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Clinical impact of vivax malaria: A collection review

['Aung Pyae Phyo', 'Myanmar Oxford Clinical Research Unit', 'Yangon', 'Prabin Dahal', 'Infectious Diseases Data Observatory Iddo', 'Oxford', 'United Kingdom', 'Centre For Tropical Medicine', 'Global Health', 'Nuffield Department Of Medicine']

Date: 2022-02 

Abstract Background Plasmodium vivax infects an estimated 7 million people every year. Previously, vivax malaria was perceived as a benign condition, particularly when compared to falciparum malaria. Reports of the severe clinical impacts of vivax malaria have been increasing over the last decade. Methods and findings We describe the main clinical impacts of vivax malaria, incorporating a rapid systematic review of severe disease with meta-analysis of data from studies with clearly defined denominators, stratified by hospitalization status. Severe anemia is a serious consequence of relapsing infections in children in endemic areas, in whom vivax malaria causes increased morbidity and mortality and impaired school performance. P. vivax infection in pregnancy is associated with maternal anemia, prematurity, fetal loss, and low birth weight. More than 11,658 patients with severe vivax malaria have been reported since 1929, with 15,954 manifestations of severe malaria, of which only 7,157 (45%) conformed to the World Health Organization (WHO) diagnostic criteria. Out of 423 articles, 311 (74%) were published since 2010. In a random-effects meta-analysis of 85 studies, 68 of which were in hospitalized patients with vivax malaria, we estimated the proportion of patients with WHO-defined severe disease as 0.7% [95% confidence interval (CI) 0.19% to 2.57%] in all patients with vivax malaria and 7.11% [95% CI 4.30% to 11.55%] in hospitalized patients. We estimated the mortality from vivax malaria as 0.01% [95% CI 0.00% to 0.07%] in all patients and 0.56% [95% CI 0.35% to 0.92%] in hospital settings. WHO-defined cerebral, respiratory, and renal severe complications were generally estimated to occur in fewer than 0.5% patients in all included studies. Limitations of this review include the observational nature and small size of most of the studies of severe vivax malaria, high heterogeneity of included studies which were predominantly in hospitalized patients (who were therefore more likely to be severely unwell), and high risk of bias including small study effects. Conclusions Young children and pregnant women are particularly vulnerable to adverse clinical impacts of vivax malaria, and preventing infections and relapse in this groups is a priority. Substantial evidence of severe presentations of vivax malaria has accrued over the last 10 years, but reporting is inconsistent. There are major knowledge gaps, for example, limited understanding of the underlying pathophysiology and the reason for the heterogenous geographical distribution of reported complications. An adapted case definition of severe vivax malaria would facilitate surveillance and future research to better understand this condition.

Author summary Why was this study done? Historically, the clinical impact of the relapsing malaria caused by Plasmodium vivax has been understudied and reported compared to falciparum malaria. What did the researchers do and find? We reviewed the literature on the clinical impact of vivax malaria focusing on children and pregnant women and performed a rapid systematic review of published evidence for severe disease and meta-analysis of selected studies.

Vivax malaria in young children is associated with severe anemia and increased mortality. Infections in pregnancy lead to maternal anemia, prematurity, fetal loss, and low birth weight. We estimated the proportion of patients with World Health Organization (WHO)-defined severe disease as 0.7% [95% confidence interval (CI) 0.19% to 2.57%] in all patients with vivax malaria and the mortality from vivax malaria as 0.01% [95% CI 0.00% to 0.07%] in all patients and 0.56% [95% CI 0.35% to 0.92%] in hospital settings. What do these findings mean? Reporting of severe vivax malaria has increased dramatically over the last 10 years, but different case definitions have been applied.

Limitations of our analysis include high risk of bias of published studies, the majority of which are in hospitalized patients (who are therefore more likely to be severely unwell), while most vivax malaria is managed in primary care. As a result, estimates should be interpreted with caution.

Prospective cohort studies using an adapted case definition of severe vivax malaria would improve estimates of incidence.

Preventing vivax malaria and subsequent relapses in children and pregnant women is a priority to reduce morbidity and mortality.

Citation: Phyo AP, Dahal P, Mayxay M, Ashley EA (2022) Clinical impact of vivax malaria: A collection review. PLoS Med 19(1): e1003890. https://doi.org/10.1371/journal.pmed.1003890 Academic Editor: James G. Beeson, Burnet Institute, AUSTRALIA Published: January 18, 2022 Copyright: © 2022 Phyo et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This research was funded in part by the Wellcome Trust [Grant number 20211/Z/20/Z]. APP is funded through a Wellcome International Training Fellowship (214208/Z/18/Z). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: We have read the journal’s policy and the authors of this manuscript have the following competing interests: EA is a member of the Editorial Board of PLOS Medicine. Abbreviations: ADEM, acute disseminated encephalomyelitis; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; CI, confidence interval; DLCO, diffusing capacity for carbon monoxide; G6PD, glucose-6-phosphate dehydrogenase; Hb, hemoglobin; HMVEC-L, human lung microvascular endothelial cell; ICU, intensive care unit; KDIGO, Kidney Disease: Improving Global Outcomes; LILACS, Literatura Latino-Americana e do Caribe em Ciências da Saúde; PAIgG, platelet-associated IgG; PMNS, postmalaria neurological syndrome; PRISMA, Preferred Reporting Items for Systematic Reviews and Meta-Analyses; RIFLE, Risk, Injury, Failure; Loss, End-Stage renal disease; SGA, small for gestational age; TNF, tumor necrosis factor; WHO, World Health Organization

Introduction Like Plasmodium falciparum, the Plasmodium vivax parasite has an intraerythrocytic life cycle lasting approximately 48 hours from red cell invasion by merozoites to schizont rupture. In synchronous infections, schizogony triggers a febrile paroxysm every 3 days, hence the term “tertian fever” given to early descriptions of patients with vivax or falciparum malaria. Malaria caused by P. vivax was termed benign tertian malaria because the clinical course was generally considered to be mild compared to falciparum malaria even though occasional descriptions of severe, including cerebral, presentations of vivax malaria have been reported since 1902 [1]. The notion that P. vivax only rarely causes severe malaria has been challenged over the last 15 years [2], and reports of severe disease have been increasing. More evidence for the negative impacts of vivax malaria on young children and pregnant women has emerged over the same time period. Here, we describe the clinical symptoms and major clinical impacts of malaria caused by P. vivax taking a narrative approach but incorporating a rapid systematic review of the evidence for severe disease.

Rapid review methods We searched PubMed for articles in English (including those with an English abstract only) documenting severe vivax malaria published until August 1, 2021, using a variety of terms to search title and abstract (S1 Table). Articles were screened by one reviewer (APP) with 20% screened by a second reviewer (PD or EAA). Extra references were identified from other systematic reviews, bibliographic searches, and searching in Google Scholar. This review is reported as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline (S2 Table). Definitions We included articles if the authors classified the episode as severe vivax malaria. We noted whether the cases met the case definition of severe (falciparum) malaria published by the World Health Organization (WHO) in 2014 [3], without taking parasite density into account in the definitions of jaundice or anemia (Table 1). PPT PowerPoint slide

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TIFF original image Download: Table 1. WHO definition of severe falciparum malaria and common adaptations used to report severe Plasmodium vivax malaria. https://doi.org/10.1371/journal.pmed.1003890.t001 Statistical analysis The proportion of patients with severe vivax malaria was estimated using a meta-analysis of single proportions using data from studies with clearly defined denominators (case reports, case series, and studies exclusively in pregnant women were excluded), after applying logit transformation. Heterogeneity was assessed using the I2 statistic, which quantifies the proportion of total variability attributable to between-study differences [4]. Pooled estimates derived from the fixed-effect and random-effects meta-analyses were expressed as percentages and presented together with the associated 95% confidence intervals (CIs). The estimates were stratified by geographical region and by hospitalization status (when the information was available) defined as hospitalized only or studies in which the denominator was patients diagnosed in community/outpatient settings as well as inpatients. Similar meta-analyses were carried out for estimating the proportion of patients with the 3 leading complications of cerebral malaria, acute kidney injury (AKI), and pulmonary edema/acute respiratory distress syndrome (ARDS). Severe anemia was not included in the meta-analysis because our search strategy was not designed to capture the literature on vivax malaria and anemia comprehensively. Small study effect was assessed by using a linear regression test of funnel plot asymmetry and bias-adjusted estimates were reported using trim-and-fill method. Risk of bias assessment The following aspects of the studies regarding patient selection and outcome assessment domains were considered: representativeness of the cohort (or cases in case–control studies), methodology used for ascertainment of exposure (microscopy, rapid diagnostic tests, and PCR), and if the assessment of exposure and outcome was blinded or not (laboratory procedures blinded or not). Case series and case reports were not included in the risk of bias assessment.

Mortality from vivax malaria A total of 553 deaths were associated with severe vivax malaria (S3 Table). Out of these, 334 were from 75 studies eligible for inclusion in the random-effects meta-analysis, and the overall estimate of mortality (all studies, regardless of setting) was 0.27% [0.15% to 0.50%] (Table 4). There were no reports of deaths from the African region. PPT PowerPoint slide

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TIFF original image Download: Table 4. Estimating mortality in studies eligible for inclusion in the meta-analysis. https://doi.org/10.1371/journal.pmed.1003890.t004 Postmortem evidence of severe malaria In a retrospective review of the postmortem findings of 17 patients who had died with vivax malaria between 1996 and 2010 in a single centre in Brazil, it was concluded that vivax malaria was the probable cause of death or contributed to the fatal outcome in 13 cases aged between 8 and 88 years [52]. Pulmonary edema or ARDS were the leading causes of death (n = 7), coexisting with splenic rupture in 2 patients. The other causes of death were multiple organ dysfunction (n = 3, including one with a cerebrovascular accident), primaquine-induced hemolytic anemia in the context of glucose-6-phosphate dehydrogenase (G6PD) deficiency (n = 2), and isolated splenic rupture (n = 1). A total of 7 patients had comorbidities such as hepatic cirrhosis or pulmonary emphysema. Postmortem findings consistent with ARDS were reported from one fatal case in India [49]. Postmortem histology from one fatal case of “infection with (the) large tertian parasite” in 1902 [1] found a spleen containing numerous large parasites, tubular degeneration in the kidneys, pigment in lung capillaries but no parasites, and very little evidence of pigment or parasitized erythrocytes in the brain. Another postmortem study of a Vietnamese patient with severe vivax malaria who died suddenly but was fully conscious on presentation found no evidence of sequestration of parasitized erythrocytes in the cerebral microvasculature [53].

Pathophysiology of severe vivax malaria Theories as to the pathophysiological processes underlying severe disease include immune dysfunction [54–59], parasite strain–specific virulence [60–62], inflammation triggered by cytokines, and endothelial cell dysfunction [63]. A proteomic study testing serum from Indian patients with vivax malaria of differing levels of severity as well as controls has given signals of possible involvement of oxidative stress pathways, cytoskeletal regulation, lipid metabolism, and complement cascades [64]. Waning immunity as transmission goes down and increasing resistance of P. vivax to chloroquine have been put forward as possible explanations for increasing reports of severe vivax malaria [54,65]. Increased expression of pvcrt-o (P. vivax chloroquine resistance transporter-o), pvmdr-1 (P. vivax multidrug resistance gene-1), and vir (variant interspersed repeats) genes has been shown in small numbers of patients with severe compared to uncomplicated vivax malaria [66–68]. Studies of patients with malaria have shown P. vivax evokes relatively higher concentrations of pro- and anti-inflammatory cytokines, such as tumor necrosis factor (TNF), and other markers of host immune response than P. falciparum at similar parasite densities [69,70]. While these findings can explain the lower pyrogenic parasite densities of vivax infections compared to falciparum, TNF is not thought to play a causal role in coma and cerebral manifestations of severe falciparum malaria [71]. Some in vitro studies have demonstrated some cytoadhesive properties of P. vivax parasitized erythrocytes [72]; however, cytoadherence and/or sequestration have not been demonstrated in vivo, and there are no published postmortem studies of patients diagnosed with cerebral vivax malaria. Binding of uninfected erythrocytes to parasitized erythrocytes (rosetting) does occur, which may lead to impaired circulation [73,74]. Modest (2-fold) increases in peripheral parasite densities in severe disease are accompanied by larger (7-fold) increases in circulating parasite lactate dehydrogenase, suggesting the possibility of parasitized erythrocytes accumulating elsewhere [75]. Impairment of endothelial function has been shown in Malaysian patients with vivax malaria [63]. Endothelial injury and excessive inflammation could also explain ARDS presentations. In a study of pulmonary gas transfer in Indonesian adults with falciparum or vivax malaria diffusing capacity for carbon monoxide (DLCO) in patients with vivax malaria was 93% (95% CI 87 to 104) of predicted values at baseline and declined for 2 weeks after treatment to 84% (95% CI 72 to 95) [76]. Evidence for cytoadherence in the pulmonary microvasculature is not that compelling, although scattered parasitized red blood cells in pulmonary capillaries have been described in one patient postmortem, and P. vivax has been shown to adhere to human lung microvascular endothelial cells (HMVEC-L) in vivo, albeit to a lesser degree than P. falciparum [52,77]. Increased concentrations of platelet-associated IgG (PAIgG) have been reported in patients with thrombocytopenia and vivax malaria, of unclear significance [78]. It has also been postulated that increased levels of macrophage colony–stimulating factor in vivax and falciparum malaria may result in increased macrophage-mediated platelet destruction and thrombocytopenia [79]. The anemia associated with P. vivax malaria has been reviewed in detail by Douglas and colleagues [25]. Mechanisms by which malaria leads to anemia include destruction of parasitized erythrocytes, destruction of nonparasitized erythrocytes, and dyserythropoeisis. Unlike in falciparum malaria, it is unusual to have parasite densities more than 2% infected erythrocytes in acute vivax malaria [80]. P. vivax has a predilection for invading younger erythrocytes, which has been thought to be one reason why unrestricted parasite multiplication does not occur as for P. falciparum. However, severity of anemia may be comparable, or worse. Collins and colleagues postulated that destruction of reticulocytes as they are produced could account for this [81]. However, Kitchen observed in another study published in 1938 that, even when reticulocyte numbers increase, only a fixed proportion will be infected; therefore, other factors may be more important [82]. Survival of uninfected red cells is shortened after an episode of malaria [81]. A mathematical modeling study using parasitemia and Hb data from patients receiving P. falciparum malariatherapy for neurosyphilis estimated that 8.5 nonparasitized erythrocytes were destroyed for each parasitized erythrocyte [83]. In malaria caused by P. vivax, the number may be even higher, given that parasites densities are lower. However, there is only indirect evidence for this. In a study of mean erythrocyte survival after P. falciparum or P. vivax parasitemia in 35 Thai patients who received transfusions of either labeled autologous or donor erythrocytes once their parasitemia had cleared, a similar reduction in erythrocyte survival was seen, regardless of the infecting species and did not appear to be antibody or complement mediated [84]. In a Colombian study comparing patients with uncomplicated and complicated (defined as platelets <50,000/μL, abnormal liver enzymes, or hypoglycemia) vivax malaria, there was an association between autoimmune antibodies and Hb concentrations in complicated disease. There was also a correlation with levels of atypical memory B cells, which have been hypothesized to contribute to anemia in malaria by secreting antibodies against phosphatidylserine on uninfected erythrocytes [85]. In malaria endemic areas, the degree of anemia associated with P. vivax infections depends on transmission intensity, patient age, and by extension degree of acquired immunity, strain relapse periodicity, and choice of antimalarial treatment, e.g., more slowly eliminated drugs will suppress the first relapse, allowing time for hematological recovery, while treatment failure due to resistance will impede recovery.

Discussion The global burden of vivax infections is vast, with estimates ranging from 7 to 14 million cases annually, leading to a substantial clinical impact, particularly in young children and pregnant women [86,15]. While it is now generally accepted that vivax malaria may manifest as severe disease, uncertainties remain. Reports of severe vivax malaria have increased over the last decade, but it is unclear to what extent this represents a genuine increase in case numbers, increased recognition of the disease, or misattribution in patients with other diagnoses and incidental parasitemia. In Manaus, Brazil, where a consistent case definition has been used over time, the incidence of severe disease has been increasing [87]. Increasing chloroquine resistance might be expected to lead to more severe disease, although in Papua, Indonesia, switching from chloroquine to artemisinin combination therapy did not lead to a mortality reduction in patients hospitalized with vivax malaria, suggesting that relapse prevention may be more important to reduce deaths [88]. This is supported by another analysis of more than 20,000 patients with vivax malaria in the same location showing that P. vivax infection was a risk factor for representation to hospital and contributed to increased mortality [89]. There are major disparities in frequencies of reporting certain complications of vivax malaria from different parts of the world (Fig 2) and a near absence of reporting of severe vivax malaria from some Southeast Asian countries, e.g., Thailand, Myanmar, Vietnam, and Lao PDR. Strain-specific virulence has been described in both induced malaria studies [90] and natural infections such as in the former United Soviet Socialist Republic where outbreaks of “fulminant malaria” caused by P. vivax were well described in the 1940s [91]. While this may be the explanation for the heterogeneous distribution of severe disease, the fact that asymptomatic vivax parasitemia is common means that a degree of misattribution is inevitable. This has been shown in individual fatal cases for whom exhaustive attempts were made to rule out other causes [52,92]. It is also suggested by variable histological findings from patients with vivax malaria who have had a renal biopsy. Only about half of the studies included in this review described attempts to exclude other diagnoses, e.g., sepsis. A 1 year prospective study from Kolkata examined the rate of concomitant bacteremia with P. vivax parasitemia and found that 6/89 (6.7% [95% CI 3.1% to 13.9%]) of patients with P. vivax infection were bacteremic [93]. Our estimate of mortality resulting from P. vivax infection from the random-effects meta-analysis ranged from 0.01% [0.00% to 0.07%] (studies of all patients, i.e., outpatient and inpatient cases) to 0.56% [0.35% to 0.92%] in studies of hospitalized patients only. These results were similar to a case fatality rate estimate of 0.3% (353/46,411) from a fixed-effect meta-analysis in another systematic review, which used a modified WHO definition of severe malaria and included thrombocytopenia [94]. However, these estimates should be interpreted with caution given the risk of bias assessment of included studies. Detailed studies from a small number of research groups so far have not identified a common pathophysiological process underlying different complications of vivax malaria. Sequestration of parasitized red blood cells in the microcirculation, which is the pathophysiological hallmark of severe falciparum malaria, has been not been demonstrated. ARDS has been reported with infection from all Plasmodium species causing malaria in humans. Incidence rates of ARDS in severe falciparum malaria have been shown to vary between 2% and 25% and are more likely to lead to a fatal outcome than ARDS with P. vivax [95,96]. The need for an adapted case definition for severe vivax malaria has been recognized for over a decade. Reporting by different groups is inconsistent, impeding gathering reliable incidence data or conducting research. A Brazilian study looking at predictors of intensive care unit (ICU) admission in patients with vivax malaria found that many of the criteria in the severe falciparum malaria definition were predictive, with the exception of hyperbilirubinemia [87]. The importance of thrombocytopenia as a diagnostic criterion for severe vivax malaria has been debated [97]. Lampah and colleagues from Papua, Indonesia reported the mortality risk of P. vivax infections in patients presenting to a referral hospital with severe thrombocytopenia to be 1.5% (25/1650) below 50 × 109/L and 3.6% (6/168) below 20 × 109/L in patients with P. vivax and proposed the latter threshold as a severity criterion [98]. The utility of this in routine practice would need to be demonstrated since complete blood count is not available in many outpatient settings where malaria is diagnosed and treated [98]. Conversely, incorporating platelet counts into case definitions of severe falciparum malaria using >200,000 per μL to rule out severe malaria has been proposed as a means to improve the specificity of clinical and parasitological diagnosis in a mathematical modeling study. Results suggested that one-third of 2,220 Kenyan children included in studies had been misdiagnosed as having severe malaria [99]. Very few articles reported platelet counts associated with severe syndromes in our review so we were unable to explore this. Limitations of our rapid systematic review include limiting our search to the English language and omitting to search other databases such as the Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS) database. A systematic review of the Brazilian published and gray literature in 2012 described a similar array of complications from P. vivax infection to those reported here [100]. The literature is dominated by case series and reports and by hospital-based studies increasing the risk of bias toward more severely ill patients. Our formal risk of bias assessment of studies included in the meta-analysis indicated a moderate to high risk of bias. There was also evidence of small study effects which was shown in an earlier systematic review by Naing [101].

Conclusions Vivax malaria has emerged from the shadow of falciparum malaria over the last decade with improved recognition of the negative clinical impacts associated with this relapsing infection. Preventing severe anemia associated with relapsing vivax malaria, particularly in very young children, is a priority to reduce morbidity and mortality in this group. Progress has been slowed by low uptake of antihypnozoiticidal treatment with 8-aminoquinoline drugs due to fears of hemolysis in patients with G6PD deficiency, compounded by lack of access to G6PD testing [102]. Prevention of infection with P. vivax in pregnancy may need to target young women preconception in order to prevent the risk of relapse during pregnancy and the consequent negative impacts of maternal anemia, increased fetal loss, and low birth weight [103]. Severe clinical presentations of vivax malaria are now well recognized, although knowledge gaps persist in terms of understanding the underlying pathophysiology of different complications and the apparent heterogeneity in incidence worldwide. An adapted case definition of severe vivax malaria would facilitate surveillance and future research.

Acknowledgments The Lao–Oxford–Mahosot Hospital–Wellcome Trust Research Unit (LOMWRU) and the Myanmar Oxford Clinical Research Unit are part of the MORU Tropical Health Network. For the purpose of open access, the author has applied a CC BY public copyright license to any author accepted manuscript version arising from this submission.

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