Accuracy of cerebrospinal leucocyte count, protein and culture for the diagnosis of acute bacterial meningitis: a comparative study using Bayesian latent class analysis.

OBJECTIVE: To examine the utility of laboratory methods other than bacterial culture in diagnosing acute bacterial meningitis (ABM). METHODS: Bayesian latent class analysis was used to estimate diagnostic precision of cerebrospinal fluid (CSF) culture, leucocyte counts and protein concentrations for ABM in Melanesian children. RESULTS: With a cut-off of ≥20 leucocytes/mm(3) , the area under the receiver operating characteristic curve (AUC ROC) was >97.5% for leucocyte counts. A lower (93%) AUC ROC was observed for CSF protein concentrations ≥1 g/l. CSF culture had poor sensitivity and high specificity. CONCLUSION: Leucocyte counts provide sufficient diagnostic precision to aid clinical decision-making in ABM.

Viral pathogens in children hospitalized with features of central nervous system infection in a malaria-endemic region of Papua New Guinea.

BACKGROUND: Viral central nervous system (CNS) infections are common in countries where malaria is endemic but, due to limited laboratory facilities, few studies have systematically examined the prevalence and clinical consequences of the presence of viruses in cerebrospinal fluid (CSF) from children with suspected CNS infection. METHODS: We performed a prospective study of Papua New Guinean children hospitalized with signs and symptoms of CNS infection. CSF samples from 300 children without proven bacterial/fungal meningitis were analyzed for human herpes viruses (HHV), picornaviruses, influenza, adenoviruses, flaviviruses and bacteria. RESULTS: Fifty-five children (18%) had viral (42), bacterial (20) or both viral and bacterial (7) nucleic acids (NA) identified in their CSF. Human herpes viruses accounted for 91% of all viruses found. The identification of viral or bacterial NA was not associated with any characteristic clinical features. By contrast, malaria was associated with increased identification of viral and bacterial NA and with impaired consciousness, multiple convulsions and age. Malaria was also inversely associated with an adverse outcome. Amongst children with HHV infection, those with HHV-6 and -7 were younger, were more likely have impaired consciousness and had a higher proportion of adverse outcomes than children with CMV. Dengue and enteroviral infections were infrequent. Adenoviral and influenza infections were not identified. CONCLUSION: Infections with HHV-6, HHV-7, dengue and enterovirus have the potential to cause serious CNS disease in young PNG children. However most HHVs in this malaria-endemic setting should be considered to be the result of reactivation from a latent reservoir without clinical sequelae.

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/mm(3)) 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.

Accuracy of initial clinical diagnosis of acute bacterial meningitis in children from a malaria-endemic area of Papua New Guinea.

BACKGROUND: The diagnosis of acute bacterial meningitis (ABM) is challenging in resource-limited settings where cerebral malaria and viral encephalitis are also common. METHODS: To assess the accuracy of an initial clinical diagnosis of ABM in a malaria-endemic area of Papua New Guinea (PNG), a retrospective chart review of hospitalized children aged 2 months to 10 years was conducted. RESULTS: Of the 481 eligible children, 240 had an initial clinical diagnosis of ABM that was confirmed independently by trained research staff under standardized conditions, with laboratory support in only 84 (17.5%; 84/481). When compared with the final laboratory-confirmed diagnosis, an initial diagnosis of ABM had a sensitivity, specificity, positive predictive value and negative predictive value of 76% (95% CI 66-85%), 56% (95% CI 51-61%), 27% (95% CI 21-33) and 92% (95% CI 87-95%), respectively. There was discordance between initial and final diagnosis of ABM in 196 children; 176 initially considered to have ABM had an alternative diagnosis, while 20 without an initial diagnosis of ABM were confirmed to have ABM. CONCLUSION: These data show that initial misdiagnosis of ABM is common in a malaria-endemic area of PNG. A diagnostic algorithm using standardized assessment for meningeal irritation, coma and malaria parasitological testing needs further evaluation in this setting.

Predictors of acute bacterial meningitis in children from a malaria-endemic area of Papua New Guinea.

Predictors of acute bacterial meningitis (ABM) were assessed in 554 children in Papua New Guinea 0.2-10 years of age who were hospitalized with culture-proven meningitis, probable meningitis, or non-meningitic illness investigated by lumbar puncture. Forty-seven (8.5%) had proven meningitis and 36 (6.5%) had probable meningitis. Neck stiffness, Kernig's and Brudzinski's signs and, in children < 18 months of age, a bulging fontanel had positive likelihood ratios (LRs) ≥ 4.3 for proven/probable ABM. Multiple seizures and deep coma were less predictive (LR = 1.5-2.1). Single seizures and malaria parasitemia had low LRs (≤ 0.5). In logistic regression including clinical variables, Kernig's sign and deep coma were positively associated with ABM, and a single seizure was negatively associated (P ≤ 0.01). In models including microscopy, neck stiffness and deep coma were positively associated with ABM and parasitemia was negatively associated with ABM (P ≤ 0.04). In young children, a bulging fontanel added to the model (P < 0.001). Simple clinical features predict ABM in children in Papua New Guinea but malaria microscopy augments diagnostic precision.

Subacute sclerosing panencephalitis in papua new guinean children: the cost of continuing inadequate measles vaccine coverage.

INTRODUCTION: subacute sclerosing panencephalitis (SSPE) is a late, rare and usually fatal complication of measles infection. Although a very high incidence of SSPE in Papua New Guinea (PNG) was first recognized 20 years ago, estimated measles vaccine coverage has remained at ≤ 70% since and a large measles epidemic occurred in 2002. We report a series of 22 SSPE cases presenting between November 2007 and July 2009 in Madang Province, PNG, including localized clusters with the highest ever reported annual incidence. METHODOLOGY/PRINCIPAL FINDINGS: as part of a prospective observational study of severe childhood illness at Modilon Hospital, the provincial referral center, children presenting with evidence of meningo-encephalitis were assessed in detail including lumbar puncture in most cases. A diagnosis of SSPE was based on clinical features and presence of measles-specific IgG in cerebrospinal fluid and/or plasma. The estimated annual SSPE incidence in Madang province was 54/million population aged <20 years, but four sub-districts had an incidence >100/million/year. The distribution of year of birth of the 22 children with SSPE closely matched the reported annual measles incidence in PNG, including a peak in 2002. CONCLUSIONS/SIGNIFICANCE: SSPE follows measles infections in very young PNG children. Because PNG children have known low seroconversion rates to the first measles vaccine given at 6 months of age, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune people surrounding the youngest and most vulnerable members of PNG communities.

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.