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Rhinoviruses: molecular diversity and clinical characteristics

Open AccessPublished:March 03, 2022DOI:https://doi.org/10.1016/j.ijid.2022.02.055

      Abstract

      Background

      Rhinoviruses are commonly considered simple “common cold” agents. The link between their molecular epidemiology and patient clinical presentation and outcomes remains unclear in adult populations.

      Materials/methods

      All nasopharyngeal or bronchoalveolar lavages were screened using multiplex PCR in 3 Parisian hospitals from January 2018 to September 2018. For all detected rhinoviruses, the VP2/VP4 region was subtyped by sequencing.

      Results

      The study included 178 unique patients who were positive for human rhinovirus (HRV). They were primarily men (56%), with a median age of 62.2 years (IQR: 46.8–71.4), frequently presenting chronic respiratory diseases (56%) and/or immunosuppression (46%). Of these, 63% were admitted for respiratory distress, including 25% for pneumonia; 95 (53%), 27 (15%), and 56 (32%) were positive for HRV-A, -B, and -C, respectively. HRV-B appeared to be more associated with immunosuppressive treatments (58% vs 30% and 36% of patients for HRV-A and -C, respectively, p = 0.038), higher coinfection rates (54% vs 34% and 23%, p = 0.03), and higher intensive care unit (ICU) admission rates (35% vs 17% and 13%, p = 0.048). Conversely, HRV-A was more frequently associated with pneumonia (54% vs 31% and 11% for HRV-B and -C, respectively, p = 0.01).

      Conclusions

      This study highlights the high proportion of chronic respiratory diseases or immunosuppression among hospitalized patients infected with a rhinovirus.

      Important

      Human rhinoviruses (HRVs) are frequently detected in patients hospitalized for respiratory distress. Understanding their molecular differences is crucial to finding target treatments and improving patient outcomes.

      Keywords

      Introduction

      Human rhinoviruses (HRVs) belong to the Picornaviridae family and the Enterovirus genus. This virus group includes hundreds of subtypes within 3 groups: A, B, and C (
      • Jacobs Samantha E.
      • Lamson DM
      • St. George K
      • Walsh TJ
      Human Rhinoviruses.
      ). These are considered responsible for the common cold and thus are relatively harmless. HRVs have also been associated with acute exacerbation of chronic bronchitis and asthma (
      • Hershenson MB.
      Rhinovirus-Induced Exacerbations of Asthma and COPD.
      ). They have also been indicated as responsible for pneumonia cases in older patients and immunocompromised patients (
      • Hayden FG.
      Rhinovirus and the lower respiratory tract.
      ). However, the high rate of asymptomatic carriage and prolonged excretion in postsymptomatic patients often complicates their interpretation, and their causative role is not widely recognized (
      • Zlateva KT
      • Vries JJC de
      • Coenjaerts FEJ
      • Loon AM van
      • Verheij T
      • Little P
      • et al.
      Prolonged shedding of rhinovirus and re-infection in adults with respiratory tract illness.
      ). Recent improvements in the molecular diagnosis of respiratory viruses have provided new information on HRVs, revealing them in immunocompromised populations, with up to 43% of detected HRVs being associated with pneumonia or presenting high mortality rates, comparable to viral pneumonia associated with other well-established respiratory viruses (
      • Jacobs SE
      • Soave R
      • Shore TB
      • Satlin MJ
      • Schuetz AN
      • Magro C
      • et al.
      Human rhinovirus infections of the lower respiratory tract in hematopoietic stem cell transplant recipients.
      ). HRVs also represent the most frequently identified viral group among lower respiratory tract infections in various populations (
      • Royston L
      • Tapparel C.
      Rhinoviruses and Respiratory Enteroviruses: Not as Simple as ABC.
      ;
      • Visseaux B
      • Burdet C
      • Voiriot G
      • Lescure F-X
      • Chougar T
      • Brugière O
      • et al.
      Prevalence of respiratory viruses among adults, by season, age, respiratory tract region and type of medical unit in Paris, France, from 2011 to 2016.
      ;
      • Voiriot G
      • Visseaux B
      • Cohen J
      • Nguyen LBL
      • Neuville M
      • Morbieu C
      • et al.
      Viral-bacterial coinfection affects the presentation and alters the prognosis of severe community-acquired pneumonia.
      ).
      Even if rhinovirus respiratory infections represent an economic burden with respect to medical visits and absenteeism (
      • Fendrick AM
      • Monto AS
      • Nightengale B
      • Sarnes M.
      The Economic Burden of Non–Influenza-Related Viral Respiratory Tract Infection in the United States.
      ), neither approved antiviral agents nor vaccines are available. Moreover, no detection or isolation recommendation exists despite their high frequency, even in nosocomial infections (
      • Loubet P
      • Voiriot G
      • Houhou-Fidouh N
      • Neuville M
      • Bouadma L
      • Lescure F-X
      • et al.
      Impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: A single-center retrospective study.
      ;
      • Visseaux B
      • Burdet C
      • Voiriot G
      • Lescure F-X
      • Chougar T
      • Brugière O
      • et al.
      Prevalence of respiratory viruses among adults, by season, age, respiratory tract region and type of medical unit in Paris, France, from 2011 to 2016.
      ). Their detection often relies on multiplex PCR (mPCR) use, allowing reliable detection of respiratory viruses. Although these assays enable rapid results, better isolation management, or, in some cases, antibiotic use, their high cost slows their implementation (
      • Bouzid D
      • Lucet J-C
      • Duval X
      • Houhou-Fidouh N
      • Casalino E
      • Visseaux B
      • et al.
      Multiplex PCR implementation as point of care testing in a French Emergency Department.
      ;
      • Brendish NJ
      • Malachira AK
      • Armstrong L
      • Houghton R
      • Aitken S
      • Nyimbili E
      • et al.
      Routine molecular point-of-care testing for respiratory viruses in adults presenting to hospital with acute respiratory illness (ResPOC): a pragmatic, open-label, randomised controlled trial.
      ;
      • Shengchen D
      • Gu X
      • Fan G
      • Sun R
      • Wang Y
      • Yu D
      • et al.
      Evaluation of a molecular point-of-care testing for viral and atypical pathogens on intravenous antibiotic duration in hospitalized adults with lower respiratory tract infection: a randomized clinical trial.
      ). These assays cannot differentiate HRVs from enteroviruses or determine the HRV group involved. Interestingly, several studies identified clinical differences between HRV types (

      Bizot E, Bousquet A, Charpié M, Coquelin F, Lefevre S, Le Lorier J, et al. Rhinovirus: A Narrative Review on Its Genetic Characteristics, Pediatric Clinical Presentations, and Pathogenesis. Front Pediatr 2021;0. https://doi.org/10.3389/fped.2021.643219.

      ). However, these data only exist for children, and to our knowledge, no other study has aimed to identify similar patterns in adult populations.
      This study exploited the systematic use of mPCR testing for all respiratory infection diagnoses in our hospital, the University Hospital Bichat-Claude Bernard in Paris, France, to sequence all HRVs. We collected the corresponding clinical information to depict HRV viral diversity in adult populations, associated diagnoses, and potential clinical differences between HRV groups.

      Methods

      Study design

      We conducted a multicenter prospective study in 3 hospitals in Paris, Bichat-Claude Bernard, Beaujon, and Louis Mourier hospitals, from January 2018 to August 2018. We included positive respiratory samples for each HRV (nasopharyngeal [NP] swabs and bronchoalveolar lavages [BALs]) after their systematic detection using an mPCR assay (FilmArray panel RP2+, BioFire, bioMérieux).

      RNA extraction and amplification

      Viral RNA extraction was performed on a MagNA Pure LC 2.0 machine (Roche, Mannheim, Germany) with the MagNA Pure LC Total Nucleic Acid Kit – Large Volume reagent kit. Reverse transcription was conducted to amplify a fragment of approximately 550 base pairs (bp) between the viral genes VP4/VP2 and the hypervariable noncoding region in 5′ untranslated region (UTR), located between the forward primer 9895 (position 1083–1058; 5′-GCATCIGGYARYTTCCACCACCANCC-3′) and reverse primer 9895 (position 534–560; 5′-GGGACCAACTACTTTGGGTGTCCGTGT-3′) (
      • Savolainen C
      • Mulders MN
      • Hovi T.
      Phylogenetic analysis of rhinovirus isolates collected during successive epidemic seasons.
      ). Samples with insufficient amplification were retested by seminested PCR for better yields. This additional amplification used the QIAGEN Taq Polymerase kit and the specific primers described by Linsuwanon et al. (
      • Linsuwanon P
      • Payungporn S
      • Samransamruajkit R
      • Posuwan N
      • Makkoch J
      • Theanboonlers A
      • et al.
      High prevalence of human rhinovirus C infection in Thai children with acute lower respiratory tract disease.
      ).

      Sequence analysis and phylogenetic typing

      The amplicons obtained were sequenced by Sanger method using the BigDye Terminator v1.1 sequencing kit (Applied Biosystems, Courtaboeuf, France). The raw sequences obtained by Sanger method were analyzed and assembled to extract the consensus sequence for each strain with Geneious software.
      The sequences were then aligned with the reference sequences extracted from the reference dataset on picornaiviridae.com. The alignment was performed using MUSCLE and manually checked using AliView. The phylogenetic tree was generated using IQ-TREE 2.1.2 by a maximum-likelihood phylogenetic model, with the nucleotide substitution model General Time Reversible (GTR) integrating the discrete gamma model for site variation rates (G4). Branch support was estimated using ultrafast bootstrap method with 1,000 replicas.

      Data collection and analysis

      The clinical information for each sample was retrieved from hospitalization reports and laboratory results. Baseline characteristics within each group were summarized using appropriate descriptive statistics. The statistical analysis was performed using R v3.6.2.

      Ethics

      The research was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (CEERB N2019-029).

      Results

      Population's characteristics

      From January 2018 to August 2018, 4,573 mPCRs were performed at Bichat hospital. Among them, 417 (9%) were positive for Enterovirus/rhinovirus, including 329 NP swabs and 88 BALs; 38 of 417 biological samples were missing or had insufficient volume for viral sequencing and were not included. The viral sequence was successfully obtained for 259 samples (68%), including 5 enteroviruses that were secondarily excluded from this study. Thus, 254 rhinoviruses (185 from NP swabs and 69 from BALs), corresponding to 196 unique patients, were included.
      Among these, 178 clinical observations were retrieved from hospitalization records.
      The included patients were mainly men (100/178, 56%) with a median age of 62 years (IQR: 47–71). The frequency of chronic respiratory diseases was 56% in this population, mainly presenting with asthma, chronic obstructive pulmonary disease (COPD), and lung transplantation. Immunosuppression was defined by immunosuppressive treatment, oral corticosteroid therapy, malignant hemopathy, solid cancer, or HIV infection with a CD4 count of <200/mm3 and concerned 46% of the included patients. Overall, 56 patients (31%) were neither immunocompromised nor had chronic respiratory disease.
      Of the included patients, 112 (63%) were admitted for respiratory distress (Table 1), and pneumonia diagnosis was made by physicians for 52 (29%) included patients. The median hospital stay was 6 days (IQR: 1–14); 32 (18%) patients were admitted to the intensive care unit (ICU), and 8 (5%) patients died during hospitalization.
      Table 1Population clinical characteristics
      TotalHRV-AHRV-BHRV-Cp-value
      n178962656
      % men100 (56%)54 (56%)12 (46%)34 (61%)0.5
      Age – median [IQR]62.35 [46.8–71.4]63.2 [51.6 –71]63.1 [47.7–69.5]58.7 [40.9–73.8]0.7
      Chronic respiratory diseases – n (%)100 (56%)53 (55%)16 (62%)31 (55%)0.9
      Asthma26 (15%)10 (10%)4 (15%)12 (21%)
      COPD36 (20%)21 (22%)5 (19%)10 (17%)
      Lung transplantation27 (15%)11 (11%)8 (31%)8 (14%)
      Chronic respiratory insufficiency26 (14.6%)14 (15%)7 (27%)5 (8.9%)
      Immunocompromised – n (%)81 (46%)45 (47%)16 (62%)20 (36%)0.08
      Immunosuppressive treatments64 (36%)29 (30%)15 (58%)20 (36%)0.038
      Solid organ transplantation41 (23%)20 (21%)10 (38%)11 (20%)
      Solid tumor13 (7%)11 (11%)02 (4%)
      Others8 (4%)6 (6%)1 (4%)0
      Smoking – n (%)53 (30%)28 (29%)8 (31%)17 (30%)1.0
      Obesity – n (%)29/115 (25%)19/63 (30%)4/20 (20%)7/32 (21.8%)0.7
      Charlson score – median [IQR]6 [3.25–8]6 [4–8]5.5 [4–7]4.5 [2.75–7.25]0.08
      Admission motivated by respiratory distress112 (62.9%)65 (68%)10 (38%)37 (66%)0.023
      Influenza-like illness23 (12.4%)13 (14%)3 (12%)7 (13%)1.0
      Bronchiolitis11 (6.2%)8 (8%)03 (5%)0.3
      Pneumonia33 (19%)20 (21%)5 (19%)8 (14%)0.7
      COPD Exacerbation13 (7.3%)7 (7.4%)1 (3.8%)5 (8.9%)0.7
      Asthma8 (4%)2 (2%)06 (11%)0.049
      Other respiratory distress24 (13%)15 (16%)1 (4%)8 (14%)0.80
      Respiratory symptoms at the time of mPCR96(54%)54(56%)17 (65%)25(45%)0.2
      Signs of ILI and pneumonia77 (43%)42 (44%)17 (65%)18 (32%)
      Signs of ILI only8(4%)6 (6%)\2 (4%)
      Signs of pneumonia only11(6%)6(6%)\5(9%)
      Retained diagnosis
      Pneumonia retained as final diagnosis – n (%)52 (29%)33 (34%)11 (42%)8 (14%)0.006
      Other diagnosis126 (70%)63 (66%)15 (58%)48 (86%)
      Influenza-like illness21 (12%)9 (9%)3 (12%)9 (16%)
      Bronchiolitis19 (11%)12 (13%)1 (4%)6 (11%)
      Exacerbation COPD17 (10%)11 (11%)1 (4%)5 (9%)
      Asthma10 (6%)2 (2%)08 (14%)
      Other respiratory distress31 (17%)16 (17%)5 (19%)10 (18%)
      Coinfection with another pathogen61 (34%)34 (35%)14 (54%)13 (23%)0.03
      Bacterial coinfection32 (18%)15 (16%)7 (27%)10 (18%)0.15
      Viral coinfection12 (7%)8 (8%)2 (8%)2 (4%)0.7
      Mixed coinfection13 (7%)7 (7%)5 (19%)1 (2%)0.23
      Hospital length of stay – median [IQR]6 [1–13.75]6 [1–14.2]10 [5–19.2]5 [0.75–12]0.060
      Intensive care unit admission – n (%)32 (18%)16 (17%)9 (35%)7 (13%)0.048
      SAPS II score – median [IQR]40 [28–65]55 [39.2–65.5]26 [23–30]58.5 [33–85.8]0.056
      Length of stay – median [IQR]6 [2–14]5.5 [1.75–13]9 [4.25–15.2]6 [5–13]0.7
      Invasive mechanical ventilation requirement – n (%)18/32 (56.2%)10/16 (62.5%)6/8 (75%)2/5 (40%)0.4
      Death – n (%)8 (4.5%)7 (7.4%)01 (1.8%)0.25
      Abbreviations: COPD, chronic obstructive pulmonary disease; HRV, human rhinovirus; SAPS II, Simplified Acute Physiology Score II; ILI, Influenza Like Illness; mPCR, multiplex PCR.

      Associated pathogen detection

      Among the 178 HRV-positive included patients, 60 (34%) were coinfected with 1 or more microbial pathogens, including 32 (18%), 12 (7%), and 13 (7%) bacterial-, viral-, and bacterioviral coinfections. Fungal coinfections with Pneumocystis jirovecii or Aspergillus fumigatus were rare (n = 4, 2%). Three sputum cultures positive for Candida were not considered exceptionally involved in pneumopathies (Table 1).
      Patients with an HRV monoinfection were more frequently immunocompromised than coinfected patients (55% vs 45%, p = 0.033) and more frequently had chronic respiratory diseases (60% vs 40%, p = 0.02). However, lung transplant patients (20/27, 75%) presented more frequently with coinfection than other immunocompromised patients (29/65, 45%), highlighting this population's greater susceptibility to multiple infections and polymicrobial airway colonization. Conversely, patients with asthma were largely spared from coinfection (5/26, 20%) (Table 2).
      Table 2Properties of HRVs coinfections
      TotalSingle HRV infectionHRV in coinfectionp-value
      All samples17811761
      Asthma26 (15%)21 (80%)5 (20%)0.116
      COPD36 (20%)18 (50%)18 (50%)0.03
      Lung transplantation27 (15%)7 (25%)20 (75%)<10–3
      Chronic respiratory insufficiency91 (51%)55 (60%)36 (40%)0.156
      Immunocompromised – n (%)65 (47%)36 (55%)29 (45%)0.033
      ICU admission – n (%)32 (18%)8(25%)24 (75%)<10–3
      Death – n (%)8 (4.5%)4 (100%)4(0%)0.448
      Abbreviations: COPD, chronic obstructive pulmonary disease; HRV, human rhinovirus; ICU, intensive care unit.

      Epidemiology of viral subgroups

      Among the 186 rhinoviruses sequenced, 98 (53%), 27 (15%), and 61 (32%) belonged to groups A, B, and C, respectively (Figure 1). The temporal distribution of each subtype is illustrated in Figure 2.
      Figure 1
      Figure 1Phylogenetic tree of all sequenced HRVs. This tree was obtained by VP4/VP2 region sequencing and phylogenetic reconstruction using maximum likelihood. The rhinoviruses sequenced in the current work appear in color (n = 254), whereas reference rhinoviruses appear in black. HRV, human rhinovirus.
      Figure 2
      Figure 2Temporal Distribution of HRV species. The weekly number of identified HRV with a successful sequencing is indicated on the x-axis. Each HRV group is indicated by a specific color. HRV, human rhinovirus.
      Interestingly, the proportion of patients treated with immunosuppressants was significantly different for HRV-A, -B, and -C at 30%, 58%, and 36%, respectively (p = 0.04). The higher prevalence of patients with immunosuppressants presenting with HRV-B was statistically significant compared with HRV-A (p = 0.01) but not HRV-C (p = 0.09). Among patients infected with HRV-B, the frequency of coinfection was also higher than among patients with HRV-A (54% vs 34%, p = 0.03) or HRV-C (54% vs 23%, p = 0.01). No difference was observed regarding coinfection rates between HRV-A and HRV-C (34% vs 23%, p = 0.4) (Table 1).
      ICU admission rate was 16% for all HRV-positive patients but statistically different across the HRV types (p = 0.048). Thus, ICU admissions were more frequent for patients with HRV-B than those with HRV-C (30% vs 9%, p = 0.02) and HRV-A even if not reaching statistical significance (30% vs 17%, p = 0.16). Likewise, the duration of hospitalization tended to be longer for patients infected with group B (10 [5–19] days vs 6 [1–14] for HRV-A, p = 0.111, and vs 5 [1–12] for HRV-C, p = 0.029) (Table 1). However, infections with HRV-C were more frequently observed in patients admitted for an asthma attack (14% vs 2% and 0% with HRV-A and HRV-B, respectively, p = 0.049) and were statistically less associated with pneumonia than infections with HRV-A (14% vs 34%, p = 0.008) and HRV-B (14% vs 42%, p = 0.01) (Table 1).

      Community and nosocomial infections

      Among the 186 HRV-positive patients, 132 were positive within the first 48 hours after admission and 38 were positive >96 hours after admission (group with possible nosocomial infection). Detections between 48 and 96 hours of hospitalization were not considered in this part of the analysis owing to the incubation period of HRV infections. This is generally between 2 and 4 days; thus, such infections could have been community or hospital-acquired (
      • Cambien G
      • Marco L
      • Leveque N
      • Bousseau A
      • Laland C
      • Castel O
      • et al.
      Infections respiratoires virales nosocomiales: incidence et intérêt de la surveillance.
      ;
      • Chow EJ
      • Mermel LA.
      Hospital-Acquired Respiratory Viral Infections: Incidence, Morbidity, and Mortality in Pediatric and Adult Patients.
      ).
      In the nosocomial infection group, we observed more severe infections than in the community-acquired infection group, as depicted by a higher ICU admission rate (33% vs 12%, p <0.01) and a longer hospital stay (22 vs 4 days, p <0.0001) (Table 3). This latter observation should be interpreted with caution, given the selection bias intrinsic to the characterization of the nosocomial group owing to recruiting patients with hospital stays of at least 96 hours.
      Table 3Clinical severity according to nosocomial (>96 hours) or community (<48 hours) acquisition of HRV infection.
      TotalPositive sample <48 hours after admissionPositive sample >96 hours after admissionp-value
      N178138 (74%)40 (22%)/
      % men100 (56%)75 (54%)25 (63%)0.4
      Age median [IQR]61.8 [46.33–71.28]63 [45.03–73.45]61.35 [49.48–65.83]0.19
      Hospital length of stay median [IQR]6 [1–13.75]4 [0–9]22 [11.75–38]<10–12
      Intensive care unit requirement – n (%)31 (17%)17 (12%)13 (33%)0.007
      SAPS II score median [IQR]39.5 [25.25–63.25]39 [23–43]56 [39–65.5]0.35
      Length of stay median [IQR]6.5 [2–15.5]5 [2–9]16 [6.5–23.75]0.02
      Invasive mechanical ventilationrequirement – n (%)19 (63%)9 (53%)10 (77%)0.13
      Death – n (%)8 (5%)4 (3%)3 (8%)0.19
      Abbreviations: HRV, human rhinovirus; SAPS II, Simplified Acute Physiology Score II.

      Discussion

      This work analyzed the molecular diversity of all detected rhinoviruses using systematic mPCR testing for all respiratory infections during a significant 8-month period in 3 university hospitals in Paris, France. We showed a large HRV diversity and several differences in clinical presentation associated with the HRV groups. HRV-B infections were more frequently identified in immunocompromised patients, in association with other pathogens, and more frequently led to ICU admissions than HRV-A and HRV-C. HRV-C infections were more frequently identified with asthma and less frequently associated with pneumonia diagnosis than HRV-A and HRV-B.
      Rhinoviruses are still commonly considered viruses with low pathogenicity limited to upper respiratory tract infections. Several recent studies have highlighted the strong frequency of HRVs in lower respiratory infections. Respiratory viruses are frequent with community-acquired pneumonia, from 13% to 56% (
      • Alimi Y
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      Systematic review of respiratory viral pathogens identified in adults with community-acquired pneumonia in Europe.
      ;
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      Comprehensive Molecular Testing for Respiratory Pathogens in Community-Acquired Pneumonia.
      ;
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      • Fakhran S
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      • et al.
      Community-Acquired Pneumonia Requiring Hospitalization among U.S. Adults.
      ). This is also true for patients with community-acquired pneumonia admitted to ICU, with 31% and 26% of these infections being of single viral and bacterioviral coinfection origins, respectively (
      • Voiriot G
      • Visseaux B
      • Cohen J
      • Nguyen LBL
      • Neuville M
      • Morbieu C
      • et al.
      Viral-bacterial coinfection affects the presentation and alters the prognosis of severe community-acquired pneumonia.
      ). In this latter study, rhinoviruses were the second most frequent viruses after influenza viruses. The same observations were made for nosocomial pneumonia in ICU, with 17% and 13% of infections having viral and bacterioviral origins, respectively, and with influenza and HRVs being the most frequent viruses (
      • Loubet P
      • Voiriot G
      • Houhou-Fidouh N
      • Neuville M
      • Bouadma L
      • Lescure F-X
      • et al.
      Impact of respiratory viruses in hospital-acquired pneumonia in the intensive care unit: A single-center retrospective study.
      ). Despite the increasingly highlighted role of HRVs in respiratory infections, minimal data exist on the molecular diversity of HRVs in hospitalized adults and potential clinical differences.
      Several studies have investigated clinical differences across HRV groups in pediatric populations (

      Bizot E, Bousquet A, Charpié M, Coquelin F, Lefevre S, Le Lorier J, et al. Rhinovirus: A Narrative Review on Its Genetic Characteristics, Pediatric Clinical Presentations, and Pathogenesis. Front Pediatr 2021;0. https://doi.org/10.3389/fped.2021.643219.

      ;
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      • Lee W-M
      • Laing IA
      • Vang F
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      • Zhang G
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      Association between human rhinovirus C and severity of acute asthma in children.
      ;
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      ;
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      ). In a study conducted in Taiwan by Su et al., the prevalence rates of HRV and HRV-C were significantly higher in the asthma exacerbation group than in the non-asthma group (67.9% vs 33.3% in HRV, p = 0.002 and 50% vs 15.2% in HRV-C, p < 0.001) (
      • Su Y-T
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      ). This tendency was also observed in the current work, with HRV-C being more frequently identified for patients admitted with asthma attacks than the other groups. However, HRV-C was overall less frequent in our adult population (14% vs 2% and 0% for HRV-A and HRV-B, respectively).
      In children, HRV-C also appeared to be associated with more severe disease leading to ICU admission in children aged <3 years (35/50, 70% of severe cases) (
      • Lauinger IL
      • Bible JM
      • Halligan EP
      • Bangalore H
      • Tosas O
      • Aarons EJ
      • et al.
      Patient characteristics and severity of human rhinovirus infections in children.
      ). HRV-A was the HRV group presenting the highest rate of severe cases in our adult population.
      HRV-B also presented a particular profile in our population as being more frequently detected in immunocompromised patients. Owing to the recruitment of our hospital group, a large proportion of our immunocompromised patients were lung transplant patients (27/65, 41%), 55% of whom presented with chronic carriage (exceeding 2 months). Moreover, the role of HRVs in graft rejection remains widely debated in the literature (
      • Ambrosioni J
      • Bridevaux P-O
      • Aubert J-D
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      • Wagner G
      • Kaiser L
      Role of rhinovirus load in the upper respiratory tract and severity of symptoms in lung transplant recipients.
      ;
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      Late viral or bacterial respiratory infections in lung transplanted patients: impact on respiratory function.
      ;
      • Kaiser L
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      • Pache J-C
      • Deffernez C
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      • et al.
      Chronic rhinoviral infection in lung transplant recipients.
      ).
      The role of HRVs in nosocomial infection has not been studied, and patients with HRV are not isolated as for SARS-CoV-2, influenza, or respiratory syncytial virus (RSV). Thus, we also evaluated the proportion of possible hospital-acquired HRV infections. These infections were associated with more frequent ICU admissions. Similar observations were made in Poitiers, France, where rhinoviruses were encountered for 17% of nosocomial viral infections (
      • Cambien G
      • Marco L
      • Leveque N
      • Bousseau A
      • Laland C
      • Castel O
      • et al.
      Infections respiratoires virales nosocomiales: incidence et intérêt de la surveillance.
      ). These results highlight the potential detection importance of these viruses and isolation management.
      Our study presents several limitations. If the definition of nosocomial bacterial infection is highly consensual, no clear definition exists for viral respiratory nosocomial infection. We chose a 4-day threshold on the basis of previous publications and HRV incubation periods (
      • Chow EJ
      • Mermel LA.
      Hospital-Acquired Respiratory Viral Infections: Incidence, Morbidity, and Mortality in Pediatric and Adult Patients.
      ;
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      Incubation periods of acute respiratory viral infections: a systematic review.
      ;
      • Reich NG
      • Perl TM
      • Cummings DAT
      • Lessler J.
      Visualizing Clinical Evidence: Citation Networks for the Incubation Periods of Respiratory Viral Infections.
      ). However, especially owing to the possibility of chronic HRV carriage, this definition is not optimal. As our hospitals are following many immunocompromised patients, especially lung transplant patients, the observations made here may not be fully reproducible for other populations. More studies are required in adult populations to confirm our findings.
      In conclusion, to our knowledge, our study is the first to assess the clinical characteristics and prognosis differences between different HRV groups in a hospitalized adult population. HRV-C appeared to be more associated with asthma exacerbation. HRV-A was more frequently associated with pneumonia, and HRV-B was more frequently detected in immunocompromised patients. The description of these patterns should help assess the burden of HRV-associated infections, identify new research axes for understanding the physiopathology of such infections among different patient populations, and help define priority targets for potential vaccines or therapeutic developments.

      Conflict of Interest

      The authors declare no conflict of interest in this work.

      Funding Source

      None.

      Ethical Approval statement

      The research was conducted in accordance with the Declaration of Helsinki and was approved by the local ethics committee (CEERB N2019-029).

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