Global trend of Plasmodium malariae and Plasmodium ovale spp. malaria infections in the last two decades (2000-2020): a systematic review and meta-analysis.

BACKGROUND: Recent studies indicate that the prevalence of non-falciparum malaria, including Plasmodium malariae and Plasmodium ovale spp., is increasing, with some complications in infected individuals. The aim of this review is to provide a better understanding of the malaria prevalence and disease burden due to P. malariae and P. ovale spp. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the Joanna Briggs Institute prevalence study assessment tool were used to select and evaluate the studies, respectively. Six databases: PubMed, WHOLIS, Wiley Library, ScienceDirect, Web of Science and Google Scholar were used to screen articles published during the period January 2000-December 2020. The pooled prevalence estimates for P. malariae and P. ovale spp. were analysed using a random-effects model and the possible sources of heterogeneity were evaluated through subgroup analysis and meta-regression. RESULTS: Out of the 3297 studies screened, only 113 studies were included; among which 51.33% were from the African Region. The P. malariae and P. ovale spp. pooled prevalence were 2.01% (95% CI 1.31-2.85%) and 0.77% (95% CI 0.50-1.10%) respectively, with the highest prevalence in the African Region. P. malariae was equally distributed among adults (2.13%), children (2.90%) and pregnant women (2.77%) (p = 0.862), whereas P. ovale spp. was more prevalent in pregnant women (2.90%) than in children ≤ 15 years (0.97%) and in patients > 15 years old (0.39%) (p = 0.021). In this review, data analysis revealed that P. malariae and P. ovale spp. have decreased in the last 20 years, but not significantly, and these species were more commonly present with other Plasmodium species as co-infections. No difference in prevalence between symptomatic and asymptomatic patients was observed for either P. malariae or P. ovale spp. CONCLUSION: Our analysis suggests that knowledge of the worldwide burden of P. malariae and P. ovale spp. is very important for malaria elimination programmes and a particular focus towards improved tools for monitoring transmission for these non-falciparum species should be stressed upon to deal with increased infections in the future.

Complicated Malaria caused by Plasmodium ovale, Salamanca, Spain

BACKGROUND: Monomicrobial imported infection by Plasmodium ovale is very rare. Case presentation: We report a case of complicated imported malaria by Plasmodium ovale in a man who suffered from subacute recurrent fever, thrombocytopenia and splenomegaly. CONCLUSION: Both the patient history and a search of epidemiological medical history were fundamental for confirming the suspicion

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Severity and mortality of severe Plasmodium ovale infection: A systematic review and meta-analysis.

Plasmodium ovale can infect humans, causing malaria disease. We aimed to investigate the severity and mortality of severe P. ovale infection to increase the awareness of physicians regarding the prognosis of this severe disease and outcome-related deaths in countries in which this disease is endemic. Articles that were published in the PubMed, Scopus, and ISI Web of Science databases prior to January 5, 2020 and reported the prevalence of severe P. ovale infection were systematically searched and reviewed. Studies that mainly reported severe P. ovale infection according to the 2014 WHO criteria for the treatment of malaria were included. Two reviewers selected, identified, assessed, and extracted data from studies independently. The pooled prevalence of severe P. ovale mono-infections was estimated using the command "metaprop case population, random/fixed", which yielded the pooled estimate, 95% confidence interval (CI) and the I2 value, indicating the level of heterogeneity. Meta-analyses of the proportions were performed using a random-effects model to explore the different proportions of severity between patients with P. ovale and those with other Plasmodium species infections. Among the eight studies that were included and had a total of 1,365 ovale malaria cases, the pooled prevalence of severe P. ovale was 0.03 (95% CI = 0.03-0.05%, I2 = 54.4%). Jaundice (1.1%), severe anemia (0.88%), and pulmonary impairments (0.59%) were the most common severe complications found in patients infected with P. ovale. The meta-analysis demonstrated that a smaller proportion of patients with P. ovale than of patients with P. falciparum had severe infections (P-value = 0.01, OR = 0.36, 95% CI = 0.16-0.81, I2 = 72%). The mortality rate of severe P. ovale infections was 0.15% (2/1,365 cases). Although severe complications of P. ovale infections in patients are rare, it is very important to increase the awareness of physicians regarding the prognosis of severe P. ovale infections in patients, especially in a high-risk population.

Severity of Plasmodium falciparum and Non-falciparum Malaria in Travelers and Migrants: A Nationwide Observational Study Over 2 Decades in Sweden.

BACKGROUND: The aim was to assess factors affecting disease severity in imported P. falciparum and non-falciparum malaria. METHODS: We reviewed medical records from 2793/3260 (85.7%) of all episodes notified in Sweden between 1995 and 2015 and performed multivariable logistic regression. RESULTS: Severe malaria according to WHO 2015 criteria was found in P. falciparum (9.4%), P. vivax (7.7%), P. ovale (5.3%), P. malariae (3.3%), and mixed P. falciparum episodes (21.1%). Factors associated with severe P. falciparum malaria were age <5 years and >40 years, origin in nonendemic country, pregnancy, HIV, region of diagnosis, and health care delay. Moreover, oral treatment of P. falciparum episodes with parasitemia ≥2% without severe signs at presentation was associated with progress to severe malaria with selected criteria. In non-falciparum, age >60 years, health care delay and endemic origin were identified as risk factors for severe disease. Among patients originating in endemic countries, a higher risk for severe malaria, both P. falciparum and non-falciparum, was observed among newly arrived migrants. CONCLUSIONS: Severe malaria was observed in P. falciparum and non-falciparum episodes. Current WHO criteria for severe malaria may need optimization to better guide the management of malaria of different species in travelers and migrants in nonendemic areas.

Malaria Elimination: Time to Target All Species.

Important strides have been made within the past decade toward malaria elimination in many regions, and with this progress, the feasibility of eradication is once again under discussion. If the ambitious goal of eradication is to be achieved by 2040, all species of Plasmodium infecting humans will need to be targeted with evidence-based and concerted interventions. In this perspective, the potential barriers to achieving global malaria elimination are discussed with respect to the related diversities in host, parasite, and vector populations. We argue that control strategies need to be reorientated from a sequential attack on each species, dominated by Plasmodium falciparum to one that targets all species in parallel. A set of research themes is proposed to mitigate the potential setbacks on the pathway to a malaria-free world.

Prospective Clinical Trial Assessing Species-Specific Efficacy of Artemether-Lumefantrine for the Treatment of Plasmodium malariae, Plasmodium ovale, and Mixed Plasmodium Malaria in Gabon.

Treatment recommendations for Plasmodium malariae and Plasmodium ovale malaria are largely based on anecdotal evidence. The aim of this prospective study, conducted in Gabon, was to systematically assess the efficacy and safety of artemether-lumefantrine for the treatment of patients with uncomplicated P. malariae or P. ovale species monoinfections or mixed Plasmodium infections. Patients with microscopically confirmed P. malariae, P. ovale, or mixed-species malaria with at least one of these two Plasmodium species were treated with an oral, fixed-dose combination of artemether-lumefantrine for 3 consecutive days. The primary endpoints were per-protocol PCR-corrected adequate clinical and parasitological response (ACPR) on days 28 and 42. Tolerability and safety were recorded throughout the follow-up period. Seventy-two participants (42 male and 30 female) were enrolled; 62.5% of them had PCR-corrected mixed Plasmodium infections. Per protocol, PCR-corrected ACPR rates were 96.6% (95% confidence interval [CI], 91.9 to 100) on day 28 and 94.2% (95% CI, 87.7 to 100) on day 42. Considering Plasmodium species independently from their coinfecting species, day 42 ACPR rates were 95.5% (95% CI, 89.0 to 100) for P. falciparum, 100% (exact CI, 84.6 to 100) for P. malariae, 100% (exact CI, 76.8 to 100) for P. ovale curtisi, and 90.9% (95% CI, 70.7 to 100) for P. ovale wallikeri Study drug-related adverse events were generally mild or moderate. In conclusion, this clinical trial demonstrated satisfying antimalarial activity of artemether-lumefantrine against P. ovalewallikeri, P. ovale curtisi, P. malariae, and mixed Plasmodium infections, with per-protocol efficacies of 90% to 100% and without evident tolerability or safety concerns. (This trial was registered in the clinical study database ClinicalTrials.gov under the identifier NCT02528279.).

Two sympatric types of Plasmodium ovale and discrimination by molecular methods.

Plasmodium ovale is widely distributed in tropical countries, whereas it has not been reported in the Americas. It is not a problem globally because it is rarely detected by microscopy owing to low parasite density, which is a feature of clinical ovale malaria. P.o. curtisi and P.o. wallikeri are widespread in both Africa and Asia, and were known to be sympatric in many African countries and in southeast Asian countries. Small subunit ribosomal RNA (SSUrRNA) gene, cytochrome b (cytb) gene, and merozoite surface protein-1 (msp-1) gene were initially studied for molecular discrimination of P.o. curtisi and P.o. wallikeri using polymerase chain reaction (PCR) and DNA sequencing. DNA sequences of other genes from P. ovale in Southeast Asia and the southwestern Pacific regions were also targeted to differentiate the two sympatric types. In terms of clinical manifestations, P.o. wallikeri tended to produce higher parasitemia levels and more severe symptoms. To date, there have been a few studies that used the quantitative PCR method for discrimination of the two distinct P. ovale types. Conventional PCR with consequent DNA sequencing is the common method used to differentiate these two types. It is necessary to identify these two types because relapse periodicity, drug susceptibility, and mosquito species preference need to be studied to reduce ovale malaria. In this article, an easier method of molecular-level discrimination of P.o. curtisi and P.o. wallikeri is proposed.

Arboviral diseases and malaria in Australia, 2012-13: Annual report of the National Arbovirus and Malaria Advisory Committee.

This report describes the epidemiology of mosquito-borne diseases of public health importance in Australia during the 2012-13 season (1 July 2012 to 30 June 2013) and includes data from human notifications, sentinel chicken, vector and virus surveillance programs. The National Notifiable Diseases Surveillance System received notifications for 9,726 cases of disease transmitted by mosquitoes during the 2012-13 season. The Australasian alphaviruses Barmah Forest virus and Ross River virus accounted for 7,776 (80%) of total notifications. However, over-diagnosis and possible false positive diagnostic test results for these 2 infections mean that the true burden of infection is likely overestimated, and as a consequence, the case definitions were revised, effective from 1 January 2016. There were 96 notifications of imported chikungunya virus infection. There were 212 notifications of dengue virus infection acquired in Australia and 1,202 cases acquired overseas, with an additional 16 cases for which the place of acquisition was unknown. Imported cases of dengue were most frequently acquired in Indonesia. No locally-acquired malaria was notified during the 2012-13 season, though there were 415 notifications of overseas-acquired malaria. There were no cases of Murray Valley encephalitis virus infection in 2012-13. In 2012-13, arbovirus and mosquito surveillance programs were conducted in most jurisdictions with a risk of vectorborne disease transmission. Surveillance for exotic mosquitoes at the border continues to be a vital part of preventing the spread of mosquito-borne diseases such as dengue to new areas of Australia, and in 2012-13, there were 7 detections of exotic mosquitoes at the border.

Diagnosis of an imported Plasmodium ovale wallikeri infection in Malaysia.

Plasmodium ovale is rare and not exactly known to be autochthonous in Malaysia. There are two distinct forms of the parasite, namely P. ovale curtisi (classic form) and P. ovale wallikeri (variant form). Here, the first sequence confirmed case of an imported P. ovale wallikeri infection in Malaysia is presented. Microscopy found Plasmodium parasites with morphology similar to P. ovale or Plasmodium vivax in the blood films. Further confirmation using polymerase chain reaction (PCR) targeting the small-subunit rRNA gene of the parasite was unsuccessful. Genus-specific PCR was then performed and the product was sequenced and analysed. Sequence analyses confirmed the aetiological agent as P. ovale wallikeri. New species-specific primers (rOVA1v and rOVA2v) were employed and P. ovale wallikeri was finally confirmed. The findings highlight the need to look out for imported malaria infections in Malaysia and the importance of a constantly updated and validated diagnostic technique.

[The vivax malaria causative agent Plasmodium ovale: the present global area, intraspecies polymorphism, importation to the Russian Federation (1992-2011)].

The global area for Plasmodium ovale is small as compared with that for other species of human malaria pathogens. It has expanded in Asian areas and remained as before in the African ones. In the past 20 years, there have been 2129 malaria cases imported from far abroad to Russia, including 84 (4%) cases of vivax malaria (P. ovale). The patients were most foreign citizens: 70 from 20 African countries and 7 from two countries of Oceania, such as Papua New Guinea and Indonesia. The other 7 patients were Russia's people who had returned from different countries of Africa. For this period there have been a total of 5 cases of mixed infection: tropical P. falciparum malaria + vivax P. ovale malaria. The mission of detected new sympatric subspecies (P. ovale curtisi and P. ovale wallikeri) inhabiting the tropical countries with continuous local transmission remains unclear. Only a thorough study of these subspecies will be able to effectively apply preventive measures and to carry out their elimination in future.

In vivo and in vitro efficacy of chloroquine against Plasmodium malariae and P. ovale in Papua, Indonesia.

Reports of potential drug-resistant strains of Plasmodium malariae in western Indonesia raise concerns that chloroquine resistance may be emerging in P. malariae and P. ovale. In order to assess this, in vivo and in vitro efficacy studies were conducted in patients with monoinfection in Papua, Indonesia. Consecutive patients with uncomplicated malaria due to P. ovale or P. malariae were enrolled in a prospective clinical trial, provided with supervised chloroquine treatment, and followed for 28 days. Blood from patients with P. malariae or P. ovale parasitemia greater than 1,000 per microliter underwent in vitro antimalarial drug susceptibility testing using a modified schizont maturation assay. Of the 57 evaluable patients in the clinical study (P. malariae, n = 46; P. ovale, n = 11), none had recurrence with the same species during follow-up. The mean parasite reduction ratio at 48 h was 86 (95% confidence interval [CI], 57 to 114) for P. malariae and 150 (95% CI, 54 to 245) for P. ovale (P = 0.18). One patient infected with P. malariae, with 93% of parasites at the trophozoite stage, was still parasitemic on day 4. In vitro drug susceptibility assays were carried out successfully for 40 isolates (34 infected with P. malariae and 6 with P. ovale). The P. malariae infections at trophozoite stages had significantly higher chloroquine 50% effective concentrations (EC(50)s) (median, 127.9 nM [range, 7.9 to 2,980]) than those initially exposed at the ring stage (median, 14.0 nM [range, 3.5 to 27.0]; P = 0.01). The EC(50) for chloroquine in P. ovale was also higher in an isolate initially at the trophozoite stage (23.2 nM) than in the three isolates predominantly at ring stage (7.8 nM). Chloroquine retains adequate efficacy against P. ovale and P. malariae, but its marked stage specificity of action may account for reports of delayed parasite clearance times.

What is the evidence for the existence of Plasmodium ovale hypnozoites?

Relapsing human malaria is regarded to be caused by Plasmodium vivax and Plasmodium ovale. P. vivax relapses originate from dormant liver stages: "hypnozoites". Also, P. ovale, a species considered as closely related to P. vivax, is in analogy assumed to display hypnozoites. A close biologic relationship is, however, not supported by molecular genetic studies. Therefore, original literature published since the description of P. ovale in 1922 was systematically screened for the demonstration of hypnozoites or circumstantial evidence for their existence, i.e. the occurrence of true relapses. In P. ovale infection, hypnozoites have never been demonstrated by biological experiments, and the few reports published on relapses have conflicting results.

Indigenous Plasmodium ovale malaria in Bangladesh.

In spite of the high prevalence of malaria in Southeastern Bangladesh, there remains a significant shortage of information regarding the presence of three of five human malaria parasites: Plasmodium ovale, P. malariae, and P. knowlesi. The presence of P. ovale and P. knowlesi has previously never been reported from Bangladesh. We used a genus- and species-specific nested polymerase chain reaction, targeting highly conserved regions of the small subunit ribosomal RNA (SSU rRNA) gene, to investigate the presence of malaria parasites in a total number of 379 patient samples in a survey of patients with febrile illnesses in the Chittagong Hill Tracts in Southeastern Bangladesh. We identified the first cases of P. ovale in Bangladesh. They were confirmed by sequence analysis; 189 of 379 samples (49.9%; 95% confidence interval = 44.9-54.9%) were positive for Plasmodium sp. by PCR. P. falciparum monoinfections accounted for 68.3% (61.3-74.5%), followed by P. vivax (15.3%; 10.9-21.2%), P. malariae (1.6%; 0.5-4.6%), P. ovale (1.6%; 0.5-4.6%), and mixed infections (13.2%; 9.1-18.8%). We found no evidence of P. knowlesi in this region.

Minor liver profile dysfunctions in Plasmodium vivax, P. malaria and P. ovale patients and normalization after treatment.

Liver function tests were performed in 61 vivax, 54 malariae and 15 ovale malaria patients who were admitted to Bangkok Hospital for Tropical Diseases between 2001 and 2004. The objective of the study was to evaluate changes in hepatic biochemical indices before and after treatment with artemisinin derivatives. On admission and prior to treatment, hepatic dysfunction was found among the 3 groups. Serum liver function tests and physical examinations were performed weekly during the 28-day follow-up period. Initially elevated serum bilirubin and diminished albumin returned to normal within 2 weeks of treatment. Serum alkaline phosphatase and aminotransferases returned to within normal limits within 3 weeks. We conclude that patients with Plasmodium vivax, P. malariae and P. ovale infections had slightly elevated serum bilirubin, aminotransferase and alkaline phosphatase levels, and hypoalbuminemia. These minor abnormalities returned to normal within a few weeks after treatment with therapies based on artemisinin derivatives.

Plasmodium ovale: parasite and disease.

Humans are infected by four recognized species of malaria parasites. The last of these to be recognized and described is Plasmodium ovale. Like the other malaria parasites of primates, this parasite is only transmitted via the bites of infected Anopheles mosquitoes. The prepatent period in the human ranges from 12 to 20 days. Some forms in the liver have delayed development, and relapse may occur after periods of up to 4 years after infection. The developmental cycle in the blood lasts approximately 49 h. An examination of records from induced infections indicated that there were an average of 10.3 fever episodes of > or = 101 degrees F and 4.5 fever episodes of > or = 104 degrees F. Mean maximum parasite levels were 6,944/microl for sporozoite-induced infections and 7,310/microl for trophozoite-induced infections. Exoerythrocytic stages have been demonstrated in the liver of humans, chimpanzees, and Saimiri monkeys following injection of sporozoites. Many different Anopheles species have been shown to be susceptible to infection with P. ovale, including A. gambiae, A. atroparvus, A. dirus, A. freeborni, A. albimanus, A. quadrimaculatus, A. stephensi, A. maculatus, A. subpictus, and A. farauti. An enzyme-linked immunosorbent assay has been developed to detect mosquitoes infected with P. ovale using a monoclonal antibody directed against the circumsporozoite protein. Plasmodium ovale is primarily distributed throughout sub-Saharan Africa. It has also been reported from numerous islands in the western Pacific. In more recent years, there have been reports of its distribution on the Asian mainland. Whether or not it will become a major public health problem there remains to be seen. The diagnosis of P. ovale is based primarily on the characteristics of the blood stages and its differentiation from P. vivax. The sometimes elliptical shape of the infected erythrocyte is often diagnostic when combined with other, subtler differences in morphology. The advent of molecular techniques, primarily PCR, has made diagnostic confirmation possible. The development of techniques for the long-term frozen preservation of malaria parasites has allowed the development diagnostic reference standards for P. ovale. Infections in chimpanzees are used to provide reference and diagnostic material for serologic and molecular studies because this parasite has not been shown to develop in other nonhuman primates, nor has it adapted to in vitro culture. There is no evidence to suggest that P. ovale is closely related phylogenetically to any other of the primate malaria parasites that have been examined.

Compensatory evolution in the human malaria parasite Plasmodium ovale.

The fixation of neutral compensatory mutations in a population depends on the effective population size of the species, which can fluctuate dramatically within a few generations, the mutation rate, and the selection intensity associated with the individual mutations. We observe compensatory mutations and intermediate states in populations of the malaria parasite Plasmodium ovale. The appearance of compensatory mutations and intermediate states in P. ovale raises interesting questions about population structure that could have considerable impact on the control of the associated disease.