Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
Records 1-30 (of 58 Records) |
Query Trace: Plucinski MM[original query] |
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Reply to Rasmussen and Ringwald, "Continued Low Efficacy of Artemether-Lumefantrine in Angola?"
Dimbu PR , Horth R , Cândido ALM , Ferreira CM , Caquece F , Garcia LEA , André K , Pembele G , Jandondo D , Bondo BJ , Nieto Andrade B , Labuda S , Ponce de León G , Kelley J , Patel D , Svigel SS , Talundzic E , Lucchi N , Morais JFM , Fortes F , Martins JF , Pluciński MM . Antimicrob Agents Chemother 12/28/2021 65 (6) We thank Rasmussen and Ringwald for further highlighting the importance of routine monitoring of antimalarial drug efficacy in sub-Saharan Africa, including Angola (1). Longitudinal monitoring is critical to identify potential new, persistent, and/or expanding foci of parasite resistance to available drugs. In 3 of the last 4 rounds, artemether-lumefantrine (AL) was estimated to have an efficacy of <90% at one of the three sentinel sites in Angola. To our knowledge, in sub-Saharan Africa, only Angola and Burkina Faso (2) have shown AL efficacy of <90% across multiple therapeutic efficacy study (TES) rounds. Thus, we chose a title to highlight this persistent concern. | | We concur that the significance of the high rates of day 2 slide positivity in Lunda Sul Province is not fully known, and as pointed out, there may be various explanations for this finding. Measuring drug levels is resource intensive and not feasible every year, but this could help rule out underdosing in future studies. However, we believe our study procedures, as described in this and previous studies, are robust and thus make systematic underdosing unlikely. We have always strictly adhered to WHO guidelines, including hemoglobin criteria and analysis of day 1 severe cases, to inform our classifications. |
Therapeutic response to four artemisinin-based combination therapies in Angola, 2021
Dimbu PR , Labuda S , Ferreira CM , Caquece F , André K , Pembele G , Pode D , João MF , Pelenda VM , Nieto Andrade B , Horton B , Kennedy C , Svigel SS , Zhou Z , Morais JFM , Rosário Jd , Fortes F , Martins JF , Plucinski MM . Antimicrob Agents Chemother 2024 e0152523 Monitoring antimalarial efficacy is important to detect the emergence of parasite drug resistance. Angola conducts in vivo therapeutic efficacy studies (TESs) every 2 years in its fixed sentinel sites in Benguela, Lunda Sul, and Zaire provinces. Children with uncomplicated Plasmodium falciparum malaria were treated with artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), dihydroartemisinin-piperaquine (DP), or artesunate-pyronaridine (ASPY) and followed for 28 (AL and ASAQ) or 42 days (DP and ASPY) to assess clinical and parasitological response to treatment. Two drugs were sequentially assessed in each site in February-July 2021. The primary indicator was the Kaplan-Meier estimate of the PCR-corrected efficacy at the end of the follow-up period. A total of 622 patients were enrolled in the study and 590 (95%) participants reached a study endpoint. By day 3, ≥98% of participants were slide-negative in all study sites and arms. After PCR correction, day 28 AL efficacy was 88.0% (95% CI: 82%-95%) in Zaire and 94.7% (95% CI: 90%-99%) in Lunda Sul. For ASAQ, day 28 efficacy was 92.0% (95% CI: 87%-98%) in Zaire and 100% in Lunda Sul. Corrected day 42 efficacy was 99.6% (95% CI: 99%-100%) for ASPY and 98.3% (95% CI: 96%-100%) for DP in Benguela. High day 3 clearance rates suggest no clinical evidence of artemisinin resistance. This was the fourth of five rounds of TES in Angola showing a corrected AL efficacy <90% in a site. For Zaire, AL has had an efficacy <90% in 2013, 2015, and 2021. ASAQ, DP, and ASPY are appropriate choices as artemisinin-based combination therapies in Angola. |
Out of Africa: increasing reports of artemether-lumefantrine treatment failures of uncomplicated plasmodium falciparum infection
Halsey ES , Plucinski MM . J Travel Med 2023 30 (8) The introduction of artemisinin-based combination therapies (ACTs) to treat Plasmodium falciparum infection in the early 2000s provided relief against the growing ineffectiveness of formerly dependable treatments such as chloroquine and sulfadoxine-pyrimethamine. Since then, six ACTs have been added to the World Health Organization’s list of recommended treatments for uncomplicated P. falciparum infection (Box 1). Of those six, artemether-lumefantrine (AL) is the most widely used, accounting for up to 85% of all ACTs procured by large donors for sub-Saharan Africa1 and is at the greatest threat of losing efficacy. Just as a traveller returning to the USA from Tanzania provided the first confirmation of high-grade chloroquine resistance in Africa in the 1970s,2 once again travellers may be offering a unique glimpse of an antimalarial’s worsening efficacy. |
An improved framework for detecting discrete epidemiologically meaningful partitions in hierarchically clustered genetic data
Jacobson DK , Low R , Plucinski MM , Barratt JLN . Bioinform Adv 2023 3 (1) vbad118 MOTIVATION: Hierarchical clustering of microbial genotypes has the limitation that hierarchical clusters are nested, where smaller groups of related isolates exist within larger groups that get progressively larger as relationships become increasingly distant. In an epidemiologic context, investigators must dissect hierarchical trees into discrete groupings that are epidemiologically meaningful. We recently described a statistical framework (Method A) for dissecting hierarchical trees that attempts to minimize investigator bias. Here, we apply a modified version of that framework (Method B) to a hierarchical tree constructed from 2111 genotypes of the foodborne parasite Cyclospora, including 639 genotypes linked to epidemiologically defined outbreaks. To evaluate Method B's performance, we examined the concordance between these epidemiologically defined groupings and the genetic partitions identified. We also used the same epidemiologic clusters to evaluate the performance of Method A, plus two tree-dissection methods (cutreeHybrid and cutreeDynamic) available within the Dynamic Tree Cut R package, in addition to the TreeCluster method and PARNAS. RESULTS: Compared to the other methods, Method B, TreeCluster, and PARNAS were the most accurate (99.4%) in identifying genetic groups that reflected the epidemiologic groupings, noting that TreeCluster and PARNAS performed identically on our dataset. CutreeHybrid identified groups reflecting patterns in the wider Cyclospora population structure but lacked finer, strain-level discrimination (Simpson's D: cutreeHybrid=0.785). CutreeDynamic displayed good strain discrimination (Simpson's D = 0.933), though lacked sensitivity (77%). At two different threshold/radius settings TreeCluster/PARNAS displayed similar utility to Method B. However, Method B computes a tree-dissection threshold automatically, and the threshold/radius settings used when executing TreeCluster/PARNAS here were computed using Method B. Using a TreeCluster threshold of 0.045 as recommended in the TreeCluster documentation, epidemiologic utility dropped markedly below that of Method B. AVAILABILITY AND IMPLEMENTATION: Relevant code and data are publicly available. Source code (Method B) and instructions for its use are available here: https://github.com/Joel-Barratt/Hierarchical-tree-dissection-framework. |
Model-based estimation of transmissibility and reinfection of SARS-CoV-2 P.1 variant (preprint)
Coutinho RM , Marquitti FMD , Ferreira LS , Borges ME , da Silva RLP , Canton O , Portella TP , Poloni S , Franco C , Plucinski MM , Lessa FC , da Silva AAM , Kraenkel RA , de Sousa Mascena Veras MA , Prado PI . medRxiv 2021 2021.03.03.21252706 The variant of concern (VOC) P.1 emerged in the Amazonas state (Brazil) in November-2020. It contains a constellation of mutations, ten of them in the spike protein. Consequences of these specific mutations at the population level have been little studied so far, despite the detection of P.1 variant in 26 countries, with local transmission in at least four other countries in the Americas and Europe. Here, we estimate P.1’s transmissibility and reinfection using a model-based approach, by fitting data from the Brazilian national health surveillance of hospitalized individuals and frequency of the P.1 variant in Manaus from December 2020 to February 2021, when the city was devastated by four times more cases than in the previous peak (April 2020). The new variant was found to be about 2.6 times more transmissible (95% Confidence Interval (CI): 2.4–2.8) than previous circulating variant(s). The city already had a high prevalence of individuals previously affected by the SARS-CoV-2 virus (estimated as 78%, CI:73–83%), and the fitted model attributed 28% of the cases during the period to reinfections by the variant P.1. Our estimates rank P.1 as the most transmissible among the current identified SARS-CoV-2 VOCs, posing a serious threat and requiring urgent measures to control its global spread.Competing Interest StatementThe authors have declared no competing interest.Clinical TrialEthics approval was not necessary because this study analysed only publicly available data, not including identifiable information.Funding StatementThis work was supported by the Coordenacao de Aperfeicoamento de Pessoal de Nivel Superior, Brazil (Finance Code 001 to FMDM, LSF and TPP), Conselho Nacional de Desenvolvimento Cientifico e Tecnologico, Brazil (grant number: 315854/2020-0 to MEB, 141698/2018-7 to RLPS, 313055/2020-3 to PIP, 312559/2020-8 to MASMV, 311832/2017-2 to RAK, 305703/2019-6 to AAMS) and Fundacao de Amparo a Pesquisa do Estado de Sao Paulo, Brazil (grant number: 2019/26310-2 and 2017/26770-8 to CF, 2018/26512-1 to OC, 2018/24037-4 to SPL and contract number: 2016/01343-7 to RAK). Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:Ethics approval was not necessary because this study analysed only publicly available data, not including identifiable information.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesAll data used are publicly available. The data sources are described in the manuscript and in supplementary file. |
Targeted and whole-genome sequencing reveal a north-south divide in P. falciparum drug resistance markers and genetic structure in Mozambique
da Silva C , Boene S , Datta D , Rovira-Vallbona E , Aranda-Díaz A , Cisteró P , Hathaway N , Tessema S , Chidimatembue A , Matambisso G , Nhama A , Macete E , Pujol A , Nhamussua L , Galatas B , Guinovart C , Enosse S , De Carvalho E , Rogier E , Plucinski MM , Colborn J , Zulliger R , Saifodine A , Alonso PL , Candrinho B , Greenhouse B , Aide P , Saute F , Mayor A . Commun Biol 2023 6 (1) 619 Mozambique is one of the four African countries which account for over half of all malaria deaths worldwide, yet little is known about the parasite genetic structure in that country. We performed P. falciparum amplicon and whole genome sequencing on 2251 malaria-infected blood samples collected in 2015 and 2018 in seven provinces of Mozambique to genotype antimalarial resistance markers and interrogate parasite population structure using genome-wide microhaplotyes. Here we show that the only resistance-associated markers observed at frequencies above 5% were pfmdr1-184F (59%), pfdhfr-51I/59 R/108 N (99%) and pfdhps-437G/540E (89%). The frequency of pfdhfr/pfdhps quintuple mutants associated with sulfadoxine-pyrimethamine resistance increased from 80% in 2015 to 89% in 2018 (p < 0.001), with a lower expected heterozygosity and higher relatedness of microhaplotypes surrounding pfdhps mutants than wild-type parasites suggestive of recent selection. pfdhfr/pfdhps quintuple mutants also increased from 72% in the north to 95% in the south (2018; p < 0.001). This resistance gradient was accompanied by a concentration of mutations at pfdhps-436 (17%) in the north, a south-to-north increase in the genetic complexity of P. falciparum infections (p = 0.001) and a microhaplotype signature of regional differentiation. The parasite population structure identified here offers insights to guide antimalarial interventions and epidemiological surveys. |
Model-based estimation of transmissibility and reinfection of SARS-CoV-2 P.1 variant.
Coutinho RM , Marquitti FMD , Ferreira LS , Borges ME , da Silva RLP , Canton O , Portella TP , Poloni S , Franco C , Plucinski MM , Lessa FC , da Silva AAM , Kraenkel RA , de Sousa Mascena Veras MA , Prado PI . Commun Med (Lond) 2021 1 48 BACKGROUND: The SARS-CoV-2 variant of concern (VOC) P.1 (Gamma variant) emerged in the Amazonas State, Brazil, in November 2020. The epidemiological consequences of its mutations have not been widely studied, despite detection of P.1 in 36 countries, with local transmission in at least 5 countries. A range of mutations are seen in P.1, ten of them in the spike protein. It shares mutations with VOCs previously detected in the United Kingdom (B.1.1.7, Alpha variant) and South Africa (B.1.351, Beta variant). METHODS: We estimated the transmissibility and reinfection of P.1 using a model-based approach, fitting data from the national health surveillance of hospitalized individuals and frequency of the P.1 variant in Manaus from December-2020 to February-2021. RESULTS: Here we estimate that the new variant is about 2.6 times more transmissible (95% Confidence Interval: 2.4-2.8) than previous circulating variant(s). Manaus already had a high prevalence of individuals previously affected by the SARS-CoV-2 virus and our fitted model attributed 28% of Manaus cases in the period to reinfections by P.1, confirming the importance of reinfection by this variant. This value is in line with estimates from blood donors samples in Manaus city. CONCLUSIONS: Our estimates rank P.1 as one of the most transmissible among the SARS-CoV-2 VOCs currently identified, and potentially as transmissible as the posteriorly detected VOC B.1.617.2 (Delta variant), posing a serious threat and requiring measures to control its global spread. |
Molecular Markers of Sulfadoxine-Pyrimethamine Resistance in Samples from Children with Uncomplicated Plasmodium falciparum at Three Sites in Angola in 2019.
Rosillo SR , Dimbu PR , Cândido ALM , Oh JM , Ferreira CM , Nieto Andrade B , Labuda S , Horth R , Kelley J , Morais JFM , Fortes F , Martins JF , Talundzic E , Pluciński MM . Antimicrob Agents Chemother 2023 67 (4) e0160122 Sulfadoxine-pyrimethamine (SP) is used for prevention of malaria in pregnant women in Angola. We sequenced the Plasmodium falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) genes, implicated in SP resistance, in samples collected during a 2019 study of artemisinin-based combination therapy efficacy in Benguela, Lunda Sul, and Zaire provinces. A total of 90 day 0 and day of failure samples were individually sequenced, while 508 day 0 samples from participants without recurrent parasitemia were pooled after DNA extraction into 61 pools. The N51I, C59R, and S108N pfdhfr mutations and A437G pfdhps mutations were present at high proportions in all provinces (weighted allele frequencies, 62% to 100%). The K540E pfdhps mutation was present at lower proportions (10% to 14%). The A581G pfdhps mutation was only observed in Zaire, at a 4.6% estimated prevalence. The I431V and A613S mutations were also only observed in Zaire, at a prevalence of 2.8% to 2.9%. The most common (27% to 66%) reconstructed haplotype in all three provinces was the canonical quadruple pfdhfr pfdhps mutant. The canonical quintuple mutant was absent in Lunda Sul and Benguela and present in 7.9% of samples in Zaire. A single canonical sextuple (2.6%) mutant was observed in Zaire Province. Proportions of the pfdhps K540E and A581G mutations were well below the World Health Organization thresholds for meaningful SP resistance (prevalence of 95% for K540E and 10% for A581G). Samples from therapeutic efficacy studies represent a convenient source of samples for monitoring SP resistance markers. |
Epidemiologic utility of a framework for partition number selection when dissecting hierarchically clustered genetic data evaluated on the intestinal parasite Cyclospora cayetanensis.
Barratt JLN , Plucinski MM . Am J Epidemiol 2023 192 (5) 772-781 Comparing parasite genotypes to inform parasitic disease outbreak investigations involves computation of genetic distances that are typically analyzed by hierarchical clustering to identify related isolates, indicating a common source. A limitation of hierarchical clustering is that hierarchical clusters are not discrete, they are nested. Consequently, small groups of similar isolates exist within larger groups that get progressively larger as relationships become increasingly distant. Investigators must dissect hierarchical trees at a partition number ensuring grouped isolates belong to the same strain; a process typically performed subjectively, introducing bias into resultant groupings. We describe an unbiased, probabilistic framework for partition number selection that ensures partitions comprise isolates that are statistically likely to belong to the same strain. We compute distances and establish a normalized distribution of background distances that is used to demarcate a threshold below which the closeness of relationships is unlikely to be random. Distances are hierarchically clustered and the dendrogram dissected at a partition number where most within-partition distances fall below the threshold. We evaluated this framework by partitioning 1,137 clustered Cyclospora cayetanensis genotypes including 552 isolates epidemiologically linked to various outbreaks. The framework was 91% sensitive and 100% specific in assigning epidemiologically-linked isolates to the same partition. |
Temporal distribution of Plasmodium falciparum recrudescence following artemisinin-based combination therapy: an individual participant data meta-analysis
WorldWide Antimalarial Resistance Network Methodology Study Group , Desai M , Hwang J , Plucinski MM , Udhayakumar V . Malar J 2022 21 (1) 106 BACKGROUND: The duration of trial follow-up affects the ability to detect recrudescent infections following anti-malarial treatment. The aim of this study was to explore the proportions of recrudescent parasitaemia as ascribed by genotyping captured at various follow-up time-points in treatment efficacy trials for uncomplicated Plasmodium falciparum malaria. METHODS: Individual patient data from 83 anti-malarial efficacy studies collated in the WorldWide Antimalarial Resistance Network (WWARN) repository with at least 28 days follow-up were available. The temporal and cumulative distributions of recrudescence were characterized using a Cox regression model with shared frailty on study-sites. Fractional polynomials were used to capture non-linear instantaneous hazard. The area under the density curve (AUC) of the constructed distribution was used to estimate the optimal follow-up period for capturing a P. falciparum malaria recrudescence. Simulation studies were conducted based on the constructed distributions to quantify the absolute overestimation in efficacy due to sub-optimal follow-up. RESULTS: Overall, 3703 recurrent infections were detected in 60 studies conducted in Africa (15,512 children aged < 5 years) and 23 studies conducted in Asia and South America (5272 patients of all ages). Using molecular genotyping, 519 (14.0%) recurrences were ascribed as recrudescent infections. A 28 day artemether-lumefantrine (AL) efficacy trial would not have detected 58% [95% confidence interval (CI) 47-74%] of recrudescences in African children and 32% [95% CI 15-45%] in patients of all ages in Asia/South America. The corresponding estimate following a 42 day dihydroartemisinin-piperaquine (DP) efficacy trial in Africa was 47% [95% CI 19-90%] in children under 5 years old treated with > 48 mg/kg total piperaquine (PIP) dose and 9% [95% CI 0-22%] in those treated with ≤ 48 mg/kg PIP dose. In absolute terms, the simulation study found that trials limited to 28 days follow-up following AL underestimated the risk of recrudescence by a median of 2.8 percentage points compared to day 63 estimates and those limited to 42 days following DP underestimated the risk of recrudescence by a median of 2.0 percentage points compared to day 42 estimates. The analysis was limited by few clinical trials following patients for longer than 42 days (9 out of 83 trials) and the imprecision of PCR genotyping which overcalls recrudescence in areas of higher transmission biasing the later distribution. CONCLUSIONS: Restricting follow-up of clinical efficacy trials to day 28 for AL and day 42 for DP will miss a proportion of late recrudescent treatment failures but will have a modest impact in derived efficacy. The results highlight that as genotyping methods improve consideration should be given for trials with longer duration of follow-up to detect early indications of emerging drug resistance. |
Evaluation of various distance computation methods for construction of haplotype-based phylogenies from large MLST dataset.
Jacobson D , Zheng Y , Plucinski MM , Qvarnstrom Y , Barratt JLN . Mol Phylogenet Evol 2022 177 107608 Multi-locus sequence typing (MLST) is widely used to investigate genetic relationships among eukaryotic taxa, including parasitic pathogens. MLST analysis workflows typically involve construction of alignment-based phylogenetic trees - i.e., where tree structures are computed from nucleotide differences observed in a multiple sequence alignment (MSA). Notably, alignment-based phylogenetic methods require that all isolates/taxa are represented by a single sequence. When multiple loci are sequenced these sequences may be concatenated to produce one tree that includes information from all loci. Alignment-based phylogenetic techniques are robust and widely used yet possess some shortcomings, including how heterozygous sites are handled, intolerance for missing data (i.e., partial genotypes), and differences in the way insertions-deletions (indels) are scored/treated during tree construction. In certain contexts, 'haplotype-based' methods may represent a viable alternative to alignment-based techniques, as they do not possess the aforementioned limitations. This is namely because haplotype-based methods assess genetic similarity based on numbers of shared (i.e., intersecting) haplotypes as opposed to similarities in nucleotide composition observed in an MSA. For haplotype-based comparisons, choosing an appropriate distance statistic is fundamental, and several statistics are available to choose from. However, a comprehensive assessment of various available statistics for their ability to produce a robust haplotype-based phylogenetic reconstruction has not yet been performed. We evaluated seven distance statistics by applying them to extant MLST datasets from the gastrointestinal parasite Cyclospora cayetanensis and two species of pathogenic nematode of the genus Strongyloides. We compare the genetic relationships identified using each statistic to epidemiologic, geographic, and host metadata. We show that Barratt's heuristic definition of genetic distance was the most robust among the statistics evaluated. Consequently, it is proposed that Barratt's heuristic represents a useful approach for use in the context of challenging MLST datasets possessing features (i.e., high heterozygosity, partial genotypes, and indel or repeat-based polymorphisms) that confound or preclude the use of alignment-based methods. |
STARTER checklist for antimalarial therapeutic efficacy reporting
Plucinski MM , Ashley EA , Bassat Q , Venkatesan M , Rosenthal PJ , Halsey ES . Malar J 2022 21 (1) 187 Efficacious antimalarials are a cornerstone of the global effort to control and eliminate malaria. However, the spread of drug resistance threatens gains achieved over the early years of this century. Of particular concern is widespread artemisinin resistance in Southeast Asia and its recent emergence in Africa, threatening the efficacy of artemisinin-based combination therapies that currently offer our best treatments for malaria [1]. Prompt identification of the emergence and spread of antimalarial drug resistance is crucial to guarantee effective case management. At a country level, efficacy data are used by ministries of health and their partners to determine national treatment guidelines. Because parasites do not respect political and administrative boundaries, coordination of surveillance and control strategies at the regional and global level is necessary to guide larger containment strategies. |
Therapeutic Efficacy of Artemisinin-Based Combination Therapies in Democratic Republic of the Congo and Investigation of Molecular Markers of Antimalarial Resistance.
Moriarty LF , Nkoli PM , Likwela JL , Mulopo PM , Sompwe EM , Rika JM , Mavoko HM , Svigel SS , Jones S , Ntamabyaliro NY , Kaputu AK , Lucchi N , Subramaniam G , Niang M , Sadou A , Ngoyi DM , Muyembe Tamfum JJ , Schmedes SE , Plucinski MM , Chowell-Puente G , Halsey ES , Kahunu GM . Am J Trop Med Hyg 2021 105 (4) 1067-1075 Routine assessment of the efficacy of artemisinin-based combination therapies (ACTs) is critical for the early detection of antimalarial resistance. We evaluated the efficacy of ACTs recommended for treatment of uncomplicated malaria in five sites in Democratic Republic of the Congo (DRC): artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP). Children aged 6-59 months with confirmed Plasmodium falciparum malaria were treated with one of the three ACTs and monitored. The primary endpoints were uncorrected and polymerase chain reaction (PCR)-corrected 28-day (AL and ASAQ) or 42-day (DP) cumulative efficacy. Molecular markers of resistance were investigated. Across the sites, uncorrected efficacy estimates ranged from 63% to 88% for AL, 73% to 100% for ASAQ, and 56% to 91% for DP. PCR-corrected efficacy estimates ranged from 86% to 98% for AL, 91% to 100% for ASAQ, and 84% to 100% for DP. No pfk13 mutations previously found to be associated with ACT resistance were observed. Statistically significant associations were found between certain pfmdr1 and pfcrt genotypes and treatment outcome. There is evidence of efficacy below the 90% cutoff recommended by WHO to consider a change in first-line treatment recommendations of two ACTs in one site not far from a monitoring site in Angola that has shown similar reduced efficacy for AL. Confirmation of these findings in future therapeutic efficacy monitoring in DRC is warranted. |
Plasmodium falciparum kelch 13 Mutations, 9 Countries in Africa, 2014-2018.
Schmedes SE , Patel D , Dhal S , Kelley J , Svigel SS , Dimbu PR , Adeothy AL , Kahunu GM , Nkoli PM , Beavogui AH , Kariuki S , Mathanga DP , Koita O , Ishengoma D , Mohamad A , Hawela M , Moriarty LF , Samuels AM , Gutman J , Plucinski MM , Udhayakumar V , Zhou Z , Lucchi NW , Venkatesan M , Halsey ES , Talundzic E . Emerg Infect Dis 2021 27 (7) 1902-1908 The spread of drug resistance to antimalarial treatments poses a serious public health risk globally. To combat this risk, molecular surveillance of drug resistance is imperative. We report the prevalence of mutations in the Plasmodium falciparum kelch 13 propeller domain associated with partial artemisinin resistance, which we determined by using Sanger sequencing samples from patients enrolled in therapeutic efficacy studies from 9 sub-Saharan countries during 2014-2018. Of the 2,865 samples successfully sequenced before treatment (day of enrollment) and on the day of treatment failure, 29 (1.0%) samples contained 11 unique nonsynonymous mutations and 83 (2.9%) samples contained 27 unique synonymous mutations. Two samples from Kenya contained the S522C mutation, which has been associated with delayed parasite clearance; however, no samples contained validated or candidate artemisinin-resistance mutations. |
Nonparametric Binary Classification to Distinguish Closely Related versus Unrelated P. Falciparum Parasites.
Plucinski MM , Barratt JLN . Am J Trop Med Hyg 2021 104 (5) 1830-1835 Assessing genetic relatedness of Plasmodium falciparum genotypes is a key component of antimalarial efficacy trials. Previous methods have focused on determining a priori definitions of the level of genetic similarity sufficient to classify two infections as sharing the same strain. However, factors such as mixed-strain infections, allelic suppression, imprecise typing methods, and heterozygosity complicate comparisons of apicomplexan genotypes. Here, we introduce a novel method for nonparametric statistical testing of relatedness for P. falciparum parasites. First, the background distribution of genetic distance between unrelated strains is computed. Second, a threshold genetic distance is computed from this empiric distribution of distances to demarcate genetic distances that are unlikely to have arisen by chance. Third, the genetic distance between paired samples is computed, and paired samples with genetic distances below the threshold are classified as related. The method is designed to work with any arbitrary genetic distance definition. We validated this procedure using two independent approaches to calculating genetic distance. We assessed the concordance of the novel nonparametric classification with a gold-standard Bayesian approach for 175 pairs of recurrent P. falciparum episodes from previously published malaria efficacy trials with microsatellite data from five studies in Guinea and Angola. The novel nonparametric approach was 98% sensitive and 84-89% specific in correctly identifying related genotypes compared with a gold-standard Bayesian algorithm. The approach provides a unified and systematic method to statistically assess relatedness of P. falciparum parasites using arbitrary genetic distance methodologies. |
Variation in Calculating and Reporting Antimalarial Efficacy against Plasmodium falciparum in Sub-Saharan Africa: A Systematic Review of Published Reports
Plucinski MM , Hastings IM , Moriarty LF , Venkatesan M , Felger I , Halsey ES . Am J Trop Med Hyg 2021 104 (5) 1820-1829 Antimalarials, in particular artemisinin-based combination therapies (ACTs), are critical tools in reducing the global burden of malaria, which is concentrated in sub-Saharan Africa. Performing and reporting antimalarial efficacy studies in a transparent and standardized fashion permit comparison of efficacy outcomes across countries and time periods. This systematic review summarizes study compliance with WHO laboratory and reporting guidance pertaining to antimalarial therapeutic efficacy studies and evaluates how well studies from sub-Saharan Africa adhered to these guidelines. We included all published studies (January 2020 or before) performed in sub-Saharan Africa where ACT efficacy for treatment of uncomplicated Plasmodium falciparum infection was reported. The primary outcome was a composite indicator for study methodology consistent with WHO guidelines for statistical analysis of corrected efficacy, defined as an article presenting a Kaplan-Meier survival analysis of corrected efficacy or reporting a per-protocol analysis where new infections were excluded from the numerator and denominator. Of 581 articles screened, we identified 279 for the review. Molecular correction was used in 83% (232/279) to distinguish new infections from recrudescences in subjects experiencing recurrent parasitemia. Only 45% (99/221) of articles with therapeutic efficacy as a primary outcome and performing molecular correction reported corrected efficacy outcomes calculated in a way consistent with WHO recommendations. These results indicate a widespread lack of compliance with WHO-recommended methods of analysis, which may result in biases in how antimalarial effectiveness is being measured and reported from sub-Saharan Africa. |
Continued low efficacy of artemether-lumefantrine in Angola, 2019.
Dimbu PR , Horth R , Cândido ALM , Ferreira CM , Caquece F , Garcia LEA , André K , Pembele G , Jandondo D , Bondo BJ , Nieto Andrade B , Labuda S , Ponce de León G , Kelley J , Patel D , Svigel SS , Talundzic E , Lucchi N , Morais JFM , Fortes F , Martins JF , Pluciński MM . Antimicrob Agents Chemother 2020 65 (2) BACKGROUND: Biennial therapeutic efficacy monitoring is a crucial activity for ensuring efficacy of currently used artemisinin-based combination therapy in Angola. METHODS: Children with acute uncomplicated P. falciparum infection in sentinel sites in Benguela, Zaire, and Lunda Sul Provinces were treated with artemether-lumefantrine (AL) or artesunate amodiaquine (ASAQ) and followed for 28 days to assess clinical and parasitological response. Molecular correction was performed using seven microsatellite markers. Samples from treatment failures were genotyped for the pfk13, pfcrt, and pfmdr1 genes. RESULTS: Day 3 clearance rates were ≥95% in all arms. Uncorrected Day-28 Kaplan-Meier efficacy estimates ranged from 84.2 to 90.1% for the AL arms, and 84.7 to 100% for the ASAQ arms. Corrected Day-28 estimates were 87.6% (95% Confidence interval [CI]: 81-95%) for the AL arm in Lunda Sul, 92.2% (95%CI: 87-98%) for AL in Zaire, 95.6% (95%CI: 91-100%) for ASAQ in Zaire, 98.4% (95%CI: 96-100%) for AL in Benguela, and 100% for ASAQ in Benguela and Lunda Sul. All 103 analyzed samples had wildtype pfk13 sequences. The 76T pfcrt allele was found in most (92%, 11/12) ASAQ late failure samples but only 16% (4/25) of AL failure samples. The N86 pfmdr1 allele was found in 97% (34/35) of treatment failures. CONCLUSION: AL efficacy in Lunda Sul was below the 90% World Health Organization threshold, the third time in four rounds that this threshold was crossed for an AL arm in Angola. In contrast, observed ASAQ efficacy has not been below 95% to date in Angola, including this latest round. |
Malaria Risk and Prevention in Asian Migrants to Angola.
Martins JF , Marques C , Nieto-Andrade B , Kelley J , Patel D , Nace D , Herman C , Barratt J , Ponce de Leon G , Talundzic E , Rogier E , Halsey ES , Plucinski MM . Am J Trop Med Hyg 2020 103 (5) 1918-1926 The number of Asian migrants working in sub-Saharan developing countries like Angola has been increasing. Their malaria risk, prevention, and care-seeking practices have not been characterized. A cross-sectional survey was conducted in 733 Chinese and Southeast Asian migrants in Angola. Respondents were interviewed and provided blood samples. Samples were analyzed to detect Plasmodium antigen and characterize host anti-Plasmodium response. Positive samples were genotyped using the pfs47 marker. Most respondents (72%; 95% CI: 68-75) reported using bed nets, but less than 1% reported using chemoprophylaxis. Depending on the assay, 1-4% of respondents had evidence of active malaria infection. By contrast, 55% (95% CI: 52-59) were seropositive for Plasmodium antibodies. Most infections were Plasmodium falciparum, but infection and/or exposure to Plasmodium vivax and Plasmodium malariae was also detected. Seroprevalence by time in Angola showed most exposure occurred locally. One respondent had sufficiently high parasitemia for pfs47 genotyping, which showed that the infection was likely locally acquired despite recent travel to home country. Asian migrants to Angola are at substantial risk of malaria. Employers should consider enhanced malaria prevention programs, including chemoprophylaxis; embassies should encourage prevention practices. Angolan healthcare workers should be aware of high malaria exposure in Asian migrants. |
COVID-19 in Americans aboard the Diamond Princess cruise ship.
Plucinski MM , Wallace M , Uehara A , Kurbatova EV , Tobolowsky FA , Schneider ZD , Ishizumi A , Bozio CH , Kobayashi M , Toda M , Stewart A , Wagner RL , Moriarty LF , Murray R , Queen K , Tao Y , Paden C , Mauldin MR , Zhang J , Li Y , Elkins CA , Lu X , Herzig CTA , Novak R , Bower W , Medley AM , Acosta AM , Knust B , Cantey PT , Pesik NT , Halsey ES , Cetron MS , Tong S , Marston BJ , Friedman CR . Clin Infect Dis 2020 72 (10) e448-e457 BACKGROUND: The Diamond Princess cruise ship was the site of a large outbreak of coronavirus disease 2019 (COVID-19). Of 437 Americans and their travel companions on the ship, 114 (26%) tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). METHODS: We interviewed 229 American passengers and crew after disembarkation following a ship-based quarantine to identify risk factors for infection and characterize transmission onboard the ship. RESULTS: The attack rate for passengers in single-person cabins or without infected cabinmates was 18% (58/329), compared with 63% (27/43) for those sharing a cabin with an asymptomatic infected cabinmate, and 81% (25/31) for those with a symptomatic infected cabinmate. Whole genome sequences from specimens from passengers who shared cabins clustered together. Of 66 SARS-CoV-2-positive American travelers with complete symptom information, 14 (21%) were asymptomatic while on the ship. Among SARS-CoV-2-positive Americans, 10 (9%) required intensive care, of whom 7 were ≥70 years. CONCLUSION: Our findings highlight the high risk of SARS-CoV-2 transmission on cruise ships. High rates of SARS-CoV-2 positivity in cabinmates of individuals with asymptomatic infections suggest that triage by symptom status in shared quarters is insufficient to halt transmission. A high rate of intensive care unit admission among older individuals complicates the prospect of future cruise travel during the pandemic, given typical cruise passenger demographics. The magnitude and severe outcomes of this outbreak were major factors contributing to the Centers for Disease Control and Prevention's decision to halt cruise ship travel in U.S. waters in March 2020. |
One-step PCR: A novel protocol for determination of pfhrp2 deletion status in Plasmodium falciparum.
Jones S , Subramaniam G , Plucinski MM , Patel D , Padilla J , Aidoo M , Talundzic E . PLoS One 2020 15 (7) e0236369 Histidine-rich protein 2 (HRP2) detecting rapid diagnostic tests (RDTs) have played an important role in enabling prompt malaria diagnosis in remote locations. However, emergence of pfhrp2 deleted parasites is threatening the efficacy of RDTs, and the World Health Organization (WHO) has highlighted surveillance of these deletions as a priority. Nested PCR is used to confirm pfhrp2 deletion but is costly and laborious. Due to spurious amplification of paralogue pfhrp3, the identity of nested exon 1 PCR product must be confirmed by sequencing. Here we describe a new one-step PCR method for detection of pfhrp2. To determine sensitivity and specificity, all PCRs were performed in triplicate. Using photo-induced electron transfer (PET) PCR detecting 18srRNA as true positive, one-step had comparable sensitivity of 95.0% (88.7-98.4%) to nested exon 1, 99.0% (94.6-99.9%) and nested exon 2, 98.0% (93.0-99.8%), and comparable specificity 93.8% (69.8-99.8%) to nested exon 1 100.0% (79.4-100.0%) and nested exon 2, 100.0% (74.4-100.0%). Sequencing revealed that one step PCR does not amplify pfhrp3. Logistic regression models applied to measure the 95% level of detection of the one-step PCR in clinical isolates provided estimates of 133p/μL (95% confidence interval (CI): 3-793p/μL) for whole blood (WB) samples and 385p/μL (95% CI: 31-2133 p/μL) for dried blood spots (DBSs). When considering protocol attributes, the one-step PCR is less expensive, faster and more suitable for high throughput. In summary, we have developed a more accurate PCR method that may be ideal for the application of the WHO protocol for investigating pfhrp2 deletions in symptomatic individuals presenting to health care facilities. |
Efficacy and safety of artesunate-amodiaquine and artemether-lumefantrine and prevalence of molecular markers associated with resistance, Guinea: an open-label two-arm randomised controlled trial.
Beavogui AH , Camara A , Delamou A , Diallo MS , Doumbouya A , Kourouma K , Bouedouno P , Guilavogui T , Dos Santos Souza S , Kelley J , Talundzic E , Fofana A , Plucinski MM . Malar J 2020 19 (1) 223 BACKGROUND: Anti-malarial resistance is a threat to recent gains in malaria control. This study aimed to assess the efficacy and safety of artesunate-amodiaquine (ASAQ) and artemether-lumefantrine (AL) in the management of uncomplicated malaria and to measure the prevalence of molecular markers of resistance of Plasmodium falciparum in sentinel sites in Maferinyah and Labe Health Districts in Guinea in 2016. METHODS: This was a two-arm randomised controlled trial of the efficacy of AL and ASAQ among children aged 6-59 months with uncomplicated Plasmodium falciparum malaria in two sites. Children were followed for 28 days to assess clinical and parasitological response. The primary outcome was the Kaplan-Meier estimate of Day 28 (D28) efficacy after correction by microsatellite-genotyping. Pre-treatment (D0) and day of failure samples were assayed for molecular markers of resistance in the pfk13 and pfmdr1 genes. RESULTS: A total of 421 participants were included with 211 participants in the Maferinyah site and 210 in Labe. No early treatment failure was observed in any study arms. However, 22 (5.3%) participants developed a late treatment failure (8 in the ASAQ arm and 14 in the AL arm), which were further classified as 2 recrudescences and 20 reinfections. The Kaplan-Meier estimate of the corrected efficacy at D28 was 100% for both AL and ASAQ in Maferinyah site and 99% (95% Confidence Interval: 97.2-100%) for ASAQ and 99% (97.1-100%) for AL in Labe. The majority of successfully analysed D0 (98%, 380/389) and all day of failure (100%, 22/22) samples were wild type for pfk13. All 9 observed pfk13 mutations were polymorphisms not associated with artemisinin resistance. The NFD haplotype was the predominant haplotype in both D0 (197/362, 54%) and day of failure samples (11/18, 61%) successfully analysed for pfmdr1. CONCLUSION: This study observed high efficacy and safety of both ASAQ and AL in Guinea, providing evidence for their continued use to treat uncomplicated malaria. Continued monitoring of ACT efficacy and safety and molecular makers of resistance in Guinea is important to detect emergence of parasite resistance and to inform evidence-based malaria treatment policies. |
Quality of malaria data in public health facilities in three provinces of Mozambique
Colborn JM , Zulliger R , Da Silva M , Mathe G , Chico AR , Castel-Branco AC , Brito F , Andela M , de Leon GP , Saifodine A , Candrinho B , Plucinski MM . PLoS One 2020 15 (4) e0231358 BACKGROUND: Malaria data reported through Mozambique's routine health information system are used to guide the implementation of prevention and control activities. Although previous studies have identified issues with the quality of aggregated data reported from public health facilities in the country, no studies have evaluated the quality of routine indicators recorded in health facility registries. This study addresses this issue by comparing indicators calculated from data from exit interviews and re-examinations of patients with data based on registry records from health facilities in order to measure the quality of registry data and data reporting in three provinces in Mozambique. METHODS: Data were collected from 1,840 outpatients from 117 health facilities in Maputo, Zambezia, and Cabo Delgado Provinces interviewed and examined as part of a malaria-specific health facility survey. Key indicators based on exit interview / re-examination data were compared to the same indicators based on records from health facility registries. Multivariable regression was performed to identify factors associated with indicators matching in re-examination / exit interview data and health facility registries. Aggregated indicators abstracted from facility registries were compared to those reported through the routine health management information system (HMIS) for the same time period. RESULTS: Sensitivity of exit interview / re-examination data compared with those recorded in facility registries was low for all indicators in all facilities. The lowest sensitivities were in Maputo, where the sensitivity for recording negative RDT results was 9.7%. The highest sensitivity was for recording positive RDT results in Cabo Delgado, at 75%. Multivariable analysis of factors associated with agreement between gold standard and registry data showed patients were less likely to be asked about having a fever in the triage ward in Maputo and Cabo Delgado (adjusted Odds Ratio 0.75 and 0.39 respectively), and in the outpatient ward in Cabo Delgado (aOR = 0.37), compared with the emergency department. Patients with positive RDT were also more likely to have RDT results recorded in all three provinces when patients had been managed according to national treatment guidelines during initial examination. Comparison of retrospective data abstracted from facility registries to HMIS data showed discrepancies in all three provinces. The proportion of outpatient cases with suspected and confirmed malaria were similar in registry and HMIS data across all provinces (a relatively low difference between registry and HMIS data of 3% in Maputo and Zambezia), though the total number of all-cause outpatient cases was consistently higher in the HMIS. The largest difference was in Maputo, where a total of 87,992 all-cause outpatient cases were reported in HMIS, compared with a total of 42,431 abstracted from facility registries. CONCLUSION: This study shows that care should be taken in interpreting trends based solely on routine data due to data quality issues, though the discrepancy in all-cause outpatient cases may be indicative that register availability and storage are important factors. As such, simple steps such as providing consistent access and storage of registers that include reporting of patient fever symptoms might improve the quality of routine data recorded at health facilities. |
Public Health Responses to COVID-19 Outbreaks on Cruise Ships - Worldwide, February-March 2020.
Moriarty LF , Plucinski MM , Marston BJ , Kurbatova EV , Knust B , Murray EL , Pesik N , Rose D , Fitter D , Kobayashi M , Toda M , Canty PT , Scheuer T , Halsey ES , Cohen NJ , Stockman L , Wadford DA , Medley AM , Green G , Regan JJ , Tardivel K , White S , Brown C , Morales C , Yen C , Wittry B , Freeland A , Naramore S , Novak RT , Daigle D , Weinberg M , Acosta A , Herzig C , Kapella BK , Jacobson KR , Lamba K , Ishizumi A , Sarisky J , Svendsen E , Blocher T , Wu C , Charles J , Wagner R , Stewart A , Mead PS , Kurylo E , Campbell S , Murray R , Weidle P , Cetron M , Friedman CR . MMWR Morb Mortal Wkly Rep 2020 69 (12) 347-352 An estimated 30 million passengers are transported on 272 cruise ships worldwide each year* (1). Cruise ships bring diverse populations into proximity for many days, facilitating transmission of respiratory illness (2). SARS-CoV-2, the virus that causes coronavirus disease (COVID-19) was first identified in Wuhan, China, in December 2019 and has since spread worldwide to at least 187 countries and territories. Widespread COVID-19 transmission on cruise ships has been reported as well (3). Passengers on certain cruise ship voyages might be aged >/=65 years, which places them at greater risk for severe consequences of SARS-CoV-2 infection (4). During February-March 2020, COVID-19 outbreaks associated with three cruise ship voyages have caused more than 800 laboratory-confirmed cases among passengers and crew, including 10 deaths. Transmission occurred across multiple voyages of several ships. This report describes public health responses to COVID-19 outbreaks on these ships. COVID-19 on cruise ships poses a risk for rapid spread of disease, causing outbreaks in a vulnerable population, and aggressive efforts are required to contain spread. All persons should defer all cruise travel worldwide during the COVID-19 pandemic. |
A robust estimator of malaria incidence from routine health facility data
Thwing J , Camara A , Candrinho B , Zulliger R , Colborn J , Painter J , Plucinski MM . Am J Trop Med Hyg 2019 102 (4) 811-820 Routine incident malaria case data have become a pillar of malaria surveillance in sub-Saharan Africa. These data provide granular, timely information to track malaria burden. However, incidence data are sensitive to changes in care seeking rates, rates of testing of suspect cases, and reporting completeness. Based on a set of assumptions, we derived a simple algebraic formula to convert crude incidence rates to a corrected estimation of incidence, adjusting for biases in variable and suboptimal rates of care seeking, testing of suspect cases, and reporting completeness. We applied the correction to routine incidence data from Guinea and Mozambique, and aggregate data for sub-Saharan African countries from the World Malaria Report. We calculated continent-wide needs for malaria tests and treatments, assuming universal testing but current care seeking rates. Countries in southern and eastern Africa reporting recent increases in malaria incidence generally had lower overall corrected incidence than countries in Central and West Africa. Under current care seeking rates, the unmet need for malaria tests was estimated to be 160 million (M) (interquartile range [IQR]: 139-188) and for malaria treatments to be 37 M (IQR: 29-51). Maps of corrected incidence were more consistent with maps of community survey prevalence than was crude incidence in Guinea and Mozambique. Crude malaria incidence rates need to be interpreted in the context of suboptimal testing and care seeking rates, which vary over space and time. Adjusting for these factors can provide an insight into the spatiotemporal trends of malaria burden. |
Multiplex malaria antigen detection by bead-based assay and molecular confirmation by PCR shows no evidence of Pfhrp2 and Pfhrp3 deletion in Haiti.
Herman C , Huber CS , Jones S , Steinhardt L , Plucinski MM , Lemoine JF , Chang M , Barnwell JW , Udhayakumar V , Rogier E . Malar J 2019 18 (1) 380 BACKGROUND: The Plasmodium falciparum parasite is the only human malaria that produces the histidine-rich protein 2 and 3 (HRP2/3) antigens. Currently, HRP2/3 are widely used in malaria rapid diagnostic tests (RDTs), but several global reports have recently emerged showing genetic deletion of one or both of these antigens in parasites. Deletion of these antigens could pose a major concern for P. falciparum diagnosis in Haiti which currently uses RDTs based solely on the detection of the HRP2/3 antigens. METHODS: From September 2012 through February 2014, dried blood spots (DBS) were collected in Haiti from 9317 febrile patients presenting to 17 health facilities in 5 departments throughout the country as part of a bed net intervention study. All DBS from RDT positive persons and a random sampling of DBS from RDT negative persons were assayed for P. falciparum DNA by nested and PET-PCR (n = 2695 total). All PCR positive samples (n = 331) and a subset of PCR negative samples (n = 95) were assayed for three malaria antigens by a multiplex bead assay: pan-Plasmodium aldolase (pAldo), pan-Plasmodium lactate dehydrogenase (pLDH), and HRP2/3. Any samples positive for P. falciparum DNA, but negative for HRP2/3 antigens were tested by nested PCR for Pfhrp2 and Pfhrp3 gene deletions. RESULTS: Of 2695 DBS tested for Plasmodium DNA, 345 (12.8%) were originally found to be positive for P. falciparum DNA; 331 of these had DBS available for antigen detection. Of these, 266 (80.4%) were positive for pAldo, 221 (66.8%) positive for pLDH, and 324 (97.9%) were positive for HRP2/3 antigens. Seven samples (2.1%) positive for P. falciparum DNA were not positive for any of the three antigens by the bead assay, and were investigated for potential Pfhrp2/3 gene deletion by PCR. These samples either successfully amplified Pfhrp2/3 genes or were at an estimated parasite density too low for sufficient DNA to perform successful genotyping. CONCLUSIONS: Malaria positive samples in multiple Haitian sites were found to contain the HRP2/3 antigens, and no evidence was found of Pfhrp2/3 deletions. Malaria RDTs based on the detection of the HRP2/3 antigens remain a reliable P. falciparum diagnostic tool as Haiti works towards malaria elimination. |
Estimation of malaria-attributable fever in malaria test-positive febrile outpatients in three provinces of Mozambique, 2018
Plucinski MM , Candrinho B , Dimene M , Smith T , Thwing J , Colborn J , Rogier E , Zulliger R . Am J Trop Med Hyg 2019 102 (1) 151-155 Like most malaria-endemic countries, Mozambique relies on tabulation of confirmed malaria test-positive febrile patients to track incidence of malaria. However, this approach is potentially biased by incidental malaria parasitemia in patients with fever of another etiology. We compared pan-Plasmodium aldolase and lactate dehydrogenase and Plasmodium falciparum HRP2 antigen concentrations measured using a laboratory bead-based assay of samples collected from 1,712 febrile and afebrile patients of all ages in Maputo, Zambezia, and Cabo Delgado provinces. We used a Bayesian latent class model to estimate the proportion of malaria-attributable fevers in malaria test-positive febrile patients. Depending on the antigen, estimated rates of malaria-attributable fever in malaria test-positive febrile patients were 100% in Maputo, 33-58% in Zambezia, and 63-74% in Cabo Delgado. Our findings indicate that most malaria test-positive febrile patients in the three provinces of Mozambique had a fever that was likely caused by the concurrent malaria infection. Counting malaria test-positive febrile patients for estimation of malaria incidence appears to be appropriate in this setting. |
Conventional and high-sensitivity malaria rapid diagnostic test performance in two transmission settings: Haiti 2017
Rogier E , Hamre KES , Joseph V , Plucinski MM , Presume J , Romilus I , Mondelus G , Elisme T , van den Hoogen L , Lemoine JF , Drakeley C , Ashton RA , Chang MA , Existe A , Boncy J , Stresman G , Druetz T , Eisele TP . J Infect Dis 2019 221 (5) 786-795 Accurate malaria diagnosis is foundational for control and elimination, and Haiti relies on HRP2-based rapid diagnostic tests (RDTs) identifying Plasmodium falciparum in clinical and community settings. In 2017, one household and two easy-access group (EAG) surveys tested all participants (N=32,506) by conventional and high-sensitivity RDTs (cRDT/hsRDT). A subset of blood samples (n=1,154) were laboratory tested for HRP2 by bead-based immunoassay and for P. falciparum 18S rDNA by PET-PCR. Both RDT types detected low concentrations of HRP2 with sensitivity estimates between 2.6 and 14.6 ng/mL. Compared to the predicate HRP2 laboratory assay,, RDT sensitivity ranged from 86.3% to 96.0% between tests and settings, and specificity from 90.0% to 99.6%. In the household survey, the hsRDT provided a significantly higher number of positive tests, but this represented a very small proportion (<0.2%) of all participants. These data show an hsRDT may have limited utility in a malaria elimination setting like Haiti. |
Assessing performance of HRP2 antigen detection for malaria diagnosis in Mozambique
Plucinski MM , Candrinho B , Dimene M , Colborn J , Lu A , Nace D , Zulliger R , Rogier E . J Clin Microbiol 2019 57 (9) Background: Rapid diagnostic tests (RDTs) that detect the Plasmodium falciparum-specific histidine-rich protein 2 (PfHRP2) antigen are the primary method for malaria diagnosis in Mozambique. However, these tests do not detect infections with non-falciparum malaria or Pfhrp2/3-deleted P. falciparum parasites.Methods: To assess the appropriateness of conventional PfHRP2-only RDTs for malaria diagnosis in Mozambique, samples collected during a health facility survey conducted in three provinces of Mozambique were screened using antigen detection methods and further characterized by molecular techniques. Samples from 1861 outpatients of all ages and symptoms attending 117 randomly-selected public health facilities in 2018 were analyzed with an ultra-sensitive bead-based immunoassay for the presence of PfHRP2, pan-Plasmodium Aldolase (pAldo), and pan-Plasmodium lactate dehydrogenase (pLDH). Presence of PfHRP2 in patient blood detected using the bead-based assay was compared to the results of PfHRP2-based RDTs performed during the routine health facility consult and during the survey re-examination at exit interview. Samples with discordant antigen profiles (negative for PfHRP2 but positive for pAldo and/or pLDH) were further characterized by photo-induced electron transfer (PET)-PCR.Results: Using the bead-based laboratory assay as the gold standard, the sensitivity of the conventional RDTs administered during the routine health facility consult and the exit interview was 90% and 83%, respectively, and specificity was 91% and 97%. Of 710 samples positive for at least one antigen, 704 (99.2%) were positive for PfHRP2. Six (0.8% of total) discordant samples lacked PfHRP2 but were positive for pAldo and/or pLDH; 3 of these (0.4% of total) were P. ovale mono-infections or co-infections where P. ovale was the dominant species. The remaining 3 discordant samples were negative by PET-PCR.Conclusions: The sensitivity and specificity of the conventional RDTs performed in the routine health facility consults and survey exit interviews were acceptable, and there was no evidence of Pfhrp2/3-deleted parasites. Mono-infections with non-falciparum malaria species comprised <1% of total malaria infections. Nearly all malaria antigen-positive patients had detectable PfHRP2, confirming this antigen remains an appropriate malaria diagnostic target in the surveyed provinces. |
Clearance dynamics of lactate dehydrogenase and aldolase following antimalarial treatment for Plasmodium falciparum infection
Plucinski MM , McElroy PD , Dimbu PR , Fortes F , Nace D , Halsey ES , Rogier E . Parasit Vectors 2019 12 (1) 293 BACKGROUND: Lingering post-treatment parasite antigen in blood complicates malaria diagnosis through antigen detection. Characterization of antigen clearance dynamics is important for interpretation of positive antigen detection tests. RESULTS: We used a bead-based serological assay to measure lactate dehydrogenase (LDH), aldolase (Aldo), and histidine-rich protein 2 (HRP2) levels in 196 children with Plasmodium falciparum malaria treated with effective antimalarials and followed for 28 to 42 days as part of therapeutic efficacy studies in Angola. Compared to pre-treatment levels, antigen concentrations two days after treatment declined by 99.7% for LDH, 96.3% for Aldo, and 54.6% for HRP2. After Day 2, assuming a first-order kinetics clearance model, half-lives of the antigens were 1.8 days (95% CI: 1.5-2.3) for LDH, 3.2 days (95% CI: 3.0-3.4) for Aldo, and 4.8 days (95% CI: 4.7-4.9) for HRP2. CONCLUSIONS: LDH and Aldo show substantially different clearance rates than HRP2, and their presence is largely indicative of active infection. |
Quality of malaria case management and reporting at public health facilities in six health districts in Guinea, 2018
Davlantes E , Camara A , Guilavogui T , Fofana A , Balde M , Diallo T , Bah I , Florey L , Sarr A , Butts J , Plucinski MM . Am J Trop Med Hyg 2019 101 (1) 148-156 Data on fever and malaria cases reported by health facilities are used for tracking incidence and quantification of malaria commodity needs in Guinea. Periodic assessments of the quality of malaria case management and routine data are a critical activity for the malaria program. In May-June 2018, survey teams visited 126 health facilities in six health districts purposefully selected to represent a spectrum (Stratum 1-high, Stratum 2-intermediate, and Stratum 3-low) of perceived quality of case management and reporting, as assessed from an a priori analysis of routine data. Surveyors performed exit interviews with 939 outpatients and compared results with registry data for interviewed patients. Availability of rapid diagnostic tests (RDTs) and artemisinin-based combination therapies (ACTs) was 100% in Strata 1 and 2, compared with 82% (95% CI: 63-92%) for RDTs and 86% (68-95%) for any formulation of ACT in Stratum 3. Correct case management for suspect malaria cases was 85% in both Stratum 1 (95% CI: 78-90%) and Stratum 2 (79-89%), but only 52% (37-67%) in Stratum 3. Concordance between exit interviews and registry entries for key malaria indicators was significantly higher in Strata 1 and 2 than in Stratum 3. Both adherence to national guidelines for testing and treatment and data quality were high in Strata 1 and 2, but substandard in Stratum 3. The survey results reflected the trends seen in the routine data, suggesting that analysis of routine data can identify areas requiring more attention to improve malaria case management and reporting. |
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