Stability and age-specific patterns of rhinovirus circulation in children observed over 3 decades.

Clinical, virological and epidemiological characteristics of rhinovirus infections in early childhood: A comparison between non-hospitalised and hospitalised children

Antisera produced in rabbits to 37 rhinovirus (RV) types have been examined for antibody to the 36 corresponding heterologous types. Reciprocal neutralization was noted between RV types 2 and 49 and RV types 13 and 41. Five additional monotypic rhinoviral rabbit antisera neutralized one heterologous rhinovirus. Neutralizing antibody titers against heterologous RV serotypes were similar to those shown in the RV 1A, 1B and RV 9, 32 reciprocal cross-reactions, and would not be expected to result in false identification of serotypes. Comparison of neutralizing antibody titers and neutralization rate constants in serial serum specimens of immunized rabbits showed that antibody response to the immunizing RV type and the cross-reacting type followed a similar time pattern.

Rhinoviruses (RVs) are ubiquitous respiratory pathogens that often cause mild or subclinical infections. Molecular detection of RVs from the upper respiratory tract can be prolonged, complicating etiologic association in persons with severe lower respiratory tract infections. Little is known about RV viremia and its value as a diagnostic indicator in persons hospitalized with community-acquired pneumonia (CAP). Sera from RV-positive children and adults hospitalized with CAP were tested for RV by real-time reverse-transcription polymerase chain reaction. Rhinovirus species and type were determined by partial genome sequencing. Overall, 57 of 570 (10%) RV-positive patients were viremic, and all were children aged <10 years (n = 57/375; 15.2%). Although RV-A was the most common RV species detected from respiratory specimens (48.8%), almost all viremias were RV-C (98.2%). Viremic patients had fewer codetected pathogens and were more likely to have chest retractions, wheezing, and a history of underlying asthma/reactive airway disease than patients without viremia. More than 1 out of 7 RV-infected children aged <10 years hospitalized with CAP were viremic. In contrast with other RV species, RV-C infections were highly associated with viremia and were usually the only respiratory pathogen identified, suggesting that RV-C viremia may be an important diagnostic indicator in pediatric pneumonia.

E Bergroth, M Aakula, V Elenius. J Allergy Clin Immunol Pract. 2020;8(2):588–595.e4 Respiratory syncytial virus (RSV) and rhinovirus (RV)-induced bronchiolitis are associated with increased asthma risk in children. Whether virus types have different risks associated with later development of asthma is not known. RV-A and RV-C cause more severe respiratory illness than RV-B. Cadherin-related family member 3, a receptor for RV-C, and atopy are risk factors for development of early-onset asthma. The current study investigates whether RSV or RV types are differentially associated with use of asthma medications in the 4 years following severe bronchiolitis in infancy. Children less than 24 months of age, hospitalized for bronchiolitis over consecutive winter …

Rationale: Rhinovirus (RV) C can cause asymptomatic infection and respiratory illnesses ranging from the common cold to severe wheezing.Objectives: To identify how age and other individual-level factors are associated with susceptibility to RV-C illnesses.Methods: Longitudinal data from the COAST (Childhood Origins of Asthma) birth cohort study were analyzed to determine relationships between age and RV-C infections. Neutralizing antibodies specific for RV-A and RV-C (three types each) were determined using a novel PCR-based assay. Data were pooled from 14 study cohorts in the United States, Finland, and Australia, and mixed-effects logistic regression was used to identify factors related to the proportion of RV-C versus RV-A detection.Measurements and Main Results: In COAST, RV-A and RV-C infections were similarly common in infancy, whereas RV-C was detected much less often than RV-A during both respiratory illnesses and scheduled surveillance visits (P < 0.001, χ2) in older children. The prevalence of neutralizing antibodies to RV-A or RV-C types was low (5-27%) at the age of 2 years, but by the age of 16 years, RV-C seropositivity was more prevalent (78% vs. 18% for RV-A; P < 0.0001). In the pooled analysis, the RV-C to RV-A detection ratio during illnesses was significantly related to age (P < 0.0001), CDHR3 genotype (P < 0.05), and wheezing illnesses (P < 0.05). Furthermore, certain RV types (e.g., C2, C11, A78, and A12) were consistently more virulent and prevalent over time.Conclusions: Knowledge of prevalent RV types, antibody responses, and populations at risk based on age and genetics may guide the development of vaccines or other novel therapies against this important respiratory pathogen.

Human rhinovirus (RV) is an important viral pathogen associated with severe acute respiratory tract infection. The present study retrospectively identified RV types in hospitalized patients with severe acute respiratory infection (SARI) from October 2017 to June 2019 in Henan Province, China. Real-time PCR was used to screen pharyngeal swab samples for RV. Then, the VP1 gene sequences of RV-positive samples were amplified and sequenced with nested primer PCR; subsequently, analyses of the molecular epidemiology and genetic diversity characteristics of the RV types were performed.Seventy-three out of 1015 respiratory samples were identified as RV-positive, from which 65 complete VP1 sequences were successfully sequenced. These RVs were classified into 41 different types, including 26 RV-A types, 2 RV-B types, and 13 RV-C types. The RVs showed an obvious seasonal distribution, with peaks in summer and autumn. The epidemic peak of RV-C was later than that of RV-A. In addition, two new types of species, B and C, were proposed, Bpat107 and Cpat58, respectively. Compared with other types in the same RV species, the pairwise nucleotide p-distances of the two novel RV types were 0.262~0.402 and 0.251~0.508, respectively. This study analyzed the seasonal and genetic characteristics of RV associated with SARI cases in Henan Province, China. Two novel RV types were proposed.

Integrated-omics endotyping of infants with rhinovirus bronchiolitis and risk of childhood asthma

Rhinoviruses (RV) are a major cause of Severe Acute Respiratory Infection (SARI) in children, with high genotypic diversity in different regions. However, RV type diversity remains unknown in several regions of the world. In this study, the genetic variability of the frequently circulating RV types in Northern Tunisia was investigated, using phylogenetic and phylogeographic analyses with a specific focus on the most frequent RV types: RV-A101 and RV-C45. This study concerned 13 RV types frequently circulating in Northern Tunisia. They were obtained from respiratory samples collected in 271 pediatric SARI cases, between September 2015 and November 2017. A total of 37 RV VP4-VP2 sequences, selected among a total of 49 generated sequences, was compared to 359 sequences from different regions of the world. Evolutionary analysis of RV-A101 and RV-C45 showed high genetic relationship between different Tunisian strains and Malaysian strains. RV-A101 and C45 progenitor viruses’ dates were estimated in 1981 and 1995, respectively. Since the early 2000s, the two types had a wide spread throughout the world. Phylogenetic analyses of other frequently circulating strains showed significant homology of Tunisian strains from the same epidemic period, in contrast with earlier strains. The genetic relatedness of RV-A101 and RV-C45 might result from an introduction of viruses from different clades followed by local dissemination rather than a local persistence of an endemic clades along seasons. International traffic may play a key role in the spread of RV-A101, RV-C45, and other RVs.

In two placebo-controlled, double-blind studies, the prophylactic efficacy of recombinant DNA-produced interferon alpha 2 (IFN-alpha 2) against induced rhinovirus (RV) type 39 infection in susceptible volunteers was assessed. IFN-alpha 2 was given by intranasal drops in either multiple treatments (11.4 X 10(6) IU four times per day for four days) or one treatment daily (42.8 X 10(6) IU once per day for five days) starting before RV type 39 challenge. The efficacy rates of multiple-dose IFN-alpha 2 for preventing infection, virus shedding, and RV type 39-specific colds were 78%, 78%, and 100%, respectively. The corresponding rates for one daily treatment were 45%, 64%, and 75%, respectively. Both dosage regimens were associated with significant reductions in days of virus shedding and nasal mucus production. In the second study, three IFN-alpha 2 recipients developed transient leukopenia (less than 4,000 leukocytes/mm3). The results suggest that intranasal IFN-alpha 2 may prove to be a safe and effective method of preventing rhinovirus infection and illness.

To explore the clinical epidemiological characteristics of rhinovirus (RV) infection in children hospitalized due to acute respiratory infection (ARI) in the Maternal and Child Health Hospital of Hubei Province. A retrospective, observational study was conducted, including 32 016 children hospitalized with acute respiratory infections (ARI) who underwent targeted high-throughput sequencing (tNGS) at the Maternal and Child Health Hospital of Hubei Province from January 2023 to December 2024. Clinical data were collected to analyze the epidemiological characteristics and related clinical manifestations of RV. Comparisons between groups were performed using the χ2 test, and multivariate logistic regression analysis was applied to identify risk factors associated with RV-related pneumonia. The results showed that the positive rate of RV was 21.28% (6 814/32 016). The positive rates in the age groups of <6 months, 6 months to <1 year, 1 to <3 years, 3 to <6 years, and 6 to ≤14 years were 20.38% (459/2 252), 23.14% (506/2 187), 23.76% (1 462/6 153), 24.66% (2 663/10 801), and 16.23% (1 724/10 623), respectively, with statistically significant differences (χ2=263.403, P<0.05). The detection rate of RV reached two peaks in February and May 2023; in 2024, it remained at a relatively high level from March to June and from October to November. Among the three types of RV, RV-A was the most frequently detected, with a detection rate of 58.95% (4 017/6 814). The mixed detection rate of RV with other pathogens was 51.91% (3 537/6 814). The pathogens mixed with RV were mainly Mycoplasma pneumoniae (MP), followed by parainfluenza virus (PIV), respiratory syncytial virus (RSV), adenovirus (ADV), human metapneumovirus (HMPV), and influenza A virus H3N2. Among the 6 814 RV-positive children included in this study, pneumonia (60.29%) was the most common clinical manifestation following RV infection.The pneumonia incidence rate in the RV mixed detection group was 68.59% (2 426/3 537), and the incidence rate of severe pneumonia was 2.71% (96/3 537). The pneumonia incidence rate in the RV single detection group was 51.33% (1 682/3 277), and the incidence rate of severe pneumonia was 1.83% (60/3 277). The pneumonia incidence rate and the incidence rate of severe pneumonia in the mixed infection group were both higher than those in the single detection group, with statistically significant differences (χ2=211.702, P<0.05; χ2=5.932, P<0.05). Multivariate logistic regression analysis showed that co-infection was the major risk factor for pneumonia in children with RV infection [OR=1.721, 95% confidence interval(CI)=1.581-1.871, P<0.001]. In conclusion, the epidemic season of RV was concentrated in spring and autumn, and the predominant type was RV-A in this study. The age group of 3 to <6 years had the highest positive rate of RV. RV is prone to co-infection with other respiratory pathogens, with MP being the most common. Mixed infection may lead to aggravated conditions and should be given attention in clinical practice.

Objective To discuss the significance of different types of human rhinovirus (HRV) as pathogen and the clinical features of different types of HRV in pediatric intensive care unit(PICU). Methods Eight hundred and fifty-two nasopharyngeal aspirates specimen (NPA) were collected from children who were admitted to PICU, the Second Affiliated Hospital of Shantou University Medical College from November 2010 to October 2015 and were tested by using nested reverse transcription-polymerase chain reaction(RT-PCR). Gene fragments for VP4/VP2 capsid protein amplified from HRV positive specimens were sequenced for HRV genotype confirmation.Then clinical characte-ristics of these HRV positive cases were analyzed. Results Among these 852 specimens tested, 214(25.12%) were HRV positive, including 95 samples(44.39%)positive for HRV-A, 17 samples(7.94%)for HRV-B, and 55 samples(25.70%)for HRV-C determined by sequence analysis; while the species of 47 samples (21.96%) of the total were unclassified clearly.HRV-A, HRV-B, HRV-C co-infection with other respiratory viruses accounted for 33.68%(32/95 cases), 29.41%(5/17 cases), and 29.09%(16/55 cases), respectively.The clinical characteristics of children infected with HRV-A, HRV-B, HRV-C were similar, and wheezing and polypnea were more common with HRV-C infections than HRV-A and HRV-B infections.The severity among children positive for different groups HRV showed no significant difference(H=0.631, P>0.05), as well as that between children co-infected with HRV and other viruses and those infected with HRV only(H=0.886, P>0.05). Conclusions Different types of HRV were major causes of infectious disease in pediatric critical disease.The clinical characteristics of children infected with HRV-A, HRV-B, HRV-C were similar.Wheezing and polypnea were more common with HRV-C infections than HRV-A and HRV-B infections. Key words: Rhinovirus; Genotype; Child; Intensive care

The aim of this study was to investigate the prevalence and seasonal distribution of respiratory viruses in pediatric and adult outpatients and inpatients who were admitted to hospital with the symptoms of upper and lower respiratory tract infections, during a 12-year period. A total of 5102 clinical samples (4372 nasopharyngeal swabs, 316 bronchoalveolar lavages, 219 transtracheal aspirates, 163 nasopharyngeal aspirates, 20 sputum, 10 nasal swabs) examined in our laboratory between January 1st 2002 and July 17th 2014, were evaluated retrospectively. Of the specimens, 1107 (21.7%) were obtained from outpatients and 3995 (78.3%) from hospitalized patients. Of the patients, 2851 (55.9%) were male and 2251 (44.1%) were female, while 1233 (24.2%) were adults and 3869 (75.8%) were children (age range: 1 day - 93 years; median: 3 years). Respiratory samples were investigated for the presence of respiratory syncytial virus (RSV), influenza virus type A and B (INF-A, INF-B), adenovirus (AdV), parainfluenza viruses (PIV types 1-4), human rhinoviruses (HRV), human coronaviruses (HCoV), human metapneumovirus (HMPV) and human bocavirus (HBoV). All specimens were tested by both direct immunofluorescence antibody (DFA) and shell vial cell culture (SVCC) methods. In DFA assay the samples were initially screened by fluorescent-labeled polyclonal antibodies, and the positive ones were typed by using monoclonal antibodies (Light Diagnostics, Merck Millipore, USA). In SVCC, HEp-2, MDCK, A-549 and Vero cell lines were used for the isolation of viruses. In addition to these methods, real-time multiplex PCR methods (RealAccurate®, Respiratory RT PCR, PathoFinder, Netherlands and Seeplex® RV15 ACE Detection, Seegene, South Korea) were used for the detection of respiratory viruses in samples (n= 2104) obtained from 2007 to 2014. Respiratory viruses were detected in a total of 1705 (33.4%) patients, of them 967 (19%) were male and 738 (14.4%) were female. Three hundred and eighteen (18.6%) of the 1705 patients were infected with multiple respiratory viruses. The most frequently observed co-infections were RSV+INF-A (40/318; 12.6%), and RSV+PIV (33/318; 10.4%). The rate of positivity for the respiratory viruses in pediatric and adult groups were 35.4% (1369/3869) and 27.3% (336/1233), respectively (p< 0.000). The most frequently detected virus in pediatric group was RSV (336/1369; 24.5%), followed by influenza viruses (314/1369; 22.9%), PIV (197/1369; 14.4%), HRV (118/1369; 8.6%), AdV (75/1369; 5.5%) and the others (49/1369; 3.6%). On the other hand the most frequently detected virus in adult group was influenza viruses (181/336; 53.8%) followed by AdV (37/336; 11%), RSV (24/336; 7.1%), PIV (24/336; 7.1%), HRV (23/336; 6.8%) and the others (9/336; 2.7%). The rate of multiple virus infections in pediatric and adult groups were 7.2% (280/3869) and 3% (38/1233), respectively. Most of the coinfections (280/318; 88%) were detected in children. Respiratory viruses were detected positive in 40.2% (445/1107) of outpatients, and in 31.5% (1260/3995) of inpatients (p< 0.000). The most frequent viruses detected in pediatric outpatients and inpatients were HRV and RSV, respectively, while influenza viruses were the first in line among both adult outpatients and inpatients. During the study period, a PIV-3 outbreak (n= 96) have emerged between December 2004-April 2005, and an influenza A (H1N1)pdm09 outbreak (n= 207) between November 2009-January 2010. When the seasonal distribution was considered, the isolation rates of 1705 respiratory viruses in winter, spring, summer and autumn were 44.4%, 27%, 8.3% and 20.3%, respectively. RSV was most frequently detected from December to March, influenza viruses from November to March, HRV from December to June, and mixed infections from January to February. In conclusion, the data of our study obtained in about 12-year period indicated that the prevalence of respiratory viruses in acute respiratory infections is 33.4%, and they typically active during the months of winter and early spring in our region.

ABSTRACTRhinoviruses (RVs) cause recurrent infections of the nasal and pulmonary tracts, life-threatening conditions in chronic respiratory illness patients, predisposition of children to asthmatic exacerbation, and large economic cost. RVs are difficult to treat. They rapidly evolve resistance and are genetically diverse. Here, we provide insight into RV drug resistance mechanisms against chemical compounds neutralizing low pH in endolysosomes. Serial passaging of RV-A16 in the presence of the vacuolar proton ATPase inhibitor bafilomycin A1 (BafA1) or the endolysosomotropic agent ammonium chloride (NH4Cl) promoted the emergence of resistant virus populations. We found two reproducible point mutations in viral proteins 1 and 3 (VP1 and VP3), A2526G (serine 66 to asparagine [S66N]), and G2274U (cysteine 220 to phenylalanine [C220F]), respectively. Both mutations conferred cross-resistance to BafA1, NH4Cl, and the protonophore niclosamide, as identified by massive parallel sequencing and reverse genetics, but not the double mutation, which we could not rescue. Both VP1-S66 and VP3-C220 locate at the interprotomeric face, and their mutations increase the sensitivity of virions to low pH, elevated temperature, and soluble intercellular adhesion molecule 1 receptor. These results indicate that the ability of RV to uncoat at low endosomal pH confers virion resistance to extracellular stress. The data endorse endosomal acidification inhibitors as a viable strategy against RVs, especially if inhibitors are directly applied to the airways.IMPORTANCE Rhinoviruses (RVs) are the predominant agents causing the common cold. Anti-RV drugs and vaccines are not available, largely due to rapid evolutionary adaptation of RVs giving rise to resistant mutants and an immense diversity of antigens in more than 160 different RV types. In this study, we obtained insight into the cell biology of RVs by harnessing the ability of RVs to evolve resistance against host-targeting small chemical compounds neutralizing endosomal pH, an important cue for uncoating of normal RVs. We show that RVs grown in cells treated with inhibitors of endolysosomal acidification evolved capsid mutations yielding reduced virion stability against elevated temperature, low pH, and incubation with recombinant soluble receptor fragments. This fitness cost makes it unlikely that RV mutants adapted to neutral pH become prevalent in nature. The data support the concept of host-directed drug development against respiratory viruses in general, notably at low risk of gain-of-function mutations.

Enteroviruses (EVs) and rhinoviruses (RVs) are significant pathogens of humans and are the subject of intensive clinical and epidemiological research and public health measures, notably in the eradication of poliovirus and in the investigation and control of emerging pathogenic EV types worldwide. EVs and RVs are highly diverse in their antigenic properties, tissue tropism, disease associations and evolutionary relationships, but the latter often conflict with previously developed biologically defined terms, such as “coxsackieviruses”, “polioviruses” and “echoviruses”, which were used before their genetic interrelationships were understood. This has created widespread formatting problems and inconsistencies in the nomenclature for EV and RV types and species in the literature and public databases. As members of the International Committee for Taxonomy of Viruses (ICTV) Picornaviridae Study Group, we describe the correct use of taxon names for these viruses and have produced a series of recommendations for the nomenclature of EV and RV types and their abbreviations. We believe their adoption will promote greater clarity and consistency in the terminology used in the scientific and medical literature. The recommendations will additionally provide a useful reference guide for journals, other publications and public databases seeking to use standardised terms for the growing multitude of enteroviruses and rhinoviruses described worldwide.

Background During the COVID-19 pandemic, seasonal respiratory virus detections decreased. However, rhinoviruses (RV) continued to circulate in high numbers. Previous data suggest that RV type circulation is heterogenous and diverse. We characterized the distribution of RV species and the diversity of RV types among children with medically attended acute respiratory infection (ARI) during the first year of the pandemic. *Spring: Feb to Apr, Summer: May to July, Fall: Aug to Oct, Winter: Nov to Jan.Table 1.Age, seasonal distribution and ED/hospitalization status based on RV species, New Vaccine Surveillance Network, 03/01/20-02/28/21 Methods During March 1, 2020 - February 28, 2021, we enrolled children (&amp;lt; 18 years) with ARI seen as either inpatients (IP) or in the emergency department (ED) via prospective surveillance at 7 sites comprising the New Vaccine Surveillance Network. Respiratory specimens were tested for multiple viral pathogens by RT-PCR at each site. A subset of RV/enterovirus (EV) positive specimens were further processed for Sanger sequencing. To obtain a representative subgroup of specimens to sequence within each site, every odd numbered specimen (including co-detections) from ED and IP from every month was selected. Sequenced regions were analyzed using Lasergene software and compared against GenBank sequences using BLAST. Selected demographic data were analyzed by RV species, month, and setting. Results Among 4881 enrolled children, RV and/or EV was detected in 1508 (31%). Of these, 675 samples (335 IP and 340 ED) were selected for sequencing based on sampling scheme. Sequencing was successful in 595/675 (88%) extracts including 257 RV-A (43.2%), 32 RV-B (5.4%) and 298 RV-C (50.1%); 7 (1.2%) were EV and 1 was a non-typeable RV. Four of the seven EV samples were reported as EV-D68 on sequencing. Overall, 37 RV-A types, 10 RV-B types and 36 types of RV-C species were identified with A101 (44, 17.1%), B6 (10, 31.1%) and C56 (34, 11.4%) as the most common RV-A, B and C types, respectively. Age, seasonal distribution, and ED/IP status by RV species are described in Table 1 with higher detections reported in children &amp;lt; 5 years. Conclusion Among children with medically attended ARI with RV detections, RV-C and RV-A predominated with high type diversity. Most detections were in younger children but occurred similarly in the IP and ED settings. Both species exhibited seasonal trends and high RV diversity that were similar to trends reported in pre-pandemic period. Disclosures Janet A. Englund, MD, Abbvie: Advisor/Consultant|AstraZeneca: Advisor/Consultant|AstraZeneca: Grant/Research Support|GlaxoSmithKline: Advisor/Consultant|GlaxoSmithKline: Grant/Research Support|Meissa Vaccines: Advisor/Consultant|Merck: Advisor/Consultant|Pfizer: Board Member|Pfizer: Grant/Research Support|Pfizer: Speaker at meeting|SanofiPasteur: Advisor/Consultant|Shinogi: Advisor/Consultant Mary A. Staat, MD, MPH, Cepheid: Grant/Research Support|Merck: Grant/Research Support|Pfizer: Grant/Research Support|Up-To-Date: Honoraria Elizabeth P. Schlaudecker, MD, MPH, Pfizer: Grant/Research Support|Sanofi Pasteur: Advisor/Consultant Natasha B. Halasa, MD, MPH, Merck: Grant/Research Support Geoffrey A. Weinberg, MD, Inhalon: Advisor/Consultant|Merck &amp; Company: Honoraria for textbook chapter preparation Mary E. Moffatt, M.D., Child Abuse Pediatrics (CAP) representative to Council of Pediatric Subspecialties (CoPS); Current Chair of CoPS Executive Committee: Board Member|I am a volunteer member of the Board of Directors, Kansas Children’s Service League: Board Member|My institution, Children’s Mercy Hospital, Kansas City, receives grant support from CDC for my participation/time dedicated to this research.: Grant/Research Support|My institution, Children’s Mercy Hospital, Kansas City, receives grant support from HRSA for my participation/time dedicated to work on research: Grant/Research Support|My institution, Children’s Mercy Hospital, Kansas City, receives grant support from NIH for my participation/time dedicated to work on research: Grant/Research Support Rangaraj Selvarangan, BVSc, PhD, D(ABMM), FIDSA, FAAM, Abbott: Grant/Research Support|Abbott: Honoraria|BioMerieux: Grant/Research Support|Cepheid: Grant/Research Support|Diasorin: Grant/Research Support|GSK: Advisor/Consultant|Hologic: Grant/Research Support|Luminex: Grant/Research Support|Qiagen: Grant/Research Support