Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections

INTRODUCTION — Rhinovirus has long been known as an etiologic agent of colds, which are frequent but otherwise relatively minor and self-limited illnesses. Rhinovirus can also infect the lower respiratory tract and trigger asthma exacerbations in both adults and children, highlighting the fact that this viral pathogen causes greater morbidity than previously recognized [1].

This topic is devoted to the epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections. More general discussions related to the "common cold" are found elsewhere. (See "The common cold in adults: Diagnosis and clinical features" and "The common cold in adults: Treatment and prevention".)

EPIDEMIOLOGY — Rhinovirus is the etiologic agent of most common colds and is responsible for one-third to one-half of cases in adults annually [2,3]. More than 100 serotypes have been identified [1,4]. The average adult experiences two to three colds per year, while children average 8 to 12 colds per year [4]. Children are the major reservoir for rhinovirus [4,5].

VIROLOGY — Rhinovirus is a member of the picornavirus family [6]. It is a small (30 nanometer) single-stranded RNA virus, about the size of a ribosome [4,7]. The capsid has icosahedral symmetry and contains 60 copies each of the four rhinoviral polypeptides (eg, VP1 through VP4) [6]. The full genomes of 99 human rhinoviruses have been fully sequenced [8]. On comparing these sequences, there are highly conserved motifs that may serve as potential targets for antiviral drug development [9].

Most notable is the viral surface, which contains numerous canyons that surround the attachment site for host-cell receptors [6]. Over 90 percent of rhinoviruses use this site to attach to the intercellular adhesion molecule-1 (ICAM-1) receptor expressed on the surface of host cells [6]. Antibody neutralization occurs when IgG binds to the viral surface, which obstructs access of the host-cell receptor to the viral attachment site at the base of the canyon [6].

TRANSMISSION — Rhinovirus is present in nasal secretions for five to seven days, but may persist as long as two to three weeks in the nasopharynx [10]. Infection occurs when virus is deposited on the nasal mucosa after inoculation into the nose or onto the conjunctival surface [4]. This most often occurs via self-inoculation, although small-particle aerosol and large-particle aerosol transmission are also possible [6].

One study, using a mask placed closely over the nose and mouth, demonstrated that rhinovirus was present by polymerase chain reaction (PCR) analysis on the mask after coughing, talking, and breathing [11], but it is unclear whether this is a result of aerosolization or close contact with the mask. In another study using married couples, the conditions required for transmission were present only on the second or third day after inoculation, as this is the time of greatest viral shedding [12]. Thus, the period of maximum contagiousness is most likely within the first five days of illness. Oral inoculation is an ineffective route of transmission [6].

The virus must attach to receptors on host cells to establish conditions necessary for intracellular release of viral RNA [13]. The nasopharynx is the initial site of infection, regardless of the route of inoculation [6,10]. The viral recovery rate in the nasopharynx remains higher than that of the nasal epithelium for 10 days following viral inoculation [10]. Infection may spread anteriorly to the nasal mucosa covering the turbinates [10].

Early apoptosis of infected cells, regulated by interferon, minimizes rhinoviral replication [14] and allows extrusion of infected cells from the mucosa. The virus is cleared from the upper airway between two and three weeks after infection [10].

PATHOLOGY — There is little histopathologic destruction of the nasal epithelium following rhinoviral infection. Studies using electron microscopy, scanning microscopy, and in situ hybridization all suggest focal findings with minimal changes in the surrounding tissue:

●In one study, microscopic examination of the nasal epithelium demonstrated well-preserved epithelium without obvious abnormalities [15]. Although neutrophils in the lamina propria and extracellular erythrocytes significantly increase within two days of inoculation [15,16], the number of mast cells remained unchanged [15].

●Studies of volunteers who were inoculated with rhinovirus show localization of virus and few infected nasal epithelial cells [17,18].

●Another study demonstrated that only one to two percent of the cells that sloughed into nasal secretions during rhinoviral infection contained rhinoviral antigen [19].

PATHOGENESIS

Entry into nasal epithelial cells — Intercellular adhesion molecule-1 (ICAM-1) is the host receptor for attachment of most rhinoviruses. It is a glycoprotein immunoglobulin with five domains, two of which fit in a lock-and-key arrangement to the attachment site at the canyon base of the rhinoviral surface [20]. ICAM-1 may exist in either a membrane bound form (mICAM-1) or a soluble form (sICAM-1) [20].

ICAM-1 is usually expressed on nonciliated epithelial cells of the adenoid and nasopharyngeal mucosa (18); in addition, ICAM-1 is present on endothelial cells, in the germinal center, and on the basal surface of the ciliated epithelium [21]. ICAM-1 is not normally present on the luminal surface of nasal epithelium, as demonstrated in studies utilizing immunohistochemical techniques in vivo [17,21].

In vitro study of bronchial epithelial cells infected with rhinovirus has shown that ICAM-1 expression is upregulated following rhinovirus infection [20,22]. In vivo studies of the nasal epithelium have shown a similar increase in ICAM-1 expression within 24 hours after rhinoviral inoculation [22] with return to baseline by day nine.

The soluble form of ICAM-1 (sICAM-1) has been shown to have antiviral properties [20] and has an mRNA distinct from that of mICAM-1. In bronchial cell cultures, sICAM-1 is down-regulated during rhinovirus infection [20]. Down-regulation of sICAM-1 combined with up-regulation of mICAM-1 promotes rhinoviral infection of respiratory epithelium.

Role of cytokines — Once rhinovirus attaches to the ICAM-1 receptor, it is taken into the cell. Entry of virus triggers a sequence of events outlined in the figure (figure 1).

In response to infection with rhinovirus, epithelial cells in culture and in vivo release interleukin-8, a chemoattractant (IL-8) for polymorphonuclear cells (PMNs) [3]. IL-8 is locally produced and rapidly increases in nasal secretions following rhinovirus challenge. Nasal challenge with IL-8 results in a significant influx of PMNs within hours and in increased nasal resistance within 10 minutes [23], suggesting that IL-8 must also act directly at the cellular level.

It is postulated that oxidative stress resulting from rhinoviral infection activates cellular mechanisms that lead to the production and release of IL-8 [24]. IL-8 has been shown to cause up-regulation of adhesion molecule receptors on neutrophils and can cause neutrophil degranulation in addition to chemotaxis of eosinophils, T lymphocytes, and basophils [23]. Thus, cytokine elaboration, especially IL-8, plays an important role in the influx of PMNs into nasal secretions and development of symptoms in rhinoviral infection.

Local production is further supported by the in vivo observation that IL-8 mRNA was significantly increased in nasal epithelium of symptomatic children during viral infection [25]. Studies of volunteers inoculated with rhinovirus also demonstrated that symptoms during infection correlated with an increase in the concentration of IL-8 in nasal secretions [26].

Role of kinins — Kinins are produced on-site in nasal mucosa and submucosa of rhinovirus-infected volunteers. The following observations have been made regarding the role of kinins:

●When applied to the nasal mucosa, bradykinin has been shown to cause symptoms that mimic the common cold, including rhinitis, nasal obstruction, and sore throat [2,27].

●Analysis of nasal secretions in adults with symptomatic experimentally-induced rhinovirus infection demonstrates significant increases in the concentrations of bradykinin and lysyl-bradykinin, both of which are vasoactive peptides [2,16]. In addition, increasing symptom scores correlate with increasing kinin concentrations [2].

●Asymptomatic infections do not result in increased kinin concentrations [16].

Kinins released in the nose following plasma exudation may augment symptomatology of the rhinoviral infection and may cause an increase in vascular permeability, vasodilatation, and glandular secretions.

Entry into airway epithelium — Rhinoviruses may be associated with acute exacerbations of asthma, although it is unclear if this effect is mediated through direct infection of the lower respiratory tract or through indirect mechanisms.

Lower respiratory tract infection was investigated in vitro by exposing human bronchial epithelial cells to rhinoviruses and in vivo after experimental infection of human study participants [28]. In situ hybridization demonstrated the presence of rhinovirus in bronchial biopsy specimens from 5 of 10 volunteers who were inoculated with rhinovirus type 16 by intranasal aerosol insufflation [28]. Hybridization signal was localized to the epithelium, with occasional detection in the basal and subepithelial cells [28]. Thus, rhinovirus may infect the lower respiratory tract during the course of a typical rhinoviral cold.

VIRAL REPLICATION — After cell entry, replication requires interaction between rhinoviral RNA and specific host factors [29,30]. As an example, SETD3 is a specific host methyltransferase that was demonstrated in vivo to be required for replication, and when interaction with SETD3 was interrupted, replication was greatly reduced [30].

Rhinovirus remains detectable by culture in the nasopharynx for two weeks following inoculation during experimental rhinovirus infections [10]. Viral detection is terminated between two and three weeks, coincident with appearance of serum neutralizing antibody. In contrast, symptoms usually diminish by five to seven days, before virus has cleared.

A plausible explanation for the discrepancy between early symptom abatement and later viral clearance is that the inflammatory response induced by infection of nasal epithelial cells is successful in reducing the elaboration of proinflammatory signals by infected epithelial cells in the nose. Infected cells undergo apoptosis and are extruded from the nasal mucosa, limiting spread of virus to neighboring cells. The extruded cells are swept posteriorly by the combination of plasma exudation and increased glandular secretion. Symptoms diminish as the number of infected epithelial cells in the nasal mucosa declines. Apoptotic infected cells may then be swallowed after transport to the nasopharynx.

It is important to further evaluate this hypothesis since it may have a direct bearing on effective therapies for rhinovirus infections. If this hypothesis is correct, effective dampening of the inflammatory response in the nose may result in increased viral replication in the nasal mucosa and, perhaps, prolongation of symptomatic illness.

CLINICAL ILLNESS — Rhinovirus infection may be asymptomatic or symptomatic with the usual signs and symptoms of the common cold. Asymptomatic infections occur most commonly in older children and adults. As an example, in a study evaluating rhinovirus transmission within families, most infections (21 of 23) in young children were symptomatic, whereas approximately half of infections (19 of 38) in older children and adults were asymptomatic [5]. This difference may be due to acquired immunity and/or differences in virus types and host factors. It is also possible that young children have an increased number of intercellular adhesion molecule-1 (ICAM-1) receptors, resulting in more symptomatic infection, as has been shown in adults with asthma.

When symptomatic infection does occur, the clinical manifestations can vary depending upon the age of the patient. As examples:

●Adults typically present with nasal discharge, nasal obstruction, cough, and/or a sore or scratchy throat [31]. Fever is not usually associated with adult illness. Symptoms typically resolve in five to seven days.

●Children have cough and nasal discharge and obstruction more frequently than adults. In addition, they may initially have fever. The duration of signs and symptoms are also longer for children, with 70 percent of children still reporting clinical manifestations by day 10 as compared with only about 20 percent of adults [32].

Rhinoviruses may also contribute to community acquired pneumonia (CAP). Surveillance studies that evaluated 2259 adults and 2222 children with CAP found that rhinovirus was one of the most common pathogens detected in respiratory specimens (nasopharyngeal and oropharyngeal swabs) [33,34]. However, these studies could not determine if rhinovirus was the cause of pneumonia. In several studies, coinfection with other pathogens has been reported [35,36]. A more detailed discussion of CAP is found elsewhere. (See "Epidemiology, pathogenesis, and microbiology of community-acquired pneumonia in adults".)

ASTHMA EXACERBATIONS — Rhinovirus may cause increased severity and duration of respiratory symptoms, including decreased lung function, in asthmatic children and adults [1].

Epidemiology — It is estimated that as many as 50 percent of asthma exacerbations are associated with viral infections [14]; more than half of the asthma exacerbations in children are specifically associated with rhinovirus infection [1]. Not surprisingly, hospital asthma admissions and asthma-related mortality correspond to the rhinoviral peak in the early fall as children return to school [37,38].

Pathogenesis — Both allergen exposure and elevated IgE levels predispose patients with asthma to more severe respiratory symptoms in response to rhinoviral infection. This may be a result of impaired antiviral immunity [1]. Atopic patients infected with rhinovirus who are then exposed to ragweed experienced increased bronchial reactivity as compared to infected atopic patients without ragweed exposure [1]. Similarly, in young adults with mild asthma and elevated IgE, rhinoviral infection produced persistent upper respiratory tract symptoms and increased lower respiratory tract symptoms, including cough and wheeze, as compared to asthmatic individuals with low IgE levels [1].

Necrosis of lower respiratory tract cells is the major predictor for the severity of asthma exacerbations in adults [1]. Infection with rhinovirus induces apoptosis in bronchial epithelial cells from normal subjects in culture [39]. Rhinoviral replication and cell necrosis is greatly increased in primary bronchial epithelial cells from asthmatic individuals [1,14].

Early apoptosis is significantly reduced in the cells of asthmatic individuals infected with rhinovirus [1,14]. This leads to cell lysis, which releases and perpetuates infection, leading to increased viral replication (up to eight times greater than in nonasthmatic subjects) [14]. Early apoptosis is regulated by Type 1 interferon; elaboration of interferon-beta is markedly deficient in primary bronchial epithelial cells from asthmatic subjects when the cells are infected with rhinovirus [14].

Treatment of cells from asthmatics with interferon-beta restored apoptosis to rhinovirus infected cells [1,14]. These studies suggest that abnormalities in the cellular response to viral infection that result in impaired apoptosis and increased viral replication may be responsible for the severe and prolonged symptoms typical of asthmatic individuals.

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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Cough, runny nose, and the common cold (The Basics)")

●Beyond the Basics topics (see "Patient education: The common cold in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Rhinovirus is one of the most common etiologic agents of the common cold and may play a role in asthma exacerbations. (See 'Introduction' above.)

●Children are the major reservoir for rhinovirus. (See 'Epidemiology' above.)

●Rhinovirus, a member of the picornavirus family, attaches to the intercellular adhesion molecule-1 (ICAM-1) receptor expressed on the surface of host cells. (See 'Virology' above.)

●Infection occurs when virus is deposited on the nasal mucosa after inoculation into the nose or onto the conjunctival surface. (See 'Transmission' above.)

●There is little histopathologic destruction of the nasal epithelium following rhinoviral infection. (See 'Pathology' above.)

●Local production of various cytokines and kinins result in a cascade of cellular events leading to classic symptoms of the common cold. (See 'Pathogenesis' above.)

●Symptoms of infection usually abate before virus has cleared. (See 'Viral replication' above.)

●Symptoms in adults and children are similar, although children may have associated fever and a longer duration of illness. (See 'Clinical illness' above.)

●Rhinovirus may play an important role in asthma exacerbations in children and in atopic individuals. (See 'Asthma exacerbations' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges J Owen Hendley, MD, now deceased, who contributed to an earlier version of this topic review.