Global burden of acute lower respiratory infections due to respiratory syncytial virus in young children: a systematic review and meta-analysis.

BACKGROUND: The global burden of disease attributable to respiratory syncytial virus (RSV) remains unknown. We aimed to estimate the global incidence of and mortality from episodes of acute lower respiratory infection (ALRI) due to RSV in children younger than 5 years in 2005. METHODS: We estimated the incidence of RSV-associated ALRI in children younger than 5 years, stratified by age, using data from a systematic review of studies published between January, 1995, and June, 2009, and ten unpublished population-based studies. We estimated possible boundaries for RSV-associated ALRI mortality by combining case fatality ratios with incidence estimates from hospital-based reports from published and unpublished studies and identifying studies with population-based data for RSV seasonality and monthly ALRI mortality. FINDINGS: In 2005, an estimated 33.8 (95% CI 19.3-46.2) million new episodes of RSV-associated ALRI occurred worldwide in children younger than 5 years (22% of ALRI episodes), with at least 3.4 (2.8-4.3) million episodes representing severe RSV-associated ALRI necessitating hospital admission. We estimated that 66 000-199 000 children younger than 5 years died from RSV-associated ALRI in 2005, with 99% of these deaths occurring in developing countries. Incidence and mortality can vary substantially from year to year in any one setting. INTERPRETATION: Globally, RSV is the most common cause of childhood ALRI and a major cause of admission to hospital as a result of severe ALRI. Mortality data suggest that RSV is an important cause of death in childhood from ALRI, after pneumococcal pneumonia and Haemophilus influenzae type b. The development of novel prevention and treatment strategies should be accelerated as a priority. FUNDING: WHO; Bill & Melinda Gates Foundation.

A real-time RT-PCR for detection of clade 1 and 2 H5N1 influenza A virus using locked nucleic acid (LNA) TaqMan probes.

BACKGROUND: The emergence and co-circulation of two different clades (clade 1 and 2) of H5N1 influenza viruses in Vietnam necessitates the availability of a diagnostic assay that can detect both variants. RESULTS: We developed a single real-time RT-PCR assay for detection of both clades of H5N1 viruses, directly from clinical specimens, using locked nucleic acid TaqMan probes. Primers and probe used in this assay were designed based on a highly conserved region in the HA gene of H5N1 viruses. The analytical sensitivity of the assay was < 0.5 PFU and 10-100 ssDNA plasmid copies. A total of 106 clinical samples (58 from patients infected with clade 1, 2.1 or 2.3 H5N1 viruses and 48 from uninfected or seasonal influenza A virus-infected individuals) were tested by the assay. The assay showed 97% concordance with initial diagnostics for H5 influenza virus infection with a specificity of 100%. CONCLUSIONS: This assay is a useful tool for diagnosis of H5N1 virus infections in regions where different genetic clades are co-circulating.

Influenza virus infection among pediatric patients reporting diarrhea and influenza-like illness.

BACKGROUND: Influenza is a major cause of morbidity and hospitalization among children. While less often reported in adults, gastrointestinal symptoms have been associated with influenza in children, including abdominal pain, nausea, vomiting, and diarrhea. METHODS: From September 2005 and April 2008, pediatric patients in Indonesia presenting with concurrent diarrhea and influenza-like illness were enrolled in a study to determine the frequency of influenza virus infection in young patients presenting with symptoms less commonly associated with an upper respiratory tract infection (URTI). Stool specimens and upper respiratory swabs were assayed for the presence of influenza virus. RESULTS: Seasonal influenza A or influenza B viral RNA was detected in 85 (11.6%) upper respiratory specimens and 21 (2.9%) of stool specimens. Viable influenza B virus was isolated from the stool specimen of one case. During the time of this study, human infections with highly pathogenic avian influenza A (H5N1) virus were common in the survey area. However, among 733 enrolled subjects, none had evidence of H5N1 virus infection. CONCLUSIONS: The detection of influenza viral RNA and viable influenza virus from stool suggests that influenza virus may be localized in the gastrointestinal tract of children, may be associated with pediatric diarrhea and may serve as a potential mode of transmission during seasonal and epidemic influenza outbreaks.

Three Indonesian clusters of H5N1 virus infection in 2005.

BACKGROUND: Since 2003, the widespread ongoing epizootic of avian influenza A (H5N1) among poultry and birds has resulted in human H5N1 cases in 10 countries. The first case of H5N1 virus infection in Indonesia was identified in July 2005. METHODS: We investigated three clusters of Indonesian cases with at least two ill persons hospitalized with laboratory evidence of H5N1 virus infection from June through October 2005. Epidemiologic, clinical, and virologic data on these patients were collected and analyzed. RESULTS: Severe disease occurred among all three clusters, including deaths in two clusters. Mild illness in children was documented in two clusters. The median age of the eight patients was 8.5 years (range, 1 to 38). Four patients required mechanical ventilation, and four of the eight patients (50%) died. In each cluster, patients with H5N1 virus infection were members of the same family, and most lived in the same home. In two clusters, the source of H5N1 virus infection in the index patient was not determined. Virus isolates were available for one patient in each of two clusters, and molecular sequence analyses determined that the isolates were clade 2 H5N1 viruses of avian origin. CONCLUSIONS: In 2005 in Indonesia, clusters of human infection with clade 2 H5N1 viruses included mild, severe, and fatal cases among family members.

Vaccine-preventable haemophilus influenza type B disease burden and cost-effectiveness of infant vaccination in Indonesia.

BACKGROUND: Most of Asia, including Indonesia, does not use Haemophilus influenzae type b (Hib) conjugate vaccines. We estimated total vaccine-preventable disease burden and the cost-effectiveness of Hib conjugate vaccine in Indonesia. METHODS: Hib pneumonia and meningitis incidences for children with access to health care were derived from a randomized vaccine probe study on Lombok Island, Indonesia during 1998-2002. Incidences were adjusted for limited access to care. Health system and patient out-of-pocket treatment cost data were collected concurrent with the probe study. For Hib vaccine in monovalent and combined (with DTP-HepB) presentations, we used 2007 UNICEF vaccine prices of US$3.30 and $3.75 per dose. RESULTS: For the 2007 Indonesian birth cohort, Hib vaccine would prevent meningitis in 1 of every 179 children, pneumonia in 1 of every 18 children, and 4.9% of mortality among those younger than 5 years. The total incremental societal costs of introducing Hib vaccine in monovalent and pentavalent presentations were, respectively, US$11.74 and $8.93 per child vaccinated. Annual discounted treatment costs averted amounted to 20% of pentavalent vaccine costs. For the pentavalent vaccine, the incremental costs per discounted death and disability adjusted life-year averted amounted to US$3102 and $74, respectively, versus $4438 and $102 for monovalent vaccine. CONCLUSIONS: Routine infant Hib vaccination would prevent a large burden of pediatric illness and death in Indonesia. Even without external funding support, Hib vaccine will be a highly cost-effective intervention in either a monovalent or pentavalent presentation based on commonly used benchmarks.

Towards mutual trust, transparency and equity in virus sharing mechanism: the avian influenza case of Indonesia.

INTRODUCTION: As the country hardest hit by avian influenza, both in poultry and in human, Indonesia's decision to withhold samples of avian influenza virus A (H5N1) has fired up a global controversy. The objective of this paper is to describe the position taken by Indonesia in the events leading to the decision and in those conducted to resolve the situation. METHODS: The sources for this paper are the Indonesian human influenza A(H5N1) case reports and study results, summaries, minutes and reports of national and international meetings of virus sharing, and other related Indonesian and WHO documents. RESULTS: The International Health Regulations 2005 have been applied in different ways based on different interpretations. While one party insists on the importance of free, non-conditional, virus sharing for risk assessment and risk response, Indonesia--as supported by most of the developing countries--stresses on the more basic principles such as sovereignty of a country over its biological materials, transparency of the global system, and equity between developed and developing nations. CONCLUSIONS: This event demonstrates the unresolved imbalance between the affluent high-tech countries and the poor agriculture-based countries. Regional, global and in-country meetings must continue to be conducted to find solutions acceptable to all.

Group A rotavirus-associated diarrhea in children seeking treatment in Indonesia.

BACKGROUND: Globally, group A rotavirus causes significant morbidity and mortality among children. Limited data exist on the epidemiology of rotavirus disease among Indonesian children. OBJECTIVES: We describe the epidemiology of rotavirus-associated diarrhea among Indonesian children <6 years of age, including clinical symptoms and genotypes. STUDY DESIGN: We conducted a hospital-based, case series study at four referral hospitals between February 2004 and February 2005 among children with diarrhea. Rotavirus positivity was defined by a positive result from either EIA or RT-PCR. A semi-nested RT-PCR was used to determine specific rotavirus genotypes. RESULTS: 1660 stools were tested for pathogens. The overall rotavirus prevalence was 45.5%. Children with rotavirus-associated diarrhea were significantly younger (p<0.0001) and more likely to be hospitalized (81.3% versus 72.2%; p<0.0001). Symptoms associated with rotavirus included, vomiting, fever, nausea, fatigue and dehydration, while bloody stool was significantly less common with rotavirus-associated diarrhea. CONCLUSION: Rotavirus was an important contributor of morbidity to our study sample. Rotavirus genotyping demonstrated a temporal shift from G1-G4 to G9, but this was highly associated with the P[8] gene, suggesting that a multivalent rotavirus vaccine, incorporating G9 P[8] antigen, may reduce the burden of diarrheal illnesses among Indonesian children.

Tracking the re-emergence of epidemic chikungunya virus in Indonesia.

Twenty-four distinct outbreaks of probable chikungunya (CHIK) etiology were identified throughout Indonesia from September 2001 to March 2003, after a near 20-year hiatus of epidemic CHIK activity in the country. Thirteen outbreak reports were based on clinical observations alone, and 11 confirmed by serological/virological methods. Detailed epidemiological profiles of two investigated outbreaks in Bogor and Bekasi are presented. Human sera were screened using an ELISA for IgM and IgG anti-CHIK antibodies. Additionally, reverse transcriptase PCR and virus isolation were attempted for virus identification. The mean age of cases was 37 +/- 18 years in Bogor and 33 +/- 20 years in Bekasi. There was no outstanding case-clustering, although outbreak-affected households were observed to be geographically grouped within villages. The attack rates in Bogor and Bekasi were 2.8/1000 and 6.7/1000 inhabitants respectively. Both outbreaks started in the rainy season following increased Aedes aegypti and A. albopictus densities.

Surveillance of influenza in Indonesia, 2003­2007.

BACKGROUND: Longitudinal data are limited about the circulating strains of influenza viruses and their public health impact in Indonesia. We conducted influenza surveillance among outpatients and hospitalized patients with influenza-like illness (ILI) across the Indonesian archipelago from 2003 through 2007. METHODOLOGY: Demographic, clinical data, and respiratory specimens were collected for 4236 ILI patients tested for influenza virus infection by RT-PCR and viral culture. PRINCIPAL FINDINGS: Influenza A and B viruses co-circulated year-round with seasonal peaks in influenza A virus activity during the rainy season (December­January). During 2003­2007, influenza viruses were identified in 20·1% (4236 / 21 030) of ILI patients, including 20·1% (4015 / 20 012) of outpatients, and 21·7% (221 / 1018) of inpatients. One H5N1 case was identified retrospectively in an outpatient with ILI. Antigenic drift in circulating influenza A and B virus strains was detected during the surveillance period in Indonesia. In a few instances, antigenically drifted viruses similar to the World Health Organization (WHO) vaccine strains were detected earlier than the date of their designation by WHO. CONCLUSIONS: Influenza A and B virus infections are an important cause of influenza-like illness among outpatients and hospitalized patients in Indonesia. While year-round circulation of influenza viruses occurs, prevention and control strategies should be focused upon the seasonal peak during rainy season months. Ongoing virologic surveillance and influenza disease burden studies in Indonesia are important priorities to better understand the public health impact of influenza in South-East Asia and the implications of influenza viral evolution and global spread.

Sexually transmissible infections among female sex workers in Manado, Indonesia, using a multiplex polymerase chain reaction-based reverse line blot assay.

BACKGROUND: Sexually transmissible infections (STIs) remain highly prevalent, and HIV is increasing, among female sex workers (FSWs) in Indonesia. Our aim was to determine the prevalence of, and risk factors for, STIs among FSWs in Manado, Indonesia. METHODS: We recruited FSWs mainly at their workplace: they completed a questionnaire and provided a urine sample and self-collected vaginal swab. Samples were tested using multiplex polymerase chain reaction, followed by reverse line blot hybridisation. RESULTS: We recruited 221 FSWs, (median age: 25 years). During the previous 3 months, 30% reported never using condoms; only 2.7% always used condoms. Of 217 women with urine samples, 49% had a 'curable STI': 10.6% with gonorrhoea, 26.7% with chlamydia, 12.4% with Mycoplasma genitalium and 22.6% with trichomoniasis. Independent risk factors for gonorrhoea were: domiciled outside North Sulawesi (P = 0.001) and age 16-25 years (P = 0.02); for chlamydia: no prior history of STI symptoms (P = 0.003) and age 16-25 years (P = 0.02); for Mycoplasma genitalium: number of clients on last day of sex work (P = 0.004); for trichomoniasis: number of clients per week (P = 0.04). When these four infections were grouped as any 'curable STI', independent associations were: number of clients on the last day of sex work (P = 0.001), age 16-25 years (P = 0.02) and sex working for fewer than 2 years (P = 0.03). CONCLUSIONS: This is the first report of M. genitalium infection in Indonesia. The high prevalence of STIs and low condom use among these FSWs suggest their vulnerability to the HIV epidemic in Indonesia. They need enhanced interventions, including outreach screening, and periodic presumptive treatment.

Outcome and extent of disability following Japanese encephalitis in Indonesian children.

OBJECTIVES: The study aimed to assess outcome, including level of disability, following Japanese encephalitis (JE) in children in Indonesia. METHODS: A cohort of children diagnosed with laboratory-confirmed JE from January 2005 to August 2006 was followed-up, with disability measured at least 4 months after discharge from hospital. An assessment tool that can be used to rapidly determine practical level of disability and the likelihood that a child will be able to live independently after illness, the Liverpool Outcome Score, was used. RESULTS: Of 72 children with JE, determination of outcome was possible for 65 (90%). Sixteen died in hospital or before follow-up assessment (25%). Sixteen children (25%) had severe sequelae, indicating their function was impaired enough to likely make them dependent. Five (7%) had moderate sequelae and 12 (18%) had minor sequelae. The remaining 16 children (25%) were considered to have recovered fully. CONCLUSIONS: Half of the children with JE either died or were left with serious disabilities likely to impair their ability to lead independent lives, demonstrating the severe impact of JE. Immunization can effectively prevent JE, and an immunization program could avert some of the economic and social burden of JE disease in Indonesia.

EWORS: using a syndromic-based surveillance tool for disease outbreak detection in Indonesia.

BACKGROUND: Electronic syndromic surveillance for early outbreak detection may be a simple, effective tool to rapidly bring reliable and actionable outbreak data to the attention of public health authorities in the developing world. METHODS: Twenty-nine signs and symptoms from patients with conditions compatible with infectious diseases are collected from selected Provincial hospitals and analyzed daily. Data is e-mailed on a daily basis to a central data management and analysis center. Automated data analysis may be viewed at the hospital or the Early Warning Outbreak Response System (EWORS) hub at the central level (National Institute of Health Research and Development/NIHRD). CONCLUSION: The Indonesian Ministry of Health (MoH) has adopted EWORS since 2006 and will use it as a complementary surveillance tool in wider catchment areas throughout the country. Socialization to more users is still being conducted under collaboration of three Directorate Generals (DGs) of the MoH; DG of NIHRD, DG of Medical Services and DG of Communicable Disease Control and Prevention. Currently, EWORS is being adapted to facilitate detecting a potential outbreak of pandemic influenza in the region, and automated procedures for outbreak detection have been added.

Statistical analyses in disease surveillance systems.

The performance of disease surveillance systems is evaluated and monitored using a diverse set of statistical analyses throughout each stage of surveillance implementation. An overview of their main elements is presented, with a specific emphasis on syndromic surveillance directed to outbreak detection in resource-limited settings. Statistical analyses are proposed for three implementation stages: planning, early implementation, and consolidation. Data sources and collection procedures are described for each analysis.During the planning and pilot stages, we propose to estimate the average data collection, data entry and data distribution time. This information can be collected by surveillance systems themselves or through specially designed surveys. During the initial implementation stage, epidemiologists should study the completeness and timeliness of the reporting, and describe thoroughly the population surveyed and the epidemiology of the health events recorded. Additional data collection processes or external data streams are often necessary to assess reporting completeness and other indicators. Once data collection processes are operating in a timely and stable manner, analyses of surveillance data should expand to establish baseline rates and detect aberrations. External investigations can be used to evaluate whether abnormally increased case frequency corresponds to a true outbreak, and thereby establish the sensitivity and specificity of aberration detection algorithms.Statistical methods for disease surveillance have focused mainly on the performance of outbreak detection algorithms without sufficient attention to the data quality and representativeness, two factors that are especially important in developing countries. It is important to assess data quality at each state of implementation using a diverse mix of data sources and analytical methods. Careful, close monitoring of selected indicators is needed to evaluate whether systems are reaching their proposed goals at each stage.

Confirmation of Japanese encephalitis as an endemic human disease through sentinel surveillance in Indonesia.

Japanese encephalitis (JE) results in significant mortality and disability in children in Asia. In Indonesia, despite recognition of JE virus transmission, reports of human disease have been few and from limited geographic areas. Hospital-based surveillance for acute encephalitis syndrome (AES) and JE in children 15 years of age and under was undertaken in 15 hospitals in six provinces from 2005 to 2006. High- and low-risk provinces in geographically dispersed areas were included. Health center-based surveillance also was undertaken in one province. Eighty-two JE cases were confirmed among 1,496 AES cases detected. JE cases were confirmed in all provinces, but the proportion varied between 18% and 2% among provinces of different risk levels. Children younger than 10 years of age represented 95% of JE cases, and 47% of all cases either died or were disabled. The study shows JE is an endemic human disease across Indonesia. Immunization strategies are being considered.

Epidemiology of cases of H5N1 virus infection in Indonesia, July 2005-June 2006.

BACKGROUND: Highly pathogenic avian influenza A (H5N1) virus was detected in domestic poultry in Indonesia beginning in 2003 and is now widespread among backyard poultry flocks in many provinces. The first human case of H5N1 virus infection in Indonesia was identified in July 2005. METHODS: Respiratory specimens were collected from persons with suspected H5N1 virus infection and were tested by reverse-transcriptase polymerase chain reaction and viral culture. Serum samples were tested by a modified hemagglutinin inhibition antibody and/or microneutralization assay. Epidemiological, laboratory, and clinical data were collected through interviews and medical records review. Close contacts of persons with confirmed H5N1 virus infection were investigated. RESULTS: From July 2005 through June 2006, 54 cases of H5N1 virus infection were identified, with a case-fatality proportion of 76%. The median age was 18.5 years, and 57.4% of patients were male. More than one-third of cases occurred in 7 clusters of blood-related family members. Seventy-six percent of cases were associated with poultry contact, and the source of H5N1 virus infection was not identified in 24% of cases. CONCLUSIONS: Sporadic and family clusters of cases of H5N1 virus infection, with a high case-fatality proportion, occurred throughout Indonesia during 2005-2006. Extensive efforts are needed to reduce human contact with sick and dead poultry to prevent additional cases of H5N1 virus infection.

Evaluation of diagnostic assays for hepatitis E virus in outbreak settings.

Hepatitis E virus (HEV) is a major cause of hepatitis. We evaluated five HEV antibody diagnostic assays by using outbreak specimens. The Abbott immunoglobulin G (IgG), Genelabs IgG, and Walter Reed Army Institute of Research (WRAIR) IgM assays were about 90% sensitive; the Abbott IgG and WRAIR total Ig and IgM assays were more than 90% specific.

Lack of transmission of H5N1 avian-human reassortant influenza viruses in a ferret model.

Avian influenza A H5N1 viruses continue to spread globally among birds, resulting in occasional transmission of virus from infected poultry to humans. Probable human-to-human transmission has been documented rarely, but H5N1 viruses have not yet acquired the ability to transmit efficiently among humans, an essential property of a pandemic virus. The pandemics of 1957 and 1968 were caused by avian-human reassortant influenza viruses that had acquired human virus-like receptor binding properties. However, the relative contribution of human internal protein genes or other molecular changes to the efficient transmission of influenza viruses among humans remains poorly understood. Here, we report on a comparative ferret model that parallels the efficient transmission of H3N2 human viruses and the poor transmission of H5N1 avian viruses in humans. In this model, an H3N2 reassortant virus with avian virus internal protein genes exhibited efficient replication but inefficient transmission, whereas H5N1 reassortant viruses with four or six human virus internal protein genes exhibited reduced replication and no transmission. These findings indicate that the human virus H3N2 surface protein genes alone did not confer efficient transmissibility and that acquisition of human virus internal protein genes alone was insufficient for this 1997 H5N1 virus to develop pandemic capabilities, even after serial passages in a mammalian host. These results highlight the complexity of the genetic basis of influenza virus transmissibility and suggest that H5N1 viruses may require further adaptation to acquire this essential pandemic trait.