Features and Prognosis of Severe Malaria Caused by Plasmodium falciparum, Plasmodium vivax and Mixed Plasmodium Species in Papua New Guinean Children

BACKGROUND: Mortality from severe pediatric falciparum malaria appears low in Oceania but Plasmodium vivax is increasingly recognized as a cause of complications and death. The features and prognosis of mixed Plasmodium species infections are poorly characterized. Detailed prospective studies that include accurate malaria diagnosis and detection of co-morbidities are lacking. METHODS AND FINDINGS: We followed 340 Papua New Guinean (PNG) children with PCR-confirmed severe malaria (77.1% P. falciparum, 7.9% P. vivax, 14.7% P. falciparum/vivax) hospitalized over a 3-year period. Bacterial cultures were performed to identify co-incident sepsis. Clinical management was under national guidelines. Of 262 children with severe falciparum malaria, 30.9%, 24.8% and 23.2% had impaired consciousness, severe anemia, and metabolic acidosis/hyperlactatemia, respectively. Two (0.8%) presented with hypoglycemia, seven (2.7%) were discharged with neurologic impairment, and one child died (0.4%). The 27 severe vivax malaria cases presented with similar phenotypic features to the falciparum malaria cases but respiratory distress was five times more common (P=0.001); one child died (3.7%). The 50 children with P. falciparum/vivax infections shared phenotypic features of mono-species infections, but were more likely to present in deep coma and had the highest mortality (8.0%; P=0.003 vs falciparum malaria). Overall, bacterial cultures were positive in only two non-fatal cases. 83.6% of the children had alpha-thalassemia trait and seven with coma/impaired consciousness had South Asian ovalocytosis (SAO). CONCLUSIONS: The low mortality from severe falciparum malaria in PNG children may reflect protective genetic factors other than alpha-thalassemia trait/SAO, good nutrition, and/or infrequent co-incident sepsis. Severe vivax malaria had similar features but severe P. falciparum/vivax infections were associated with the most severe phenotype and worst prognosis

Subacute Sclerosing Panencephalitis in Papua New Guinean Children: The Cost of Continuing Inadequate Measles Vaccine Coverage

Subacute sclerosing panencephalitis (SSPE) is a disabling and usually fatal brain disorder that typically occurs 3–10 years after acute measles infection. Papua New Guinea (PNG) has particularly high rates of SSPE. We report 22 cases of PNG children presenting to the provincial referral hospital in Madang Province who probably contracted acute measles when <12 months of age during a national epidemic in 2002 and who developed SSPE 5–7 years later. Based on these cases, the estimated annual SSPE incidence in Madang province in 2007–2009 was 54/million population aged <20 years. Four sub-districts had an annual incidence >100/million population aged <20 years, the highest rates ever reported. Young PNG children do not respond well to measles vaccine. Because of this, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune older people surrounding the youngest and most vulnerable members of PNG communities

Meningeal Inflammation Increases Artemether Concentrations in Cerebrospinal Fluid in Papua New Guinean Children Treated with Intramuscular Artemether ▿

Although the artemisinin-associated neurotoxicity identified in vitro and in animal studies has not been confirmed clinically, only one adult study has measured cerebrospinal fluid (CSF) concentrations after administration of conventional doses. Potential artemisinin neurotoxicity could be serious in children, especially those with meningitis and, consequently, a compromised blood-brain barrier. We measured CSF/plasma artemether and dihydroartemisinin (DHA) concentrations in 32 Papua New Guinean children with a mean age of 39 months with suspected or proven severe falciparum malaria who underwent a single lumbar puncture after intramuscular artemether administration. CSF artemether concentrations were 0 to 43.5 μg/liter and CSF concentration/plasma concentration ratios were 0 to 38.1%. DHA was measurable in CSF in only two children. The seven children with meningeal inflammation (CSF white cell count > 20/mm3) had higher CSF artemether concentration/plasma artemether concentration ratios than those without (median, 6.7% [interquartile ratio, 2.5 to 27.8%]% versus 0.0% [interquartile ratio, 0.0 to 2.5%]; P = 0.002). Meningeal inflammation was associated with a 4.6-fold increase in the CSF artemether concentration/plasma artemether concentration ratio in a population pharmacokinetic model. These data suggest that pharmacovigilance should be heightened when intramuscular artemether is given to severely ill children with evidence of meningeal inflammation

Overlapping clinical phenotypes of severe malaria caused by <i>Plasmodium falciparum</i>.

<p>Overlapping clinical phenotypes of severe malaria caused by <i>Plasmodium falciparum</i>.</p

Baseline clinical and laboratory data for children with severe malaria categorized by <i>Plasmodium</i> species.

<p>Data are, unless otherwise stated, median and [inter-quartile range].</p>a<p><i>P</i><0.05 for post-test comparison between <i>P. falciparum</i> vs <i>P. falciparum/vivax</i>;</p>b<p><i>P</i><0.05 for post-test comparison between <i>P. falciparum</i> vs <i>P. vivax</i>;</p>c<p><i>P</i><0.05 for post-test comparison between <i>P. vivax</i> vs <i>P. falciparum/vivax</i>;</p><p>*Kruskal-Wallis or Chi-squared test;</p>#<p>Mann-Whitney test for <i>P. falciparum</i> vs <i>P. falciparum/vivax</i>; wt, wildtype; α^del/wt, heterozygous for either 3.7 or 4.2 kb deletions; α^del/α^del, homozygous or compound heterozygous for either 3.7 or 4.2 kb deletion.</p

Uncomplicated and severe malaria numbers, and incidence of severe malaria, by infecting <i>Plasmodium</i> species from a longitudinal surveillance study of 264 children followed over 17 months in neighbouring East Sepik Province.

<p>Data are from Lin <i>et al.</i><a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0029203#pone.0029203-Lin1" target="_blank">[32]</a>.</p><p>*Single or mixed infections with <i>P. malariae</i> or <i>P. ovale</i>;</p>¶<p>(95% confidence intervals);</p>†<p><i>P</i><0.05 vs <i>P. vivax</i>.</p

Consort diagram outlining categorization of children presenting to Modilon Hospital, Madang Province, during the study period.

<p>Severe malaria cases were identified by clinical and laboratory features at presentation including blood film microscopy, and subsequent nPCR for <i>Plasmodium</i> speciation.</p