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Enterovirus 68 (EV68) is a rare enterovirus associated with respiratory illness that, unlike other enteroviruses, has been identified only from respiratory specimens. We identified EV68 from respiratory specimens of children hospitalized with a diagnosis of severe pneumonia in Leyte, Republic of the Philippines. Twenty-one samples showed high similarity with EV68 by sequencing of 5' nontranslated region; 17 of these samples were confirmed as EV68 by sequencing of viral protein 1 capsid coding region. Most previously reported EV68 cases had been identified as sporadic cases. All 21 patients we identified had severe illness, and 2 died, possibly the first reported fatal cases associated with EV68 infection. Our study suggests that EV68 may be a possible causative agent of severe respiratory illnesses. [ABSTRACT FROM AUTHOR]

Abstract Background Pneumonia remains a leading cause of child death in developing countries. The viruses in severe pneumonia remain poorly defined. Methods The study was conducted at the Eastern Visayas Regional Medical Center in Tacloban City, Philippines from May 2008 to May 2009. Patients aged 8 days to 13 years old who were admitted to the Department of Pediatrics with severe pneumonia were enrolled for the study. Upon admission, polymerase chain reaction was performed using nasopharyngeal swabs and blood cultures to detect respiratory viruses and bacteria, respectively. Result Among the 819 patients enrolled, at least one virus was detected in 501 cases (61.2%). In addition, 423 cases were positive for a single virus while bacteria were detected in the blood culture sample of 31 cases. The most commonly detected viruses were human rhinoviruses (n = 189), including types A (n = 103), B (n = 17), and C (n = 69), and respiratory syncytial virus (RSV) (n = 165). Novel viruses such as human metapneumovirus, human coronavirus NL63, human bocavirus, and human polyomaviruses WU and KI were also detected. There were 70 deaths, and one or more viruses were detected in 35 (50%) of these cases. Positivity only for influenza A virus (OR = 4.3, 95% CI = 1.3-14.6) was significantly associated with fatal outcome. From the blood culture, Burkholderia cepacia group (n = 9), Streptococcus pneumoniae (n = 4), Staphylococcus aureus (n = 4), Haemophilus influenzae (n = 1), and Salmonella C1 (n = 1) were also isolated. Conclusion Viruses were commonly detected in children with severe pneumonia in the Philippines. Hence, viral etiologies should be considered while developing better effective strategies to reduce child pneumonia-related deaths in developing countries.

Background: Community-acquired pneumonia (CAP) is a common cause of morbidity and mortality among adults worldwide. However, the distribution of the etiology of CAP varies from one country to another, with limited data from rural areas., Methods: A prospective hospital-based study on adult CAP was conducted in Leyte, Central Philippines from May 2010 to May 2012. Blood, sputum, and nasopharyngeal samples obtained from patients were used to identify pathogens using standard microbiological culture methods and PCR., Results: Of the 535 patients enrolled, 38% were younger than 50 years old. More than half of the patients had an underlying disease, including pulmonary tuberculosis (22%). The detection rate was higher for bacteria (40%) than viruses (13%). Haemophilus influenzae (12%) was the most commonly detected bacterium and influenza virus (5%) was the most commonly detected virus. The proportion of CAP patients with Mycobacterium tuberculosis infection was higher in the younger age group than in the older age group. Among CAP patients, 14% died during hospitalization, and drowsiness on admission and SpO 2 <90% were independent risk factors for mortality., Conclusions: Bacterial infections contribute substantially to the number of hospitalizations among CAP patients in rural Philippines. This study also highlights the importance of treatment of tuberculosis in reducing the burden of adult CAP in the country., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Human adenovirus (HAdV) serotype 7 is an important etiological agent of severe childhood pneumonia. The aim of this study was to define the role of HAdV7 and to describe its clinical and molecular epidemiological characteristics in the Philippines in 2011. HAdVs were detected by viral culture, and a partial region of hexon gene was sequenced. A total of 700 patients were enrolled, of which 22 (3.1%) died. Nine (1.3%) HAdV cases were confirmed, of which 7 were positive for HAdV7, 1 for HAdV3, and 1 for HAdV5. Among the 9 HAdV-positive cases, 4 (44%) with HAdV7 died. Molecular analysis revealed that all HAdV7 isolates were closely related to genome type h strains. This study demonstrated the significance of HAdV7 as an etiological agent of severe pediatric pneumonia with a high fatality rate. Hence, continuous monitoring is required to define the clinical and public health significance of HAdV7 infection.

Background: Detection of Enterovirus 68 (EV68) has recently been increased. However, underlying evolutionary mechanism of this increasing trend is not fully understood., Methods: Nasopharyngeal swabs were collected from 5,240 patients with acute respiratory infections in the Philippines from June 2009 to December 2011. EV68 was detected by polymerase chain reaction (PCR) targeting for 5' untranslated region (5'UTR), viral protein 1 (VP1), and VP4/VP2. Phylogenetic trees were generated using the obtained sequences., Results: Of the 5,240 tested samples, 12 EV68 positive cases were detected between August and December in 2011 (detection rate, 0.23%). The detection rate was higher among inpatients than outpatients (p<0.0001). Among VP1 sequences detected from 7 patients in 2011, 5 in lineage 2 were diverged from those detected in the Philippines in 2008, however, 2 in lineage 3 were not diverged from strains detected in the Philippines in 2008 but closely associated with strains detected in the United States. Combined with our previous report, EV68 occurrences were observed twice in the Philippines within the last four years., Conclusions: EV68 detections might be occurring in cyclic patterns, and viruses might have been maintained in the community while some strains might have been newly introduced.

Background: Human respiratory syncytial virus (HRSV) is the leading cause of acute lower respiratory tract infection in infants and young children. However, molecular characteristic of HRSV is still unknown in the Philippines., Objective: To describe the molecular epidemiology of circulating HRSV detected in the Philippines., Study Design: From May 2008 to April 2012, nasopharyngeal swabs were collected from infants and children aged between 7 days and 14 years who were hospitalized with severe pneumonia. HRSV was detected by nested PCR targeting M2 gene, and C-terminus of the G gene was sequenced for phylogenetic analysis., Result: Out of total 2150 samples, 19.3% (n = 415) were positive for HRSV, and 65.0% of them (n = 270) were identified as HRSV-A and 35.0% (n = 145) as HRSV-B. There were two major HRSV outbreaks: between June 2008 and February 2009, and between June and March 2012. Majority of HRSV strains detected during the former outbreak were HRSV-A (97.5%, 203/208) whereas during the later outbreak, both HRSV-A (54/158, 34.2%) and HRSV-B (104/158, 65.8%) were detected. All HRSV-A strains were classified as genotype NA1 and all HRSV-B as genotype BA, which had 60-nucleotide duplication in secondary hypervariable region of the G gene. Among HRSV-B positive samples, there were 2 distinct clusters with unique amino acid changes and low homology in compared to other strains in BA, suggesting emergence of new variant of HRSV-B., Conclusion: The study provides an overview of the genetic variation in circulating HRSV viruses in the Philippines along with identification of possibly a novel variant of HRSV-B., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Human rhinovirus (HRV) C was recently identified as the third species of HRV using a molecular technique. Infections caused by previously identified HRVs (A and B) are thought to be limited to the respiratory tract; however, pathogenesis of HRVC is still largely unknown. A total of 816 nasopharyngeal swabs from hospitalized children with severe respiratory infections in the Philippines (May 2008-May 2009) were tested for HRV by reverse transcription polymerase chain reaction (RT-PCR), and 243 samples (29.8%) were positive for HRV. Among these patients, serum samples were also tested to determine whether specific HRV species were associated with viremia. Only 30 serum samples (12.3%) were positive for HRV. However, the HRV positive rates were different among HRV species, 3% (4/135) for HRVA, 0% (0/25) for HRVB, and 31% (26/83) for HRVC, and were the highest on 2 days after the onset of symptoms. These results suggest that HRVC may have a different pathogenicity and can more commonly cause viremia than HRVA and HRVB. Serum positive rates for HRV are affected by age, i.e., higher positive rates for those aged 1 year or more. HRVC that were detected from serum exhibited the same level of sequence diversity as those positive only for nasopharyngeal samples in phylogenetic analysis. However, all HRVA which were detected from serum were clustered in a monophyletic clade based on their 5' non-coding region (NCR) sequences, which is closely related with a certain HRVC genotype (A2) in 5'-NCR. This finding suggests that the 5'NCR region may be associated with viremia.

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.

Epidemiological features of blood culture confirmed typhoid fever and antibiotic sensitivity of isolated Salmonella typhi strains were investigated in Bohol Province in Central Philippines from where no earlier information of these was avialable. Typhoid fever is endemic elsewhere in the Philippines (eg Metropolitan Manila and surroundings) where also multidrug resistant S. typhi strains have been detected. A laboratory for surveillance of invasive bacterial infections was established in a tertiary care government hospital, in Bohol, Central Philippines, in 1994. Patients with suspected typhoid fever or other serious infection were managed and blood cultures from them were taken according to clinicians' judgment. Blood cultures were processed and the isolated bacteria identified using generally accepted methods. S. typhi and other Salmonella isolates were identified using commercial antisera. Patient data were collected from hospital records. Of a total of 4,699 blood cultures done during a period of 3 3/4 years, 1,530 (32%) were requested for suspected typhoid fever. S. typhi was the most common pathogen isolated from 422 patients (8.9%), followed by S. paratyphi A from 55 patients (1%). Most patients were young adults (43%) and school age children (28%). Male:female ratio was 1.5:1. Among the 422 patients, there were 9 (2%) deaths due to typhoid fever, all with complications. All S. typhi isolates were sensitive to chloramphenicol, cotrimoxazole, and ampicillin. Our observation on blood culture confirmed typhoid fever demonstrates its importance as a major infectious disease in Bohol and gives a sound basis for treatment of typhoid patients and for further clinical and epidemiologic studies of typhoid fever and for following antibiotic sensitivity of S. typhi in Bohol and elsewhere in the Philippines.

Objective: Pneumonia, meningitis and other serious infections are leading causes of death in developing countries. As part of a multicenter study we aimed to determine the etiology of pneumonia, meningitis and other serious infections in a cohort of Filipino infants ages 90 days or younger., Method: During a 2-year period, 2053 infants age 90 days or younger presenting to 1 of 3 Manila community hospitals were screened; 873 had signs or symptoms suggestive of an infectious illness, and 608 were judged to have clinical features suggestive of severe infection and had laboratory workup including blood for culture and white blood cell count, nasopharyngeal aspirate for virology, cerebrospinal fluid culture when indicated and chest radiograph. Chest radiographs were read independently by 3 radiologists without knowledge of clinical findings., Results: Of the 873 enrolled infants, 81 died (91%). After exclusion of presumed contaminants, positive bacterial culture from blood and/or cerebrospinal fluid was obtained in 35 infants (5.8%; 95% confidence interval 4%, 8%), 9 of whom died. The organisms responsible for meningitis were Acinetobacter spp. (4), Streptococcus pneumoniae (2), Escherichia coli (2), Enterobacter spp. (1), Pseudomonas aeruginosa (1), Haemophilus influenzae (1) and Staphylococcus aureus (1); those responsible for the other clinical diagnoses were Salmonella spp. (6), Enterobacter spp. (3), Streptococcus pyogenes (3), other Gram-negative organisms (8), S. pneumoniae (1) and Staphylococcus aureus (2). In 685 infants examined for viral causes of their illness, 223 viruses were isolated from 219 infants (32%; 95% confidence interval 28%, 36%). Enteroviruses were the most common potential pathogens identified (22% of infants studied), followed by respiratory syncytial virus (17%), rhinovirus (10%) and adenovirus (4%). Concomitant virus identification occurred in 10 of those with positive bacterial culture (29%; 95% confidence interval, 15%, 46%), with enterovirus being found in 7 of these cases., Conclusion: Many young Filipino infants with life-threatening illness were evaluated in this study. Thirty-five had infections attributable to bacteria, with Salmonella spp. being the most common, followed by Gram-negative organisms. Pneumococcus was an unusual cause.

Background: Measles continues to be a significant health problem in developing countries., Objectives: To describe the clinical features of measles-associated pneumonia (MAP) and to identify other pathogens involved., Methods: Measles diagnosis was ascertained either by the typical symptom complex or by a sensitive enzyme immunoassay for antibody among children < 5 years of age admitted to the hospital with pneumonia. Other pathogens were identified by blood culture, virus isolation or antigen detection from nasopharyngeal aspirate and antibody determination from serum., Results: Of 182 MAP cases 162 (89%) had clinically typical measles. Twenty patients had a diagnostic antibody finding with an atypical clinical presentation. Thirteen percent were younger than 9 months of age. The case fatality rate was 17%, with a significantly increased odds ratio (OR) for those with cyanosis [OR 4.6, 95% confidence interval (CI) 1.7 to 13], respiratory rate > or = 60/min (OR 3, 95% CI 1.3 to 7) or fulfilling criteria for very severe pneumonia (OR 5.3, 95% CI 2.3 to 12). Mixed infection was found in 53% of patients. Blood culture was positive in 10 patients, Streptococcus pneumoniae (N = 5) being the most common finding. Adenovirus (19%) and parainfluenza (25%) viruses were the most frequent other viruses. A dense infiltrate was seen significantly more often among measles patients with bacterial coinfection (87.5%) than those with other viruses (36%, P = 0.007) or no evidence of other infection (33%, P = 0.004)., Conclusion: In MAP, coinfection with other microbes is common. Cyanosis and a respiratory rate of > or = 60/min predict a greater risk of dying.

Objectives: The value of measurements of serum C-reactive protein (CRP) in differentiating central nervous system (CNS) infections of varying etiologies in the Philippines was investigated., Methods: A wide array of bacteriologic and virologic methods as well as computed tomography, typical clinical presentation, and autopsy were used for etiologic diagnosis., Results: Among 103 patients with CNS infection, etiology was identified in 60 (58%) cases. Bacteria were found in 19 (including 7 Streptococcus pneumoniae, 5 Haemophilus influenzae, 3 Neisseria meningitidis), tuberculosis in 4, viruses in 38 (including 20 coxsackievirus, 8 measles, 4 adenovirus, and 4 poliovirus infections), and brain abscess in 3 patients. C-reactive protein was elevated on admission in all 18 cases of bacterial meningitis tested, exceeding 50 mg/L in 17 (94%), and was not affected by prior antibacterial treatment. The mean CRP was significantly higher in the bacterial group than in the viral group (207 +/- 111 mg/L vs. 39 +/- 34 mg/L; P < 0.001). In the viral group one third had CRP above 50 mg/L. In patients with tuberculous meningitis, brain abscess, or cryptococcal meningitis, CRP was moderately to highly elevated., Conclusions: In the presence of a normal CRP concentration (below 10 mg/mL) acute bacterial meningitis is excluded even in a developing country setting and antimicrobial therapy is not warranted.

Serum antibody responses to three Haemophilus influenzae type b (Hib) capsular polysaccharide-protein conjugate vaccine (PRP-OMP, PRP-T, and HbOC) were evaluated in 174 Philippine infants after a primary vaccination series. Children were randomized to receive one of the Hib vaccines (Hib groups) or into a control group. Vaccination was carried out at six, 10 and 14 weeks of age based on the local Expanded Program of Immunization schedule. Sera were collected at six weeks of age for the Hib groups and one month after the third dose for all subjects. Anti-Hib concentrations were determined by the Farr-type radioimmunoassay. There were no significant differences (P = 0.3626) in the prevaccination anti-Hib geometric mean concentration (GMC) among the three Hib groups. Differences in the GMC after the primary series of three doses were significant (P < 0.0001); GMC was highest for PRP-T (6.62 micrograms/ml), followed by HbOC (1.9 micrograms/ml), then PRP-OMP (1.06 micrograms/ml), and lowest for the control group (0.11 microgram/ml). We conclude that all three Hib conjugate vaccines (PRP-T, HbOC, and PRP-OMP) were immunogenic after three primary doses among Philippine infants.

This study conducted at the Research Institute for Tropical Medicine from April 1990 to December 1992, identified the etiology of acute lower respiratory tract infection (ALRI) in 119 (36.9%) of 317 hospitalized children < 5 years of age. A higher proportion of respiratory viruses (27.2%) than bacterial agents (10.7%) were identified. Viral agents (adenovirus, RSV, parainfluenza 3, influenza A and influenza B) and bacterial agents (mainly Haemophilus influenzae and Streptococcus pneumoniae) are the pathogenic agents involved in ALRI among Filipino children less than 5 years old.

The usefulness of a single Widal test was evaluated in an endemic area. This test was done on 62 bacteriologically proven enteric fever cases, 69 non-enteric fever cases and healthy individuals. Using an 0 antibody cut-off of greater than or equal to 1:20, the Widal tube agglutination test yielded a sensitivity of 61% and a specificity of 88%. At a pre-test probability of around 50%, the positive predictive value was 83% and the negative predictive value was 72%. A 4% prevalence of 0 antibodies was noted in the healthy population.