New Aspects on Human Rhinovirus Infections

Divya J

INF ESPID Reports and Reviews 203095 CONTENTS Human Rhinovirus Infections Antifungal Resistance in Children Ruuskanen et al EDITORIAL BOARD Co-Editors: Delane Shingadia and Irja Lutsar Human Rhinovirus Infections Board Members

David Burgner (Melbourne, Australia) Nicole Ritz (Basel, Switzerland) Tobias Tenenbaum (Mannhein, Germany) XXX Luisa Galli (Florence, Italy) Ira Shah (Mumbai, India) Marc Tebruegge (Southampton, UK) Cristiana Nascimento-Carvalho Matthew Snape (Oxford, UK) Marceline van Furth (Amsterdam, (Bahia, Brazil) George Syrogiannopoulos The Netherlands) Ville Peltola (Turku, Finland) (Larissa, Greece) Anne Vergison (Brussels, Belgium) Pediatr Infect Dis J

Lippincott Williams & Wilkins New Aspects on Human Rhinovirus Infections

Olli Ruuskanen, MD, PhD,* Matti Waris, PhD,† and Octavio Ramilo, MD‡ Hagerstown, MD

Key Words: rhinovirus, common cold, pneumonia uncultivable but detectable by PCR, resulted infections both in young children, adults and in classification of new species C with a cur- elderly people. HRVs were detected in 52% (Pediatr Infect Dis J 2013;32: 553–555) rent number of 60 genotypes. They also show of 200 young adults with common cold and that recombinatorial events have taken place in 92% during September and October.11 In during the evolution of HRVs. HRV-C viruses 194 young children with newly onset com- any large studies performed in 1960s do not use intercellular adhesion molecule-1 mon cold at least 1 respiratory virus was Mdetected human rhinovirus (HRV) by (major) or the low-density lipoprotein recep- detected in 92% of the patients. HRV was virus isolation in one quarter of the cases tor (minor) as receptors as do HRV-A and the most common respiratory virus, found in with acute upper respiratory infections, and HRV-B species.2,4–7 71% of the children.12 HRV was mainly considered a common cold virus. Virus culture, the standard method for Clinical Profile on Natural Acute Otitis Media detection, was carried out in research labora- Rhinovirus Infections Respiratory syncytial virus (RSV) has tories with special expertise and the role of HRV is undoubtly the most commonly earlier been considered a major predisposing HRV outside common cold remained unclear. detected respiratory virus in all age groups factor to development of AOM. Studies with During 1990s, polymerase chain reaction and probably the most common causative HRV PCR suggest a dominant role of also 2013 (PCR) techniques for HRV became gener- agent of all acute infections in humans. By 2 HRVs.13 In the Finnish Otitis Media Cohort ally available and they revolutionized HRV years of age, >90% of the children have expe- Study, 759 AOM events were recorded and studies bringing important new biologic and rienced at least 1 HRV infection.8 HRVs are 42% of these events were associated with 1–3 clinical observations. associated with 5 hospitalizations per 1000 HRV infections. In the second part of this Copyright © 2013 by Lippincott Williams & Wilkins children <5 years old in the United States.9 study, HRV was detected in 32% of 1416 Virology HRV infection is associated with a wide AOM events. Rhinovirus RNA has been HRVs are positive-strand RNA range of clinical presentations including clas- detected in 17%–41% of the middle ear fluid 00 viruses of the genus Enterovirus in the fam- sic common cold, acute otitis media (AOM), specimens from children with AOM.14 ily Picornaviridae. In addition to HRV, sinusitis, severe bronchiolitis, asthma, pneu- enterovirus, parechovirus and hepatovirus in monia, fever alone, infections in preterm Bronchiolitis, Recurrent 00 the picornavirus family cause human infec- infants, severe infections in immunosup- Wheezing and Asthma tions. With virus culture techniques 100 pressed patients, as well as worsening of HRV is associated in up to one quarter HRV serotypes have been identified. Genome chronic conditions particularly asthma, cystic of bronchiolitis cases in infants. In a 3-year sequencing revealed originally 2 species, A 0891-3668 fibrosis and chronic obstructive pulmonary prospective study, Calvo and colleagues15 and B. Recent studies of strains, which were disease. It is becoming well established that investigated the frequency of 16 respiratory HRV-A and HRV-C are more common and viruses in 318 children (mean age 6 months) 10.1097/INF.0b013e3182833c90 From the *Department of Pediatrics, Division of may cause more severe illnesses in infants hospitalized with bronchiolitis. A virus was Infectious Diseases, Turku University Hospital; than HRV-B.7 PCR studies also suggest that found in 87% of the cases, RSV in 61% and †Department of Virology, University of Turku, Turku, Finland; and ‡Division of Infectious Dis- subclinical infections may be much more HRV in 17%. In a prospective multicenter The Pediatric Infectious Disease Journal eases, Nationwide Children’s Hospital and Ohio common than earlier understood. Subclini- 3-year study in the United States, Mans- State University, Columbus, OH. cal infections have also been recorded many bach and colleagues examined 2207 children The authors have no funding or conflicts of interest younger than 2 years hospitalized for severe to disclose. years ago in experimental HRV studies, in 10 32 Address for correspondence: Olli Ruuskanen, MD, which virus culture was used. bronchiolitis. A virus was detected in 94% PhD, Department of Pediatrics, Turku, University of the cases, RSV in 72% and HRV in 26%, Hospital, 20520 Turku, Finland. E-mail: olli.ruus- Common Cold and other viruses in 7%.16 RSV dominates 5 [email protected]. Compared with other respiratory in infants and HRV in children older than Copyright © 2013 by Lippincott Williams & Wilkins 17 ISSN: 0891-3668/13/3205-0553 viruses, HRVs have a dominant role as 12 months. Interestingly, HRV-infected DOI: 10.1097/INF.0b013e3182833c90 causative agents of upper respiratory tract children had a significantly shorter hospital May The Pediatric Infectious Disease Journal • Volume 32, Number 5, May 2013 www.pidj.com | 553 2013 Ruuskanen et al The Pediatric Infectious Disease Journal • Volume 32, Number 5, May 2013

length of stay as compared with children with that HRVs are important causative agents of increase the risk of secondary bacterial infec- RSV bronchiolitis.16 Fatal HRV bronchiolitis pneumonia both in children and in adults and tion by attenuating TLR-dependent immune was recently reported in Vietnam.18 Innate in immunosuppressed subjects. responses.35 immune responses inversely correlate with the HRV disease severity.19 HRV RNA in Asymptomatic Diagnosis Several studies have shown that infants Individuals Today RT-PCR is the method of choice with bronchiolitis will have significantly The clinical importance of detection for the detection of HRV because it is easier more often recurrent wheezing than controls HRV RNA by RT-PCR can be questioned. to perform, more sensitive than HRV culture without bronchiolitis. HRV as the causative HRV RNA can be detected before, during and detects HRV-C. However, it should be agent is the most important risk factor, fol- and after symptomatic infection, in subclini- emphasized, that a positive PCR test result lowed by a positive family history for asthma cal infection, or it may just be an innocent does not necessarily reflect active virus rep- or atopy.20–22 Severe episodes of bronchioli- contamination. Several studies have inden- lication, as does positive virus culture. A dif- tis increases the odds of early asthma.23 In a tified HRV RNA in 12%–35% of asympto- ficulty with HRV is the paucity of serologic tests to verify acute infection. long-term postbronchiolitis follow-up in Fin- matic subjects.10 In 1 recent study, HRV was Including HRV into multiplex PCR land, asthma at 7 years of age was more com- detected in the nasopharynx of 433 6- to assays has increased the number of diag- mon after HRV (52%) than after RSV (15%) 24-month-old healthy children from 31% to noses. The most sensitive PCRs for HRVs bronchiolitis.20 At the moment it is not under- 50% of samples.31 It is important to recognize amplify parts of the 5′ noncoding region. stood whether HRV infection causes asthma that in otherwise healthy subjects, HRV is not They are not always selective for HRVs but or whether it only identifies the susceptible known to induce chronic illness and virus also detect human enteroviruses. The dif- children and promotes the development. shedding lasts 2–4 weeks after acute HRV ferentiation requires additional confirmation There is evidence that early prednisolone infection. For these reasons, Jartti and cow- like sequencing, although melting tempera- treatment of HRV-induced wheezing may orkers10 concluded that PCR-positive respira- ture determination can be used as a screen- reduce recurrent wheezing. This requires fur- tory HRV finding detects most probably true ing tool.36 Flocked swabs with nylon fibres ther confirmation, as prednisolone treatment infection with or without symptoms. are now preferred for nasal or nasopharyn- does not achieve a similar benefit in bronchi- geal sampling because they are convenient to olitis caused by RSV.24 Coinfections With Other Viruses use and have similar or better sensitivity than Up to 90% of asthma exacerbations and Bacteria nasopharyngeal aspirates or nasopharyngeal in children are associated with virologically In 4 recent studies, HRV was detected washes.36–38 Self sampling conducted at home defined natural respiratory virus infections. in association with one or more other respira- by the parents with subsequent shipping of HRV is the most commonly found virus and tory viruses in 24%, 34%, 37% and 70% of the samples by mail to the laboratory has 12,15,16,30 is detected approximately in two thirds of the the cases. The clinical relevance of been successfully used in clinical studies.36 cases. Children with asthma and allergic sen- detection of several viruses is uncertain and The clinical significance of HRV load sitization are more prone to HRV infections. it certainly can be asked what is the role of is not well established. Jansen and cowork- There is evidence that asthmatic patients have HRV when it is detected by PCR with 3 other ers39 detected higher HRV loads in children more frequent HRV, more severe, and longer viruses. with acute symptomatic respiratory infec- lasting lower respiratory tract infections than Interest has grown with respect to tions compared with asymptomatic controls. 25 nonasthmatics. the interaction of bacteria and viruses in Utokaparch and associates40 detected signifi- Many studies have unveiled the the pathogenesis of respiratory infections. cantly higher HRV load in lower respiratory mechanisms of increased susceptibility to Earlier, in contrast to for example influenza tract infections versus nonlower respiratory HRV infections in asthmatic patients. They viruses, HRVs have not been considered to tract infections. On the other hand, no correla- include changes in airway epithelium, defec- facilitate bacterial coinfections. Ruohola tion between HRV load and the disease sever- tive HRV-induced secretion of interferon-β, and coworkers studied etiology of AOM ity was reported by Takeyama et al.41 interferon-λ, interleukin-10 and probably in 79 middle ear fluids suctioned through interferon-α, and impaired alveolar mac- tympanostomy tube. In 16 cases HRV was Treatment and Prevention rophage function.20,25 detected, and in all cases they were detected No antiviral drug has been approved together with pathogenic bacteria.13 Honki- for clinical use in HRV infections. All possible Pneumonia nen and colleagues28 studied induced sputum candidates have turned out to be disappoint- HRV has been indentified from of 76 children with CAP and found HRV ments. Oral capsid-binding HRV inhibitor, induced sputum, tracheal brushing, bron- plus Streptococcus pneumoniae in 12 of 23 vapendavir and inhaled interferon-β are being choalveolar lavage samples and lung tissue HRV cases. Similarly, in adults with CAP the studied.42 New HRV murine models may samples strongly suggesting that HRV can most frequent viral–bacterial combination facilitate the development of new agents.43 induce lower respiratory tract infections. Nine has been HRV plus S. pneumoniae.32 Peltola The antigenic diversity of HRV makes studies on childhood community-acquired and coworkers33 found a temporal association development of effective vaccines difficult. pneumonia (CAP) (N = 4279 episodes) using between HRV infection and invasive pneu- At the moment, the only way to reduce HRV PCR methods for virus detection found HRV mococcal disease in children. disease burden is prevention of transmis- in 18% of the cases.26 In 1 new study in Italy, Experimental HRV infection in sion. In a family setting, the rates of HRV 592 children with CAP were included and patients with chronic obstructive pulmonary infections were 1.00 cases per person among HRV was identified in 172 cases (29%).27 disease was followed by secondary bacte- siblings and 0.50 cases per person among The clinical profile of 643 HRV infections in rial infection in 60% of the subjects. Bacte- parents of HRV-positive index patients.36 children admitted to hospital were reported in rial infections were associated with reduced Studies carried out 15–25 years ago showed 7 studies and 11%–53% had pneumonia.26,28 levels of antimicrobial peptides.34 In healthy that a major route of transmission is probably HRVs are commonly detected in children children, S. pneumoniae was positively asso- from hands of infected subjects to an inter- with severe pneumonia also in developing ciated with HRV in the nasopharynx.31 New mediary surface or directly to the fingers of countries.29,30 These new findings suggest observations in mice suggest that HRV may the susceptible recipient. HRV may remain

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