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Vivax Malaria - Science topic

Malaria caused by plasmodium vivax. This form of malaria is less severe than malaria, falciparum, but there is a higher probability for relapses to occur. Febrile paroxysms often occur every other day.
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Summary
Background: Primaquine is the only widely used drug that prevents Plasmodium vivax malaria relapses, but adherence to the standard 14-day regimen is poor. We aimed to assess the efficacy of a shorter course (7 days) of primaquine for radical cure of vivax malaria.
Methods: We did a randomised, double-blind, placebo-controlled, non-inferiority trial in eight health-care clinics(two each in Afghanistan, Ethiopia, Indonesia, and Vietnam). Patients (aged ≥6 months) with normal glucose-6-phosphate dehydrogenase (G6PD) and presenting with uncomplicated vivax malaria were enrolled. Patients were given standard blood schizontocidal treatment and randomly assigned (2:2:1) to receive 7 days of supervised primaquine (1·0 mg/kg per day), 14 days of supervised primaquine (0·5 mg/kg per day), or placebo. The primary endpoint was the incidence rate of symptomatic P vivaxparasitaemia during the 12-month follow-up period, assessed in the intention-to-treat population. A margin of 0·07 recurrences per person-year was used to establish non-inferiority of the 7-day regimen compared with the 14-day regimen. This trial is registered at ClinicalTrials.gov (NCT01814683).
Findings: Between July 20, 2014, and Nov 25, 2017, 2336 patients were enrolled. The incidence rate of symptomatic recurrent P vivaxmalariawas 0·18 (95% CI 0·15 to 0·21) recurrences per person-year for 935 patients in the 7-day primaquine group and 0·16 (0·13 to 0·18) for 937 patients in the 14-day primaquine group, a difference of 0·02 (–0·02 to 0·05, p=0·3405). The incidence rate for 464 patients in the placebo group was 0·96 (95% CI 0·83 to 1·08) recurrences per person-year. Potentially drug-related serious adverse events within 42 days of starting treatmentwere reported in nine (1·0%) of 935 patients in the 7-day group, one (0·1%) of 937 in the 14-day group and none of 464 in the control arm. Four of the serious adverse events were significant haemolysis (three in the 7-day group and one in the 14-day group).
Interpretation: In patients with normal G6PD, 7-day primaquine was well tolerated and non-inferior to 14-day primaquine. The short-course regimen might improve adherence and therefore the effectiveness of primaquine for radical cure of P vivax malaria.
Funding: UK Department for International Development, UK Medical Research Council, UK National Institute for Health Research, and the Wellcome Trust through the Joint Global Health Trials Scheme (MR/K007424/1) and the Bill & Melinda Gates Foundation (OPP1054404).
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It is known from previous studies using primaquine is better than placebo for preventing relapse of plasmodium vivax malaria. And primaquine is already included in practice guidelines. Thus it was at least less important to include a placebo arm in this study if not unethical. This is my view.
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Detection of new infections from relapses in vivax malaria elimination programme is a big challenge, as a routine diagnostic method that can distinguish these cases from there. Please help us out if you have experience in this field.
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Thanks for all the tips! This was extremely helpful
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Would like to know the Plasmodium spp. image database that contains the labeled 5 kinds of species (falciparum, vivax, malariae, ovale, knowlesi) in 4 forms (ring, trophozoite, schizont, gametocyte). The image databases having some of the species and forms are also ok! The image number should be large enough to train a neural network (~1000)
Thank you!
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In recent past many sporadic cases of P. vivax infection in duffy negative individuals have been reported. However by scientific fact, we have developed an understanding that vivax parasite can not infects to duffy negative individuals. Duffy receptor interact with parasite ligand (PvDBP protein) and mediates tight junction step of invasion process, which is irreversible process. So this indicates that P. vivax may has identified an alternate receptor that helps mediating essential tight-junction step of invasion process. It is interesting to know if human reticulocytes expresses receptor protein that can mimic function of Duffy receptor. 
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Additional papers have reported the presence of P. vivax in Duffy-negative individuals. See this 2019 publication on "Growing evidence of [the occurrence of] Plasmodium vivax across malaria-endemic Africa".
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No, it is not merely hypnozoite activation or recrudescence as conventionally understood. This is a rhetorical question, because the answer is here:
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I am guilty of naming (41 years ago!) the plasmodial stage to which you refer, Alan, viz. the hypnozoite. Leaving aside the situation as regards P. ovale, it would seem that P. vivax recurrences can also (in addition to hypnozoites) have extravascular merozoites as their origin. It is a long and complicated story. The article for which the website is given in the question contains links to about 13 recent publications on the subject. This stuff isn't in textbooks (yet).
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is it new strain of P.vivax?
is it related to liver maturity?
is it related to failure of parents to observe the initial symptoms?
or is it due to other factors?
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I think we must study the evolution of P.vivax
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i have two models in predicting recurrence of vivax malaria. Each models were tested on both 2/3 and 1/3 of the data population to determine the predictive ability. I used area under receiver operating characteristic curve(ROC AUC) to assess the predictive ability. here are the details:
Model A: AUC 2/3- 0.72; AUC 1/3- 0.78
Model B: AUC 2/3- 0.7; AUC 1/3- 0.7
My question, which one predicts better, Model A which closes to 1 or Model B which 2/3 and 1/3 the area under the curve remains the same?
Thanks
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Dear Norliza Mat Ariffin,
The AUC will provide you the rate of accuracy of the model. Could you please send me the ROC plots so that I can help you out. 
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Despite treatment with the anti-relapse drug primaquine, Plasmodium vivax malaria often recurs. One reason might be related to CYP 2D6 (Marcsisin SR, Reichard G, Pybus BS. 2016. Primaquine pharmacology in the context of CYP 2D6 pharmacogenomics: current state of the art. Pharmacology & Therapeutics 161: 1-10). Another suggestion as to why relapse can occur even if primaquine has been administered, is based on the possible persistence of non-hypnozoite, non-bloodstream quiescent merozoites in Plasmodium vivax malaria. Will primaquine necessarily always "work" if tissue parasites are extra-hepatic? I think perhaps not. See the drug and other background to this question at:
As regards the latter potential scenario (i.e. not the CYP 2D6 one), are there any drug metabolism or associated pharmacological comments?
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Primaquine itself is not active, but must be metabolized to generate metabolites which are active. It is possible that something interfered with primaquine metabolism so that these active metabolites were not generated.
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This question is concerned only with recurrences that are neither reinfections nor recrudescences originating from persisting parasites in the bloodstream.
Given these two exclusions, when a Plasmodium vivax infection recurs clinically or there is renewed parasitaemia in the absence of symptoms, an explanation in terms of contemporary understanding is, then, that there has been a hypnozoite-mediated relapse. Related hereto, some excellent genetic epidemiological research on malaria has been carried out in recent years, and it is ongoing. Consequently, I am vaguely wondering how many (if any) experts in this field think at present that there could be a non-hypnozoite explanation for some of the homologous (as opposed to heterologous, which is a different subject), relapse-like P. vivax recurrences?
This question arises in the light of indirect biological and potential genetic support for the possible existence of (inter alia) quiescent, non-hepatic, non-bloodstream, tissue merozoites in P. vivax malaria. A calculated and semi-evidence-based idea is involved, rather than an uninformed and totally wild, half-baked amateur theory. Technical details can be accessed via:
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P. vivax type of malaria always appear in homogenous reddish color at thick smear as well as at thin smear, is it due to the presence of Schuffner's dot? 
At thin smear some experts point out scattered dark dots as Schuffner's dot but other references say the color is pink or brick-red. In ultra structure of P. vivax  caveola-vesicle complexes is indicated as the Schuffner's dot which is reasonable to be in dark color. However, where does the homogenous reddish color come from as always seen in thick and thin smear of Giemsa stained P. vivax?.     
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Yes, you can. Look at the CDC guideline ( attached ) . 
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Case 1: When treating a P.falciaprum patient, we consider that treatment failure is due to recrudescence or new infections. The new infection may already be present in the patient in a hepatic form.
Case 2: When malaria control efforts reach the stage that elimination is being thought of, major mass drug campaigns may be considered. Mass campaigns conducted with drugs killing the blood stage will, unfortunately, not eliminate the hepatic stages. Even with several campaigns with virtually 100% coverage, there may still be 'one man' (P.falciparum) somewhere in the liver.
(I ignored the mosquito stages for simplicity)
I have some other reasonings but I think the question is clear.
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The situation is not entirely straightforward. This makes definitive study design difficult. There are some additional drug-related and parasite source possibilities that have mostly not been considered hitherto. See the discussion in various places in my article (despite its title) in the June 2015 issue of Trends in Parasitology (Vol. 31, No. 6, Pages 239 to 245): http://dx.doi.org/10.1016/j.pt.2015.02.003
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Could it be explained by mixing between different ethnic groups or disease evolution ?
The definite thing is that the theory of protective duffy blood group is no more valid
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Dear Hamdan
One point please why  P.  vivax was not familiar  as agent causing severe disease before. Even  it was named as benign  tertiary fevere 
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Is necessary to have glucose 6 Glucose-6-phosphate dehydrogenase level in every setting where there is vivax malaria?
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I think in Sudan it does not need to have G6PD investigation in every patient infected with vivax malaria, because the prevalence of G6PD is less than 1% among population not like that in SEA ( around 30%). So historical background of GCPD  infection for elude every vivax malaria case is quite enough to exclude it.
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What is the reason for the epidemic of severe Plasmodium vivax malaria in East Africa?
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It might be, but that is very unlikely given that the reduction of P. falciparum is mostly related to the effect of the many interventions implemented in the region that are also efficient against P vivax. Epidemiologically, you will need to increase the population at risk (susceptible subjects ~ Duffy positives) as well as the population of mosquitoes that are efficient P. vivax vectors to close the malaria cycle. Both can be driven by migration, which occurs often and very intensively in some African regions. I do believe that this will offer you a partial answer to your question, although I'm afraid that the reality is far more complex than that. Africa offers a very favorable environment for vivax malaria transmission so once we have more subjects that are protected against it there is no reason to don't expect more P vivax malaria cases.
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I would like to know the molecular markers for diagnosing relapse cases versus reinfection cases of P. vivax.
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Dear Habibollah,
Part of the answer can be find in a WHO report on parasite genotyping http://www.mmv.org/sites/default/files/uploads/docs/news/MalariaGenotyping2.pdf
There is no consensus on the markers to distinguish between reinfection and relapse. A paper from N White also stressed that point. Radical cure of vivax patients with primaquine (check G6PD) is probably needed to solve part of the problem.
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I would like to know a molecular method to distinguish between relapse and reinfection in patients toward malaria elimination program.
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Hello my dear
Thanks for your tips and good response.
I am grateful for your wise guidance.
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I was wondering whether it is feasible to segregate live micro-and-macro-gametocytes of Plasmodium falciparum.
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Hi Anil,
Your best bet would be to create a new line where male and female gametocytes express different coloured proteins (e.g. GFP and RFP) under male and female specific promotors integrated in a part of genome which doesn't affect the parasite. something similar to what has been done in P.berghei (RMgm-164) (http://www.pberghei.eu/index.php?rmgm=164 ) . You can then do FACS sorting to seperate them while they are still viable. It does involve a lot of molecular work but once you have got this line, the possibilities for useful experiments are endless!
I hope that helps.
Anubhav
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The lack of a “gold standard” definition for severe malaria has been a longstanding problem for both clinicians and researchers. According to the CDC, severe malaria occurs when P. falciparum infections are complicated by a set of clinical and laboratory parameters associated with an increased risk of death.
Can P. vivax cause severe malaria?
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P. vivax can cause severe malaria.Haematological morbidity associated with P. vivax infection is greatest in young children, especially in tropical countries where transmission is intense and local parasite strains relapse very frequently (Douglas, 2012). severe anemia and thrombocytopenia that causes bleeding diathesis is produced by hemolysis, reduced cell deformity of parasitized and nonparasitized erythrocytes, increased splenic clearance, reduction of platelet survival, decreased platelet production, and increased splenic uptake of platelets, and can be produced by P. vivax and P. falciparum infection (Luxemburger et al, 1997).
I am pleased to send you this paper about P Vivax.