Effectiveness of artemether/lumefantrine for the treatment of uncomplicated Plasmodium vivax and P. falciparum malaria in young children in Papua New Guinea.

BACKGROUND: Artemisinin combination therapy is recommended as treatment for uncomplicated Plasmodium falciparum (Pf) malaria, whereas chloroquine is still widely used for non-Pf infections. A common treatment for both vivax and falciparum malaria would be welcome. METHODS: A longitudinal prospective effectiveness study of 1682 children aged 3-27 months in outpatient clinics in Papua New Guinea. The main outcome was clinical treatment failure rate following treatment with artemether/lumefantrine (AL). RESULTS: Among 5670 febrile episodes, 1682 (28%) had positive rapid diagnostic test (RDT) results and were treated with AL. A total of 1261 (22%) had an infection confirmed by blood slide examination. Of these, 594 Pv and 332 Pf clinical malaria cases were included in the primary effectiveness analysis. Clinical treatment failure rates at 7, 28, and 42 days were 0.2%, 2.2%, and 12.0%, respectively, for Pv and 0.3%, 1.2%, and 3.6%, respectively, for Pf. A single malaria-unrelated death occurred within 42 days following treatment with AL, in a child who was aparasitemic by blood slide at reattendance. CONCLUSIONS: AL provides a rapid clinical response against both Pf and Pv malaria, but is associated with a high rate of Pv recurrent clinical episodes between days 28 and 42. In order to prevent relapsing infections from long-lasting hypnozoites, AL should ideally be complemented with a course of primaquine. In the absence of better treatment and diagnostic options, the use of AL in young children in routine practice is an acceptable, interim option in coendemic areas where Pv is resistant to chloroquine and specific treatment for Pv hypnozoites not feasible.

Rapid diagnostic test-based management of malaria: an effectiveness study in Papua New Guinean infants with Plasmodium falciparum and Plasmodium vivax malaria.

BACKGROUND: In malaria-endemic areas it is recommended that febrile children be tested for malaria by rapid diagnostic test (RDT) or blood slide (BS) and receive effective malaria treatment only if results are positive. However, RDTs are known to perform less well for Plasmodium vivax. We evaluated the safety of withholding antimalarial drugs from young Papua New Guinean children with negative RDT results in areas with high levels of both Plasmodium falciparum and P. vivax infections. METHODS: Longitudinal prospective study of children aged 3-27 months visiting outpatient clinics for fever. RDT was administered at first visit. RDT and microscopy were performed if children returned because of persistent symptoms. Outcomes were rates of reattendance and occurrence of severe illnesses. RESULTS: Of 5670 febrile episodes, 3942 (70%) involved a negative RDT result. In 133 cases (3.4%), the children reattended the clinic within 7 days for fever, of whom 29 (0.7%) were parasitemic by RDT or microscopy. Of children who reattended, 24 (0.7%) presented with a severe illness: 2 had lower respiratory tract infections (LRTIs) with low-density P. vivax on BS; 2 received a diagnosis of P. vivax malaria on the basis of RDT but BSs were negative; 16 had LRTIs; 3 had alternative diagnoses. Of these 24, 22 were cured at day 28. Two children died of illnesses other than malaria and were RDT and BS negative at the initial and subsequent visits. CONCLUSION: Treatment for malaria based on RDT results is safe and feasible even in infants living in areas with moderate to high endemicity for both P. falciparum and P. vivax infections.

Intermittent preventive treatment for malaria in Papua New Guinean infants exposed to Plasmodium falciparum and P. vivax: a randomized controlled trial.

BACKGROUND: Intermittent preventive treatment in infants (IPTi) has been shown in randomized trials to reduce malaria-related morbidity in African infants living in areas of high Plasmodium falciparum (Pf) transmission. It remains unclear whether IPTi is an appropriate prevention strategy in non-African settings or those co-endemic for P. vivax (Pv). METHODS AND FINDINGS: In this study, 1,121 Papua New Guinean infants were enrolled into a three-arm placebo-controlled randomized trial and assigned to sulfadoxine-pyrimethamine (SP) (25 mg/kg and 1.25 mg/kg) plus amodiaquine (AQ) (10 mg/kg, 3 d, n = 374), SP plus artesunate (AS) (4 mg/kg, 3 d, n = 374), or placebo (n = 373), given at 3, 6, 9 and 12 mo. Both participants and study teams were blinded to treatment allocation. The primary end point was protective efficacy (PE) against all episodes of clinical malaria from 3 to 15 mo of age. Analysis was by modified intention to treat. The PE (compared to placebo) against clinical malaria episodes (caused by all species) was 29% (95% CI, 10-43, p ≤ 0.001) in children receiving SP-AQ and 12% (95% CI, -11 to 30, p = 0.12) in those receiving SP-AS. Efficacy was higher against Pf than Pv. In the SP-AQ group, Pf incidence was 35% (95% CI, 9-54, p = 0.012) and Pv incidence was 23% (95% CI, 0-41, p = 0.048) lower than in the placebo group. IPTi with SP-AS protected only against Pf episodes (PE = 31%, 95% CI, 4-51, p = 0.027), not against Pv episodes (PE = 6%, 95% CI, -24 to 26, p = 0.759). Number of observed adverse events/serious adverse events did not differ between treatment arms (p > 0.55). None of the serious adverse events were thought to be treatment-related, and the vomiting rate was low in both treatment groups (1.4%-2.0%). No rebound in malaria morbidity was observed for 6 mo following the intervention. CONCLUSIONS: IPTi using a long half-life drug combination is efficacious for the prevention of malaria and anemia in infants living in a region highly endemic for both Pf and Pv.

Use of antibiotics within the IMCI guidelines in outpatient settings in Papua New Guinean children: an observational and effectiveness study.

INTRODUCTION: There is a need to investigate the effectiveness and appropriateness of antibiotics prescription within the Integrated Management of Childhood Illness (IMCI) strategy in the context of routine outpatient clinics. METHODS: Making use of a passive case detection system established for a malaria prevention trial in outpatient clinics in Papua New Guinea, the appropriateness and effectiveness of the use of antibiotics within the IMCI was assessed in 1605 young children. Main outcomes were prescription of antibiotics and re-attendances within 14 days for mild pneumonia, mild diarrhoea and uncomplicated malaria whether they were managed with or without antibiotics (proxy of effectiveness). Appropriateness was assessed for both mild and severe cases, while effectiveness was assessed only for mild diseases. RESULTS: A total of 6975 illness episodes out of 8944 fulfilled inclusion criteria (no previous attendance <14 days+full medical records). Clinical incidence rates (episodes/child/year; 95% CI) were 0.85 (0.81-0.90) for pneumonia, 0.62 (0.58-0.66) for malaria and 0.72 (0.65-0.93) for diarrhoea. Fifty three percent of 6975 sick children were treated with antibiotics, 11% were not treated with antibiotics when they should have been and in 29% antibiotics were prescribed when they should not have been. Re-attendance rates within 14 days following clinical diagnosis of mild pneumonia were 9% (126/1401) when managed with antibiotics compared to 8% (56/701) when managed without (adjusted Hazard Ratio (aHR) = 1.00 (0.57-1.76), p = 0.98). Rates for mild diarrhoea were 8% (73/874) and 9% (79/866) respectively (aHR = 0.8 (0.42-1.57), p = 0.53). CONCLUSION: Non-adherence to IMCI recommendations for prescription of antibiotics is common in routine settings in Papua New Guinea. Although recommended, the use of antibiotics in young children with mild pneumonia as defined by IMCI criteria did not impact on their outcome. Better tools and new strategies for the identification of bacterial infections that require antibiotics are urgently needed.

Contribution of dengue fever to the burden of acute febrile illnesses in Papua New Guinea: an age-specific prospective study.

Malaria is a major contributor to the burden of febrile illnesses in Papua New Guinea (PNG). Dengue fever (DF) is likely to contribute; however, its epidemiology in PNG is poorly understood. We performed a prospective age-stratified study in outpatient clinics investigating the prevalence of DF; 578 patients were enrolled, and 317 patients with a negative rapid diagnostic test (RDT) for malaria were tested for dengue. Malaria was confirmed in 52% (301/578, 95% confidence interval [CI] = 48-56%), DF was diagnosed in 8% (46/578, 95% CI = 6-10%), and 40% (95% CI = 36-44%) had neither diagnosis. Among the 317 malaria RDT-negative patients, 14% (45/317, 95% CI = 10-18%) had DF. The seroprevalence of dengue immunoglobulin G (IgG) was 83% (204/247, 95% CI = 78-87%), and no dengue hemorrhagic fever was seen. This study provides good evidence for the first time that DF is common in PNG and is responsible for 8% of fever episodes. The common occurrence of DF in a population with presumed previous exposure to dengue is an important observation.