Vivax Relapses Research Articles

Blood-stage dynamics and clinical implications of mixed Plasmodium vivax-Plasmodium falciparum infections.

We present a mathematical model of the blood-stage dynamics of mixed Plasmodium vivax-Plasmodium falciparum malaria infections in humans. The model reproduces features of such infections found in nature and suggests several phenomena that may merit clinical attention, including the potential recrudescence of a long-standing, low-level P. falciparum infection following a P. vivax infection or relapse and the capacity of an existing P. vivax infection to reduce the peak parasitemia of a P. falciparum superinfection. We simulate the administration of antimalarial drugs, and illustrate some potential complications in treating mixed-species malaria infections. Notably, our model indicates that when a mixed-species infection is misdiagnosed as a single-species P. vivax infection, treatment for P. vivax can lead to a surge in P. falciparum parasitemia.

Re-examining the `Cycle Concept' in Malaria

I was astonished to come across an article in the August issue of Parasitology Today entitled `Why does Plasmodium have a pre-erythrocytic cycle?', by T.V. Rajan[1xRajan, T.V. Parasitol. Today. 1997; 13: 284–286Abstract | Full Text PDF | PubMedSee all References[1], along with `A response', by J.A. Stoute et al.[2xStoute, J.A. et al. Parasitol. Today. 1997; 13: 286–287Abstract | Full Text PDFSee all References[2] My surprise was due to the use of the word `cycle' in connection with the pre-erythrocytic (hepatic) stage of Plasmodium infection, as this hypothetical concept, originally used to explain malarial relapse[3xShortt, H.E. and Garnham, P.C.C. Nature. 1948; 161: 126Crossref | PubMedSee all References[3], is now outdated and incorrect. In the simplest terms, the immediate answer to the title question is `It doesn't.'Despite T.V. Rajan's assertion that `multiple rounds (P. vivax) of extra-erythrocytic schizogony [occur] in hepatocytes,' there is no good evidence that such a cycle exists, based on data from multiple experimental sources accumulated by the 1970s and early 1980s. In fact, P.C.C. Garnham himself, one of the two original discoverers of the pre-erythrocytic stage in primate malaria and co-author of the Shortt–Garnham theory of malarial relapse[4xShortt, H.E. and Garnham, P.C.C. Br. Med. J. 1948; 1: 1225–1228Crossref | PubMed | Scopus (27)See all References[4], had clearly identified insurmountable problems with the `cycle' concept as early as 1967 (Ref. [5xGarnham, P.C.C. Protozoology. 1967; 2: 55–64See all References[5]); he later collaborated with myself and others in experiments that finally did identify the true relapse stage, the hypnozoite[6xKrotoski, W.A. et al. Br. Med. J. 1980; 1: 153–154Crossref | Scopus (45)See all References, 7xKrotoski, W.A. Trans. R. Soc. Trop. Med. Hyg. 1985; 79: 1–11PubMed | Scopus (21)See all References, 8xKrotoski, W.A. Prog. Clin. Parasitol. 1989; 1: 1–19PubMedSee all References]. This collaboration and the still-current state of knowledge regarding the ontogeny of hepatic stages of primate Plasmodium spp have been reviewed in papers by Krotoski[7xKrotoski, W.A. Trans. R. Soc. Trop. Med. Hyg. 1985; 79: 1–11PubMed | Scopus (21)See all References, 8xKrotoski, W.A. Prog. Clin. Parasitol. 1989; 1: 1–19PubMedSee all References] and by Cogswell[9xCogswell, F.B. et al. Am. J. Trop. Med. Hyg. 1991; 45: 211–213PubMedSee all References, 10xCogswell, F.B. Clin. Microbiol. Rev. 1992; 5: 26–35PubMedSee all References]. In addition to the capping discovery of the hypnozoite in 1979–1980, the grounds for refutation of the 1948 postulate (ie. the Shortt–Garnham `cycle') include the geographically based disparities observed in P. vivax relapse patterns[11xContacos, P.G. et al. Am. J. Trop. Med. Hyg. 1972; 21: 707–712PubMedSee all References[11], in particular: the existence of strains consistently exhibiting delayed patency[12xTiburskaya, N.A. Med. Parazit. (Moscow). 1964; 33: 204–216PubMedSee all References[12]; the incompatibility of a `cycle' concept with the latter and with immunologic explanations therefore[13xSee all References[13]; the lack of any direct evidence to support the cycle theory, including the failure to demonstrate any `nests' of maturing tissue schizonts in experimental or clinical pathologic specimens[13xSee all References[13]; the susceptibility of human volunteers with mosquito-transmitted P. vivax infection to superinfection with the homologous strain by blood transfer during latency[14xCooper, W.C. et al. Am. J. Hyg. 1947; 46: 141–148PubMedSee all References[14]; and serologic observations on human P. malariae infection, in which anti-plasmodial antibody levels gradually fell after treatment aimed exclusively at blood stages[15xCollins, W.E. et al. Am. J. Trop. Med. Hyg. 1964; 13: 1–5PubMedSee all References[15].To base immunologic explanations of the hepatic tropism, behavior and development of pre-erythrocytic stages of Plasmodium on a non-existent `cycle' does not appear appropriate. In other words, although Rajan logically proposes that `by undergoing one or more rounds of replication in the liver, the parasite ensures primary exposure of its antigens to the mammalian immune system', there is simply no evidence to support the idea that the parasite does actually undergo such putative rounds of replication; in fact, the contrary seems to be the case.

Molecular analysis of Plasmodium vivax relapses using the MSP1 molecule as a genetic marker.

Plasmodium vivax has hepatocytic dormant stages, hypnozoites, that cause relapses. This work compared paired isolates from primary attacks and relapses obtained from 10 individuals in Brazil using the merozoite surface protein 1 gene, PvMSP1, as a genetic marker. Four samples from primary attacks contained genetically mixed parasites harboring the 2 major PvMSP1 allelic forms. PCR revealed the presence of these 2 forms in the relapse parasites of 2 patients, demonstrating that the activation of hypnozoites is not clonal. DNA sequences from paired primary/relapse samples demonstrated that the parasites from the primary attack are identical to those in relapse samples in which the same allele forms were detected in both infections. Studies on the naturally acquired humoral immune responses of these patients against a recombinant protein expressing the C-terminus PvMSP1 demonstrated an increase in the titers, affinity maturation, and predominance of the IgG1 subclass during the relapse.

HIGH RATE OF PLASMODIUM VIVAX RELAPSE FOLLOWING TREATMENT OF FALCIPARUM MALARIA IN THAILAND

Within two months of treatment for falciparum malaria, Plasmodium vivaxinfections developed in 58 (33%) of 174 patients who had received a quinine or quinidine regimen and in 46 (32%) of 145 patients who had received mefloquine with inpatient follow-up of more than six weeks. The time to vivax relapse was significantly longer after mefloquine treatment (median 47 days, range 30-65) than after quinine or quinidine treatment (21 days, 15-36; p<0·0001). All patients remained outside areas of malaria transmission. These findings suggest a very high rate of double infection in Thailand with acute suppression of vivax by falciparum malaria, and warrant evaluation of radical therapy with primaquine in certain patients with acute falciparum malaria.

Antimalarial effects of clindamycin in man.

Clindamycin 450 mg every 8 hours for 3 days cured three non-immune patients of falciparum malaria, although the response was slow. The addition of quinine to this regimen provided an accelerated response and cured 3 of 5 other patients. Single doses of clindamycin given daily for 3 days, with or without quinine, cured 1 of 3 patients. Gastric intolerance to the drugs, probably accentuated by the clinical condition, was pronounced in some cases, the course of treatment being interrupted in three patients for this reason. Chesson strain Plasmodium vivax relapses in man were not inhibited by ingestion of 450 mg of clindamycin every 6 hours for 14 days.

Field Experiments with Chloroquine Diphosphate 1

Summary and Conclusions 1. Chloroquine diphosphate in adequate dosage is completely satisfactory for the control of clinical attacks of malaria encountered in the Middle East; it is effective against P. vivax, P. falciparum and P. malariae. 2. Chloroquine diphosphate, when administered orally, is sufficiently harmless that effective doses may be given with impunity to infants and during the course of pregnancy. 3. The following therapeutic dosage schedule for chloroquine diphosphate is recommended but may be increased for massive infections: No. of 0.25 gm. tablets No. of 0.25 gm. tablets AGE DAY OF TREATMENT TOTAL 1st 2nd 3rd 1–6 months 4 × ¼ ¼ ¼ 1½ 7–9 months 4 × ¼ ½ ½ 2 10–24 months 4 × ½ ½ ½ 3 2–5 years 4 × ½ 1 1 4 6–10 year 3 × 1 1 1 5 Over 10 years 3 × 2 2 2 10 Therapy should be followed by weekly suppressive medication for 4–6 months where proved or latent vivax infection may exist. 4. Chloroquine diphosphate, administered at an adult dose level of 10 tablets (2.5 gm.) in three days, without follow-up with suppressive doses, yielded a vivax relapse rate of 28 per cent. When followed by fortnightly suppressive doses of 4 tablets (1.0 gm.) for 14–29 weeks, the relapse rate was reduced to 9.34 per cent, and when followed by weekly suppressive doses of 2 tablets (0.5 gm.) the relapse rate was further reduced to 5.74 per cent. Among the 21 adults in the vivax group who received an initial 10 tablet course, followed by weekly suppressive medication, no relapses occurred in seven and one-half months after the last dose. None of 53 proved cases of P. falciparum infection relapsed. 5. Chloroquine diphosphate has the combined requisites of both an effective therapeutic and prophylactic antimalarial which is safe enough to be given with a minimum of supervision throughout a malaria transmission season. By combining weekly prophylactic medication with chloroquine diphosphate (only 2 tablets per person) with adequate DDT antimosquito measures, it is possible to eradicate malaria from a community within the period of a single transmission season. In the absence of mosquito control, chloroquine diphosphate offers the means of suppressing new infections and reducing the reservoir of infection to a sub-critical threshold. Effective mass chemoprophylactic control of malaria was attained in Saideh under proved conditions of severe exposure.