Gelsolin Attenuates Neonatal Hyperoxia-Induced Inflammatory Responses to Rhinovirus Infection and Preserves Alveolarization.

Prematurity and bronchopulmonary dysplasia (BPD) increase the risk of asthma later in life. Supplemental oxygen therapy is a risk factor for chronic respiratory symptoms in infants with BPD. Hyperoxia induces cell injury and release of damage-associated molecular patterns (DAMPs). Cytoskeletal filamentous actin (F-actin) is a DAMP which binds Clec9a, a C-type lectin selectively expressed on CD103+ dendritic cells (DCs). Co-stimulation of Clec9a and TLR3 induces maximal proinflammatory responses. We have shown that neonatal hyperoxia (a model of BPD) increases lung IL-12+Clec9a+CD103+ DCs, pro-inflammatory responses and airway hyperreactivity following rhinovirus (RV) infection. CD103+ DCs and Clec9a are required for these responses. Hyperoxia increases F-actin levels in bronchoalveolar lavage fluid (BALF). We hypothesized that the F-actin severing protein gelsolin attenuates neonatal hyperoxia-induced Clec9a+CD103+ DC-dependent pro-inflammatory responses to RV and preserves alveolarization. We exposed neonatal mice to hyperoxia and treated them with gelsolin intranasally. Subsequently we inoculated the mice with RV intranasally. Alternatively, we inoculated normoxic neonatal mice with BALF from hyperoxia-exposed mice (hyperoxic BALF), RV and gelsolin. We analyzed lung gene expression two days after RV infection. For in vitro studies, lung CD11c+ cells were isolated from C57BL/6J or Clec9agfp-/- mice and incubated with hyperoxic BALF and RV. Cells were analyzed by flow cytometry. In neonatal mice, gelsolin blocked hyperoxia-induced Il12p40, TNF-α and IFN-γ mRNA and protein expression in response to RV infection. Similar effects were observed when gelsolin was co-administered with hyperoxic BALF and RV. Gelsolin decreased F-actin levels in hyperoxic BALF in vitro and inhibited hyperoxia-induced D103lo DC expansion and inflammation in vivo. Gelsolin also attenuated hyperoxia-induced hypoalveolarization. Further, incubation of lung CD11c+ cells from WT and Clec9agfp-/- mice with hyperoxic BALF and RV, showed Clec9a is required for maximal hyperoxic BALF and RV induced IL-12 expression in CD103+ DCs. Finally, in tracheal aspirates from mechanically ventilated human preterm infants the F-actin to gelsolin ratio positively correlates with FiO2, and gelsolin levels decrease during the first two weeks of mechanical ventilation. Collectively, our findings demonstrate a promising role for gelsolin, administered by inhalation into the airway to treat RV-induced exacerbations of BPD and prevent chronic lung disease.

Rhinovirus Incidence Rates Indicate We Are Tired of Non-pharmacological Interventions Against Coronavirus Disease 2019.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, the incidence of rhinovirus (RV) is inversely related to the intensity of non-pharmacological interventions (NPIs), such as universal mask wearing and physical distancing. METHODS: Using RV surveillance data, changes in the effect of NPIs were investigated in South Korea during the pandemic. The time to the first visible effect of NPIs after the onset of NPIs (T1), time to the maximum effect (T2), and duration of the maximum effect (T3) were measured for each surge. For each week, the RVdiff [(RV incidence during the pandemic) - (RV incidence within 5 years before the pandemic)] was calculated, and number of weeks for RVdiff to be below zero after NPIs (time to RVdiff ≤ 0) and number of weeks RVdiff remains below zero after NPIs (duration of RVdiff ≤ 0) were measured for each surge. RESULTS: During the study period, four surges of COVID-19 were reported. As the pandemic progressed, T1 and T2 increased, but T3 decreased. Additionally, the "time to RVdiff of ≤ 0" increased and "duration of RVdiff of ≤ 0" decreased. These changes became more pronounced during the third surge (mid-November 2020), before the introduction of the COVID-19 vaccine, and from the emergence of the delta variant. CONCLUSION: The effect of NPIs appears slower, the duration of the effect becomes shorter, and the intensity also decreases less than a year after the onset of the pandemic owing to people's exhaustion in implementing NPIs. These findings suggest that the COVID-19 response strategy must be completely overhauled.

Nasopharyngeal microbiota in hospitalized children with Bordetella pertussis and Rhinovirus infection.

Despite great advances in describing Bordetella pertussis infection, the role of the host microbiota in pertussis pathogenesis remains unexplored. Indeed, the microbiota plays important role in defending against bacterial and viral respiratory infections. We investigated the nasopharyngeal microbiota in infants infected by B. pertussis (Bp), Rhinovirus (Rv) and simultaneously by both infectious agents (Bp + Rv). We demonstrated a specific nasopharyngeal microbiome profiles for Bp group, compared to Rv and Bp + Rv groups, and a reduction of microbial richness during coinfection compared to the single infections. The comparison amongst the three groups showed the increase of Alcaligenaceae and Achromobacter in Bp and Moraxellaceae and Moraxella in Rv group. Furthermore, correlation analysis between patients' features and nasopharyngeal microbiota profile highlighted a link between delivery and feeding modality, antibiotic administration and B. pertussis infection. A model classification demonstrated a microbiota fingerprinting specific of Bp and Rv infections. In conclusion, external factors since the first moments of life contribute to the alteration of nasopharyngeal microbiota, indeed increasing the susceptibility of the host to the pathogens' infections. When the infection is triggered, the presence of infectious agents modifies the microbiota favoring the overgrowth of commensal bacteria that turn in pathobionts, hence contributing to the disease severity.

Human Rhinoviruses in Adult Patients in a Tertiary Care Hospital in Germany: Molecular Epidemiology and Clinical Significance.

Rhinoviruses (RVs) constitute a substantial public health burden. To evaluate their abundance and genetic diversity in adult patients, RV RNA in respiratory samples was assessed using real-time RT-PCR and the partial nucleic acid sequencing of viral genomes. Additionally, clinical data were retrieved from patient charts to determine the clinical significance of adult RV infections. In total, the respiratory specimens of 284 adult patients (18-90 years), collected from 2013 to 2017, were analyzed. Infections occurred throughout the entire year, with peaks occurring in fall and winter, and showed a remarkably high intra- and interseasonal diversity of RV genotypes. RV species were detected in the following ratios: 60.9% RV-A 173, 12.7% RV-B, and 26.4% RV-C. No correlations between RV species and underlying comorbidities such as asthma (p = 0.167), COPD (p = 0.312) or immunosuppression (p = 0.824) were found. However, 21.1% of the patients had co-infections with other pathogens, which were associated with a longer hospital stay (p = 0.024), LRTI (p < 0.001), and pneumonia (p = 0.01). Taken together, this study shows a pronounced genetic diversity of RV in adults and underlines the important role of co-infections. No correlation of specific RV species with a particular clinical presentation could be deduced.

Respiratory Pathogen Coinfections in SARS-CoV-2-Positive Patients in Southeastern Wisconsin: A Retrospective Analysis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the etiological agent of coronavirus disease 2019 (COVID-19), has infected all age groups and disproportionately impacted vulnerable populations globally. Polymicrobial infections may play an important role in the development of SARS-CoV-2 infection in susceptible hosts. These coinfections may increase the risk of disease severity and pose challenges to the diagnosis, treatment, and prognosis of COVID-19. There have been limited SARS-CoV-2 coinfection studies. In this retrospective study, residual nucleic acid extracts from 796 laboratory-confirmed COVID-19-positive specimens, collected between March 2020 and February 2021, were analyzed using a Luminex NxTAG respiratory pathogen panel (RPP). Of these, 745 returned valid results and were used for analysis; 53 (7.1%) were positive for one or more additional pathogens. Six different respiratory viruses were detected among the 53 SARS-CoV-2-positive patient specimens, and 7 of those specimens tested positive for more than one additional respiratory virus. The most common pathogens include rhinovirus/enterovirus (RV/EV) (n = 22, 41.51%), human metapneumovirus (hMPV) (n = 18, 33.9%), and adenovirus (n = 12, 22.6%). Interestingly, there were no SARS-CoV-2 coinfections involving influenza A or influenza B in the study specimens. The median age of the SARS-CoV-2-positive patients with coinfections was 38 years; 53% identified as female, and 47% identified as male. Based on our retrospective analysis, respiratory coinfections associated with SARS-CoV-2-positive patients were more common in young children (≤9 years old), with white being the most common race. Our findings will likely prompt additional investigation of polymicrobial infection associated with SARS-CoV-2 during seasonal respiratory pathogen surveillance by public health laboratories. IMPORTANCE This examination of respiratory pathogen coinfections in SARS-CoV-2 patients will likely shed light on our understanding of polymicrobial infection associated with COVID-19. Our results should prompt public health authorities to improve seasonal respiratory pathogen surveillance practices and address the risk of disease severity.

Diagnostic Efficacy and Tolerability of Molded Plastic Nasopharyngeal Swab (FinSwab) Compared to Flocked Nylon Swab in Detection of SARS-CoV-2 and Other Respiratory Viruses.

The supply of testing equipment is vital in controlling the spread of SARS-CoV-2. We compared the diagnostic efficacy and tolerability of molded plastic (FinSwab; Valukumpu, Finland) versus flocked nylon (FLOQSwab; Copan, Italy) nasopharyngeal swabs in a clinical setting. Adults (n = 112) with suspected symptomatic COVID-19 infection underwent nasopharyngeal sampling with FinSwab and FLOQSwab from the same nostril at a drive-in coronavirus testing station. In a subset of 36 patients the samples were collected in a randomized order to evaluate the discomfort associated with sampling. SARS-CoV-2 and 16 other respiratory viruses, as well as human ß-actin mRNA were analyzed by using reverse transcriptase PCR (RT-PCR) assays. Among the 112 patients (mean age, 38 [standard deviation (SD), 14] years) ß-actin mRNA was found in all samples. There was no difference in the ß-actin mRNA cycle threshold (CT) values between FinSwab (mean, 22.3; SD, 3.61) and FLOQSwab (mean, 22.1; SD, 3.50; P = 0.46) swabs. There were 31 virus-positive cases (26 rhinovirus, 4 SARS-CoV-2, and 1 coronavirus-OC43), 24 of which were positive in both swabs; 3 rhinovirus positives were only found in the FinSwab, and similarly 4 rhinovirus positives were only found in the FLOQSwab. Rhinovirus CT values were similar between swab types. Of the 36 patients, 22 (61%) tolerated the sampling with the FinSwab better than with the FLOQSwab (P = 0.065). The molded plastic nasopharyngeal swab (FinSwab) was comparable to the standard flocked swab in terms of efficacy for respiratory virus detection and tolerability of sampling. IMPORTANCE We demonstrate that a molded plastic swab is a valid alternative to conventional brush-like swabs in collection of a nasopharyngeal sample for virus diagnostics.

Characterization of Conserved and Promiscuous Human Rhinovirus CD4 T Cell Epitopes.

Human rhinovirus (RV) is the most common cause of upper respiratory infections and exacerbations of asthma. In this work, we selected 14 peptides (6 from RV A and 8 from RV C) encompassing potential CD4 T cell epitopes. Peptides were selected for being highly conserved in RV A and C serotypes and predicted to bind to multiple human leukocyte antigen class II (HLA II) molecules. We found positive T cell recall responses by interferon gamma (IFNγ)-ELISPOT assays to eight peptides, validating seven of them (three from RV A and four from RV C) as CD4 T cell epitopes through intracellular cytokine staining assays. Additionally, we verified their promiscuous binding to multiple HLA II molecules by quantitative binding assays. According to their experimental HLA II binding profile, the combination of all these seven epitopes could be recognized by >95% of the world population. We actually determined IFNγ responses to a pool encompassing these CD4 T cell epitopes by intracellular cytokine staining, finding positive responses in 29 out of 30 donors. The CD4 T cell epitopes identified in this study could be key to monitor RV infections and to develop peptide-based vaccines against most RV A and C serotypes.

The Reemergence of Seasonal Respiratory Viruses in Houston, Texas, after Relaxing COVID-19 Restrictions.

Measures intended to limit the spread of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus at the start of the coronavirus disease 2019 (COVID-19) pandemic resulted in a rapid decrease in other respiratory pathogens. Herein, we describe the trends of respiratory pathogens in a major metropolitan health care system central microbiology reference laboratory before and during the COVID-19 pandemic, with attention to when COVID-19 mitigation measures were implemented and relaxed. During the initial lockdown period, COVID-19 was the primary respiratory pathogen detected by multiplex respiratory panels. As COVID-19 containment measures were relaxed, the first non-COVID respiratory viruses to return to prepandemic levels were members of the rhinovirus/enterovirus family. After the complete removal of COVID-19 precautions at the state level, including an end to mask mandates, we observed the robust return of seasonal coronaviruses, parainfluenza virus, and respiratory syncytial virus. Inasmuch as COVID-19 has dominated the landscape of respiratory infections since early 2020, it is important for clinicians to recognize that the return of non-COVID respiratory pathogens may be rapid and significant when COVID-19 containment measures are removed. IMPORTANCE We describe the return of non-COVID respiratory viruses after the removal of COVID-19 mitigation measures. It is important for the public and physicians to recognize that, after months of COVID-19 being the primary driver of respiratory infection, more typical seasonal respiratory illnesses have returned, and this return is out of the normal season for some of these pathogens. Thus, clinicians and the public must now consider both COVID-19 and other respiratory illnesses when a patient presents with symptomatic respiratory illness.

Unsupervised machine learning reveals key immune cell subsets in COVID-19, rhinovirus infection, and cancer therapy.

For an emerging disease like COVID-19, systems immunology tools may quickly identify and quantitatively characterize cells associated with disease progression or clinical response. With repeated sampling, immune monitoring creates a real-time portrait of the cells reacting to a novel virus before disease-specific knowledge and tools are established. However, single cell analysis tools can struggle to reveal rare cells that are under 0.1% of the population. Here, the machine learning workflow Tracking Responders EXpanding (T-REX) was created to identify changes in both rare and common cells across human immune monitoring settings. T-REX identified cells with highly similar phenotypes that localized to hotspots of significant change during rhinovirus and SARS-CoV-2 infections. Specialized MHCII tetramer reagents that mark rhinovirus-specific CD4+ cells were left out during analysis and then used to test whether T-REX identified biologically significant cells. T-REX identified rhinovirus-specific CD4+ T cells based on phenotypically homogeneous cells expanding by ≥95% following infection. T-REX successfully identified hotspots of virus-specific T cells by comparing infection (day 7) to either pre-infection (day 0) or post-infection (day 28) samples. Plotting the direction and degree of change for each individual donor provided a useful summary view and revealed patterns of immune system behavior across immune monitoring settings. For example, the magnitude and direction of change in some COVID-19 patients was comparable to blast crisis acute myeloid leukemia patients undergoing a complete response to chemotherapy. Other COVID-19 patients instead displayed an immune trajectory like that seen in rhinovirus infection or checkpoint inhibitor therapy for melanoma. The T-REX algorithm thus rapidly identifies and characterizes mechanistically significant cells and places emerging diseases into a systems immunology context for comparison to well-studied immune changes.

The Positive Rhinovirus/Enterovirus Detection and SARS-CoV-2 Persistence beyond the Acute Infection Phase: An Intra-Household Surveillance Study.

We aimed to assess the duration of nasopharyngeal severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA persistence in adults self-confined at home after acute infection; and to identify the associations of SARS-CoV-2 persistence with respiratory virus co-detection and infection transmission. A cross-sectional intra-household study was conducted in metropolitan Barcelona (Spain) during the time period of April to June 2020. Every adult who was the first family member reported as SARS-CoV-2-positive by reverse transcription polymerase chain reaction (RT-PCR) as well as their household child contacts had nasopharyngeal swabs tested by a targeted SARS-CoV-2 RT-PCR and a multiplex viral respiratory panel after a 15 day minimum time lag. Four-hundred and four households (404 adults and 708 children) were enrolled. SARS-CoV-2 RNA was detected in 137 (33.9%) adults and 84 (11.9%) children. Rhinovirus/Enterovirus (RV/EV) was commonly found (83.3%) in co-infection with SARS-CoV-2 in adults. The mean duration of SARS-CoV-2 RNA presence in adults' nasopharynx was 52 days (range 26-83 days). The persistence of SARS-CoV-2 was significantly associated with RV/EV co-infection (adjusted odds ratio (aOR) 9.31; 95% CI 2.57-33.80) and SARS-CoV-2 detection in child contacts (aOR 2.08; 95% CI 1.24-3.51). Prolonged nasopharyngeal SARS-CoV-2 RNA persistence beyond the acute infection phase was frequent in adults quarantined at home during the first epidemic wave; which was associated with RV/EV co-infection and could enhance intra-household infection transmission.

Respiratory viruses in the healthy middle ear and middle ear with otitis media with effusion.

To investigate the presence of respiratory viruses in the middle ear cavity of the individuals with a healthy middle ear and the children with otitis media with effusion (OME). A total of 72 middle ear samples were collected from 25 children with OME (Group 1) and 47 individuals with no middle ear disease (Group 2). Multiplex real-time polymerase chain reaction was used to investigate the presence of 20 different respiratory viruses. Virus results were compared with bacteriomes of the same populations. At least one respiratory virus was detected in 56% of the patients in Group 1 and 12.8% of the individuals in Group 2. The viral co-infection rate for Group 1 and 2 was 8% and 2.1%, respectively. In Group 1, adenovirus was the most frequently detected virus with a rate of 24%, either alone (16%) or concurrent with other viruses (8%), followed by influenza B (12%), rhinovirus, and bocavirus (8%) each. Parainfluenza 4, coronavirus OC43, and RSV A/B were detected in 4% of the sample each. In Group 2, rhinovirus was detected in two samples (4.3%) followed by adenovirus, coronavirus OC43, coronavirus E299, and coronavirus NL63 with a rate of 2.1% each. The detection rate of respiratory viruses was significantly higher in children aged 6 to 11 years. There was no positive association between virus and bacteria found in the middle ear cavity. The current study has provided comprehensive data indicating the presence of diverse respiratory viruses in the healthy middle ear cavity. Our results also suggest that respiratory viruses might have a contribution to OME pathogenesis.

High genotypic diversity of Rhinoviruses obtained from Tunisian children with severe acute respiratory infection.

INTRODUCTION: Rhinoviruses (HRV) are among the leading causes of Severe Acute Respiratory Infection (SARI). Their burden and genetic diversity vary from one region to another and little is known in Northern African regions. This study describes epidemiological patterns and genotypic diversity of HRV in SARI cases during a two and half year's study, in Northern Tunisia. METHODOLOGY: A total of 271 SARI cases, admitted into the Pediatric Intensive Care Unit of Bechir Hamza Children's Hospital in Tunis, were collected between September 2015 and December 2017. The investigation concerned 104 samples positive for HRV and/or HEV (Human Enterovirus) obtained among these cases. Specific HRV and HEV detections were assessed by real-time PCRs. The HRV molecular typing was based on the VP4-VP2 genomic region analyses. RESULTS: Among the viral SARI cases, 33.5% and 12.3% were positive for HRV and HEV respectively. Molecular investigations showed high prevalence of HRV-A (63.3%) followed by HRV-C (30.6%) and HRV-B (6.1%) and high genotypic diversity with 27 types. HRV cases were mostly detected in toddlers younger than 6 months. A total of 16 cases (28%) were found with bacterial and/or viral co-infection. HRV-C infection and HRV-A with bacterial co-infection were associated with complicated infection. Some of the detected types showed a continuous circulation or turnover during an extended period. HRV-A101 and HRV-C45 were the most frequently detected types. CONCLUSIONS: This study revealed, for the first time, the high HRV diversity in Tunisia, a North-African region. Specific phylogenetic investigations may help to evaluate their diversity and to trace their spread and epidemiological origin.

Detection of respiratory viruses in primary cholesteatoma tissues.

Cholesteatomas are frequent middle ear benign tumors of unknown etiology. Infectious agents have been considered as possible contributing factors in the pathogenesis of cholesteatomas. Aiming to investigate the presence of respiratory viruses in primary cholesteatoma tissues, 26 formalin-fixed paraffin-embedded primary cholesteatoma tissues obtained from patients seen at the of the Clinical Hospital of the University of São Paulo School of Medicine, in Ribeirão Preto, Brazil were tested by real-time polymerase chain reaction (PCR). Considering the PCR results, 35% of the tissues were positive for human rhinovirus (HRV), 15.3% for human enterovirus (EV), 3.8% for human metapneumovirus (HMPV), and 3.8% for human bocavirus (HBoV). Serial immunohistochemistry for virus antigens and cell surface markers evidenced that the viruses were associated with fibroblasts, dendritic cells, macrophages, B lymphocytes, CD4+ , and CD8+ T lymphocytes. These findings indicate for the first time the presence of active respiratory virus infection in primary cholesteatoma tissues, suggesting that persisting virus infection in the middle could play a role in the pathogenesis and evolution of cholesteatomas.

Seasonal variation of respiratory viral infections: a comparative study between children with cancer undergoing chemotherapy and children without cancer.

Respiratory viral infections (RVIs) affect children year-round, with seasonal-specific patterns. Pediatric oncology patients are uniquely vulnerable to infection, but whether this predisposes them to different patterns of RVIs than healthy children is unknown. There is also limited data on the impact of RVIs on cancer patients. We conducted a retrospective study of children ages 1-21 with cancer presenting to the clinic and emergency department (ED) and a randomly selected subset of patients without cancer presenting to the ED who had positive nasopharyngeal viral polymerase chain reactions at our institution from 2014 to 2019. Sixty-seven cancer patients (206 RVI episodes) and 225 pediatric non-cancer patients (237 RVI episodes) were included. Human rhino/enterovirus (HRE) was the most common infection in both groups in the spring, summer, and fall. In the winter, the most common RVI was influenza in cancer patients verses respiratory syncytial virus in non-cancer patients. On age-adjusted analysis, the likelihood of detecting coronavirus in the winter, HRE in the spring and fall, and parainfluenza in the summer was significantly greater in cancer patients (OR = 2.60, 2.52, 5.73, 3.59 respectively). Among cancer RVI episodes, 50% received parenteral antibiotics, 22% were severely neutropenic, 22% had chemotherapy delays for a median of six days, 16% were hospitalized, and 6% received intravenous immunoglobulin. We conclude that there are differences in the seasonal patterns of RVIs between children with and without cancer. RVIs also cause significant morbidity in children with cancer.

Low circulation of Influenza A and coinfection with SARS-CoV-2 among other respiratory viruses during the COVID-19 pandemic in a region of southern Brazil.

With the arrival of coronavirus disease 2019 (COVID-19) in Brazil in February 2020, several preventive measures were taken by the population aiming to avoid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection including the use of masks, social distancing, and frequent hand washing then, these measures may have contributed to preventing infection also by other respiratory viruses. Our goal was to determine the frequencies of Influenza A and B viruses (FLUAV/FLUBV), human mastadenovirus C (HAdV-C), Enterovirus 68 (EV-68), and rhinovirus (RV) besides SARS-CoV-2 among hospitalized patients suspect of COVID-19 with cases of acute respiratory disease syndrome (ARDS) in the period of March to December 2020 and to detect possible coinfections among them. Nucleic acid detection was performed using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in respiratory samples using naso-oropharyngeal swabs and bronchoalveolar lavage. A total of 418 samples of the 987 analyzed (42.3%) were positive for SARS-CoV-2, 16 (1.62%) samples were positive for FLUAV, no sample was positive for FLUBV or EV-68, 67 (6.78%) samples were positive for HAdV-C, 55 samples were positive for RV 1/2 (26.3%) and 37 for RV 2/2 (13.6%). Coinfections were also detected, including a triple coinfection with SARS-CoV-2, FLUAV, and HAdV-C. In the present work, a very low frequency of FLUV was reported among hospitalized patients with ARDS compared to the past years, probably due to preventive measures taken to avoid COVID-19 and the high influenza vaccination coverage in the region in which this study was performed.

Significant impact of nationwide SARS-CoV-2 lockdown measures on the circulation of other respiratory virus infections in Austria.

BACKGROUND: Since the worldwide spread of SARS-CoV-2, different European countries reacted with temporary national lockdowns with the aim to limit the virus transmission in the population. Also Austria started a lockdown of public life in March 2020. OBJECTIVES: In this study we investigated whether the circulation of different respiratory virus infections in Austria, as assessed by the established respiratory virus surveillance system, is affected by these measures as well and may reflect the success of the lockdown in limiting respiratory virus transmission. STUDY DESIGN: Sentinel data obtained for influenza virus, respiratory syncytial virus, human metapneumovirus and rhinovirus cases were analyzed and compared between the season 2019/2020 and the five previous seasons. RESULTS: We observed a rapid and statistically significant reduction of cumulative cases for all these viruses within short time after the lockdown in March 2020, compared to previous seasons (each p < 0.001). Also, sentinel screening for SARS-CoV-2 infections was performed and a decrease of SARS-CoV-2 was seen after the lockdown. While for the seasonally occurring viruses as influenza, respiratory syncytial virus or human metapneumovirus the lockdown led to the end of the annual epidemics, a re-increase of rhinovirus infections was observed after liberalization of numerous lockdown measures. CONCLUSIONS: Our data provide evidence that occurrence of different respiratory virus infections reflect not only the efficiency of lockdown measures taken against SARS-CoV-2 but it shows also the effects of lockdown releases on the transmission of respiratory viruses.

Increased risk of rhinovirus infection in children during the coronavirus disease-19 pandemic.

BACKGROUND: Coronavirus disease (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Japan in January 2020 and has spread throughout the country. Previous studies have reported that viral interference among influenza virus, rhinovirus, and other respiratory viruses can affect viral infections at the host and population level. METHODS: To investigate the impact of COVID-19 on influenza and other respiratory virus infections, we analyzed clinical specimens collected from 2244 patients in Japan with respiratory diseases between January 2018 and September 2020. RESULTS: The frequency of influenza and other respiratory viruses (coxsackievirus A and B; echovirus; enterovirus; human coronavirus 229E, HKU1, NL63, and OC43; human metapneumovirus; human parainfluenza virus 1, 2, 3, and 4; human parechovirus; human respiratory syncytial virus; human adenovirus; human bocavirus; human parvovirus B19; herpes simplex virus type 1; and varicella-zoster virus) was appreciably reduced among all patients during the COVID-19 pandemic except for that of rhinovirus in children younger than 10 years, which was appreciably increased. COVID-19 has not spread among this age group, suggesting an increased risk of rhinovirus infection in children. CONCLUSIONS: Rhinovirus infections should be continuously monitored to understand their increased risk during the COVID-19 pandemic and viral interference with SARS-CoV-2.

PACIFIC: a lightweight deep-learning classifier of SARS-CoV-2 and co-infecting RNA viruses.

Viral co-infections occur in COVID-19 patients, potentially impacting disease progression and severity. However, there is currently no dedicated method to identify viral co-infections in patient RNA-seq data. We developed PACIFIC, a deep-learning algorithm that accurately detects SARS-CoV-2 and other common RNA respiratory viruses from RNA-seq data. Using in silico data, PACIFIC recovers the presence and relative concentrations of viruses with > 99% precision and recall. PACIFIC accurately detects SARS-CoV-2 and other viral infections in 63 independent in vitro cell culture and patient datasets. PACIFIC is an end-to-end tool that enables the systematic monitoring of viral infections in the current global pandemic.

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.

Associations Between IFI44L Gene Variants and Rates of Respiratory Tract Infections During Early Childhood.

BACKGROUND: Genetic heterogeneity in type I interferon (IFN)-related gene IFI44L may account for variable susceptibility to respiratory tract infections (RTIs) in children. METHODS: In 2 prospective, population-based birth cohorts, the STEPS Study and the FinnBrain Birth Cohort Study, IFI44L genotypes for rs273259 and rs1333969 were determined in relation to the development of RTIs until 1 or 2 years of age, respectively. At age 3 months, whole-blood transcriptional profiles were analyzed and nasal samples were tested for respiratory viruses in a subset of children. RESULTS: In the STEPS Study (n = 1135), IFI44L minor/minor gene variants were associated with lower rates of acute otitis media episodes (adjusted incidence rate ratio, 0.77 [95% confidence interval, .61-.96] for rs273259 and 0.74 [.55-.99] for rs1333969) and courses of antibiotics for RTIs (0.76 [.62-.95] and 0.73 [.56-.97], respectively. In the FinnBrain cohort (n = 971), IFI44L variants were associated with lower rates of RTIs and courses of antibiotics for RTIs. In respiratory virus-positive 3-month-old children, IFI44L gene variants were associated with decreased expression levels of IFI44L and several other IFN-related genes. CONCLUSIONS: Variant forms of IFI44L gene were protective against early-childhood RTIs or acute otitis media, and they attenuated IFN pathway activation by respiratory viruses.