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Rhinoviruses are among the most frequent causes of viral infections in humans. They are the major cause of the common cold and are significant contributors to other upper respiratory syndromes as well as certain lower respiratory illnesses. The term common cold is believed to derive from ancient descriptions of illness in traditional Chinese and Roman sources, in which the illness was believed to be caused by cold temperatures and being chilled. Scientific investigations into the cause of the common cold began in the early 20th century in studies by Kruse, in which filtrates of nasal secretions from individuals with colds were administered to volunteers and subsequently induced colds. These studies, along with similar investigations conducted later by Dochez and colleagues indicated that colds were caused by filterable agents (i.e., presumed to be viruses).
The first isolation of rhinoviruses was achieved by Price and Pelon and coworkers, who inoculated nasopharyngeal washings from individuals with colds into rhesus monkey kidney tissue cultures. Andrewes and colleagues suggested the name “rhinovirus,” and a group designation was proposed by Tyrrell and Chanock in 1963. Once in vitro isolation techniques were established, the filtrates used in transmission experiments were demonstrated to contain rhinoviruses. Subsequently the application of sensitive molecular techniques led to characterization of rhinovirus strains that did not grow in tissue culture and to extensive new knowledge of the epidemiology and pathogenesis of rhinovirus infection.
Virology
Classification
Rhinoviruses are members of the Enterovirus genus of the Piconoviridae family and comprise the RV-A, RV-B, and RV-C species. Classification is based on genome organization, capsid properties, and sequence conservation. Within species, rhinoviruses are subdivided into numerical genotypes. Rhinoviruses have also historically been characterized by immunologic serotype, as defined by neutralization with antiserum. A total of 101 serotypes, numbered 1A, 1B, and 2 to 100, were identified. Classification into new serotypes ended in 1987 and has been supplanted by genomic characterization, which includes newly discovered strains that do not grow in tissue cultures. The recognized serotypes are divided into two species, RV-A and RV-B (except for RV-A87, which is actually an enterovirus, EVD68). The third species, RV-C, consists of previously unrecognized strains of rhinoviruses detected by genomic sequencing and currently has 55 genotypes.
Receptor specificity for rhinovirus has also been used for group designations. The major receptor group consists of 88 serotypes that use the intercellular adhesion molecule 1 (ICAM-1) to infect cells. The minor receptor group consists of 11 serotypes that use the low-density lipoprotein and related proteins as receptors. The major receptor group comprises both RV-A and RV-B species, whereas the minor receptor group comprises RV-A species only. The receptor for the RV-C species is human cadherin-related family member 3. Susceptibility to antiviral compounds has also been used to divide rhinoviruses into two groups (A and B) by Andries and coworkers, who suggested that those groups reflect sequence and possibly pathogenic differences.
Structure
Rhinoviruses are single-stranded RNA viruses of approximately 30 nm in diameter that have a rigid protein shell (capsid) composed of four viral proteins, VP1, VP2, VP3, and VP4. The protein subunits are called protomers; consist of one copy of each of the viral proteins; and are organized into 12 pentamers, each of which contains 5 protomers ( Fig. 175.1 ). In each of the pentamers, VP1 has a prominent symmetrical depression or “canyon,” which extends around the fivefold axis of symmetry and contains the binding site for the ICAM-1 receptor. This canyon also provides immunogenic surfaces. Antibodies with neutralizing activities against rhinovirus bind to the receptor site in the canyon. A hydrophobic “pocket” is present at the base of the canyon, which is the site of binding for antiviral drugs such as pleconaril or WIN 52084.
The overall structure of the rhinovirus capsid is similar to that of enteroviruses in general; however, in contrast to enteroviruses, rhinoviruses are unstable at acid pH (<5 or 6) and are completely inactivated at pH <3. Rhinoviruses retain stability for hours to days at 24°C to 34°C on environmental surfaces and have viability for years at freezer temperatures of −70°C.
Rhinoviruses lack envelopes and thus are relatively resistant to lipid solvents such as chloroform and ether. Polar organic solvents decrease infectivity of rhinoviruses, perhaps because of partial denaturation of their protein shell or because of inactivation of the hydrophobic pocket. Rhinoviruses are resistant to nonionic detergents but are sensitive to commonly used disinfectants such as chlorine, iodine, hydrogen peroxide, and ozone. Physical treatments such as gentle heating, desiccation, or ultraviolet light also decrease infectivity of rhinoviruses.
Genomic Organization
The rhinovirus genome consists of a single strand of positive sense RNA of approximately 7200 bases, which codes for a single open reading frame for a large polyprotein with almost 2200 amino acids. The RNA genome also contains multiple important RNA motifs. The 5′ end has a cloverleaf structure that is believed to serve as a regulatory element for translation and replication. Distinct secondary and tertiary structures are present that represent internal ribosomal entry sites that enable ribosomes to initiate translation without the necessary “caps” required by most cellular messenger RNAs. A shorter nontranslated region is present at the 3′ end, which is believed to play a role in termination of translation ( Fig. 175.2 ).
Epidemiology
Age
Rhinoviruses are worldwide in distribution. Infections occur most commonly in infants and young children. Infections appear to be less frequent in first the 6 months of life and then have high rates in infancy and early childhood. Among children in the United States, the rate is 1.2 to 6 infections per person-year, and among adults, it is 0.75 infections per person-year. Infection rates appear to be higher in young women with children than in men of similar age; however, rates are higher in older men than in older women.
Seasonality
Rhinovirus infection occurs throughout the year, with increased rates in the spring and fall in the temperate climates. The fall peak usually occurs in late August or early September in the Northern Hemisphere, and then the rates are usually lower until the peak in early April and May. Overall, rhinovirus infections may account for up to 80% of upper respiratory illnesses during peak seasons. Even during the low periods in the summer months, rhinoviruses may still be responsible for up to 50% of upper respiratory illnesses.
The reasons for the seasonality of rhinovirus infections are not fully understood. Environmental high humidity improves rhinovirus survival, and high indoor humidity has been associated with an increased incidence of rhinovirus infections. An increase in transmission has also been attributed to periods of time when schools are in session. In tropical climates, rhinovirus infections appear to occur with little relationship to climatic factors.
Pathogenesis
The pathogenesis of rhinovirus infections has been studied in experimental infection of volunteers and in naturally occurring infection in patients with various rhinovirus-associated illnesses. Initial infection occurs in the nasal mucus or the eye. Experimental studies have shown that extremely low quantities of rhinovirus (1 median tissue culture infective dose) can induce infection when administered via the conjunctiva or nasal mucosa.
The primary site of infection is the epithelium of the upper respiratory tract via receptors described earlier. Inoculation of rhinoviruses into the nasal cavity is followed by spread to the posterior nasopharynx. Infection of the upper respiratory tract includes involvement of the paranasal sinuses, and rhinovirus can be detected in sinus secretions by polymerase chain reaction (PCR). Sinus abnormalities are frequently noted on computed tomography or magnetic resonance imaging in both experimentally induced and naturally occurring colds. Rhinoviruses grow preferentially at temperatures of 33°C to 35°C, rather than at higher temperatures of 37°C or greater. Studies indicate that rhinovirus replication at higher temperatures results in more expression of interferon types 1 and 3 and of interferon-stimulated genes, and this may account for the preferential growth at lower temperatures. These observations led to the early concept that rhinoviruses may not be able to infect lower airways that have higher core temperatures. More recent studies indicate that medium and lower airways have core temperatures lower than 37°C and that they support rhinovirus replication efficiently. After experimental infection of the upper airway, rhinoviruses are found in the lower airway by bronchoscopy or bronchoalveolar lavage in 50% of specimens. It has also been noted that RV-C species grow well at 37°C in human sinus epithelial cells in contrast to RV-A and RV-B species. Thus it is clear that rhinoviruses can infect the lower respiratory tract, but how frequently this occurs remains undetermined.
Once symptoms of a cold are already present, biopsy specimens of the nasal mucosa and nasopharynx surprisingly show only small foci of infection, along with large areas of apparently uninfected cells. Examination of specimens of nasal epithelium during rhinovirus infection by light or electron microscopy do not show consistent histopathology.
Rhinovirus infection involves primarily epithelial ciliated cells, although nonciliated cells are also infected. It has been suggested that most of the rhinovirus-infected cells are likely shed into nasal secretions.
Inflammatory Responses
Although histopathologic changes in the nasal mucosa are not prominent in rhinovirus infection, even when symptoms are clearly present, a variety of inflammatory and cellular immune responses can be seen. Polymorphonuclear leukocytes are present in both nasal mucosa and secretions. A modest increase in peripheral polymorphonuclear leukocytes is seen during the first 2 to 3 days after experimental virus infection, which is not observed in volunteers who did not become ill. Modest increases in T-cell lymphocyte counts in the nasal mucosa and nasal secretions also occur during rhinovirus infection, but data are conflicting on the effect of rhinovirus infection on peripheral lymphocyte counts.
Rhinovirus infections stimulate a variety of innate immune responses including proinflammatory cytokines and mediators of inflammation. The signaling pathways that induce these effects are not fully determined, but Toll-like receptor 3, phosphatidylinositol 3-kinase, virus-induced oxidant stress, and mitogen protein kinases all have been implicated. Ceramide-enriched cell membrane platforms may also play a role in stimulation of the signaling pathways. Chemokines and cytokines that are present in increased concentrations in nasal secretions include interleukin-1β, interleukin-6, interleukin-8, and interferon-γ-induced protein 10. Concentrations of interleukin-6, interleukin-8, and interferon-γ-induced protein 10 in nasal secretions are increased during colds, correlate with symptom severity, and decrease as symptoms abate.
Kinins, including bradykinin and lysyl-bradykinin are found in nasal mucosa during colds, and their concentrations correlate with the severity and time course of illness. However, administration of a bradykinin antagonist did not reduce cold symptoms in one study ; reduction of the concentration of kinins by administration of steroids also did not reduce symptoms. Histamine is present in nasal mucosa, and although antihistamines are commonly used for symptomatic treatment of colds, a trial of a second-generation antihistamine did not show an effect on rhinovirus-induced colds.
Nasal Fluid Production
Parasympathetic innervation controls secretory function of nasal seromucous glands. Most of the nasal fluid produced by colds is derived from these glands, along with fluid that emerges by transudation. Intranasal administration of drugs with anticholinergic activity such as atropine or ipratropium and oral administration of first-generation antihistamines reduce nasal fluid by one-third in experimentally induced colds.
The inflammatory processes that result in increased passage of serum into the nasal mucosa and nasal secretions are particularly prominent early in the course of illness and are major components of nasal obstruction. Increased secretion from nasal glands becomes more prominent later during the course of a cold.
Transmission
Person-to-person transmission of rhinovirus infection occurs by direct contact or by aerosol. Direct contact appears to be the more efficient route of transmission. Rhinovirus survives for several hours on the skin of infected volunteers and can be recovered from 65% of fingers of infected subjects after finger-to-nose contact. Self-inoculation into the eye or nasal mucosa can result via rhinovirus-contaminated fingers. Larger particle aerosols such as those produced by sneezing or coughing transmit infection in experimental studies. Small particle aerosols appear to have a lesser role in transmission, although rhinovirus RNA has been detected in such aerosols. In experimentally induced infection, rhinovirus transmission was most efficient when there were large concentrations of virus in the nose (>1000 median tissue culture infective dose), when virus was present on the hands and nasal mucosa, and when symptoms of a cold were most severe. These findings occurred most commonly during the second or third day after virus inoculation.
The efficiency of transmission of rhinovirus infection is increased by time and closeness of contact between infected and susceptible individuals. Children not only have the highest rates of infection but also have the highest rates of transmission to other children and to adults. In experimental studies, the highest transmission rates occurred among married couples, under crowded living conditions, and in association with severity of illness.
In studies of naturally occurring rhinovirus infection, the importance of the direct contact route of transmission is less clear cut. Rhinovirus can be isolated from approximately 40% of individuals with colds and from 6% to 15% of objects found in their environment. Individuals routinely make finger-to-nose or finger-to-eye contact that can self-inoculate infection. Application of 2% aqueous iodine to fingers of mothers of children with colds appeared to prevent infection in the mothers in one study. However, a study of the use of a virucidal hand disinfectant in young adults did not reduce acquisition of rhinovirus infections.
The role of fomites in transmission of rhinovirus infection remains uncertain. Although objects in the environment can be readily contaminated by contact with hands that contain virus, attempts to demonstrate experimental transmission from such fomites have not succeeded.
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