Hospitalized Children With Common Human Coronavirus Clinical Impact of Codetected Respiratory Syncytial Virus and Rhinovirus.

BACKGROUND: The clinical impact of common human coronavirus (cHCoV) remains unclear. We studied the clinical manifestations of pediatric cHCoV infections and the possible modifying effects of codetected human rhinovirus (RV) and respiratory syncytial virus (RSV). METHODS: We used data from an 11-year-long prospective study of hospitalized children with community-acquired respiratory tract infections. Nasopharyngeal aspirates were analyzed with real-time polymerase chain reaction assay for cHCoV OC43, NL63, HKU1 and 229E, and 15 other respiratory viruses. We assessed disease severity based on the clinical factors hospitalization length, oxygen requirement, other respiratory support and supplementary fluids. RESULTS: cHCoV was detected in 341 (8%) of 4312 children. Among 104 children with single cHCoV detections, 58 (56%) had lower respiratory tract infection (LRTI) and 20 (19%) developed severe disease. The proportion with severe disease was lower among single cHCoV detections compared with single RSV detections (338 of 870; 39%), but similar to single RV detections (136 of 987; 14%). Compared with single cHCoV, codetected cHCoV-RSV was more often associated with LRTI (86 of 89; 97%) and severe disease (adjusted odds ratio, 3.3; 95% confidence interval: 1.6-6.7). LRTI was more frequent in codetected cHCoV-RV (52 of 68; 76%) than single cHCoV, but the risk of severe disease was lower (adjusted odds ratios, 0.3; 95% confidence interval: 0.1-1.0). CONCLUSIONS: cHCoV was associated with severe LRTI in hospitalized children. Viral codetections were present in two-thirds. Codetections of cHCoV-RV were associated with lower proportions of severe disease, suggesting a modifying effect of RV on HCoV.

Incidence and Outcome of Coinfections with SARS-CoV-2 and Rhinovirus.

BACKGROUND: We aimed to compare the clinical severity in patients who were coinfected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and rhinovirus or monoinfected with a single one of these viruses. METHODS: The study period ranged from 1 March 2020 to 28 February 2021 (one year). SARS-CoV-2 and other respiratory viruses were identified by real-time reverse-transcription-PCR as part of the routine work at Marseille University hospitals. Bacterial and fungal infections were detected by standard methods. Clinical data were retrospectively collected from medical files. This study was approved by the ethical committee of our institute. RESULTS: A total of 6034/15,157 (40%) tested patients were positive for at least one respiratory virus. Ninety-three (4.3%) SARS-CoV-2-infected patients were coinfected with another respiratory virus, with rhinovirus being the most frequent (62/93, 67%). Patients coinfected with SARS-CoV-2 and rhinovirus were significantly more likely to report a cough than those with SARS-CoV-2 monoinfection (62% vs. 31%; p = 0.0008). In addition, they were also significantly more likely to report dyspnea than patients with rhinovirus monoinfection (45% vs. 36%; p = 0.02). They were also more likely to be transferred to an intensive care unit and to die than patients with rhinovirus monoinfection (16% vs. 5% and 7% vs. 2%, respectively) but these differences were not statistically significant. CONCLUSIONS: A close surveillance and investigation of the co-incidence and interactions of SARS-CoV-2 and other respiratory viruses is needed. The possible higher risk of increased clinical severity in SARS-CoV-2-positive patients coinfected with rhinovirus warrants further large scale studies.

Sex differences in innate anti-viral immune responses to respiratory viruses and in their clinical outcomes in a birth cohort study.

The mechanisms explaining excess morbidity and mortality in respiratory infections among males are poorly understood. Innate immune responses are critical in protection against respiratory virus infections. We hypothesised that innate immune responses to respiratory viruses may be deficient in males. We stimulated peripheral blood mononuclear cells from 345 participants at age 16 years in a population-based birth cohort with three live respiratory viruses (rhinoviruses A16 and A1, and respiratory syncytial virus) and two viral mimics (R848 and CpG-A, to mimic responses to SARS-CoV-2) and investigated sex differences in interferon (IFN) responses. IFN-α responses to all viruses and stimuli were 1.34-2.06-fold lower in males than females (P = 0.018 - < 0.001). IFN-ß, IFN-γ and IFN-induced chemokines were also deficient in males across all stimuli/viruses. Healthcare records revealed 12.1% of males and 6.6% of females were hospitalized with respiratory infections in infancy (P = 0.017). In conclusion, impaired innate anti-viral immunity in males likely results in high male morbidity and mortality from respiratory virus infections.

Dynamic innate immune response determines susceptibility to SARS-CoV-2 infection and early replication kinetics.

Initial replication of SARS-CoV-2 in the upper respiratory tract is required to establish infection, and the replication level correlates with the likelihood of viral transmission. Here, we examined the role of host innate immune defenses in restricting early SARS-CoV-2 infection using transcriptomics and biomarker-based tracking in serial patient nasopharyngeal samples and experiments with airway epithelial organoids. SARS-CoV-2 initially replicated exponentially, with a doubling time of ∼6 h, and induced interferon-stimulated genes (ISGs) in the upper respiratory tract, which rose with viral replication and peaked just as viral load began to decline. Rhinovirus infection before SARS-CoV-2 exposure accelerated ISG responses and prevented SARS-CoV-2 replication. Conversely, blocking ISG induction during SARS-CoV-2 infection enhanced viral replication from a low infectious dose. These results show that the activity of ISG-mediated defenses at the time of SARS-CoV-2 exposure impacts infection progression and that the heterologous antiviral response induced by a different virus can protect against SARS-CoV-2.

Kallikreins emerge as new regulators of viral infections.

Kallikrein-related peptidases (KLKs) or kallikreins have been linked to diverse (patho) physiological processes, such as the epidermal desquamation and inflammation, seminal clot liquefaction, neurodegeneration, and cancer. Recent mounting evidence suggests that KLKs also represent important regulators of viral infections. It is well-established that certain enveloped viruses, including influenza and coronaviruses, require proteolytic processing of their hemagglutinin or spike proteins, respectively, to infect host cells. Similarly, the capsid protein of the non-enveloped papillomavirus L1 should be proteolytically cleaved for viral uncoating. Consequently, extracellular or membrane-bound proteases of the host cells are instrumental for viral infections and represent potential targets for drug development. Here, we summarize how extracellular proteolysis mediated by the kallikreins is implicated in the process of influenza (and potentially coronavirus and papillomavirus) entry into host cells. Besides direct proteolytic activation of viruses, KLK5 and 12 promote viral entry indirectly through proteolytic cascade events, like the activation of thrombolytic enzymes that also can process hemagglutinin, while additional functions of KLKs in infection cannot be excluded. In the light of recent evidence, KLKs represent potential host targets for the development of new antivirals. Humanized animal models to validate their key functions in viral infections will be valuable.

Can Measurements of Inflammatory Biomarkers be Used to Spot Respiratory Viral Infections?

Accurate detection of human respiratory viral infections is highly topical. We investigated how strongly inflammatory biomarkers (FeNO, eosinophils, neutrophils, and cytokines in nasal lavage fluid) and lung function parameters change upon rhinovirus 16 infection, in order to explore their potential use for infection detection. To this end, within a longitudinal cohort study, healthy and mildly asthmatic volunteers were experimentally inoculated with rhinovirus 16, and time series of these parameters/biomarkers were systematically recorded and compared between the pre- and post-infection phases of the study, which lasted two months and one month, respectively. We found that the parameters'/biomarkers' ability to discriminate between the infected and the uninfected state varied over the observation time period. Consistently over time, the concentration of cytokines, in nasal lavage fluid, showed moderate to very good discrimination performance, thereby qualifying for disease progression monitoring, whereas lung function and FeNO, while quickly and non-invasively measurable using cheap portable devices (e.g., at airports), performed poorly.

Human Rhinovirus Infection Blocks Severe Acute Respiratory Syndrome Coronavirus 2 Replication Within the Respiratory Epithelium: Implications for COVID-19 Epidemiology.

Virus-virus interactions influence the epidemiology of respiratory infections. However, the impact of viruses causing upper respiratory infections on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication and transmission is currently unknown. Human rhinoviruses cause the common cold and are the most prevalent respiratory viruses of humans. Interactions between rhinoviruses and cocirculating respiratory viruses have been shown to shape virus epidemiology at the individual host and population level. Here, we examined the replication kinetics of SARS-CoV-2 in the human respiratory epithelium in the presence or absence of rhinovirus. We show that human rhinovirus triggers an interferon response that blocks SARS-CoV-2 replication. Mathematical simulations show that this virus-virus interaction is likely to have a population-wide effect as an increasing prevalence of rhinovirus will reduce the number of new coronavirus disease 2019 cases.

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.

Identification of pathogens from the upper respiratory tract of adult emergency department patients at high risk for influenza complications in a pre-Sars-CoV-2 environment.

The emergence of SARS-CoV-2 and subsequent COVID-19 pandemic highlights the morbidity and potential disease severity caused by respiratory viruses. To elucidate pathogen prevalence, etiology of coinfections and URIs from symptomatic adult Emergency department patients in a pre-SARS-CoV-2 environment, we evaluated specimens from four geographically diverse Emergency departments in the United States from 2013-2014 utilizing ePlex RP RUO cartridges (Genmark Diagnostics). The overall positivity was 30.1% (241/799), with 6.6% (16/241) coinfections. Noninfluenza pathogens from most to least common were rhinovirus/enterovirus, coronavirus, human metapneumovirus and RSV, respectively. Broad differences in disease prevalence and pathogen distributions were observed across geographic regions; the site with the highest detection rate (for both mono and coinfections) demonstrated the greatest pathogen diversity. A variety of respiratory pathogens and geographic variations in disease prevalence and copathogen type were observed. Further research is required to evaluate the clinical relevance of these findings, especially considering the SARS-CoV-2 pandemic and related questions regarding SARS-CoV-2 disease severity and the presence of co-infections.

Respiratory viruses and febrile response in children with febrile seizures: A cohort study and embedded case-control study.

OBJECTIVE: There are limited data on the pathogen-related and host-related factors in the pathogenesis of febrile seizures (FS). We designed a controlled study to compare the role of different respiratory viruses and febrile response in FS. METHODS: In a prospective cohort study of 1899 pediatric emergency room patients aged 6 months-6 years with a positive respiratory virus multiplex PCR, we identified 225 patients with FSs. We first compared the distribution of respiratory viruses in age-stratified patients with FSs with that in other patients. In an embedded case-control study, we compared the febrile response in patients with FSs with that in the controls matched for age, season and the same respiratory virus. RESULTS: The relative risk for FS was the highest for coronavirus OC43, 229E, and NL63 infections [RR: 3.2, 95 % confidence interval (CI): 1.4-7.2) and influenza A and B [RR: 2.5, 95 % CI: 1.4-4.7] as compared to those with other respiratory viral infections. The patients with FSs had a stronger febrile response of 39.2 °C (difference: 0.8 °C, 95 % CI: 0.5-1.2) later during hospitalization after acute care than the controls matched for the same respiratory virus. CONCLUSIONS: Influenza and coronaviruses caused relatively more FS-related emergency room visits than other respiratory viruses. Furthermore, the febrile response was stronger in the patients with FSs than in the controls matched for the same respiratory virus. The results suggest that the pathomechanism of FSs includes modifiable pathogen-related and host-related factors with possible potential in the prevention of FSs.

Rhinovirus and asthma: Challenges and opportunities.

Human rhinoviruses (RVs) are the primary aetiological agent of the common cold. Generally, the associated infection is mild and self-limiting, but may also be associated with bronchiolitis in infants, pneumonia in the immunocompromised and exacerbation in patients with pulmonary conditions such as asthma or chronic obstructive pulmonary disease. Viral infection accounts for as many as two thirds of asthma exacerbations in children and more than half in adults. Allergy and asthma are major risk factors for more frequent and severe RV-related illnesses. The prevalence of RV-induced wheezing will likely continue to increase given that asthma affects a significant proportion of the population, with allergic asthma accounting for the majority. Several new respiratory viruses and their subgroups have been discovered, with various degrees of relevance. This review will focus on RV infection in the context of the epidemiologic evidence, genetic variability, pathobiology, clinical studies in the context of asthma, differences with other viruses including COVID-19 and current treatment interventions.

Detection and clinical characteristics analysis of respiratory viruses in hospitalized children with acute respiratory tract infections by a GeXP-based multiplex-PCR assay.

BACKGROUND: The information regarding viral epidemiology and clinical characteristics in hospitalized children with acute respiratory tract infection (ARTI) in central Fujian is limited. In this study, we aimed at analyzing the viral epidemiology and clinical characteristics of ARTI in hospitalized children admitted to The First Affiliated Hospital of Fujian Medical University. METHODS: Cohort of 386 hospitalized children (31 days to 15 years) diagnosed with ARTI admitted to the Department of Pediatrics from January 1, 2018, to December 31, 2018, was enrolled in this study. Nasopharyngeal swab or sputum samples on the day of hospitalization were tested for 11 viruses via a GeXP-based multiplex-PCR assay. The viral profiles and clinical characteristics were analyzed. RESULTS: The overall positive rate of the samples was 43.26% (167/386). Among the 167 positive samples, 134 (80.24%, 134/167) had a single virus and 33 (19.76%, 33/167) had multiple viruses. There was a significant difference in the frequency of single vs mixed infections among positive samples (80.24% vs 19.76%; χ2  = 122.168, P = .000) as well as among the total examined samples (34.72% vs 8.55%; χ2  = 77.945, P = .000). Human rhinovirus was the most prevalent virus (17.36%, 67/386), followed by influenza A (5.96%, 23/386) and human adenovirus (5.70%, 22/386). There was no significant difference in the etiological distribution of viral pathogens between males and females (χ2  = 0.480, P = .489). Viral infections were more likely to occur in the winter-spring months than in the summer-autumn months (52.51% vs 33.53%, χ2  = 13.830, P = .000). CONCLUSIONS: The GeXP-based multiplex PCR is an accurate and high-throughput assay allows us to quickly detect multiple respiratory viruses simultaneously in pediatric patients. Our study provides information on the viral profiles and clinical characteristics in hospitalized children with ARTI, which would help better effective prevention strategies.

A 14-year Prospective Study of Human Coronavirus Infections in Hospitalized Children: Comparison With Other Respiratory Viruses.

BACKGROUND: Human coronaviruses (HCoVs) have been recognized as causative agents of respiratory tract infections.Our aim was to describe HCoV infections in hospitalized children in a prospective surveillance study for 14 years and compare them with other respiratory viruses. METHODS: As a part of an ongoing prospective study to identify the etiology of viral respiratory infections in Spain, we performed the analysis of HCoV infections in children hospitalized in a secondary hospital in Madrid, between October 2005 and June 2018. Clinical data of HCoV patients were compared with those infected by rhinovirus, respiratory syncytial virus and influenza. RESULTS: The study population consisted of 5131 hospitalizations for respiratory causes in children. A total of 3901 cases (75.9%) had a positive viral identification and 205 cases (4.1%) were positive for HCoV. Only 41 cases (20%) of HCoV infection were detected as single infections. Episodes of recurrent wheezing were the most common diagnosis, and 112 children (54%) had hypoxia. Clinical data in HCoV cases were similar to those associated with rhinovirus; however, patients with HCoV were younger. Other viruses were associated with hypoxia more frequently than cases with HCoV; high fever was more common in influenza infections and bronchiolitis in respiratory syncytial virus group. Although a slight peak of circulation appears mostly in winter, HCoV has been detected throughout the year as well. CONCLUSIONS: HCoV infections represent a small fraction of respiratory infections that require hospitalization in children and their characteristics do not differ greatly from other respiratory viral infections.

Seasonality of Respiratory Viral Infections.

The seasonal cycle of respiratory viral diseases has been widely recognized for thousands of years, as annual epidemics of the common cold and influenza disease hit the human population like clockwork in the winter season in temperate regions. Moreover, epidemics caused by viruses such as severe acute respiratory syndrome coronavirus (SARS-CoV) and the newly emerging SARS-CoV-2 occur during the winter months. The mechanisms underlying the seasonal nature of respiratory viral infections have been examined and debated for many years. The two major contributing factors are the changes in environmental parameters and human behavior. Studies have revealed the effect of temperature and humidity on respiratory virus stability and transmission rates. More recent research highlights the importance of the environmental factors, especially temperature and humidity, in modulating host intrinsic, innate, and adaptive immune responses to viral infections in the respiratory tract. Here we review evidence of how outdoor and indoor climates are linked to the seasonality of viral respiratory infections. We further discuss determinants of host response in the seasonality of respiratory viruses by highlighting recent studies in the field.