Santiago M.C. Lopez, John V. Williams
Human rhinoviruses (HRVs) are the most frequent cause of the common cold in both adults and children. Although HRVs were once thought to cause only the common cold, it is now known that they are also associated with lower respiratory infections in adults and children. Many HRVs do not grow in culture. Recent studies using molecular diagnostic tools such as the polymerase chain reaction (PCR) have revealed that HRVs are leading causes of both mild and serious respiratory illnesses in children.
HRVs are members of the Picornaviridae family (“pico” = small; “rna” = RNA genome). Traditional methods of virus typing using immune antiserum have identified approximately 100 serotypes, classified into HRVA, HRVB, and, recently, HRVC species on the basis of the genetic sequence similarity. HRVCs can be detected by reverse transcriptase PCR but have been cultured only using highly specialized methods. Virus gene sequence analysis demonstrates that HRVCs are a genetically distinct and diverse species. The increased proportions of HRV reported in recent PCR-based studies are likely the result of detection of these previously unknown HRVC viruses in addition to improved detection of known HRVA and HRVB strains.
Rhinoviruses are distributed worldwide. There is no consistent correlation between serotypes and epidemiologic or clinical characteristics. Several studies suggest that HRVCs may be more strongly associated with lower respiratory infection and asthma than other HRVs, but the overall disease severity is not increased. Multiple types circulate in a community simultaneously, and particular HRV strains may be isolated during consecutive epidemic seasons, suggesting persistence in a community over an extended period. In temperate climates, the incidence of HRV infection peaks in the fall, with another peak in the spring, but HRV infections occur year-round. HRVC appears to circulate with seasonal variation, exchanging dominance with HRVA. HRVs are the major infectious trigger for asthma among young children, and numerous studies have described a sharp increase in asthmatic attacks in this age-group when school opens in the fall. The peak HRV incidence in the tropics occurs during the rainy season, from June to October.
HRVs are present in high concentrations in nasal secretions and can be detected in the lower airways. HRV particles are nonenveloped and quite hardy, persisting for hours to days in secretions on hands or other surfaces such as telephones, light switches, doorknobs, and stethoscopes. Sneezing and coughing are inefficient methods of transfer. Transmission occurs when infected secretions carried on contaminated fingers are rubbed onto the nasal or conjunctival mucosa. HRVs are present in aerosols produced by talking, coughing, and sneezing. Children are the most important reservoir of these viruses.
The majority of HRVs infect respiratory epithelial cells via intercellular adhesion molecule-1, but some HRV strains utilize the low-density lipoprotein receptor. The receptor for HRVC is cadherin-related family member 3 (CDHR3); however, distinct genetic alleles of this protein confer different susceptibility to HRVC infection. Infection begins in the nasopharynx and spreads to the nasal mucosa and, in some cases, to bronchial epithelial cells in the lower airway. There is no direct cellular damage from the virus, and it is thought that many of the pathogenic effects are produced by the host immune response. Infected epithelial cells release a number of cytokines and chemokines, which induce an influx of neutrophils to the upper airway. Both innate and adaptive immune mechanisms are important in HRV pathogenesis and clearance. HRV-specific nasal immunoglobulin (Ig) A can be detected on day 3 after infection, followed by the production of serum IgM and IgG after 7-8 days. Neutralizing IgG to HRVs may prevent or limit the severity of illness following reinfection. However, cross protection by antibodies to different HRV serotypes is limited in breadth and duration, allowing recurrent infection. Both allergen exposure and elevated IgE values predispose patients with asthma to more severe respiratory symptoms in response to HRV infection. Abnormalities in the host cellular response to HRV infection that result in impaired apoptosis, and increased viral replication, may be responsible for the severe and prolonged symptoms in individuals with asthma.
Most HRV infections produce clinical symptoms, but many are asymptomatic; however, symptomatic HRV infection induces a much more robust host immune response in the blood than asymptomatic infection. Typical symptoms of sneezing, nasal congestion, rhinorrhea, and sore throat develop following an incubation period of 1-4 days. Cough and hoarseness are present in one third of cases. Fever is less common with HRV than with other common respiratory viruses, including influenza virus, respiratory syncytial virus, and human metapneumovirus. Symptoms are frequently more severe and last longer in children, with 70% of children compared with 20% of adults still reporting symptoms by day 10. Virus can be shed for as long as 3 wk.
HRVs are the most prevalent agents associated with acute wheezing, otitis media, and hospitalization for respiratory illness in children and are an important cause of severe pneumonia and exacerbation of asthma or chronic obstructive pulmonary disease in adults. HRV-associated hospitalizations are more frequent in young infants than in older children and in children with a history of wheezing or asthma. HRV infection in immunocompromised hosts may be life threatening. Certain strains or species of HRV, namely HRVC, may be more pathogenic than others.
Culturing HRVs is labor intensive and of relatively low yield; HRVC has only been cultivated in a polarized primary airway epithelial cell culture, a highly specialized method. Sensitive and specific diagnostic methods based on reverse transcriptase PCR are commercially available. However, because commercially available reverse transcriptase PCR tests do not identify the HRV types, it can be difficult to distinguish prolonged shedding from newly acquired infection. An important caveat of HRV detection is the fact that HRV infection can be asymptomatic, and thus the presence of the virus does not prove causality in all cases. Serology is impractical because of the great number of HRV serotypes. A presumptive clinical diagnosis based on symptoms and seasonality is not specific, because many other viruses cause similar clinical illnesses. Rapid detection techniques for HRV might lessen the use of unnecessary antibiotics or procedures.
Possible complications of HRV infection include sinusitis, otitis media, asthma exacerbation, bronchiolitis, pneumonia, and, rarely, death. HRV-associated wheezing during infancy is a significant risk factor for the development of childhood asthma. This effect appears to remain until adulthood, but the mechanisms have not been elucidated. One large study determined that genetic variants at the 17q21 locus were associated with asthma in children who had experienced HRV wheezing illnesses during infancy. A prospective study on a preterm cohort showed that a single nucleotide polymorphism on the gene coding for the vitamin D receptor was associated with development of lower respiratory infection with HRV. Further studies are required to determine the likely multiple genetic and environmental factors that contribute to HRV-related asthma.
Supportive care is the mainstay of HRV treatment. The symptoms of HRV infection are commonly treated with analgesics, decongestants, antihistamines, or antitussives. Data are limited on the effectiveness of such nonprescription cold medications for children. If bacterial superinfections are highly suspected or diagnosed, antibiotics may be appropriate. Antibiotics are not indicated for uncomplicated viral upper respiratory infection. Vaccines have not been successfully developed because of the numerous HRV serotypes and limited cross protection between serotypes.
Good handwashing remains the mainstay of the prevention of HRV infection and should be reinforced frequently, especially in young children, the predominant “vectors” for disease. A polyvalent inactivated vaccine showed promise in a nonhuman primate model, but there are no licensed vaccines or antivirals.