adaptive genes highlighted their functional processes linked to neuronal organizations or nervous system development. These genes could be related to cerebral malaria and may reduce the inflammatory response and the severity of malaria symptoms. Remarkably, our novel population genomic approach identified population-specific adaptive genes potentially against malaria infection without the need for patient samples or individual medical records.

X-ray Structure Determination, Antioxidant Voltammetry Studies of Butein and 2',4'-Dihydroxy-3,4-dimethoxychalcone. Computational Studies of 4 Structurally Related 2',4'-diOH Chalcones to Examine Their Antimalarial Activity by Binding to Falcipain-2.

Malaria is a huge global health burden with resistance to currently available medicines resulting in the search for newer antimalarial compounds from traditional medicinal plants in malaria-endemic regions. Previous studies on two chalcones, homobutein and 5-prenylbutein, present in E. abyssinica, have shown moderate antiplasmodial activity. Here, we describe results from experimental and computational investigations of four structurally related chalcones, butein, 2′,4′-dihydroxy-3,4-dimethoxychalcone (DHDM), homobutein and 5-prenylbutein to elucidate possible molecular mechanisms by which these compounds clear malaria parasites. The crystal structures of butein and DHDM show that butein engages in more hydrogen bonding and consequently, more intermolecular interactions than DHDM. Rotating ring-disk electrode (RRDE) voltammetry results show that butein has a higher antioxidant activity towards the superoxide radical anion compared to DHDM. Computational docking experiments were conducted to examine the inhibitory potential of all four compounds on falcipain-2, a cysteine protease that is involved in the degradation of hemoglobin in plasmodium-infected red blood cells of the host. Overall, this work suggests butein as a better antimalarial compound due to its structural features which allow it to have greater intermolecular interactions, higher antioxidant activity and to create a covalent complex at the active site of falcipain-2.

Diagnostic value of electrocardiograms to identify pericardial effusion in acute malaria: a cross-sectional study

Abstract Background Patients with acute malaria are at risk of pericarditis and may benefit from timely identification of pericardial effusion. However, diagnostic imaging tools, such as echocardiography, are not always available in malaria endemic regions. Purpose The aim of this study is to examine the diagnostic yield of pathology in electrocardiograms (ECG) to identify pericardial effusion in acute malaria. Methods We enrolled adult acute malaria patients in community healthcare clinics in a remote area in South America. All patients underwent ECG, echocardiography, and peripheral blood smears. We excluded patients on anti-malarial medication, suspected concomitant infection and pregnant women. All ECGs were examined for the following criteria: (i) PR-depression >0.5mm and/or ST-elevation 0.5–1mm (I, II, aVL, aVF, V2–6) (ii) PR-elevation >0.5mm (only aVR), (iii) ST/T-ratio >0.25 (only V6), (v) low voltage, defined as QRS amplitude <5 mm in limb leads or <10 mm in precordial leads, and (vi) Spodick's sign (all leads). A criterion was positive when present in ≥2 leads. Information on shortness of breath and/or chest pain was also collected. Pericardial effusion was diagnosed by echocardiography and had to be ≥0.5cm in width. Results We included 99 non-severe malaria patients (age 40±15 years, 55% men, median parasite density 1517/mm3, [interquartile range 528 to 6,585/mm3]) who suffered from Plasmodium vivax (n=75), falciparum (n=22 falciparum) and mixed vivax/falciparum (n=2). The ECGs showed a mean frequency of 78±16bpm, PR-interval 147±20ms, QRS 88±11ms and QT-interval 376±34ms. A total of 11 patients displayed pericardial effusion (mean width 0.9±0.3cm, n=7 vivax, n=2 falciparum, n=2 mixed). Patients with effusion were older (mean age 39 vs 53 years, P=0.003), but displayed no difference in sex, parasite density or parasite species compared to patients without pericardial effusion (P>0.05). Distribution of ECG findings and symptoms are displayed in figure 1A. PR-depression had a sensitivity and specificity for diagnosing pericardial effusion of 73% and 90%, respectively. The sensitivity and specificity for other ECG findings and clinical symptoms are displayed in Figure 1B. Conclusion ECG findings may aid in identifying pericardial effusion in acute malaria, specifically PR depression which had a diagnostic yield of 73% sensitivity and 90% specificity. Based on this, ECG in acute malaria may improve treatment and risk stratification when echocardiography is not an option. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Novo Nordisk Foundation, Independent Research Fund Denmark ECG findings in malaria patients

Immunosuppression in Malaria: Do Plasmodium falciparum Parasites Hijack the Host?

Malaria reflects not only a state of immune activation, but also a state of general immune defect or immunosuppression, of complex etiology that can last longer than the actual episode. Inhabitants of malaria-endemic regions with lifelong exposure to the parasite show an exhausted or immune regulatory profile compared to non- or minimally exposed subjects. Several studies and experiments to identify and characterize the cause of this malaria-related immunosuppression have shown that malaria suppresses humoral and cellular responses to both homologous (Plasmodium) and heterologous antigens (e.g., vaccines). However, neither the underlying mechanisms nor the relative involvement of different types of immune cells in immunosuppression during malaria is well understood. Moreover, the implication of the parasite during the different stages of the modulation of immunity has not been addressed in detail. There is growing evidence of a role of immune regulators and cellular components in malaria that may lead to immunosuppression that needs further research. In this review, we summarize the current evidence on how malaria parasites may directly and indirectly induce immunosuppression and investigate the potential role of specific cell types, effector molecules and other immunoregulatory factors.

Prevalence and characteristics of malaria among COVID-19 individuals: A systematic review, meta-analysis, and analysis of case reports.

BackgroundThe world population is currently at a very high risk of Coronavirus disease-2019 (COVID-19), caused by the severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). People who live in malaria-endemic areas and get infected by SARS-CoV-2 may be at increased risk of severe COVID-19 or unfavorable disease outcomes if they ignore their malaria status. Therefore, the present study aimed to synthesize, qualitatively and quantitatively, information on the prevalence and characteristics of malaria infection among COVID-19-infected individuals. The findings will help us better understand this particular comorbidity during the COVID-19 pandemic.MethodsThe systematic review protocol was registered at the International Prospective Register of Systematic Reviews (PROSPERO) with the identification number: CRD42021247521. We searched for studies reporting on the coinfection of COVID-19 and malaria in PubMed, Web of Science, and Scopus from inception to March 27, 2021 using Medical Subject Headings (MeSH) terms. The study’s methodological quality in the search output was assessed using the Joanna Briggs Institute (JBI) Critical Appraisal Tools for cross-sectional study. The pooled prevalence of Plasmodium spp. infection among patients infected with COVID-19 was estimated using the random effect model and then graphically presented as forest plots. The heterogeneity among the included studies was assessed using Cochrane Q and I2 statistics. The characteristics of patients co-infected with COVID-19 and malaria were derived from case reports and series and were formally analyzed using simple statistics.ResultsTwelve of 1,207 studies reporting the coinfection of COVID-19 and malaria were selected for further analysis. Results of quantitative synthesis show that the pooled prevalence of Plasmodium spp. infection (364 cases) among COVID–19 individuals (1,126 cases) is 11%, with a high degree of heterogeneity (95% CI: 4%–18%, I2: 97.07%, 5 studies). Most of the coinfections were reported in Nigeria (336 cases), India (27 cases), and the Democratic Republic of Congo (1 case). Results of qualitative synthesis indicate that patients with coinfection are typically symptomatic at presentation with mild or moderate parasitemia. An analysis of case reports and series indicates that co-infected individuals often display thrombocytopenia, lymphopenia, and elevated bilirubin levels. Among four patients (30%) who required treatment with intravenous artesunate, one experienced worsened clinical status after administering the drug. One serious outcome of coinfection involved a pregnant woman who experienced fetal abortion due to the initial misdiagnosis of malaria.ConclusionsAll individuals in malaria-endemic regions who are febrile or display symptoms of COVID-19 should be evaluated for malaria to avoid serious complications. Further prospective studies are required to investigate the burden and outcomes of COVID-19 in malaria-endemic regions. Prompt management is required to prevent serious outcomes in individuals co-infected with COVID-19 and malaria.

Antibody signatures of asymptomatic Plasmodium falciparum malaria infections measured from dried blood spots

BackgroundScreening malaria-specific antibody responses on protein microarrays can help identify immune factors that mediate protection against malaria infection, disease, and transmission, as well as markers of past exposure to both malaria parasites and mosquito vectors. Most malaria protein microarray work has used serum as the sample matrix, requiring prompt laboratory processing and a continuous cold chain, thus limiting applications in remote locations. Dried blood spots (DBS) pose minimal biohazard, do not require immediate laboratory processing, and are stable at room temperature for transport, making them potentially superior alternatives to serum. The goals of this study were to assess the viability of DBS as a source for antibody profiling and to use DBS to identify serological signatures of low-density Plasmodium falciparum infections in malaria-endemic regions of Myanmar.MethodsMatched DBS and serum samples from a cross-sectional study in Ingapu Township, Myanmar were probed on protein microarrays populated with P. falciparum antigen fragments. Signal and trends in both sample matrices were compared. A case-control study was then performed using banked DBS samples from malaria-endemic regions of Myanmar, and a regularized logistic regression model was used to identify antibody signatures of ultrasensitive PCR-positive P. falciparum infections.ResultsApproximately 30% of serum IgG activity was recovered from DBS. Despite this loss of antibody activity, antigen and population trends were well-matched between the two sample matrices. Responses to 18 protein fragments were associated with the odds of asymptomatic P. falciparum infection, albeit with modest diagnostic characteristics (sensitivity 58%, specificity 85%, negative predictive value 88%, and positive predictive value 52%).ConclusionsMalaria-specific antibody responses can be reliably detected, quantified, and analysed from DBS, opening the door to serological studies in populations where serum collection, transport, and storage would otherwise be impossible. While test characteristics of antibody signatures were insufficient for individual diagnosis, serological testing may be useful for identifying exposure to asymptomatic, low-density malaria infections, particularly if sero-surveillance strategies target individuals with low previous exposure as sentinels for population exposure.

Adolescent Health Series: HPV infection and vaccination in sub-Saharan Africa: 10 years of research in Tanzanian female adolescents - narrative review.

Cervical cancer is the leading cause of cancer-related morbidity and mortality in many sub-Saharan African (SSA) countries, including Tanzania. Most cervical cancer cases worldwide are attributable to infection of the cervix with Human Papillomavirus (HPV), a vaccine-preventable sexually transmitted infection (STI). Over the past 10years, we have conducted a programme of HPV research in pre-adolescents and adolescents in Mwanza, the second-largest city in Tanzania, which is situated in a malaria-endemic region. In this narrative review article, we summarise the contribution of our work, alongside work of others, to improve the understanding of HPV epidemiology in SSA and development of setting-appropriate, evidence-based intervention strategies. We present evidence for very high prevalence and incidence of HPV infection among female SSA adolescents around the time of sexual debut, describe risk factors for HPV acquisition, and discuss associations between HPV, HIV and other STIs, which are also highly prevalent within this population. We summarise findings from early clinical trials of HPV vaccines in SSA, the first of which was an immunogenicity and safety trial conducted in Mwanza, Tanzania, and Dakar, Senegal. Within the trial, we evaluated for the first time the potential impact of malaria and helminth infection on vaccine-induced antibody responses in Tanzanian girls. We describe research evaluating optimal HPV vaccine delivery strategies within this setting, perceived requirements for and barriers to vaccine implementation among key informants from LMIC, vaccine acceptability among girls and parents, and opportunities for co-delivery of interventions alongside HPV vaccination to an adolescent population. Finally, we discuss country-level barriers to vaccine uptake in LMIC, and ongoing studies in Tanzania and other SSA countries of reduced-dose HPV vaccination schedules that may alleviate cost and logistical barriers to vaccine implementation.

A cross-sectional observational study assessing the liver function in malarial patients

Background: Malaria is a major cause of morbidity in the tropics, being a disease of global importance that results in 300-500 million cases annually. Liver involvement manifests as jaundice, hyperbilirubinemia, hepatomegaly and elevated enzymes (transaminases and alkaline phosphatase). Our objective in this study was to evaluate the role of liver function as an indicator of malaria in endemic regions and as a marker of disease severity.Methods: This was an observational cross-sectional study conducted in central laboratory, department of pathology, central laboratory, department of biochemistry, and out-patient department, department of medicine, medical college Baroda and SSG hospital over a period of ten months, from February, 2019 to November, 2019 and included 137 microscopy proven malaria positive cases. The parasite density on peripheral smear was graded as scanty, moderate and heavy. After procuring the records of serum bilirubin, SGPT and SGOT, statistical analysis of the data was performed.Results: All the 3 parameters show maximum derangement in severe parasitemia with mean values of 3.57, 81.44, and 92.9. While comparing vivax and falciparum malaria, all the LFTs studied show greater derangement in Plasmodium Falciparum when compared to Plasmodium vivax, with greatest difference seen in bilirubin levels (27.78% cases with hyperbilirubinemia in Plasmodium vivax versus 71.43% cases of Plasmodium falciparum showing hyperbilirubinemia).Conclusions: We conclude that altered liver function in form of hyperbilirubinemia and increased liver enzymes in a patient with acute febrile illness increase the probability of malaria, hence directing the clinician along the correct path of further work-up and accurate treatment.

Genetic diversity in two leading Plasmodium vivax malaria vaccine candidates AMA1 and MSP119 at three sites in India.

Plasmodium vivax, a major contributor to the malaria burden in India, has the broadest geographic distribution and shows higher genetic diversity than P. falciparum. Here, we investigated the genetic diversity of two leading P. vivax vaccine candidate antigens, at three geographically diverse malaria-endemic regions in India. Pvama1 and Pvmsp119 partial coding sequences were generated from one hundred P. vivax isolates in India (Chennai n = 28, Nadiad n = 50 and Rourkela n = 22) and ~1100 published sequences from Asia, South America, North America, and Oceania regions included. These data were used to assess the genetic diversity and potential for vaccine candidacy of both antigens on a global scale. A total of 44 single nucleotide polymorphism (SNPs) were identified among 100 Indian Pvama1 sequences, including 10 synonymous and 34 nonsynonymous mutations. Nucleotide diversity was higher in Rourkela and Nadiad as compared to Chennai. Nucleotide diversity measures showed a strong balancing selection in Indian and global population for domain I of Pvama1, which suggests that it is a dominant target of the protective immune response. In contrast, the Pvmsp119 region showed highly conserved sequences in India and across the Oceania, South America, North America and Asia, demonstrating low genetic diversity in the global population when compared to Pvama1. Results suggest the possibility of including Pvmsp119 in a multivalent vaccine formulation against P. vivax infections. However, the high genetic diversity seen in Pvama1 would be more challenging for vaccine development.

Severe long-delayed malaria caused by Plasmodium malariae in an elderly French patient

BackgroundPlasmodium malariae is the cause of the rare but severe form of malaria that sometimes affects individuals travelling to malaria-endemic regions. This report presents the unique case of a patient exhibiting severe malaria symptoms caused by P. malariae with no record of recent travel to any malaria-endemic areas.Case presentationAn 81-year-old French woman was admitted to the emergency department with sustained fever and severe weakness for the past 5 days. She suffered from anaemia, thrombocytopenia, confusion, somnolence, pulmonary complications, and hypoxaemia. In the absence of any concrete aetiology that could explain the fever together with thrombocytopenia, physicians suspected malaria as a probable diagnosis.The LAMP-PCR and lateral flow test confirmed the presence of malaria parasite, Plasmodium sp. Microscopic examination (May-Grünwald Giemsa-stained thin blood smear) revealed the presence of trophozoites, schizonts, and gametocytes with 0.93 % parasitaemia. Conventional PCR amplification targeting 510 bp DNA fragment of small subunit ribosomal RNA (ssrRNA) and bidirectional sequencing identified the parasite as Plasmodium malariae. The travel history of this patient revealed her visits to several countries in Europe (Greece), North Africa (Tunisia and Morocco), and the West Indies (Dominican Republic). Of these, the latter was the only country known to be endemic for malaria at the time (three malaria parasite species were prevalent: Plasmodium falciparum, Plasmodium vivax, and P. malariae). The patient had most likely got infected when she visited the Dominican Republic in the summer of 2002. This time interval between the initial parasite infection (2002) till the onset of symptoms and its subsequent diagnosis (2020) is a reminder of the ability of P. malariae to persist in the human host for many years.ConclusionsThis report highlights the persistent nature and ability of P. malariae to cause severe infection in the host even after a prolonged time interval.

Pharmacotherapy for artemisinin-resistant malaria

ABSTRACT Introduction Malaria, the most devastating parasitic disease, is currently treated with artemisinin-based combination therapies (ACTs). Unfortunately, some ACTs are unable to rapidly clear Plasmodium falciparum parasites from the blood stream and are failing to cure malaria patients; a problem, so far, largely confined to Southeast Asia. There is a fear of resistant Plasmodium falciparum emerging in other parts of the world including Sub-Saharan Africa. Strategies for alternative treatments, ideally non-artemisinin based, are needed. Areas covered This narrative review gives an overview of approved antimalarials and of some compounds in advanced drug development that could be used when an ACT is failing. The selection was based on a literature search in PubMed and WHO notes for malaria treatment. Expert opinion The ACT drug class can still cure malaria in malaria endemic regions. However, the appropriate ACT drug should be chosen considering the background resistance of the partner drug of the local parasite population. Artesunate-pyronaridine, the ‘newest’ recommended ACT, and atovaquone-proguanil are, so far, effective, and safe treatments for uncomplicated falciparum malaria. Therefore, all available ACTs should be safeguarded from parasite resistance and the development of new antimalarial drug classes needs to be accelerated.

Analysis of clinical presentation, hematological factors, self-reported bed net usage, and malaria burden in sickle cell disease patients.

BackgroundSickle cell anemia (SCA) is a severe monogenic disorder, caused by single nucleotide mutations in the hemoglobin (Hb) gene, that is prevalent in malaria endemic regions of the world. Sickle cell trait (SCT) individuals carry only one of the mutated alleles and were shown to be protected against malaria. However, defining the relative contribution of hematological, clinical, and environmental factors to the overall burden of malaria in individuals with hemoglobinopathies such as SCA has been challenging.MethodsWe hypothesized that hematological differences, clinical presentations, and self-reported bed net usage among Plasmodium-infected and uninfected individuals may govern overall malaria burden in individuals with sickle cell disease (SCD). We conducted a cross-sectional study in Ghana from 2014 to 2019 and described clinical presentations, hematological characteristics, and bed net use based on a comprehensive questionnaire. Hematological characteristics were compared using a parametric or nonparametric ANOVA, pending if data passed D'Agostino & Pearson normality test. When comparing only two Hb genotypes hematological characteristics a Mann–Whitney U-test were used. Logistic regressions and Chi-squared tests were used to compare questionnaire responses between Hb genotypes. All statistical significance was set at p < 0.05.FindingsMultiple hematological parameters were significantly (p < 0.05) altered depending on sickle cell genotype and/or malaria status. When compared to other Hb genotypes, SCA individuals with or without malaria had significantly (p < 0.05) higher WBC and platelets counts and lower Hb levels. While the sickle cell genotype may affect malaria severity, SCT and SCA participants were found to significantly (p < 0.007) use bet nets more than HbAA participants.InterpretationsOur findings can be utilized to enhance national guidelines for reducing the incidence of malaria especially among individuals with SCD, SCT protection and health disparities among hemoglobinopathies.FundingThis study was supported by the National Institute for Health.

Clustering of subpatent infections in households with asymptomatic rapid diagnostic test-positive cases in Bioko Island, Equatorial Guinea independent of travel to regions of higher malaria endemicity: a cross-sectional study

BackgroundPrevalence of falciparum malaria on Bioko Island remains high despite sustained, intensive control. Progress may be hindered by high proportions of subpatent infections that are not detected by rapid diagnostic tests (RDT) but contribute to onward transmission, and by imported infections. Better understanding of the relationship between subpatent infections and RDT-detected infections, and whether this relationship is different from imported versus locally acquired infections, is imperative to better understand the sources of infection and mechanisms of transmission to tailor more effective interventions.MethodsQuantitative reverse transcriptase polymerase chain reaction (qRT-PCR) was performed on a sub-set of samples from the 2015 Malaria Indicator Survey to identify subpatent infections. Households with RDT(+) individuals were matched 1:4 with households with no RDT(+) individuals. The association between living in a household with an RDT(+) individual and having a subpatent infection was evaluated using multivariate hierarchical logistic regression models with inverse probability weights for selection. To evaluate possible modification of the association by potential importation of the RDT(+) case, the analysis was repeated among strata of matched sets based on the reported eight-week travel history of the RDT(+) individual(s).ResultsThere were 142 subpatent infections detected in 1,400 individuals (10.0%). The prevalence of subpatent infections was higher in households with versus without an RDT(+) individual (15.0 vs 9.1%). The adjusted prevalence odds of subpatent infection were 2.59-fold greater (95% CI: 1.31, 5.09) for those in a household with an RDT(+) individual compared to individuals in a household without RDT(+) individuals. When stratifying by travel history of the RDT(+) individual, the association between subpatent infections and RDT(+) infections was stronger in the strata in which the RDT(+) individual(s) had not recently travelled (adjusted prevalence odds ratio (aPOR) 2.95; 95% CI:1.17, 7.41), and attenuated in the strata in which recent travel was reported (aPOR 1.76; 95% CI: 0.54, 5.67).ConclusionsThere is clustering of subpatent infections around RDT(+) individual(s) when both imported and local infection are suspected. Future control strategies that aim to treat whole households in which an RDT(+) individual is found may target a substantial portion of infections that would otherwise not be detected.

Surveillance of molecular markers of Plasmodium falciparum artemisinin resistance (kelch13 mutations) in Papua New Guinea between 2016 and 2018

Plasmodium falciparum resistance to artemisinin-based combination therapy (ACT) is a global threat to malaria control and elimination efforts. Mutations in the P. falciparum kelch13 gene (Pfk13) that are associated with delayed parasite clearance have emerged on the Thai-Cambodian border since 2008. There is growing evidence of widespread Pfk13 mutations throughout South-East Asia and they have independently emerged in other endemic regions. In Papua New Guinea (PNG), Pfk13 “C580Y” mutant parasites with reduced in vitro sensitivity to artemisinin have been isolated in Wewak, a port town in East Sepik Province. However, the extent of any local spread of these mutant parasites in other parts of PNG is unknown. We investigated the prevalence of Pfk13 mutations in multiple malaria-endemic regions of PNG. P. falciparum isolates (n = 1152) collected between 2016 and 2018 and assessed for Pfk13 variation by sequencing. Of 663 high quality Pfk13 sequences a total of five variants were identified. They included C580Y, a mutation at a previously documented polymorphic locus: N499K, and three previously undescribed mutations: R471C, K586E and Y635C. All variants were found in single isolates, indicating that these Pfk13 mutations were rare in the areas surveyed. Notably, C580Y was absent from Maprik district, which neighbours Wewak where C580Y mutant parasites were previously identified. The single C580Y isolate was found in the port town of Lae, Morobe Province, a potential entry site for the importation of drug resistant parasites into PNG. Although sample size in this location was small (n = 5), our identification of a C580Y mutant in this second location is concerning, highlighting the urgent need for further surveillance in Lae. Other Pfk13 mutants were rare in PNG between 2016 and 2018. Continued surveillance for molecular markers of drug resistance is critically important to inform malaria control in PNG.

Naturally Acquired Antibodies against Plasmodium falciparum: Friend or Foe?

Antibodies are central to acquired immunity against malaria. Plasmodium falciparum elicits antibody responses against many of its protein components, but there is also formation of antibodies against different parts of the red blood cells, in which the parasites spend most of their time. In the absence of a decisive intervention such as a vaccine, people living in malaria endemic regions largely depend on naturally acquired antibodies for protection. However, these antibodies do not confer sterile immunity and the mechanisms of action are still unclear. Most studies have focused on the inhibitory effect of antibodies, but here, we review both the beneficial as well as the potentially harmful roles of naturally acquired antibodies, as well as autoantibodies formed in malaria. We discuss different studies that have sought to understand acquired antibody responses against P. falciparum antigens, and potential problems when different antibodies are combined, such as in naturally acquired immunity.