Publications by authors named "Marilla G Lucero"

27 Publications

  • Page 1 of 1

Population-based otoscopic and audiometric assessment of a birth cohort recruited for a pneumococcal vaccine trial 15-18 years earlier: a protocol.

BMJ Open 2021 Feb 17;11(2):e042363. Epub 2021 Feb 17.

Department of Epidemiology, Colorado School of Public Health, Aurora, Colorado, USA.

Introduction: A cohort of 12 000 children in the Philippines who had enrolled in a 2000-2004 (current ages 16 to 20 years) Phase 3 11-valent pneumococcal conjugate vaccine for the prevention of radiographically confirmed pneumonia are now being asked to participate in a separate study (expected completion date September 2021) to assess the cohort's current long-term audiometric and otologic status. This new study would allow assessments of the utility of the pneumococcal vaccine in conferring its protective effects on the long-term sequelae of otitis media (OM), if any. Lack of trained local healthcare providers in otolaryngology/audiology and testing equipment in Bohol, Philippines, necessitates the development of a distinct methodology that would lead to meaningful data analysis.

Methods And Analysis: Reliable data collection and transfer are achieved by a US otolaryngologist/audiologist team training local nurses on all procedures in a didactic and hands-on process. An assortment of portable otolaryngologic and audiologic equipment suitable for field testing has been acquired, including an operating otoscope (Welch-Allyn), a video-otoscope (JedMed), a tympanometer with distortion product otoacoustic emission measurements (Path Sentiero) and a screening audiometer (HearScreen). Data will then be uploaded to a Research Electronic Data Capture database in the USA.Tympanometric and audiologic data will be codified through separate conventional algorithms. A team of paediatric otolaryngology advanced practice providers (APPs) have been trained and validated in interpreting video otoscopy. The protocol for classification of diagnostic outcome variables based on video otoscopy and tympanometry has been developed and is being used by APPs to evaluate all otoscopy data.

Ethics And Dissemination: The study was approved by the Research Institute of Tropical Medicine, Alabang, Manila, Philippines, and the institutional review board and the Colorado Multiple Institutional Review Board of the University of Colorado School of Medicine, Aurora, Colorado, USA.Research results will be made available to children and their caregivers with abnormal audiologic outcomes, the funders and other researchers.

Trial Registration Number: ISRCTN 62323832; Post-results.
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February 2021

Global burden of acute lower respiratory infection associated with human metapneumovirus in children under 5 years in 2018: a systematic review and modelling study.

Lancet Glob Health 2021 01 26;9(1):e33-e43. Epub 2020 Nov 26.

Centre for Global Health, Usher Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Human metapneumovirus is a common virus associated with acute lower respiratory infections (ALRIs) in children. No global burden estimates are available for ALRIs associated with human metapneumovirus in children, and no licensed vaccines or drugs exist for human metapneumovirus infections. We aimed to estimate the age-stratified human metapneumovirus-associated ALRI global incidence, hospital admissions, and mortality burden in children younger than 5 years.

Methods: We estimated the global burden of human metapneumovirus-associated ALRIs in children younger than 5 years from a systematic review of 119 studies published between Jan 1, 2001, and Dec 31, 2019, and a further 40 high quality unpublished studies. We assessed risk of bias using a modified Newcastle-Ottawa Scale. We estimated incidence, hospital admission rates, and in-hospital case-fatality ratios (hCFRs) of human metapneumovirus-associated ALRI using a generalised linear mixed model. We applied incidence and hospital admission rates of human metapneumovirus-associated ALRI to population estimates to yield the morbidity burden estimates by age bands and World Bank income levels. We also estimated human metapneumovirus-associated ALRI in-hospital deaths and overall human metapneumovirus-associated ALRI deaths (both in-hospital and non-hospital deaths). Additionally, we estimated human metapneumovirus-attributable ALRI cases, hospital admissions, and deaths by combining human metapneumovirus-associated burden estimates and attributable fractions of human metapneumovirus in laboratory-confirmed human metapneumovirus cases and deaths.

Findings: In 2018, among children younger than 5 years globally, there were an estimated 14·2 million human metapneumovirus-associated ALRI cases (uncertainty range [UR] 10·2 million to 20·1 million), 643 000 human metapneumovirus-associated hospital admissions (UR 425 000 to 977 000), 7700 human metapneumovirus-associated in-hospital deaths (2600 to 48 800), and 16 100 overall (hospital and community) human metapneumovirus-associated ALRI deaths (5700 to 88 000). An estimated 11·1 million ALRI cases (UR 8·0 million to 15·7 million), 502 000 ALRI hospital admissions (UR 332 000 to 762 000), and 11 300 ALRI deaths (4000 to 61 600) could be causally attributed to human metapneumovirus in 2018. Around 58% of the hospital admissions were in infants under 12 months, and 64% of in-hospital deaths occurred in infants younger than 6 months, of which 79% occurred in low-income and lower-middle-income countries.

Interpretation: Infants younger than 1 year have disproportionately high risks of severe human metapneumovirus infections across all World Bank income regions and all child mortality settings, similar to respiratory syncytial virus and influenza virus. Infants younger than 6 months in low-income and lower-middle-income countries are at greater risk of death from human metapneumovirus-associated ALRI than older children and those in upper-middle-income and high-income countries. Our mortality estimates demonstrate the importance of intervention strategies for infants across all settings, and warrant continued efforts to improve the outcome of human metapneumovirus-associated ALRI among young infants in low-income and lower-middle-income countries.

Funding: Bill & Melinda Gates Foundation.
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January 2021

Cost of Respiratory Syncytial Virus-Associated Acute Lower Respiratory Infection Management in Young Children at the Regional and Global Level: A Systematic Review and Meta-Analysis.

J Infect Dis 2020 10;222(Suppl 7):S680-S687

Centre for Global Health, Usher Institute, University of Edinburgh, Edinburgh, United Kingdom.

Background: Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory infection (ALRI) in young children aged <5 years.

Methods: We aimed to identify the global inpatient and outpatient cost of management of RSV-ALRI in young children to assist health policy makers in making decisions related to resource allocation for interventions to reduce severe morbidity and mortality from RSV in this age group. We searched 3 electronic databases including Global Health, Medline, and EMBASE for studies reporting cost data on RSV management in children under 60 months from 2000 to 2017. Unpublished data on the management cost of RSV episodes were collected through collaboration with an international working group (RSV GEN) and claim databases.

Results: We identified 41 studies reporting data from year 1987 to 2017, mainly from Europe, North America, and Australia, covering the management of a total of 365 828 RSV disease episodes. The average cost per episode was €3452 (95% confidence interval [CI], 3265-3639) and €299 (95% CI, 295-303) for inpatient and outpatient management without follow-up, and it increased to €8591(95% CI, 8489-8692) and €2191 (95% CI, 2190-2192), respectively, with follow-up to 2 years after the initial event.

Conclusions: Known risk factors (early and late preterm birth, congenital heart disease, chronic lung disease, intensive care unit admission, and ventilator use) were associated with €4160 (95% CI, 3237-5082) increased cost of hospitalization. The global cost of inpatient and outpatient RSV ALRI management in young children in 2017 was estimated to be approximately €4.82 billion (95% CI, 3.47-7.93), 65% of these in developing countries and 55% of global costs accounted for by hospitalization. We have demonstrated that RSV imposed a substantial economic burden on health systems, governments, and the society.
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October 2020

Global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study.

Lancet Glob Health 2020 04 20;8(4):e497-e510. Epub 2020 Feb 20.

Centre for Global Health, Usher Institute, Edinburgh Medical School, University of Edinburgh, Edinburgh, UK. Electronic address:

Background: Seasonal influenza virus is a common cause of acute lower respiratory infection (ALRI) in young children. In 2008, we estimated that 20 million influenza-virus-associated ALRI and 1 million influenza-virus-associated severe ALRI occurred in children under 5 years globally. Despite this substantial burden, only a few low-income and middle-income countries have adopted routine influenza vaccination policies for children and, where present, these have achieved only low or unknown levels of vaccine uptake. Moreover, the influenza burden might have changed due to the emergence and circulation of influenza A/H1N1pdm09. We aimed to incorporate new data to update estimates of the global number of cases, hospital admissions, and mortality from influenza-virus-associated respiratory infections in children under 5 years in 2018.

Methods: We estimated the regional and global burden of influenza-associated respiratory infections in children under 5 years from a systematic review of 100 studies published between Jan 1, 1995, and Dec 31, 2018, and a further 57 high-quality unpublished studies. We adapted the Newcastle-Ottawa Scale to assess the risk of bias. We estimated incidence and hospitalisation rates of influenza-virus-associated respiratory infections by severity, case ascertainment, region, and age. We estimated in-hospital deaths from influenza virus ALRI by combining hospital admissions and in-hospital case-fatality ratios of influenza virus ALRI. We estimated the upper bound of influenza virus-associated ALRI deaths based on the number of in-hospital deaths, US paediatric influenza-associated death data, and population-based childhood all-cause pneumonia mortality data in six sites in low-income and lower-middle-income countries.

Findings: In 2018, among children under 5 years globally, there were an estimated 109·5 million influenza virus episodes (uncertainty range [UR] 63·1-190·6), 10·1 million influenza-virus-associated ALRI cases (6·8-15·1); 870 000 influenza-virus-associated ALRI hospital admissions (543 000-1 415 000), 15 300 in-hospital deaths (5800-43 800), and up to 34 800 (13 200-97 200) overall influenza-virus-associated ALRI deaths. Influenza virus accounted for 7% of ALRI cases, 5% of ALRI hospital admissions, and 4% of ALRI deaths in children under 5 years. About 23% of the hospital admissions and 36% of the in-hospital deaths were in infants under 6 months. About 82% of the in-hospital deaths occurred in low-income and lower-middle-income countries.

Interpretation: A large proportion of the influenza-associated burden occurs among young infants and in low-income and lower middle-income countries. Our findings provide new and important evidence for maternal and paediatric influenza immunisation, and should inform future immunisation policy particularly in low-income and middle-income countries.

Funding: WHO; Bill & Melinda Gates Foundation.
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April 2020

A rapid triage test for active pulmonary tuberculosis in adult patients with persistent cough.

Sci Transl Med 2019 10;11(515)

Broad Institute of Harvard and MIT, 415 Main Street, Cambridge, MA 02142, USA.

Improved tuberculosis (TB) prevention and control depend critically on the development of a simple, readily accessible rapid triage test to stratify TB risk. We hypothesized that a blood protein-based host response signature for active TB (ATB) could distinguish it from other TB-like disease (OTD) in adult patients with persistent cough, thereby providing a foundation for a point-of-care (POC) triage test for ATB. Three adult cohorts consisting of ATB suspects were recruited. A bead-based immunoassay and machine learning algorithms identified a panel of four host blood proteins, interleukin-6 (IL-6), IL-8, IL-18, and vascular endothelial growth factor (VEGF), that distinguished ATB from OTD. An ultrasensitive POC-amenable single-molecule array (Simoa) panel was configured, and the ATB diagnostic algorithm underwent blind validation in an independent, multinational cohort in which ATB was distinguished from OTD with receiver operator characteristic-area under the curve (ROC-AUC) of 0.80 [95% confidence interval (CI), 0.75 to 0.85], 80% sensitivity (95% CI, 73 to 85%), and 65% specificity (95% CI, 57 to 71%). When host antibodies against TB antigen Ag85B were added to the panel, performance improved to 86% sensitivity and 69% specificity. A blood-based host response panel consisting of four proteins and antibodies to one TB antigen can help to differentiate ATB from other causes of persistent cough in patients with and without HIV infection from Africa, Asia, and South America. Performance characteristics approach World Health Organization (WHO) target product profile accuracy requirements and may provide the foundation for an urgently needed blood-based POC TB triage test.
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October 2019

Underdetection of laboratory-confirmed influenza-associated hospital admissions among infants: a multicentre, prospective study.

Lancet Child Adolesc Health 2019 11 3;3(11):781-794. Epub 2019 Sep 3.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Background: Since influenza often presents non-specifically in infancy, we aimed to assess the extent to which existing respiratory surveillance platforms might underestimate the frequency of severe influenza disease among infants.

Methods: The Influenza and Respiratory Syncytial Virus in Infants (IRIS) study was a prospective observational study done at four hospitals in Albania, Jordan, Nicaragua, and the Philippines. We included acutely ill infants aged younger than 1 year admitted to hospital within 10 days or less of illness onset during two influenza seasons (2015-16 and 2016-17) in Albania, Jordan, and Nicaragua, and over a continuous 34 week period (2015-16) in the Philippines. We assessed the frequency of influenza virus infections by real-time RT-PCR (rRT-PCR) and serology. The main study outcome was seroconversion, defined as convalescent antibody titres more than or equal to four-fold higher than acute sera antibody titres, and convalescent antibody titres of 40 or higher. Seroconverison was confirmed by haemagglutination inhibition assay for influenza A viruses, and by hemagglutination inhibition assay and microneutralisation for influenza B viruses.

Findings: Between June 27, 2015, and April 21, 2017, 3634 acutely ill infants were enrolled, of whom 1943 were enrolled during influenza seasons and had complete acute-convalescent pairs and thus were included in the final analytical sample. Of the 1943 infants, 94 (5%) were influenza-positive by both rRT-PCR and serology, 58 (3%) were positive by rRT-PCR-only, and 102 (5%) were positive by serology only. Seroconversion to at least one of the influenza A or B viruses was observed among 196 (77%) of 254 influenza-positive infants. Of the 254 infants with influenza virus, 84 (33%) only had non-respiratory clinical discharge diagnoses (eg, sepsis, febrile seizures, dehydration, or other non-respiratory viral illness). A focus on respiratory diagnoses and rRT-PCR-confirmed influenza underdetects influenza-associated hospital admissions among infants by a factor of 2·6 (95% CI 2·0-3·6). Findings were unchanged when syndromic severe acute respiratory infection criteria were applied instead of clinical diagnosis.

Interpretation: If the true incidence of laboratory-confirmed influenza-associated hospital admissions among infants is at least twice that of previous estimates, this substantially increases the global burden of severe influenza and expands our estimates of the preventive value of maternal and infant influenza vaccination programmes.

Funding: US Centers for Disease Control and Prevention.
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November 2019

Strain Level Colonization Patterns during the First Year of Life.

Front Microbiol 2017 6;8:1661. Epub 2017 Sep 6.

J. Craig Venter InstituteRockville, MD, United States.

Pneumococcal pneumonia has decreased significantly since the implementation of the pneumococcal conjugate vaccine (PCV), nevertheless, in many developing countries pneumonia mortality in infants remains high. We have undertaken a study of the nasopharyngeal (NP) microbiome during the first year of life in infants from The Philippines and South Africa. The study entailed the determination of the sp. carriage using a qPCR assay, whole metagenomic sequencing, and serotyping of , as well as 16S rRNA amplicon based community profiling. The carriage in both populations increased with infant age and + samples ranged from 24 to 85% of the samples at each sampling time point. We next developed informatic tools for determining community composition and pneumococcal serotype from metagenomic sequences derived from a subset of longitudinal -positive enrichment cultures from The Philippines ( = 26 infants, 50% vaccinated) and South African ( = 7 infants, 100% vaccinated). NP samples from infants were passaged in enrichment media, and metagenomic DNA was purified and sequenced. capsular serotyping of these 51 metagenomic assemblies assigned known serotypes in 28 samples, and the co-occurrence of serotypes in 5 samples. Eighteen samples were not typeable using known serotypes but did encode for capsule biosynthetic cluster genes similar to non-encapsulated reference sequences. In addition, we performed metagenomic assembly and 16S rRNA amplicon profiling to understand co-colonization dynamics of sp. and other NP genera, revealing the presence of multiple species as well as potential respiratory pathogens in healthy infants. A range of virulence and drug resistant elements were identified as circulating in the NP microbiomes of these infants. This study revealed the frequent co-occurrence of multiple strains along with sp. and other potential pathogens such as in the NP microbiome of these infants. In addition, the serotype analysis proved powerful in determining the serotypes in carriage, and may lead to developing better targeted vaccines to prevent invasive pneumococcal disease (IPD) in these countries. These findings suggest that NP colonization by during the first years of life is a dynamic process involving multiple serotypes and species.
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September 2017

Global respiratory syncytial virus-associated mortality in young children (RSV GOLD): a retrospective case series.

Lancet Glob Health 2017 10;5(10):e984-e991

Department of Paediatric Infectious Diseases and Immunology, Wilhelmina Children's Hospital, University Medical Centre Utrecht, Utrecht, Netherlands; ReSViNET Respiratory Syncytial Virus Network, Utrecht, Netherlands. Electronic address:

Background: Respiratory syncytial virus (RSV) infection is an important cause of pneumonia mortality in young children. However, clinical data for fatal RSV infection are scarce. We aimed to identify clinical and socioeconomic characteristics of children aged younger than 5 years with RSV-related mortality using individual patient data.

Methods: In this retrospective case series, we developed an online questionnaire to obtain individual patient data for clinical and socioeconomic characteristics of children aged younger than 5 years who died with community-acquired RSV infection between Jan 1, 1995, and Oct 31, 2015, through leading research groups for child pneumonia identified through a comprehensive literature search and existing research networks. For the literature search, we searched PubMed for articles published up to Feb 3, 2015, using the key terms "RSV", "respiratory syncytial virus", or "respiratory syncytial viral" combined with "mortality", "fatality", "death", "died", "deaths", or "CFR" for articles published in English. We invited researchers and clinicians identified to participate between Nov 1, 2014, and Oct 31, 2015. We calculated descriptive statistics for all variables.

Findings: We studied 358 children with RSV-related in-hospital death from 23 countries across the world, with data contributed from 31 research groups. 117 (33%) children were from low-income or lower middle-income countries, 77 (22%) were from upper middle-income countries, and 164 (46%) were from high-income countries. 190 (53%) were male. Data for comorbidities were missing for some children in low-income and middle-income countries. Available data showed that comorbidities were present in at least 33 (28%) children from low-income or lower middle-income countries, 36 (47%) from upper middle-income countries, and 114 (70%) from high-income countries. Median age for RSV-related deaths was 5·0 months (IQR 2·3-11·0) in low-income or lower middle-income countries, 4·0 years (2·0-10·0) in upper middle-income countries, and 7·0 years (3·6-16·8) in high-income countries.

Interpretation: This study is the first large case series of children who died with community-acquired RSV infection. A substantial proportion of children with RSV-related death had comorbidities. Our results show that perinatal immunisation strategies for children aged younger than 6 months could have a substantial impact on RSV-related child mortality in low-income and middle-income countries.

Funding: Bill & Melinda Gates Foundation.
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October 2017

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study.

Ting Shi David A McAllister Katherine L O'Brien Eric A F Simoes Shabir A Madhi Bradford D Gessner Fernando P Polack Evelyn Balsells Sozinho Acacio Claudia Aguayo Issifou Alassani Asad Ali Martin Antonio Shally Awasthi Juliet O Awori Eduardo Azziz-Baumgartner Henry C Baggett Vicky L Baillie Angel Balmaseda Alfredo Barahona Sudha Basnet Quique Bassat Wilma Basualdo Godfrey Bigogo Louis Bont Robert F Breiman W Abdullah Brooks Shobha Broor Nigel Bruce Dana Bruden Philippe Buchy Stuart Campbell Phyllis Carosone-Link Mandeep Chadha James Chipeta Monidarin Chou Wilfrido Clara Cheryl Cohen Elizabeth de Cuellar Duc-Anh Dang Budragchaagiin Dash-Yandag Maria Deloria-Knoll Mukesh Dherani Tekchheng Eap Bernard E Ebruke Marcela Echavarria Carla Cecília de Freitas Lázaro Emediato Rodrigo A Fasce Daniel R Feikin Luzhao Feng Angela Gentile Aubree Gordon Doli Goswami Sophie Goyet Michelle Groome Natasha Halasa Siddhivinayak Hirve Nusrat Homaira Stephen R C Howie Jorge Jara Imane Jroundi Cissy B Kartasasmita Najwa Khuri-Bulos Karen L Kotloff Anand Krishnan Romina Libster Olga Lopez Marilla G Lucero Florencia Lucion Socorro P Lupisan Debora N Marcone John P McCracken Mario Mejia Jennifer C Moisi Joel M Montgomery David P Moore Cinta Moraleda Jocelyn Moyes Patrick Munywoki Kuswandewi Mutyara Mark P Nicol D James Nokes Pagbajabyn Nymadawa Maria Tereza da Costa Oliveira Histoshi Oshitani Nitin Pandey Gláucia Paranhos-Baccalà Lia N Phillips Valentina Sanchez Picot Mustafizur Rahman Mala Rakoto-Andrianarivelo Zeba A Rasmussen Barbara A Rath Annick Robinson Candice Romero Graciela Russomando Vahid Salimi Pongpun Sawatwong Nienke Scheltema Brunhilde Schweiger J Anthony G Scott Phil Seidenberg Kunling Shen Rosalyn Singleton Viviana Sotomayor Tor A Strand Agustinus Sutanto Mariam Sylla Milagritos D Tapia Somsak Thamthitiwat Elizabeth D Thomas Rafal Tokarz Claudia Turner Marietjie Venter Sunthareeya Waicharoen Jianwei Wang Wanitda Watthanaworawit Lay-Myint Yoshida Hongjie Yu Heather J Zar Harry Campbell Harish Nair

Lancet 2017 Sep 7;390(10098):946-958. Epub 2017 Jul 7.

Centre for Global Health Research, Usher Institute of Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland, UK; Public Health Foundation of India, New Delhi, India. Electronic address:

Background: We have previously estimated that respiratory syncytial virus (RSV) was associated with 22% of all episodes of (severe) acute lower respiratory infection (ALRI) resulting in 55 000 to 199 000 deaths in children younger than 5 years in 2005. In the past 5 years, major research activity on RSV has yielded substantial new data from developing countries. With a considerably expanded dataset from a large international collaboration, we aimed to estimate the global incidence, hospital admission rate, and mortality from RSV-ALRI episodes in young children in 2015.

Methods: We estimated the incidence and hospital admission rate of RSV-associated ALRI (RSV-ALRI) in children younger than 5 years stratified by age and World Bank income regions from a systematic review of studies published between Jan 1, 1995, and Dec 31, 2016, and unpublished data from 76 high quality population-based studies. We estimated the RSV-ALRI incidence for 132 developing countries using a risk factor-based model and 2015 population estimates. We estimated the in-hospital RSV-ALRI mortality by combining in-hospital case fatality ratios with hospital admission estimates from hospital-based (published and unpublished) studies. We also estimated overall RSV-ALRI mortality by identifying studies reporting monthly data for ALRI mortality in the community and RSV activity.

Findings: We estimated that globally in 2015, 33·1 million (uncertainty range [UR] 21·6-50·3) episodes of RSV-ALRI, resulted in about 3·2 million (2·7-3·8) hospital admissions, and 59 600 (48 000-74 500) in-hospital deaths in children younger than 5 years. In children younger than 6 months, 1·4 million (UR 1·2-1·7) hospital admissions, and 27 300 (UR 20 700-36 200) in-hospital deaths were due to RSV-ALRI. We also estimated that the overall RSV-ALRI mortality could be as high as 118 200 (UR 94 600-149 400). Incidence and mortality varied substantially from year to year in any given population.

Interpretation: Globally, RSV is a common cause of childhood ALRI and a major cause of hospital admissions in young children, resulting in a substantial burden on health-care services. About 45% of hospital admissions and in-hospital deaths due to RSV-ALRI occur in children younger than 6 months. An effective maternal RSV vaccine or monoclonal antibody could have a substantial effect on disease burden in this age group.

Funding: The Bill & Melinda Gates Foundation.
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September 2017

Influenza and respiratory syncytial virus in infants study (IRIS) of hospitalized and non-ill infants aged <1 year in four countries: study design and methods.

BMC Infect Dis 2017 03 22;17(1):222. Epub 2017 Mar 22.

Sustainable Sciences Institute, Managua, Nicaragua.

Background: This multi-country prospective study of infants aged <1 year aims to assess the frequency of influenza virus and respiratory syncytial virus (RSV) infections associated with hospitalizations, to describe clinical features and antibody response to infection, and to examine predictors of very severe disease requiring intensive care.

Methods/design: We are enrolling a hospital-based cohort and a sample of non-ill infants in four countries (Albania, Jordan, Nicaragua, and the Philippines) using a common protocol. We are currently starting year 2 of a 2- to 3-year study and will enroll approximately 3,000 infants hospitalized for any acute illness (respiratory or non-respiratory) during periods of local influenza and/or RSV circulation. After informed consent and within 24 h of admission, we collect blood and respiratory specimens and conduct an interview to assess socio-demographic characteristics, medical history, and symptoms of acute illness (onset ≤10 days). Vital signs, interventions, and medications are documented daily through medical record abstraction. A follow-up health assessment and collection of convalescent blood occurs 3-5 weeks after enrollment. Influenza and RSV infection is confirmed by singleplex real time reverse transcriptase polymerase chain reaction (rRT-PCR) assays. Serologic conversion will be assessed comparing acute and convalescent sera using hemagglutination inhibition assay for influenza antibodies and enzyme-linked immunosorbent assay (ELISA) for RSV. Concurrent with hospital-based enrollment, respiratory specimens are also being collected (and tested by rRT-PCR) from approximately 1,400 non-ill infants aged <1 year during routine medical or preventive care.

Discussion: The Influenza and RSV in Infants Study (IRIS) promises to expand our knowledge of the frequency, clinical features, and antibody profiles of serious influenza and RSV disease among infants aged <1 year, quantify the proportion of infections that may be missed by traditional surveillance, and inform decisions about the potential value of existing and new vaccines and other prevention and treatment strategies.
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March 2017

National Influenza Surveillance in the Philippines from 2006 to 2012: seasonality and circulating strains.

BMC Infect Dis 2016 12 19;16(1):762. Epub 2016 Dec 19.

Department of Health, Research Institute for Tropical Medicine, Filinvest Corporate City, Alabang, Muntinlupa City, Philippines.

Background: The results of routine influenza surveillance in 13 regions in the Philippines from 2006 to 2012 are presented, describing the annual seasonal epidemics of confirmed influenza virus infection, seasonal and alert thresholds, epidemic curve, and circulating influenza strains.

Methods: Retrospective analysis of Philippine influenza surveillance data from 2006 to 2012 was conducted to determine seasonality with the use of weekly influenza positivity rates and calculating epidemic curves and seasonal and alert thresholds using the World Health Organization (WHO) global epidemiological surveillance standards for influenza.

Results: Increased weekly influenza positive rates were observed from June to November, coinciding with the rainy season and school opening. Two or more peaks of influenza activity were observed with different dominant influenza types associated with each peak. A-H1N1, A-H3N2, and two types of B viruses circulated during the influenza season in varying proportions every year. Increased influenza activity for 2012 occurred 8 weeks late in week 29, rather than the expected week of rise of cases in week 21 as depicted in the established average epidemic curve and seasonal threshold. The intensity was severe going above the alert threshold but of short duration. Southern Hemisphere vaccine strains matched circulating influenza virus for more surveillance years than Northern Hemisphere vaccine strains.

Conclusions: Influenza seasonality in the Philippines is from June to November. The ideal time to administer Southern Hemisphere influenza vaccine should be from April to May. With two lineages of influenza B circulating annually, quadrivalent vaccine might have more impact on influenza control than trivalent vaccine. Establishment of thresholds and average epidemic curve provide a tool for policy-makers to assess the intensity or severity of the current influenza epidemic even early in its course, to help plan more precisely resources necessary to control the outbreak. Influenza surveillance activities should be continued in the Philippines and funding for such activities should already be incorporated into the Philippine health budget.
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December 2016

WU and KI polyomavirus infections in Filipino children with lower respiratory tract disease.

J Clin Virol 2016 09 26;82:112-118. Epub 2016 Jul 26.

University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, CO, USA; Center for Global Health, Colorado School of Public Health, Aurora, CO, USA. Electronic address:

Background: WU and KI are human polyomaviruses initially detected in the respiratory tract, whose clinical significance remains uncertain.

Objectives: To determine the epidemiology, viral load and clinical characteristics of WU and KI polyomaviruses.

Study Design: We tested respiratory specimens collected during a randomized, placebo-controlled pneumococcal conjugate vaccine trial and related epidemiological study in the Philippines. We analyzed 1077 nasal washes from patients aged 6 weeks to 5 years who developed lower respiratory tract illness using quantitative real-time PCR for WU and KI. We collected data regarding presenting symptoms, signs, radiographic findings, laboratory data and coinfection.

Results: The prevalence and co-infection rates for WU were 5.3% and 74% respectively and 4.2% and 84% respectively for KI. Higher KI viral loads were observed in patients with severe or very severe pneumonia, those presenting with chest indrawing, hypoxia without wheeze, convulsions, and with KI monoinfection compared with co-infection. There was no significant association between viral load and clinical presentation for WU.

Conclusions: These findings suggest a potential pathogenic role for KI, and that there is an association between KI viral load and illness severity.
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September 2016

Using mathematical transmission modelling to investigate drivers of respiratory syncytial virus seasonality in children in the Philippines.

PLoS One 2014 27;9(2):e90094. Epub 2014 Feb 27.

Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Queensland, Australia.

We used a mathematical transmission model to estimate when ecological drivers of respiratory syncytial virus (RSV) transmissibility would need to act in order to produce the observed seasonality of RSV in the Philippines. We estimated that a seasonal peak in transmissibility would need to occur approximately 51 days prior to the observed peak in RSV cases (range 49 to 67 days). We then compared this estimated seasonal pattern of transmissibility to the seasonal patterns of possible ecological drivers of transmissibility: rainfall, humidity and temperature patterns, nutritional status, and school holidays. The timing of the seasonal patterns of nutritional status and rainfall were both consistent with the estimated seasonal pattern of transmissibility and these are both plausible drivers of the seasonality of RSV in this setting.
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October 2014

Malnutrition: a risk factor for severe respiratory syncytial virus infection and hospitalization.

Pediatr Infect Dis J 2014 Mar;33(3):267-71

From the *School of Population Health; †Queensland Children's Medical Research Institute, University of Queensland, Brisbane, Australia; ‡Research Institute of Tropical Medicine, Manila, the Philippines; §Department of Vaccines and Immune Protection, National Institute for Health and Welfare, Helsinki, Finland; ¶Barbara Hardy Institute, University of South Australia, Adelaide, Australia; ‖University of Colorado Denver, School of Medicine; Center for Global Health, Colorado School of Public Health; and **Children's Hospital Colorado, Aurora, CO.

Background: Longitudinal information examining the effect of poor infant growth on respiratory syncytial virus (RSV) severity is limited. Children hospitalized with RSV lower respiratory infection represent those at the severe end of the disease spectrum.

Methods: We followed up a cohort of 12,191 infants enrolled in a previous pneumococcal vaccine trial in Bohol, Philippines. Exposure measures were weight for age z-score at the first vaccination visit (median age 1.8 months) as well as the growth (the difference in weight for age z-score) between the first and third vaccination visits. The outcome was hospitalization with RSV lower respiratory infection.

Results: Children with a weight for age z-score ≤ -2 at their first vaccination visit had the highest rate of hospitalization with RSV lower respiratory infection, but this association was only evident in children whose mothers had >10 years of education (hazard ratio: 3.38; 95% confidence interval: 1.63-6.98). Children who had lower than median growth between their first and third vaccinations had a higher rate of RSV-associated hospitalization than those with growth above the median (hazard ratio: 1.34; 95% confidence interval: 1.02-1.76).

Conclusions: Poor infant growth increases the risk for severe RSV infection leading to hospitalization.
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March 2014

Poor growth and pneumonia seasonality in infants in the Philippines: cohort and time series studies.

PLoS One 2013 28;8(6):e67528. Epub 2013 Jun 28.

School of Population Health, University of Queensland, Brisbane, Queensland, Australia.

Children with poor nutrition are at increased risk of pneumonia. In many tropical settings seasonal pneumonia epidemics occur during the rainy season, which is often a period of poor nutrition. We have investigated whether seasonal hunger may be a driver of seasonal pneumonia epidemics in children in the tropical setting of the Philippines. In individual level cohort analysis, infant size and growth were both associated with increased pneumonia admissions, consistent with findings from previous studies. A low weight for age z-score in early infancy was associated with an increased risk of pneumonia admission over the following 12 months (RR for infants in the lowest quartile of weight for age z-scores 1.28 [95% CI 1.08 to 1.51]). Poor growth in smaller than average infants was also associated with an increased risk of pneumonia (RR for those in the lowest quartile of growth in early infancy 1.31 [95%CI 1.02 to 1.68]). At a population level, we found that seasonal undernutrition preceded the seasonal increase in pneumonia and respiratory syncytial virus admissions by approximately 10 weeks (pairwise correlation at this lag was -0.41 [95%CI -0.53 to -0.27] for pneumonia admissions, and -0.63 [95%CI -0.72 to -0.51] for respiratory syncytial virus admissions). This lag appears biologically plausible. These results suggest that in addition to being an individual level risk factor for pneumonia, poor nutrition may act as a population level driver of seasonal pneumonia epidemics in the tropics. Further investigation of the seasonal level association, in particular the estimation of the expected lag between seasonal undernutrition and increased pneumonia incidence, is recommended.
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April 2014

Global and regional burden of hospital admissions for severe acute lower respiratory infections in young children in 2010: a systematic analysis.

Lancet 2013 Apr 29;381(9875):1380-1390. Epub 2013 Jan 29.

Centre for Population Health Sciences, Global Health Academy, The University of Edinburgh, Edinburgh, UK.

Background: The annual number of hospital admissions and in-hospital deaths due to severe acute lower respiratory infections (ALRI) in young children worldwide is unknown. We aimed to estimate the incidence of admissions and deaths for such infections in children younger than 5 years in 2010.

Methods: We estimated the incidence of admissions for severe and very severe ALRI in children younger than 5 years, stratified by age and region, with data from a systematic review of studies published between Jan 1, 1990, and March 31, 2012, and from 28 unpublished population-based studies. We applied these incidence estimates to population estimates for 2010, to calculate the global and regional burden in children admitted with severe ALRI in that year. We estimated in-hospital mortality due to severe and very severe ALRI by combining incidence estimates with case fatality ratios from hospital-based studies.

Findings: We identified 89 eligible studies and estimated that in 2010, 11·9 million (95% CI 10·3-13·9 million) episodes of severe and 3·0 million (2·1-4·2 million) episodes of very severe ALRI resulted in hospital admissions in young children worldwide. Incidence was higher in boys than in girls, the sex disparity being greatest in South Asian studies. On the basis of data from 37 hospital studies reporting case fatality ratios for severe ALRI, we estimated that roughly 265,000 (95% CI 160,000-450,000) in-hospital deaths took place in young children, with 99% of these deaths in developing countries. Therefore, the data suggest that although 62% of children with severe ALRI are treated in hospitals, 81% of deaths happen outside hospitals.

Interpretation: Severe ALRI is a substantial burden on health services worldwide and a major cause of hospital referral and admission in young children. Improved hospital access and reduced inequities, such as those related to sex and rural status, could substantially decrease mortality related to such infection. Community-based management of severe disease could be an important complementary strategy to reduce pneumonia mortality and health inequities.

Funding: WHO.
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April 2013

The data management of a phase III efficacy trial of an 11-valent pneumococcal conjugate vaccine and related satellite studies conducted in the Philippines.

BMC Res Notes 2012 Jun 7;5:274. Epub 2012 Jun 7.

Background: A large phase III placebo-controlled, randomized efficacy trial of an investigational 11-valent pneumococcal conjugate vaccine against pneumonia in children less than 2 years of age was conducted in the Philippines from July 2000 to December 2004. Clinical data from 12,194 children who were given either study vaccine or placebo was collected from birth up to two years of age for the occurrence of radiologically proven pneumonia as the primary endpoint, and for clinical pneumonia and invasive pneumococcal disease as the secondary endpoints. Several tertiary endpoints were also explored. Along the core trial, several satellite studies on herd immunity, cost-effectiveness of the study vaccine, acute otitis media, and wheezing were conducted.

Results: We describe here in detail how the relevant clinical records were managed and how quality control procedures were implemented to ensure that valid data were obtained respectively for the core trial and for the satellite studies. We discuss how the task was achieved, what the challenges were and what might have been done differently.

Conclusions: There were several factors that made the task of data management doable and efficient. First, a pre-trial data management system was available. Secondly, local committed statisticians, programmers and support staff were available and partly familiar to clinical trials. Thirdly, the personnel had undergone training during trial and grew with the task they were supposed to do. Thus the knowledge needed to develop and operate clinical data system was fully transferred to local staff.

Trial Registration: Current Controlled Trials ISRCTN62323832.
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June 2012

Rapid molecular testing for multi-resistant tuberculosis in Mongolia: A diagnostic accuracy study.

Int J Mycobacteriol 2012 Mar 31;1(1):40-4. Epub 2012 Jan 31.

Research Institute of Tuberculosis, Tokyo, Japan.

Objective: The aim of this study was to assess the performance of a molecular line probe assay, GenoType® MTBDRplus, for rapid detection of rifampicin and isoniazid resistance in the Mongolian situation. The sensitivity and specificity of GenoType® MTBDRplus to detect rifampicin and isoniazid resistance-associated mutations in culture specimens and directly in smear-positive clinical specimens was examined.

Method: 218 MDR-TB subjects aged between 14 and 75years old from eight districts in Ulaanbaatar city (between July 2009 and May 2010) were included in this study .The GenoType Mycobacterium tuberculosis drug resistance first line (MTBDR plus) assay (Hain Life-science, Nehren, Germany) was tested on 109 clinical isolates and directly on 41 sputum specimens for the ability to detect the resistances. Results were compared with conventional culture and drug susceptibility testing on solid medium.

Results: The high correlation of the results from GenoType® MTBDRplus and conventional drug susceptibility testing was obtained from this study. The results clearly showed a high performance of GenoType® MTBDRplus with almost 100% accuracy for all the important indicators, such as sensitivity, specificity, positive and negative predictive values and detection of rifampicin resistance. Discrepancies were obtained in comparison with DNA sequencing results.

Conclusions: The Genotype® MTBDRplus assay was demonstrated as a rapid, reliable and highly accurate tool for early detection of MDR-TB through examining smear positive cases.
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March 2012

Geographic Information System and tools of spatial analysis in a pneumococcal vaccine trial.

BMC Res Notes 2012 Jan 20;5:51. Epub 2012 Jan 20.

Research Institute for Tropical Medicine, Muntinlupa City, Philippines.

Background: The goal of this Geographic Information System (GIS) study was to obtain accurate information on the locations of study subjects, road network and services for research purposes so that the clinical outcomes of interest (e.g., vaccine efficacy, burden of disease, nasopharyngeal colonization and its reduction) could be linked and analyzed at a distance from health centers, hospitals, doctors and other important services. The information on locations can be used to investigate more accurate crowdedness, herd immunity and/or transmission patterns.

Method: A randomized, placebo-controlled, double-blind trial of an 11-valent pneumococcal conjugate vaccine (11PCV) was conducted in Bohol Province in central Philippines, from July 2000 to December 2004. We collected the information on the geographic location of the households (N = 13,208) of study subjects. We also collected a total of 1982 locations of health and other services in the six municipalities and a comprehensive GIS data over the road network in the area.

Results: We calculated the numbers of other study subjects (vaccine and placebo recipients, respectively) within the neighborhood of each study subject. We calculated distances to different services and identified the subjects sharing the same services (calculated by distance). This article shows how to collect a complete GIS data set for human to human transmitted vaccine study in developing country settings in an efficient and economical way.

Conclusions: The collection of geographic locations in intervention trials should become a routine task. The results of public health research may highly depend on spatial relationships among the study subjects and between the study subjects and the environment, both natural and infrastructural.

Trial Registration Number: ISRCTN: ISRCTN62323832.
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January 2012

Pneumococcal conjugate vaccines for preventing vaccine-type invasive pneumococcal disease and X-ray defined pneumonia in children less than two years of age.

Cochrane Database Syst Rev 2009 Oct 7(4):CD004977. Epub 2009 Oct 7.

Department of Epidemiology and Biostatistics, Research Institute for Tropical Medicine, Alabang, Muntinlupa City, Philippines, 1781.

Background: Pneumonia, caused by Streptococcus pneumoniae, is a major cause of morbidity and mortality among children in low-income countries. The effectiveness of pneumococcal conjugate vaccines (PCVs) against invasive pneumococcal disease (IPD), pneumonia, and mortality needs to be evaluated.

Objectives: To update the 2004 review on the efficacy of PCVs in preventing vaccine-serotypes IPD (VT-IPD) , X-ray defined pneumonia among HIV-1 negative children, and other new outcomes.

Search Strategy: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 1), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register; MEDLINE (1990 to Week 4 February 2009); and EMBASE (1974 to March 2009).

Selection Criteria: Randomised controlled trials (RCTs) comparing PCV with placebo, or another vaccine, in children under two with IPD and clinical / radiographic pneumonia as outcomes.

Data Collection And Analysis: Two review authors independently identified studies, extracted data, and evaluated their corresponding risks of bias. Differences were resolved by discussion. Meta-analysis used the inverse variance method.

Main Results: We identified 11 publications from six RCTs conducted in Africa, US, Philippines and Finland where 57,015 children received PCV; while 56,029 received placebo or another vaccine. Seven publications provided high quality evidence on PCV efficacy against IPD and four provided moderate quality evidence against pneumonia. None of the five trials with all-cause mortality data were powered to investigate this outcome. Only two trials have data on all-cause admissions.The main analysis for this review involved HIV-1 negative children and used the pooled results of random-effects model, intent-to-treat analysis (ITT).Pooled vaccine efficacy (VE) for VT-IPD was 80% (95% confidence interval (CI) 58% to 90%, P < 0.0001); all serotypes-IPD, 58% (95% CI 29% to 75%, P = 0.001); World Health Organization X-ray defined pneumonia was 27% (95% CI 15% to 36%, P < 0.0001); clinical pneumonia, 6% (95% CI 2% to 9%, P = 0.0006); and all-cause mortality, 11% (95% CI -1% to 21%, P = 0.08). Analysis involving HIV-1 positive children had similar findings.

Authors' Conclusions: PCV is effective in preventing IPD, X-ray defined pneumonia, and clinical pneumonia among HIV-1 negative and HIV-1 positive children under two years. The impact was greater for VT-IPD than for all serotypes-IPD, and for X-ray defined pneumonia than for clinical pneumonia. An 11% reduction with a 95% CI of -1% to 21% and a P = 0.08 is compatible with reduction in all-cause mortality.
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October 2009

Efficacy of an 11-valent pneumococcal conjugate vaccine against radiologically confirmed pneumonia among children less than 2 years of age in the Philippines: a randomized, double-blind, placebo-controlled trial.

Pediatr Infect Dis J 2009 Jun;28(6):455-62

Research Institute for Tropical Medicine, Manila, the Philippines.

Background: Pneumococcus is a leading cause of childhood pneumonia worldwide. Pneumococcal conjugate vaccines (PCV) have demonstrated efficacy against childhood invasive pneumococcal disease (IPD) and pneumonia in the United States and Africa. No information is available from Asia on the impact of PCV on childhood pneumonia.

Methods: We conducted a randomized, placebo-controlled, double-blind trial in Bohol, the Philippines (ISRCTN 62323832). Children 6 weeks to <6 months of age were randomly allocated to receive 3 doses of either an 11-valent PCV (11PCV, sanofi pasteur, Lyon, France) or a saline placebo, with a minimum interval of 4 weeks between doses to determine vaccine efficacy (VE) against the primary outcome of a child experiencing first episode of community-acquired radiologically defined pneumonia in the first 2 years of life. Secondary end points were clinical pneumonia, IPD, safety, and immunogenicity.

Results: Twelve thousand one hundred ninety-one children were enrolled. By per protocol (PP) analysis, 93 of 6013 fully vaccinated 11PCV recipient children had a first episode of radiologic pneumonia compared with 120 of 6018 placebo recipients. VE against radiologically defined pneumonia for the PP cohort of children 3 to 23 months old was 22.9% (95% CI: -1.1, 41.2; P = 0.06), for the prespecified subgroups of children 3 to 11 months of age, 34.0% (95% CI: 4.8, 54.3; P = 0.02), and of those 12 to 23 months old, 2.7% (95% CI: -43.5, 34.0; P = 0.88). By intent-to-treat (ITT) analysis, 119 of 6097 11PCV recipient children had an episode of radiologic pneumonia compared with 141 of 6094 placebo recipients. VE against radiologic pneumonia for the ITT cohort of children <2 years old was 16.0% (95% CI -7.3, 34.2; P = 0.16), for a subgroup of children <12 months of age, 19.8% (95% CI: -8.8, 40.8; P = 0.15). VE against clinical pneumonia by PP was not significant (VE 0.1%; 95% CI -9.4, 8.7; P = 0.99). IPD was rare: only 3 cases of IPD due to vaccine serotypes were observed during the study. 11PCV was immunogenic and well tolerated. Among 11PCV recipients, a small excess of serious adverse respiratory events was observed in the first 28 days after the first and second dose of vaccine, and of nonrespiratory events after the first dose. An excess of pneumonia episodes in 11PCV recipients in the month following the second dose of vaccination was the principal reason for lower VE by ITT analysis than by PP analysis.

Conclusions: In PP analysis, a 22.9% reduction of community-acquired radiologically confirmed pneumonia in children younger than 2 years of age in the 11-valent tetanus-diphtheria toxoid-conjugated PCV vaccinated group was observed; a reduction similar as observed in other PCV trials. We could not demonstrate any VE against clinical pneumonia. Our finding confirms for the first time that in a low-income, low-mortality developing country in Asia, at least one-fifth of radiologically confirmed pneumonia is caused by pneumococcus, and thus preventable by PCV. Whether PCV should be included in national program in such settings, however, depends on careful country specific disease burden measurement and cost-effectiveness calculation.
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June 2009

Clinical case review: a method to improve identification of true clinical and radiographic pneumonia in children meeting the World Health Organization definition for pneumonia.

BMC Infect Dis 2008 Jul 21;8:95. Epub 2008 Jul 21.

National Public Health Institute, Mannerheimintie 166, FIN-00300 Helsinki, Finland.

Background: The World Health Organization's (WHO) case definition for childhood pneumonia, composed of simple clinical signs of cough, difficult breathing and fast breathing, is widely used in resource poor settings to guide management of acute respiratory infections. The definition is also commonly used as an entry criteria or endpoint in different intervention and disease burden studies.

Methods: A group of paediatricians conducted a retrospective review of clinical and laboratory data including C-reactive protein concentration and chest radiograph findings among Filipino children hospitalised in the Bohol Regional Hospital who were enrolled in a pneumococcal vaccine efficacy study and had an episode of respiratory disease fulfilling the WHO case definition for clinical pneumonia. Our aim was to evaluate which disease entities the WHO definition actually captures and what is the probable aetiology of respiratory infections among these episodes diagnosed in this population.

Results: Among the 12,194 children enrolled to the vaccine study we recorded 1,195 disease episodes leading to hospitalisation which fulfilled the WHO criteria for pneumonia. In total, 34% of these episodes showed radiographic evidence of pneumonia and 11% were classified as definitive or probable bacterial pneumonia. Over 95% of episodes of WHO-defined severe pneumonia (with chest indrawing) had an acute lower respiratory infection as final diagnosis whereas 34% of those with non-severe clinical pneumonia had gastroenteritis or other non-respiratory infection as main cause of hospitalisation.

Conclusion: The WHO definition for severe pneumonia shows high specificity for acute lower respiratory infection and provides a tool to compare the total burden of lower respiratory infections in different settings.

Trial Registration: ISRCTN62323832.
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July 2008

Radiology quality assurance in a developing country setting: the 11-valent pneumococcal conjugate vaccine trial, Bohol, Philippines.

Vaccine 2007 Mar 20;25(13):2528-32. Epub 2006 Sep 20.

Bohol Regional Hospital, Tagbilaran City, Bohol, Philippines.

The endpoint used for a phase 3 pneumococcal conjugate vaccine (PCV) trial in Bohol, Philippines was radiographic consolidation. Only one (Bohol Regional Hospital, BRH) of the four surveillance hospitals had a quality control/quality assurance program (QC/QA) prior to the trial. QC/QA was initiated in the three private hospitals. Radiologists from BRH evaluated radiographs from all hospitals based on recommended standards. Four thousand nine hundred and eighty nine films were analyzed. In 2000, the proportion of good quality films was 65% and 29% in BRH and private hospitals, respectively. By 2004, these increased to 92% and 79%, respectively. Poor film quality was commonly due to absence of collimation and poor contrast. The regular QC/QA implementation was necessary to improve film quality and was particularly important in our PCV trial that used X-ray proven consolidation as an endpoint.
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March 2007

Vaccine trial as "probe" to define the burden of pneumococcal pneumonia disease.

Lancet 2005 Mar 26-Apr 1;365(9465):1113-4

Research Institute for Tropical Medicine, Filinvest Corporate City 1770, Alabang, MetroManila, Philippines.

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April 2005

Similar antibody concentrations in Filipino infants at age 9 months, after 1 or 3 doses of an adjuvanted, 11-valent pneumococcal diphtheria/tetanus-conjugated vaccine: a randomized controlled trial.

J Infect Dis 2004 Jun 10;189(11):2077-84. Epub 2004 May 10.

Research Institute for Tropical Medicine, Muntinlupa, Manila, Philippines.

In Filipino infants, 1 dose of an adjuvanted, 11-valent pneumococcal conjugate vaccine (serotypes 1, 4, 5, 7F, 9V, 19F, and 23F conjugated to tetanus protein; and serotypes 3, 6B, 14, and 18C conjugated to diphtheria toxoid) administered alone at age 18 weeks (11PncTD1) elicited similar antibody concentrations at age 9 months as those elicited by 3 doses (11PncTD3) administered concomitantly with national program vaccines, at ages 6, 10, and 14 weeks. Geometric mean antibody concentrations ranged from 0.36 microg/mL (for serotype 18C) to 5.81 microg/mL (for serotype 4), for the 11PncTD1 vaccine, and from 0.32 microg/mL (for serotype 18C) to 5.01 microg/mL (for serotype 19F), for the 11PncTD3 vaccine. The proportion of infants with threshold antibody concentrations > or =0.35 microg/mL was also similar (ranges, 55.6%-100% for the 11PncTD1 vaccine and 42.9%-100% for the 11PncTD3 vaccine). The functional activity of antibodies expressed as opsonophagocytic activity titers was similar in the 11PncTD1 and 11PncTD3 groups. This finding is an important one for countries with financial constraints and high pneumococcal disease burden.
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June 2004

Safety and immunogenicity of three doses of an eleven-valent diphtheria toxoid and tetanus protein--conjugated pneumococcal vaccine in Filipino infants.

BMC Infect Dis 2003 Aug 10;3:17. Epub 2003 Aug 10.

Research Institute for Tropical Medicine, Metro Manila, Philippines.

Background: An 11-valent pneumococcal conjugate vaccine could provide significantly larger reduction in pneumococcal disease burden than the currently available 7-valent vaccine formulation in many countries.

Methods: In total, 50 infants were enrolled to this open, uncontrolled study, which evaluated the safety and immunogenicity of an aluminium adjuvanted 11-valent mixed-carrier diphtheria toxoid or tetanus protein-conjugated vaccine (11-PncTD) when administered in three doses at 6, 10 and 14 weeks of age simultaneously with DTwP//PRP-T and OPV vaccines in Filipino infants.

Results: The rates of local reactions between the two injection sites, those associated with the 11-PncTD vaccine and those with the DTwP//PRP-T were almost of equal frequency for all three vaccine doses except for induration, which was significantly more common in the DTP//PRP-T injection site. Fever was present in 39%, 22% and 21% of infants following each of the three doses. Antibody responses were determined by an enzyme immunoassay method before the first vaccination and after the three doses. The vaccine elicited a significant anti-pneumococcal polysaccharide antibody response against all serotypes included in the vaccine, except for type 14, for which the pre-vaccination geometric mean antibody concentration (GMC) was high (1.61 microg/ml). The GMCs one month after the vaccination series ranged from 1.1 micrograms/ml for type 6B to 23.4 microg/ml for type 4.

Conclusion: The 11-PncTD vaccine is safe, well-tolerated and immunogenic. The effectiveness of the non-adjuvanted formulation of the vaccine in preventing pneumonia is currently being evaluated in the Philippines.
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August 2003

Antibody response to an eleven valent diphtheria- and tetanus-conjugated pneumococcal conjugate vaccine in Filipino infants.

Pediatr Infect Dis J 2002 Apr;21(4):309-14

National Public Health Institute, Department of Vaccines, Helsinki, Finland.

Background: Pneumococcal conjugate vaccines are intended to provide effective protection against pneumococcal infections, but very little information on antibody responses in infants living in countries with high pneumococcal disease burden exists.

Methods: In this study 50 healthy Filipino infants were enrolled at a village health center in Cabuyao to receive 11-valent diphtheria- and tetanus-conjugated pneumococcal vaccine at 6, 10 and 14 weeks of age (primary series) simultaneously with diphtheria-tetanus-whole cell pertussis/polyribosylribitol phosphate conjugated to tetanus toxoid, hepatitis B virus and oral poliovirus vaccines and at 9 months of age (booster dose) simultaneously with measles vaccine. The alum-adjuvanted study vaccine contained pneumococcal polysaccharide of serotypes 1, 4, 5, 7F, 9V, 19F and 23F conjugated to tetanus protein and pneumococcal polysaccharide of serotypes 3, 6B, 14 and 18C conjugated to diphtheria toxoid. Serum samples for enzyme immunoassay analyses were collected at 6, 10 and 14 weeks and 9 and 10 months of age.

Results: Very high geometric mean antibody concentrations (GMCs) against most pneumococcal serotypes were observed after the first three doses of vaccine (range, serotype 23F, 3.89 microg/ml to serotype 4, 23.41 microg/ml) with the exception of serotype 6B and 14, with GMCs of 1.12 and 2.18 microg/ml, respectively. The fourth dose increased the GMCs against most serotypes (range, serotype 14, 1.65 to serotype 19F, 33.43 microg/ml). The maternally derived antibodies did not decrease the response to the vaccine.

Conclusions: This first pneumococcal conjugate vaccine study in Asia confirms that the 11-valent diphtheria- and tetanus-conjugated pneumococcal vaccine is highly immunogenic in Filipino infants. The GMCs against most pneumococcal serotypes were substantially higher than described with the same or other pneumococcal conjugate vaccines in other populations.
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April 2002