Epidemiology, clinical manifestations, and pathogenesis of rhinovirus infections

INTRODUCTION — 

Rhinovirus has long been known as an etiologic agent of colds, which are frequent but usually minor, self-limited illnesses. However, 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 will review 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]. The average adult experiences two to three colds per year. Children average 8 to 12 colds per year [4], with most children experiencing at least one rhinovirus infection during the first year of life [5]. Children are the major reservoir for rhinovirus [4,6,7].

More than 100 rhinovirus serotypes have been identified [1,4,8], belonging to three species known as RV-A, RV-B, and RV-C, which are further subdivided into a major group and a minor group. RV-A and RV-C are both associated with asthma exacerbations, but those associated with RV-C are more severe [9]. (See 'Asthma exacerbations' below.)

The major group (most RV-A and all RV-B) binds to the intercellular adhesion molecule-1 (ICAM-1), while the minor group (all RV-A) binds to low-density lipoprotein receptors (LDLR) [10]; RV-C binds to cadherin-related family member 3 (CDHR3) [11]. These receptors are found on the apical surfaces of ciliated epithelial cells [10]. (See 'Entry into nasal epithelial cells' below.)

VIROLOGY — 

Rhinovirus is a member of the picornavirus family [12]. It is a small (30 nanometer) single-stranded RNA virus, about the size of a ribosome [4,13]. The capsid has icosahedral symmetry and contains 60 copies each of the four rhinoviral polypeptides (eg, VP1 through VP4) [12]. Each capsid contains one positive-sense single-stranded RNA. The full genomes of 99 human rhinoviruses have been fully sequenced [14]. When comparing these sequences, there are highly conserved motifs that may serve as potential targets for antiviral drug development [15].

The most notable feature of rhinovirus is the viral capsid surface, which contains plateaus and canyons that surround the intercellular adhesion molecule-1 (ICAM-1) attachment site for host-cell receptors used by over 90 percent of rhinoviruses [12,16]. The structural proteins VP1, VP2, and VP3 form the icosahedral capsid [17]. They are arranged with the c-termini on the outside capsid surface and the n-termini on the inside surface where they may interact with the RNA genome. VP4 proteins are attached to the inner surface of the capsid. For many rhinoviruses, VP1 contains hydrophobic pockets located just below the canyons which are thought to contain small molecules called "pocket factors," which may function to stabilize the capsid [17].

Rhinovirus infection activates host defenses leading to interferon production and can inhibit infection with other respiratory viruses. As an example, the host-cell interferon response generated in response to rhinovirus infection impairs influenza replication [18]. In vitro studies suggest that replication of SARS-CoV-2 is similarly inhibited in the setting of the rhinovirus-induced interferon response [19]. It has been shown that rhinovirus infection either just before or just after SARS-CoV-2 infection decreases SARS-CoV-2 replication [19]. More detailed information on the immune response is found below. (See 'Pathogenesis' below and 'Immune response' below.)

TRANSMISSION — 

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 [12]. Oral inoculation is an ineffective route of transmission.

The virus must attach to receptors on host cells to establish conditions necessary for intracellular release of viral RNA [20]. The nasopharynx is the initial site of infection, regardless of the route of inoculation [12,21]. The viral recovery rate in the nasopharynx remains higher than that of the nasal epithelium for 10 days following viral inoculation [21]. Infection may spread anteriorly to the nasal mucosa covering the turbinates [21]. (See 'Entry into nasal epithelial cells' below.)

Rhinovirus is present in nasal secretions for five to seven days but remains detectable by culture in the nasopharynx for as long as two to three weeks [21]. Symptoms usually diminish by five to seven days, before virus has cleared. Viral detection is terminated coincident with appearance of serum neutralizing antibody.

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 pro-inflammatory 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.

Several studies have described the transmission of rhinoviruses. In 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 [22], 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 [23]. This supports that the period of maximum contagiousness is most likely within the first five days of illness.

Although the COVID-19 pandemic impacted usual seasonal patterns for many respiratory viruses, disruption of rhinovirus transmission appeared to be relatively short-lived. Studies from both New Zealand [24] and the United States [25] observed great reductions in rhinovirus transmission following early implementation of strict nonpharmaceutical infection control measures, but the incidence of rhinovirus illness quickly returned to near-normal or greater than normal levels as infection control measures were eased. In contrast, more sustained disruption of usual seasonal patterns persisted for other respiratory viruses [25]. The reasons for this finding are unclear but may be due in part to rhinovirus infections being frequently transmitted in the home, where restrictions are not required. In addition, they are commonly transmitted through children who likely practice less effective handwashing.

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 [26-30]. In one report, microscopic examination of the nasal epithelium demonstrated well-preserved epithelium without obvious abnormalities [26]. Although neutrophils in the lamina propria and extracellular erythrocytes significantly increased within two days of inoculation, the number of mast cells remained unchanged [26,27]. In other studies that included volunteers who were inoculated with rhinovirus, there was localization of virus and few infected nasal epithelial cells [28,29].

The same has been shown for endothelial cells and bronchial epithelial cells following rhinovirus infection. In an in vitro study of rhinovirus-infected endothelial cells, <5 percent of cells became apoptotic, leaving the endothelium well preserved [31]. In another study of human bronchial epithelial cells exposed to rhinovirus, only 4 to 6 percent of the cells stained positive for dsRNA (marker for rhinovirus infection) [32].

Following rhinovirus infection, mucociliary clearance is impaired [33], which may contribute to the risk of secondary bacterial infection following rhinovirus infection [34]. There is also increased mucus production. Tight epithelial junctions are weakened, increasing permeability [33]; vascular leakage occurs, likely as a result of the weakened tight cell junctions [35].

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 [36].

ICAM-1 is present on the ciliated side of nasal epithelial cells [10] and is also expressed on nonciliated epithelial cells of the adenoid and nasopharyngeal mucosa. In addition, ICAM-1 is present on endothelial cells, in the germinal center, and on the basal surface of the ciliated epithelium [37]. It has been shown that vascular endothelium can be infected by human rhinovirus and may generate both an antiviral (though increased interferon production) and inflammatory (through the release of chemokines) response [31].

ICAM-1 may exist in either a membrane bound form (mICAM-1) or a soluble form (sICAM-1) [36]. In vitro studies of bronchial epithelial cells infected with rhinovirus have shown that mICAM-1 expression is upregulated following rhinovirus infection [36,37]. In vivo studies of the nasal epithelium have shown a similar increase in ICAM-1 expression within 24 hours after rhinoviral inoculation [37], with return to baseline by day 9.

sICAM-1 has been shown to have antiviral properties [36] and has an mRNA distinct from that of mICAM-1. In bronchial cell cultures, sICAM-1 is down-regulated during rhinovirus infection [36]. 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 the receptor-rhinovirus complex triggers a sequence of events outlined in the figure (figure 1) [31]. Activated signaling pathways release cytokines chemokines, vasoactive peptides, and growth factors [10]. In response to infection with rhinovirus, epithelial cells in culture and in vivo release interleukin-8 (IL-8), a chemoattractant 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 [38], suggesting that IL-8 must also act directly at the cellular level. Other inflammatory cells, such as granulocytes and monocytes, are also activated and collect in the submucosa [10].

It is postulated that oxidative stress resulting from rhinoviral infection activates cellular mechanisms that lead to the production and release of IL-8 [39]. 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 [38]. 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 [40]. 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 [41].

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 [2,42].

●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 [2,27]. In addition, increasing symptom scores correlate with increasing kinin concentrations [2].

●Asymptomatic infections do not result in increased kinin concentrations [27].

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.

VIRAL REPLICATION — 

Replication of rhinovirus occurs in both the upper and lower respiratory tracts [10]. For most rhinoviruses, the optimal temperature for replication is 33 to 35°C [5]. Viral RNA synthesis takes place in replication organelles, double-membrane organelles formed from cellular membranes (eg, Golgi or endoplasmic reticulum) of the host cell [43,44]. Host cell ribosomes are recruited to an internal ribosome entry site (IRES) located in the 5' noncoding region of the rhinoviral RNA [45].

Protein synthesis ensues, producing a single polyprotein that is then cleaved by viral proteases into structural and nonstructural viral components [43,45]. Using viral RNA polymerase, replication of the viral RNA occurs, which can then either be used as mRNA for additional viral protein synthesis or packaged into newly formed capsids for release [32,43]. This appears to be an efficient process, as positive sense RNA is present about 10,000 times more than negative sense RNA [32]. Newly assembled virions are released from the cell via cell lysis or via vesicles which transport virions out of the host cell [46].

In order to prevent host antiviral responses and promote viral replication and release, rhinoviruses interfere with many normal host cell processes [43]. Inhibition of apoptosis early in infection appears to be one of these processes [43]. Nuclear membrane disruption is another; during replication, viral proteases target components of the nuclear pore complex (NPC), allowing nuclear proteins to pass through into the cytoplasm [45]. These proteins are thought to function to promote viral RNA replication [45].

In order to promote viral replication, rhinoviruses alter the immune response of the host cell by downregulating interferon type 1 and its receptor while triggering the release of an immunosuppressive cytokine (TGF-beta) [47]. At least one rhinovirus (HRV-2, a minor group rhinovirus) has been found to induce autophagy with resultant promotion of replication [48]. Interestingly, a host cell protein called STING, whose normal function is to promote antiviral interferon synthesis, is found in substantial amounts in replication organelles and is required for RV-A and RV-C replication [44]. STING does not appear to be essential to RV-B replication [44]. STING's essential role in RV-A and RV-C replication does not appear to significantly impair its antiviral role [44].

IMMUNE RESPONSE — 

After infection with rhinovirus, pattern recognition receptors (PRR) on the cell surface and within the endosome recognize viral capsid proteins, dsRNA, or ssRNA [49]. This recognition triggers the release of chemokines and cytokines, including interferons [47,49], inhibiting viral replication, limiting spread to nearby cells, and initiating host cell immune responses [47]. For some PRRs, recognition of rhinovirus leads to the expression of additional PRRs [49].

Epithelial cells can release both Type I and Type III interferons in response to viral infection [32]. Interferon-stimulated genes (ISGs), including those with antiviral functions, are activated and inhibit viral replication by enzymatically degrading the viral RNA [47]; an antiviral state results in both the host and surrounding cells [50,51]. In response to interferon, other immune cells (eg, NK cells, T cells, B cells) are recruited to assist in the clearance of the viral infection [47].

Local antiviral host cell responses are adequate to clear rhinovirus infection in the absence of immune cells. An in vitro study of human bronchial epithelial cell cultures exposed to RV-A16 showed that rhinovirus infection was cleared after 144 hours by epithelial antiviral responses without the need for immune cells, and the time to clearance was unaffected by the level of Type I and Type III interferons produced [32]. Neutralizing antibodies (IgA, IgG) are not present until at least one week after infection [10] and are generally serotype-specific [52].

CLINICAL ILLNESS — 

Rhinovirus infection may be asymptomatic or symptomatic with the usual signs and symptoms of the common cold. (See "The common cold in adults: Diagnosis and clinical features" and "The common cold in children: Clinical features and diagnosis".)

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 [6]. 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 on the age of the patient. As examples:

●Adults typically present with nasal discharge, nasal obstruction, cough, and/or a sore or scratchy throat [53]. 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 a 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 [54].

●Young children may have febrile seizures with rhinovirus infection [55].

●Around age two, rhinovirus is a common cause of bronchiolitis; cough, rhinorrhea, and wheezing may be severe, and those requiring hospitalization are at increased risk of asthma development [56].

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) [57,58]. However, these studies could not determine if rhinovirus was the cause of pneumonia. In several studies, coinfection with other pathogens has been reported [59,60]. 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 — Over 50 percent of asthma exacerbations in adults, and as many as 90 percent of wheezing illnesses in children, are specifically associated with rhinovirus infection [50]. Not surprisingly, hospital asthma admissions and asthma-related mortality correspond to the rhinoviral peak in the early fall as children return to school [61,62].

RV-C is associated with severe asthma exacerbations, contributing to 50 percent or more of asthma exacerbations in children requiring hospital care [16]. Rhinovirus can cause bronchiolitis in infants, with an increased likelihood of asthma in those requiring hospitalization [63]. In infants with bronchiolitis, those with the highest risk of developing asthma were those with rhinovirus bronchiolitis combined with a history of eczema, a predominance of Haemophilus influenzae and Moraxella catarrhalis in their microbiome, and eosinophilia [64].

Pathogenesis — The relationship between rhinovirus and asthma involves a complex interplay between many factors, including the environment (eg, viral infection, allergies), the immune system, and genetic vulnerabilities.

Rhinovirus may infect the lower respiratory tract during the course of a typical rhinoviral cold. In one study, 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 [65]. 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. Hybridization signal was localized to the epithelium, with occasional detection in the basal and subepithelial cells [65], thus confirming that rhinovirus can infect the lower respiratory tract.

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 [66]. Rhinoviral replication and cell necrosis is greatly increased in primary bronchial epithelial cells from asthmatic individuals [1,67].

Early apoptosis is significantly reduced in the cells of asthmatic individuals infected with rhinovirus [1,67]. This leads to increased viral replication and then cell lysis, which perpetuates infection [67]. 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 [67]. Treatment of cells from asthmatics with interferon-beta restored apoptosis to rhinovirus-infected cells [1,67]. 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.

Just as with viral infection, allergen exposure in asthmatic patients with allergies also triggers release of the epithelial cell cytokines (IL-33, IL-25, TLSP) that initiate the type 2 response [68]. Both allergen exposure and elevated immunoglobulin (Ig)E levels predispose patients with asthma to more severe respiratory symptoms in response to rhinoviral infection [69]. Atopic patients infected with rhinovirus who were 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]. The effectiveness of omalizumab in decreasing the frequency of asthma exacerbations caused by both viral and allergic triggers underscores the important role that IgE plays in both [68].

The role of interferon in asthma exacerbations remains unclear. Some studies have shown decreased production of interferon and increased rhinovirus replication in bronchial epithelial cells, while others have not [70,71]. Interestingly, most asthma patients treated with Type 1 interferon do not improve significantly [72].

Gene dysregulation is characteristic of patients with asthma and is exacerbated by rhinovirus infection. Patients with asthma show significantly different gene expression at baseline when compared to nonasthma control patients; expression of inflammatory genes is increased while genes involved with inhibition of viral replication are decreased [73]. Rhinovirus infection in patients with asthma resulted in both an increase in the number of genes dysregulated and the duration of dysregulation when compared with control patients [73]. In patients with severe asthma, overexpression of TLSP and GM-CSF have been demonstrated [68]. Rhinoviral infection has been shown to increase expression of interferon-responsive genes as well as decrease inhibitory ability of Treg cells in both healthy and asthmatic patients [74]. However, patients with asthma failed to upregulate immunosuppression in the same way as their healthy counterparts [74].

Additionally, a genetic variant with a single base change has been identified (asthma-associated CDHR3 allele, rs6967330-A [Tyr]) and is associated with increased frequency and severity of RV-C infections in children during the first three years of life by increasing CDHR3 expression in apical ciliated cells, leading to increased RV-C binding and replication [75]. Other genetic studies have shown that patients with certain single nucleotide polymorphisms (SNP) are at increased risk for asthma (eg, those involving IL-33, TSLP, IL-25) [68].

INFORMATION FOR PATIENTS — 

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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 colds (The Basics)")

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

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Rhinovirus is one of the most common etiologic agents of the common cold and may play a role in asthma exacerbations. Children are the major reservoir for rhinovirus. (See 'Epidemiology' above.)

●Virology – 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.)

●Transmission – Infection occurs when virus is deposited on the nasal mucosa after inoculation into the nose or onto the conjunctival surface. Rhinovirus is present in nasal secretions for five to seven days but may persist as long as two to three weeks in the nasopharynx. Symptoms of infection usually abate before virus has cleared. (See 'Transmission' above.)

●Pathogenesis – Local production of various cytokines and kinins result in a cascade of cellular events leading to classic symptoms of the common cold. There is little histopathologic destruction of the nasal epithelium following rhinoviral infection. (See 'Pathology' above and 'Pathogenesis' above.)

●Clinical manifestations – Rhinovirus infection may be asymptomatic or symptomatic with the usual signs and symptoms of the common cold. Symptoms in adults and children are similar, although children may have associated fever and a longer duration of illness. (See 'Clinical illness' above.)

●Role in asthma exacerbations – 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, who contributed to an earlier version of this topic review.