The 'non-falciparum' malarias: the roles of epidemiology, parasite biology, clinical syndromes, complications and diagnostic rigour in guiding therapeutic strategies.

Plasmodium vivax, P. ovale, P. malariae and P. falciparum routinely infect humans. The infections caused by these parasites are loosely referred to as vivax (or benign tertian), ovale, malariae (or quartan) and falciparum (or malignant tertian) malaria, respectively. Recently, P. knowlesi, a parasite of macaque monkeys in South-east Asia, has been identified as the cause of uncomplicated and severe human malaria in Malaysian Borneo. The prescription of appropriate therapies for reliably diagnosed malaria requires a grasp of the epidemiology of the 'non-falciparum' malarias, the biology of the parasites involved, the chemotherapeutic strategies that are available and the problems of emerging drug resistance and changing clinical syndromes. This review is intended to increase clinicians' understanding of how these factors relate to the selection of the antimalarial drugs to be given to a case of 'non-falciparum' malaria, with the aims of improving outcomes and preventing relapses and recrudescences.

Randomized, parallel placebo-controlled trial of primaquine for malaria prophylaxis in Papua, Indonesia.

Malaria causes illness or death in unprotected travelers. Primaquine prevents malaria by attacking liver-stage parasites, a property distinguishing it from most chemoprophylactics and obviating 4-week postexposure dosing. A daily adult regimen of 30 mg primaquine prevented malaria caused by Plasmodium falciparum and P. vivax for 20 weeks in 95 of 97 glucose-6-phosphate dehydrogenase (G6PD)-normal Javanese transmigrants in Papua, Indonesia. In comparison, 37 of 149 subjects taking placebo in a parallel trial became parasitemic. The protective efficacy of primaquine against malaria was 93% (95% confidence interval [CI] 71%-98%); against P. falciparum it was 88% (95% CI 48%-97%), and >92% for P. vivax (95% CI >37%-99%). Primaquine was as well tolerated as placebo. Mild methemoglobinemia (mean of 3.4%) returned to normal within 2 weeks. Blood chemistry and hematological parameters revealed no evidence of toxicity. Good safety, tolerance, and efficacy, along with key advantages in dosing requirements, make primaquine an excellent drug for preventing malaria in nonpregnant, G6PD-normal travelers.

Role of fluconazole in a case of rapid onset ritonavir and inhaled fluticasone-associated secondary adrenal insufficiency.

A 52-year-old man with well-controlled HIV infection taking ritonavir and increasing doses of inhaled fluticasone for chronic bronchitis developed thrush. Within days of discontinuing fluticasone and initiating fluconazole, he presented with fatigue, malaise, lower-extremity oedema and orthostasis. Testing confirmed exogenous Cushing's syndrome and secondary adrenal insufficiency. Although ritonavir-fluticasone interactions have been previously reported as a cause for adrenal insufficiency, we propose that fluconazole increased the rapidity of onset and severity of symptoms through synergistic inhibition of the adrenal axis.

Oerskovia xanthineolytica bacteremia in an immunocompromised host: case report and review.

Oerskovia species, once thought to be nocardiform-like bacteria, have been only rarely associated with human infection. In this report we describe a case of central venous catheter-associated infection that was successfully treated with antibiotics. With the increased use of indwelling devices, these organisms may be more commonly recognized causes of infection. Appropriate antibiotic therapy appears to successfully treat oerskovia infection and may decrease the need for removal of some indwelling access devices.

The T76 mutation in the pfcrt gene of Plasmodium falciparum and clinical chloroquine resistance phenotypes in Papua, Indonesia.

The T76 mutation in the pfcrt gene has been linked to chloroquine (CQ) resistance in Plasmodium falciparum. PCR-based analysis of pfcrt alleles was performed on pre-treatment samples from 107 individuals who had P. falciparum infections and lived in Papua, Indonesia. The results of a 28-day, in-vivo test revealed clinical resistance to CQ in 79 (74%) of the samples. The crude sensitivity of the pfcrt T76 assay for detecting the CQ-resistant infections in the samples was 96% and the crude specificity 52%. Discordance between pfcrt genotype and in-vivo phenotype was analysed either by genotyping of the merozoite surface protein-2 (to distinguish re-infection from recrudescence) or by amplification of the P. falciparum-specific small-subunit ribosomal RNA (ssrRNA) gene, using nested PCR (to detect any sub-patent but resistant parasites in infections misclassified as sensitive by the in-vivo test). When adjusting for the results of these analyses, the sensitivity and specificity of the pfcrt T76 assay for detecting the CQ-resistant infections became 93% and 82%, respectively. Overall, the present results indicate that the pfcrt T76 assay may be used to forecast therapeutic failure caused by CQ resistance. Validation requires exploration of the phenotype classifications based on the results of in-vivo tests, using genetic analyses that distinguish re-infection from recrudescence and detect microscopically subpatent parasitaemias.

Adult Javanese migrants to Indonesian Papua at high risk of severe disease caused by malaria.

Migrants from Java arrive in hyperendemic Papua, Indonesia lacking exposure to endemic malaria. We evaluated records of evacuation to hospital with a diagnosis of severe malaria from a transmigration village in northeastern Papua. During the first 30 months, 198 residents with severe disease were evacuated (7.5 evacuations/100 person-years). During this period the risk of evacuation for adults (> 15 years of age) was 2.8. (95% CI = 2.1-3.8; P < 0.0001) relative to children, despite apparently equal exposure to risk of infection. Relative risk (RR) for adults was greatest during the first 6 months (RR > 16; 95% CI > or = 2.0-129; P = 0.0009), and diminished during the second 6 months (RR = 9.4; 95% CI = 2.7-32.8; P < 0.0001) and the third 6 months (RR = 3.7; 95% CI = 1.7-7.9; P = 0.0004). During the next two 6-month intervals, the RR for adults was 1.6 and 1.5 (95 % CI range 0.8-2.6; P < 0.18). Adults lacking chronic exposure were far more likely to progress to severe disease compared to children during initial exposure, but not after chronic exposure to infection.

Onset of clinical immunity to Plasmodium falciparum among Javanese migrants to Indonesian Papua.

Onset of clinical immunity to Plasmodium falciparum occurred among Javanese migrants to Indonesian Papua. Surveillance of the 243 migrants investigated began on the day of their arrival in Indonesian Papua and continued for 33 months. Asexual parasitaemia without fever constituted objective evidence of clinical immunity. Compared with first infection, the odds ratio (OR) for not having fever at the fourth infection within 24 months was 3.2 [95% confidence interval (CI)=1.03-10.2; P=0.02]. The corresponding OR with fewer infections within 24 months was not distinguishable from 1.0. The level of the fourth parasitaemia within 24 months (N=58) was classified as 'high' or 'low' in relation to the median count at first infection (840 parasites/microl; N=187). Fourth parasitaemias that were low-but not those that were high (OR=1.8; CI=0.6-5.4; P=0.35)-were associated with dramatic protection from fever (OR=31; CI=3.5-1348; P=0.0001). Among the adult subjects, the risk of fever with low parasitaemia was significantly higher at the first infection than at the fourth (OR=12.6; CI=1.7-530; P=0.005), indicating the development of clinical immunity. A similar but less marked pattern appeared among the children investigated (OR=6.5; CI=0.8-285; P=0.06).

Safety, tolerability and humoral immune responses after intramuscular administration of a malaria DNA vaccine to healthy adult volunteers.

DNA-based vaccines are considered to be potentially revolutionary due to their ease of production, low cost, long shelf life, lack of requirement for a cold chain and ability to induce good T-cell responses. Twenty healthy adult volunteers were enrolled in a Phase I safety and tolerability clinical study of a DNA vaccine encoding a malaria antigen. Volunteers received 3 intramuscular injections of one of four different dosages (20, 100, 500 and 2500 microg) of the Plasmodium falciparum circumsporozoite protein (PfCSP) plasmid DNA at monthly intervals and were followed for up to twelve months. Local reactogenicity and systemic symptoms were few and mild. There were no severe or serious adverse events, clinically significant biochemical or hematologic changes, or detectable anti-dsDNA antibodies. Despite induction of excellent CTL responses, intramuscular DNA vaccination via needle injection failed to induce detectable antigen-specific antibodies in any of the volunteers.

Chloroquine or sulfadoxine-pyrimethamine for the treatment of uncomplicated, Plasmodium falciparum malaria during an epidemic in Central Java, Indonesia.

A recent malaria epidemic in the Menoreh Hills of Central Java has increased concern about the re-emergence of endemic malaria on Java, which threatens the island's 120 million residents. A 28-day, in-vivo test of the efficacy of treatment of malaria with antimalarial drugs was conducted among 167 villagers in the Menoreh Hills. The treatments investigated, chloroquine (CQ) and sulfadoxine-pyrimethamine (SP), constitute, respectively, the first- and second-line treatments for uncomplicated malaria in Indonesia. The prevalence of malaria among 1389 residents screened prior to enrollment was 33%. Treatment outcomes were assessed by microscopical diagnoses, PCR-based confirmation of the diagnoses, measurement of the whole-blood concentrations of CQ and desethylchloroquine (DCQ), and identification of the Plasmodium falciparum genotypes. The 28-day cumulative incidences of therapeutic failure for CQ and SP were, respectively, 47% (N = 36) and 22% (N = 50) in the treatment of P. falciparum, and 18% (N = 77) and 67% (N = 6) in the treatment of P. vivax. Chloroquine was thus an ineffective therapy for P. falciparum malaria, and the presence of CQ-resistant P. vivax and SP-resistant P. falciparum will further compromise efforts to control resurgent malaria on Java.

Primary infection by Plasmodium falciparum or P. vivax in a cohort of Javanese migrants to Indonesian Papua.

The clinical and parasitological characteristics of the first naturally acquired malarial infection have rarely been documented in humans. When 243 migrants from non-endemic Java were followed from the day of their arrival in Indonesian Papua, 217 (89%) were found to become infected with Plasmodium falciparum and/or P. vivax before they were lost to follow-up. The incidence of malarial infection in the children investigated (who were aged 6-10 years) was indistinguishable from that in the adults (aged >20 years), with 1.10 and 1.14 P. falciparum infections/person-year (relative risk=0.97; 95% confidence interval=0.72-1.29) and 1.47 and 1.49 P. vivax infections/person-year (relative risk=0.99; 95% confidence interval=0.72-1.29), respectively. During their first infections, the children had higher P. falciparum parasitaemias than the adults (with geometric means of 1318 and 759 parasites/microl, respectively; P=0.04) but similar P. vivax parasitaemias (with geometric means of 355 and 331 parasites/microl, respectively; P=0.76). At first infection, 56% of the subjects were febrile and 90% complained of symptoms. There were no differences between children and adults with respect to these two parameters, either for P. falciparum or P. vivax. These findings indicate that, with promptly diagnosed and treated uncomplicated malaria, migrant children and adults in north-eastern Indonesian Papua have an equal risk of malarial infection and of disease following their first infections with P. falciparum and P. vivax.