Circadian regulation of pulmonary disease: the importance of timing.

Circadian regulation causes the activity of biological processes to vary over a 24-h cycle. The pathological effects of this variation are predominantly studied using two different approaches: pre-clinical models or observational clinical studies. Both these approaches have provided useful insights into how underlying circadian mechanisms operate and specifically which are regulated by the molecular oscillator, a key time-keeping mechanism in the body. This review compares and contrasts findings from these two approaches in the context of four common respiratory diseases (asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, and respiratory infection). Potential methods used to identify and measure human circadian oscillations are also discussed as these will be useful outcome measures in future interventional human trials that target circadian mechanisms.

The first occurrence of an avian-style respiratory infection in a non-avian dinosaur.

Other than repaired fractures, osteoarthritis, and periosteal reaction, the vertebrate fossil record has limited evidence of non-osseous diseases. This difficulty in paleontological diagnoses stems from (1) the inability to conduct medical testing, (2) soft-tissue pathologic structures are less likely to be preserved, and (3) many osseous lesions are not diagnostically specific. However, here reported for the first time is an avian-style respiratory disorder in a non-avian dinosaur. This sauropod presents irregular bony pathologic structures stemming from the pneumatic features in the cervical vertebrae. As sauropods show well-understood osteological correlates indicating that respiratory tissues were incorporated into the post-cranial skeleton, and thus likely had an 'avian-style' form of respiration, it is most parsimonious to identify these pathologic structures as stemming from a respiratory infection. Although several extant avian infections produce comparable symptoms, the most parsimonious is airsacculitis with associated osteomyelitis. From actinobacterial to fungal in origin, airsacculitis is an extremely prevalent respiratory disorder in birds today. While we cannot pinpoint the specific infectious agent that caused the airsacculitis, this diagnosis establishes the first fossil record of this disease. Additionally, it allows us increased insight into the medical disorders of dinosaurs from a phylogenetic perspective and understanding what maladies plagued the "fearfully great lizards".

Early-life viral infections are associated with disadvantageous immune and microbiota profiles and recurrent respiratory infections.

The respiratory tract is populated by a specialized microbial ecosystem, which is seeded during and directly following birth. Perturbed development of the respiratory microbial community in early-life has been associated with higher susceptibility to respiratory tract infections (RTIs). Given a consistent gap in time between first signs of aberrant microbial maturation and the observation of the first RTIs, we hypothesized that early-life host-microbe cross-talk plays a role in this process. We therefore investigated viral presence, gene expression profiles and nasopharyngeal microbiota from birth until 12 months of age in 114 healthy infants. We show that the strongest dynamics in gene expression profiles occurred within the first days of life, mostly involving Toll-like receptor (TLR) and inflammasome signalling. These gene expression dynamics coincided with rapid microbial niche differentiation. Early asymptomatic viral infection co-occurred with stronger interferon activity, which was related to specific microbiota dynamics following, including early enrichment of Moraxella and Haemophilus spp. These microbial trajectories were in turn related to a higher number of subsequent (viral) RTIs over the first year of life. Using a multi-omic approach, we found evidence for species-specific host-microbe interactions related to consecutive susceptibility to RTIs. Although further work will be needed to confirm causality of our findings, together these data indicate that early-life viral encounters could impact subsequent host-microbe cross-talk, which is linked to later-life infections.

Disparities in Outcomes During Lower Respiratory Tract Infection in American Indian Children: A 9-Year Retrospective Analysis in a Rural Population in South Dakota.

BACKGROUND: American Indian (AI) children are at increased risk for severe disease during lower respiratory tract infection (LRTI). The reasons for this increased severity are poorly understood. The objective of this study was to define the clinical presentations of LRTI and highlight the differences between AI and non-AI previously healthy patients under the age of 24 months. METHODS: We performed a retrospective chart review between October 2010 and December 2019. We reviewed 1245 patient charts and 691 children met inclusion criteria for this study. Data records included demographics, clinical, laboratory data, and illness outcomes. RESULTS: Of 691 patients, 120 were AI and 571 were non-AI. There was a significant difference in breast-feeding history (10% of AI vs. 28% of non-AI, P < 0.0001) and in secondhand smoke exposure (37% of AI vs. 21% of non-AI, P < 0.0001). AI children had increased length of hospitalization compared with non-AI children (median of 3 vs. 2 days, P < 0.001). In addition, AI children had higher rates of pediatric intensive unit admission (30%, n = 37) compared with non-AI children (11%; n = 67, P < 0.01). AI children also had higher rates (62.5%, n = 75) and duration of oxygen supplementation (median 3 days) than non-AI children (48%, n = 274, P = 0.004; median 2 days, P = 0.0002). On a multivariate analysis, AI race was an independent predictor of severe disease during LRTI. CONCLUSIONS: AI children have increased disease severity during LRTI with longer duration of hospitalization and oxygen supplementation, a higher rate of oxygen requirement and Powered by Editorial Manager and ProduXion Manager from Aries Systems Corporation pediatric intensive care unit admissions, and a greater need for mechanical ventilation. These results emphasize the need for improvement in health policies and access to health care in this vulnerable population.

Antibiotic Timing and Progression to Septic Shock Among Patients in the ED With Suspected Infection.

BACKGROUND: Recent medical society opinions have questioned the use of early antimicrobials in patients with sepsis, but without septic shock. RESEARCH QUESTION: Is time from ED presentation to administration of antibiotics associated with progression to septic shock among patients with suspected infection? STUDY DESIGN AND METHODS: This was a retrospective cohort study from March 2007 through March 2020. All adults with suspected infection and first antimicrobial administered within 24 h of triage were included. Patients with shock on presentation were excluded. We performed univariate and multivariate logistic regression analyses predicting progression to septic shock. RESULTS: Seventy-four thousand one hundred fourteen patient encounters were included in the study. Five thousand five hundred ten patients (7.4%) progressed to septic shock. Of the patients who progressed to septic shock, 88% had received antimicrobials within the first 5 h from triage. In the multivariate logistic model, time (in hours) to first antimicrobial administration showed an OR of 1.03 (95% CI, 1.02-1.04; P < .001) for progression to septic shock and 1.02 (95% CI, 0.99-1.04; P = .121) for in-hospital mortality. When adjusted for severity of illness, each hour delayed until initial antimicrobial administration was associated with a 4.0% increase in progression to septic shock for every 1 h up to 24 h from triage. Patients with positive quick Sequential Organ Failure Assessment (qSOFA) results were given antibiotics at an earlier time point than patients with positive systemic inflammatory response syndrome (SIRS) score (0.82 h vs 1.2 h; P < .05). However, median time to septic shock was significantly shorter (P < .05) for patients with positive qSOFA results at triage (11.2 h) compared with patients with positive SIRS score at triage (26 h). INTERPRETATION: Delays in first antimicrobial administration in patients with suspected infection are associated with rapid increases in likelihood of progression to septic shock. Additionally, qSOFA score has higher specificity than SIRS score for predicting septic shock, but is associated with a worse outcome, even when patients receive early antibiotics.

A 70-Year-Old Man With Cough and Recurrent Respiratory Infections.

CASE PRESENTATION: A 70-year-old man was referred for evaluation of recurrent respiratory infections requiring antibiotics and chronic cough over 3 years. Two months prior to presentation, he started to develop blood-tinged sputum but not frank hemoptysis. He otherwise denied any fever, chills, night sweats, or weight loss. He had dyspnea during the respiratory infections but not otherwise. His medical history was significant for chronic rhinitis without sinusitis and a low serum IgM level. He was a never smoker and a farmer but otherwise had no significant or specific exposures or travel history. His family history was significant for alpha-1 antitrypsin deficiency in his mother.

Physiological respiratory parameters in pre-hospital patients with suspected COVID-19: A prospective cohort study.

BACKGROUND: The COVID-19 pandemic has presented emergency medical services (EMS) worldwide with the difficult task of identifying patients with COVID-19 and predicting the severity of their illness. The aim of this study was to investigate whether physiological respiratory parameters in pre-hospital patients with COVID-19 differed from those without COVID-19 and if they could be used to aid EMS personnel in the prediction of illness severity. METHODS: Patients with suspected COVID-19 were included by EMS personnel in Uppsala, Sweden. A portable respiratory monitor based on pneumotachography was used to sample the included patient's physiological respiratory parameters. A questionnaire with information about present symptoms and background data was completed. COVID-19 diagnoses and hospital admissions were gathered from the electronic medical record system. The physiological respiratory parameters of patients with and without COVID-19 were then analyzed using descriptive statistical analysis and logistic regression. RESULTS: Between May 2020 and January 2021, 95 patients were included, and their physiological respiratory parameters analyzed. Of these patients, 53 had COVID-19. Using adjusted logistic regression, the odds of having COVID-19 increased with respiratory rate (95% CI 1.000-1.118), tidal volume (95% CI 0.996-0.999) and negative inspiratory pressure (95% CI 1.017-1.152). Patients admitted to hospital had higher respiratory rates (p<0.001) and lower tidal volume (p = 0.010) compared to the patients who were not admitted. Using adjusted logistic regression, the odds of hospital admission increased with respiratory rate (95% CI 1.081-1.324), rapid shallow breathing index (95% CI 1.006-1.040) and dead space percentage of tidal volume (95% CI 1.027-1.159). CONCLUSION: Patients taking smaller, faster breaths with less pressure had higher odds of having COVID-19 in this study. Smaller, faster breaths and higher dead space percentage also increased the odds of hospital admission. Physiological respiratory parameters could be a useful tool in detecting COVID-19 and predicting hospital admissions, although more research is needed.

An organ systems-based review of outcomes associated with sleep apnea in hospitalized patients.

ABSTRACT: The current global health crisis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has prompted the medical community to investigate the effects of underlying medical conditions, including sleep-disordered breathing, on inpatient care. Obstructive sleep apnea (OSA) is a common form of sleep-disordered breathing that may complicate numerous acquired conditions, particularly in inpatient and critical care settings. Viral pneumonia is a major contributor to intensive care unit (ICU) admissions and often presents more severely in patients with underlying pulmonary disease, especially those with obesity and OSA. This review summarizes the most recent data regarding complications of both OSA and obesity and highlights their impact on clinical outcomes in hospitalized patients. Additionally, it will highlight pertinent evidence for the complications of OSA in an organ-systems approach. Finally, this review will also discuss impatient treatment approaches for OSA, particularly in relation to the SARS-CoV-2 pandemic.

Quantifying dose-, strain-, and tissue-specific kinetics of parainfluenza virus infection.

Human parainfluenza viruses (HPIVs) are a leading cause of acute respiratory infection hospitalization in children, yet little is known about how dose, strain, tissue tropism, and individual heterogeneity affects the processes driving growth and clearance kinetics. Longitudinal measurements are possible by using reporter Sendai viruses, the murine counterpart of HPIV 1, that express luciferase, where the insertion location yields a wild-type (rSeV-luc(M-F*)) or attenuated (rSeV-luc(P-M)) phenotype. Bioluminescence from individual animals suggests that there is a rapid increase in expression followed by a peak, biphasic clearance, and resolution. However, these kinetics vary between individuals and with dose, strain, and whether the infection was initiated in the upper and/or lower respiratory tract. To quantify the differences, we translated the bioluminescence measurements from the nasopharynx, trachea, and lung into viral loads and used a mathematical model together a nonlinear mixed effects approach to define the mechanisms distinguishing each scenario. The results confirmed a higher rate of virus production with the rSeV-luc(M-F*) virus compared to its attenuated counterpart, and suggested that low doses result in disproportionately fewer infected cells. The analyses indicated faster infectivity and infected cell clearance rates in the lung and that higher viral doses, and concomitantly higher infected cell numbers, resulted in more rapid clearance. This parameter was also highly variable amongst individuals, which was particularly evident during infection in the lung. These critical differences provide important insight into distinct HPIV dynamics, and show how bioluminescence data can be combined with quantitative analyses to dissect host-, virus-, and dose-dependent effects.

Pulmonary Manifestations of GATA2 Deficiency.

BACKGROUND: GATA2 deficiency is a genetic disorder of hematopoiesis, lymphatics, and immunity caused by autosomal dominant or sporadic mutations in GATA2. The disease has a broad phenotype encompassing immunodeficiency, myelodysplasia, leukemia, and vascular or lymphatic dysfunction as well as prominent pulmonary manifestations. RESEARCH QUESTION: What are the pulmonary manifestations of GATA2 deficiency? STUDY DESIGN AND METHODS: A retrospective review was conducted of clinical medical records, diagnostic imaging, pulmonary pathologic specimens, and tests of pulmonary function. RESULTS: Of 124 patients (95 probands and 29 ascertained), the lung was affected in 56%. In addition to chronic infections, pulmonary alveolar proteinosis (11 probands) and pulmonary arterial hypertension (nine probands) were present. Thoracic CT imaging found small nodules in 54% (54 probands and 12 relatives), reticular infiltrates in 40% (45 probands and four relatives), paraseptal emphysema in 25% (30 probands and one relative), ground-glass opacities in 35% (41 probands and two relatives), consolidation in 21% (23 probands and two relatives), and a typical crazy-paving pattern in 7% (eight probands and no relatives). Nontuberculous mycobacteria were the most frequent organisms associated with chronic infection. Allogeneic hematopoietic stem cell transplantation successfully reversed myelodysplasia and immune deficiency and also improved pulmonary hypertension and pulmonary alveolar proteinosis in most patients. INTERPRETATION: GATA2 deficiency has prominent pulmonary manifestations. These clinical observations confirm the essential role of hematopoietic cells in many aspects of pulmonary function, including infections, alveolar proteinosis, and pulmonary hypertension, many of which precede the formal diagnosis, and many of which respond to stem cell transplantation.

Validation and clinical evaluation of a Polish translation of the Wisconsin Upper Respiratory Symptom Survey for Kids (WURSS-K).

BACKGROUND: The Wisconsin Upper Respiratory Symptom Survey for Kids (WURSS-K) is a self-administered questionnaire developed to evaluate the severity of the common cold. It is a patient-oriented instrument that evaluates quality of life in an illness-specific manner to be used in children aged 10 years. The purpose of this study was to validate the Polish version of the Wisconsin Upper Respiratory Symptom Survey for Kids. METHODS: The validation process consisted of five stages: forward translation, backward translation, cognitive debriefing, a pilot study (Study A and Study B), and statistical analysis. The first study (Study A, n = 10, aged 5-13) was conducted in the Emergency Room and an Outpatient Clinic of the Pediatric University Hospital in Warsaw. The purpose of the study was to obtain data for testing the convergent validity of the questionnaire. The second study (Study B, n = 56), consisted of children aged four to six enrolled in three kindergartens in the Warsaw suburbs. The obtained data were subjected to detailed statistical analysis. RESULTS: The WURSS Kids Polish showed excellent reliability. The Cronbach's alpha of the 13 items was 0.791 for the six symptom items and 0.854 for the seven functional items. The Jonckheere-Terpstra trend test was used to evaluate criterion validity. Compliance of the measurement performed independently by the examined person and the doctor on the first day was high (convergent validity). Each particular item was characterized by a different sensitivity to clinical change. The Guyatt's Responsiveness index ranged from 0.083 to 0.464. CONCLUSION: The internal consistency of the measurements and cross-cultural adaptation of the Polish version of WURSS Kids was satisfactory. The WURSS Kids Polish is a reliable, valid, and responsive disease-specific questionnaire for assessing symptoms and QOL in Polish patients in the pediatric population with the common cold. It may be used both in clinical practice and for research among Polish children with URTI.

Interactions of genetic variants and prenatal stress in relation to the risk for recurrent respiratory infections in children.

Genetic variants may predispose children to recurrent respiratory infections (RRIs) but studies on genotype-environment interaction are rare. We hypothesized that the risk for RRIs is elevated in children with innate immune gene variants, and that prenatal exposure to maternal psychological distress further increases the risk. In a birth cohort, children with RRIs (n = 96) were identified by the age of 24 months and compared with the remaining cohort children (n = 894). The risk for RRIs in children with preselected genetic variants and the interaction between maternal distress during pregnancy and child genotype were assessed with logistic regression. The IL6 minor allele G was associated with elevated risk for RRIs (OR 1.55; 95% CI 1.14-2.12). Overall, there was no interaction between maternal psychological distress and child genotype. Exploratory analyses showed that, the association between the variant type of IL6 and the risk for RRIs was dependent on prenatal exposure to maternal psychological distress in males (OR 1.96; 95% CI 1.04-3.67). Our study didn't find genotype-environment interaction between prenatal maternal distress and child genotype. Exploratory analyses suggest sex differences in gene-environment interaction related to susceptibility to RRIs.

Clinical features of parainfluenza infections among young children hospitalized for acute respiratory illness in Amman, Jordan.

BACKGROUND: Parainfluenza virus (PIV) is a leading cause of acute respiratory illness (ARI) in children. However, few studies have characterized the clinical features and outcomes associated with PIV infections among young children in the Middle East. METHODS: We conducted hospital-based surveillance for ARI among children < 2 years of age in a large referral hospital in Amman, Jordan. We systematically collected clinical data and respiratory specimens for pathogen detection using reverse transcription polymerase chain reaction. We compared clinical features of PIV-associated ARI among individual serotypes 1, 2, 3, and 4 and among PIV infections compared with other viral ARI and ARI with no virus detected. We also compared the odds of supplemental oxygen use using logistic regression. RESULTS: PIV was detected in 221/3168 (7.0%) children hospitalized with ARI. PIV-3 was the most commonly detected serotype (125/221; 57%). Individual clinical features of PIV infections varied little by individual serotype, although admission diagnosis of 'croup' was only associated with PIV-1 and PIV-2. Children with PIV-associated ARI had lower frequency of cough (71% vs 83%; p < 0.001) and wheezing (53% vs 60% p < 0.001) than children with ARI associated with other viruses. We did not find a significant difference in supplemental oxygen use between children with PIV-associated infections (adjusted odds ratio [aOR] 1.12, 95% CI 0.66-1.89, p = 0.68) and infections in which no virus was detected. CONCLUSIONS: PIV is frequently associated with ARI requiring hospitalization in young Jordanian children. Substantial overlap in clinical features may preclude distinguishing PIV infections from other viral infections at presentation.

Wisconsin Upper Respiratory Symptom Survey for Kids: Validation of an Illness-specific Quality of Life Instrument.

BACKGROUND: Acute respiratory infections (ARIs) are the most common illness seen in the pediatric ambulatory setting. Research in this area is hampered by the lack of validated ARI measures. The aim of this study was to assess the reliability and validity of the Wisconsin Upper Respiratory Symptom Survey for Kids (WURSS-K), a 15-item instrument, which measures illness-specific symptoms and impact on quality of life during an ARI. METHODS: WURSS-K was administered to two populations: (1) children aged 4-10 years recruited from the local community and (2) 9- and 10-year-old children from an ongoing study, the Urban Environment and Childhood Asthma. RESULTS: Overall, 163 children with 249 ARI episodes completed WURSS-K. WURSS-K was analyzed using multiple models to evaluate reliability and validity for a two-factor structure (symptom and functionality) and a single global structure. These models provided evidence of reliability and validity with omega of 0.72 and 0.91 for symptoms and functionality along with the single structure with omega of 0.90. CONCLUSIONS: WURSS-K shows strong psychometric properties for validity and reliability as either a single global factor or a two-factor structure. This instrument will be useful in both therapeutic trials and observational studies among children with ARI in ambulatory settings. IMPACT: WURSS-K is a valid and reliable illness-specific quality of life instrument that evaluates the impacts of ARIs on children. WURSS-K is designed for children 4-10 years of age, for whom there is a lack of validated assessment tools. This now validated instrument will be useful for future observational studies and therapeutic trials among children with ARIs in ambulatory settings.

Evaluation of patients with respiratory infections during the first pandemic wave in Germany: characteristics of COVID-19 versus non-COVID-19 patients.

BACKGROUND: Characteristics of COVID-19 patients have mainly been reported within confirmed COVID-19 cohorts. By analyzing patients with respiratory infections in the emergency department during the first pandemic wave, we aim to assess differences in the characteristics of COVID-19 vs. Non-COVID-19 patients. This is particularly important regarding the second COVID-19 wave and the approaching influenza season. METHODS: We prospectively included 219 patients with suspected COVID-19 who received radiological imaging and RT-PCR for SARS-CoV-2. Demographic, clinical and laboratory parameters as well as RT-PCR results were used for subgroup analysis. Imaging data were reassessed using the following scoring system: 0 - not typical, 1 - possible, 2 - highly suspicious for COVID-19. RESULTS: COVID-19 was diagnosed in 72 (32,9%) patients. In three of them (4,2%) the initial RT-PCR was negative while initial CT scan revealed pneumonic findings. 111 (50,7%) patients, 61 of them (55,0%) COVID-19 positive, had evidence of pneumonia. Patients with COVID-19 pneumonia showed higher body temperature (37,7 ± 0,1 vs. 37,1 ± 0,1 °C; p = 0.0001) and LDH values (386,3 ± 27,1 vs. 310,4 ± 17,5 U/l; p = 0.012) as well as lower leukocytes (7,6 ± 0,5 vs. 10,1 ± 0,6G/l; p = 0.0003) than patients with other pneumonia. Among abnormal CT findings in COVID-19 patients, 57 (93,4%) were evaluated as highly suspicious or possible for COVID-19. In patients with negative RT-PCR and pneumonia, another third was evaluated as highly suspicious or possible for COVID-19 (14 out of 50; 28,0%). The sensitivity in the detection of patients requiring isolation was higher with initial chest CT than with initial RT-PCR (90,4% vs. 79,5%). CONCLUSIONS: COVID-19 patients show typical clinical, laboratory and imaging parameters which enable a sensitive detection of patients who demand isolation measures due to COVID-19.

Breath can discriminate tuberculosis from other lower respiratory illness in children.

Pediatric tuberculosis (TB) remains a global health crisis. Despite progress, pediatric patients remain difficult to diagnose, with approximately half of all childhood TB patients lacking bacterial confirmation. In this pilot study (n = 31), we identify a 4-compound breathprint and subsequent machine learning model that accurately classifies children with confirmed TB (n = 10) from children with another lower respiratory tract infection (LRTI) (n = 10) with a sensitivity of 80% and specificity of 100% observed across cross validation folds. Importantly, we demonstrate that the breathprint identified an additional nine of eleven patients who had unconfirmed clinical TB and whose symptoms improved while treated for TB. While more work is necessary to validate the utility of using patient breath to diagnose pediatric TB, it shows promise as a triage instrument or paired as part of an aggregate diagnostic scheme.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2): a Systemic Infection.

To date, seven identified coronaviruses (CoVs) have been found to infect humans; of these, three highly pathogenic variants have emerged in the 21st century. The newest member of this group, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected at the end of 2019 in Hubei province, China. Since then, this novel coronavirus has spread worldwide, causing a pandemic; the respiratory disease caused by the virus is called coronavirus disease 2019 (COVID-19). The clinical presentation ranges from asymptomatic to mild respiratory tract infections and influenza-like illness to severe disease with accompanying lung injury, multiorgan failure, and death. Although the lungs are believed to be the site at which SARS-CoV-2 replicates, infected patients often report other symptoms, suggesting the involvement of the gastrointestinal tract, heart, cardiovascular system, kidneys, and other organs; therefore, the following question arises: is COVID-19 a respiratory or systemic disease? This review aims to summarize existing data on the replication of SARS-CoV-2 in different tissues in both patients and ex vivo models.

Claustrum hyperintensity: a rare radiological correlate in Niemann-Pick disease.

A 5-year-old male child of consanguineous parentage, without any adverse perinatal history, presented with progressive cognitive regression predominantly in the language and attention domains, for 2 years. He had simultaneous pyramidal and extrapyramidal involvement, frequent generalised tonic-clonic seizures and recurrent respiratory tract infections. Examination was significant for vertical supranuclear gaze palsy, coarse facial features and splenomegaly. Given the clinical features, in the background of consanguinity and mother's history of spontaneous pregnancy losses, inborn errors of metabolism were suspected. Following relevant investigations including tailored genetic study, Niemann-Pick disease type C (NPC) was diagnosed. Interestingly, MRI brain showed bilateral T2/fluid-attenuated inversion recovery claustrum hyperintensities, which are more commonly associated with autoimmune encephalitis and febrile infection-related epilepsy syndrome and not reported previously in NPC. Additionally, language regression as a presenting manifestation in NPC as opposed to classical dysarthria makes this case truly unique.

Epidemiological and clinical characteristics of children with acute respiratory viral infections in the Philippines: a prospective cohort study.

OBJECTIVES: Viral acute respiratory infection (ARI) remains a major global health problem, especially among children in low- and middle-income countries. The study was conducted to reveal aetiological significance of respiratory viruses among both non-hospitalized and hospitalized children. METHODS: A cohort study of children with ARI at the household, primary healthcare facility, and hospital levels was conducted alongside a hospital-based study including non-cohort children from 2014 to 2016 in the Philippines. The ARI cases were recorded at households and healthcare facilities, and a clinical investigation was performed. Nasopharyngeal swabs were collected from the symptomatic children and tested for respiratory viruses via polymerase chain reaction. Then, the association between healthcare facility utilization and viral detection was investigated. RESULTS: Overall, 18,514 ARI cases were enrolled in the cohort study, and samples were collected from 4735 of these cases. The hospital-based study detected 648 ARI cases, all of which were sampled. Rhinovirus (22.2%; 1052/4735) was most frequently detected followed by respiratory syncytial virus (12.0%; 566/4735). Enterovirus (adjusted odds ratio, 1.8; 95% confidence interval, 1.1-2.8), human metapneumovirus (2.1, 1.4-3.2), rhinovirus (2.1, 1.8-2.6), and respiratory syncytial virus (1.6, 1.2-1.9) were significantly more prevalent in the ARI cases at healthcare facilities than in those in households. Of all ARI cases, 0.6% required hospitalization while 1.8% were hospitalized among the respiratory syncytial virus-positive cases (3.8, 3.0-4.9). CONCLUSIONS: We determined the prevalence of respiratory viruses among children with ARIs at the household, primary healthcare facility, and hospital levels and the association with clinical characteristics. In particular, we discovered a significant disease burden and impact of respiratory syncytial virus infections as well as a considerable aetiological implication of rhinovirus infections.