key: cord-0885378-q5xp7pa1
authors: Turner, Ronald B
title: Epidemiology, Pathogenesis, and Treatment of the Common Cold
date: 1997-06-30
journal: Annals of Allergy, Asthma & Immunology
DOI: 10.1016/s1081-1206(10)63213-9
sha: c815c04f8e5c88e2d40bad9d5502dff934004c3a
doc_id: 885378
cord_uid: q5xp7pa1

Objective Reading this article will reinforce the reader's knowledge of the pathogenesis of the common cold. The rationale for current and potential therapies for the common cold are reviewed in the context of current concepts of the pathogenesis of these illnesses. Data sources and study selection A MEDLINE literature search was done using the search terms common cold, rhinovirus, and viral respiratory infection. The search was restricted to the English language. Articles were selected for review if the title and/or abstract suggested the content was relevant to the subject of this review. The bibliographies of selected articles were used as a source of additional literature. Results Recent studies suggest that the host response to the virus is an important contributor to the pathogenesis of the common cold. Inflammatory mediators, especially the pro-inflammatory cytokines, appear to be an important component of this response and present an attractive target for new interventions for common cold therapies. Currently available treatments for the common cold have limited efficacy against specific symptoms. These therapies should be selected to treat the specific symptoms that are perceived to be the most bothersome by the patient.

Viral upper respiratory infections account for approximately 50% of all illnesses and approximately 75% of illnesses in young infants. 1, 2 Although these illnesses are generally mild and self-limited, they are associated with an enormous economic burden both in lost productivity and in expenditures for treatment. The common cold results in approximately 26 million days of school absence and 23 million days of work absence in the United States annually. 3 Each year we make approximately 27 million physician visits and purchase almost $2 billion worth of over-the-counter (OTC) cough and cold medications for treatment of common cold symptoms. 4 A recent survey of a representative sample of children 27 to 48 months of age found that 35% of children had received an OTC cold remedy in the preceding 30 days. 5 

The pathogens most frequently associated with common cold symptoms are the rhinoviruses. Other important pathogens include the coronaviruses and respiratory syncytial virus (RSV). Influenza, parainfluenza, and adenoviruses may cause cold symptoms; however, these agents frequently cause lower respiratory or systemic symptoms in addition to the nasal symptoms characteristic of the common cold. 6 Colds occur year-round but have a decreased incidence during the summer months. 2, 6, 7 The "respiratory virus season" usually begins with an increase in incidence of rhinovirus infections in August or September and ends following the spring peak of rhinovirus infections in April or May. This period of increased incidence of disease is caused by sequential and relatively discreet outbreaks of different viral pathogens. 6,7 An increased incidence of common cold symptoms is associated with each of these outbreaks; however, other clinical syndromes are usually also present in the community during epidemics caused by pathogens other than rhinovirus or coronavirus.

The onset of common cold symptoms typically occurs one to two days after viral infection and the time to peak symptoms is generally two to four days. 8 The onset of illness and the time to peak symptoms is about one day later for the coronaviruses than for rhinoviruses or respiratory syncytial virus. A recent study suggests that subjects infected with rhinovirus may be able to detect the onset of symptoms as early as 16 hours after virus challenge. 9 Nasal obstruction, rhinorrhea, and sneezing are present early in the course of the cold; however, sore or "scratchy" throat is frequently reported as the most bothersome symptom on the first day of illness. 8,10,11 The sore throat resolves quickly and by the second and third day of illness the nasal symptoms are predominant. Cough is associated with approximately 30% of colds and typically does not become the most bothersome symptom until the 4th or 5th day of illness when the nasal symptoms decrease in severity. 8,10 The usual cold lasts about a week, although 25% last 2 weeks. 10 Virus shedding persists after the reso-lution of symptoms and virus may be cultured from 10% to 20% of subjects for 2 to 3 weeks after infection. 12, 13 The average incidence of the common cold in preschool children is 5 to 7 per year but 10% to 15% of children will have at least 12 infections per year. 1, 14, 15 The incidence of illness decreases with age and averages 2 to 3 per year by adulthood. The incidence of common colds in young children is affected by conditions that increase exposure such as other children in the home or extensive contact with children outside the home, as in childcare centers. 16 -18 The difference in the incidence of illness between these groups of children decreases as the length of time spent in daycare increases; however, the incidence of illness remains higher in the daycare group through at least the first 3 years of life. 17 Although the frequency of common colds suggests that person-to-person spread must be fairly efficient, natural transmission of rhinovirus appears to be surprisingly inefficient. A transmission rate of 38% was reported in a study in which one partner of a married couple was infected with rhinovirus and then the spouse, documented to be susceptible to the virus, was observed for acquisition of infection. 19 In another study, exposure of susceptible recipients to experimentally infected donors resulted in an infection rate of 44% in the recipients after 150 donorhours of exposure. 20 Virus transmission rates are less than 10% following brief (3 to 36 hr) exposure to virusinfected subjects. 21 There are three general mechanisms by which common cold viruses might be spread: (1) small-particle aerosols, (2) large-particle aerosols, and (3) direct contact. Although the various common cold viruses may presumably be spread by any of these mechanisms, some routes of transmission may be more efficient than others for particular viruses. Studies of experimental rhinovirus colds in human volunteers suggest that direct contact is the most efficient mechanism of transmission of this virus, although transmission by large particle aerosols has also been documented. 22, 23 A study of natural colds found that treatment of the hands with a virucidal compound significantly reduced transmission of colds. 24 There were no rhinovirus infections in the subjects using the virucidal hand treatment in this study, a finding that supports the hypothesis that hand-tohand transmission may be important in a natural setting. The transmission of the other pathogens associated with colds is less well studied. Respiratory syncytial virus appears to require close contact for spread and, in the experimental setting, has been spread by direct contact with contaminated fomites. 25 In contrast to rhinovirus and RSV, influenza appears to spread from person-to-person by small particle aerosol. 26, 27 Regardless of the route of transmission, studies of rhinovirus infection indicate that contact between the virus and the nasal mucosa appears to be important for initiation of infection. A very small inoculum of virus applied to the nasal cavity consistently results in infection in contrast to inoculation of virus into the oral cavity. The inoculum required for a 50% infection rate is calculated to be 0.3 tissue culture infectious dose 50 by the nasal route and 2260 tissue culture infectious dose 50 by the oral route. 21, 28, 29 Conjunctival inoculation of virus is also an efficient mechanism for initiation of rhinovirus infection, presumably because virus reaches the nasal cavity via the nasolacrimal duct. 13,29

Much of the information relevant to the pathogenesis of the common cold is derived from studies in subjects experimentally infected with rhinovirus. The site of infection during rhinovirus infection is generally limited to the mucosa of the upper respiratory tract. Some of the pathogens associated with common cold syndromes (eg, parainfluenza viruses, RSV, and influenza) may produce different clinical syndromes by infecting the lower respiratory tract. Following inoculation into the nasal cavity, rhinovirus is first detected by cultures of the posterior na-sopharynx. 13 As the cold progresses, virus is detected at more anterior sites in one or both nares. 13, 30 Biopsies of the nasal mucosa and nasopharynx during experimental colds reveal focal infection that involves relatively few cells. 31 Ciliated epithelial cells are the primary cell involved although nonciliated cells are also infected. The apparent paucity of rhinovirus-infected cells may be a result of desquamation of infected cells into the nasal secretions. 32 Abnormalities of the paranasal sinuses may frequently be detected by computerized tomography or magnetic resonance imaging during both natural colds and experimentally-induced rhinovirus colds; however, studies to isolate virus from the sinuses during uncomplicated colds have not been done. 33, 34 Although rhinovirus has been isolated from the lower respiratory tract of experimentally infected volunteers by bronchoscopy, it is difficult to exclude the possibility of contamination from the upper respiratory tract. 35, 36 The prominent symptoms of the common cold are rhinorrhea and nasal obstruction. Increased vascular permeability with leakage of serum into the nasal mucosa and nasal secretions is a major contributor to these symptoms. 37, 38 The contribution of glandular secretions from the nose to the rhinorrhea becomes more important later in the course of the illness. 38 The mechanisms by which rhinovirus infection of the nasal epithelium results in increased vascular permeability and increased glandular secretions is not clear. Specimens of nasal secretions from human volunteers infected with rhinovirus contain small numbers of rhinovirus infected and uninfected ciliated epithelial cells, however, examination of specimens of the nasal epithelium by light or electron microscopy reveals no consistent lesions. 32, 39, 40 Similarly, no morphologic changes were seen in monolayers of human nasal epithelium infected with rhinovirus. 41 The absence of detectable histopathology during rhinovirus infection led to the suggestion that the host response to the virus may play a primary role in the production of common cold symptoms.

Early studies of the host response to rhinovirus infection concentrated on the humoral immune response. Viral neutralizing activity, apparently associated with IgA, first appears in nasal secretions two to three weeks after infection at about the same time that neutralizing activity is detected in serum. 28, [42] [43] [44] This neutralizing antibody in serum or nasal secretions is associated with serotype-specific protection from rhinovirus infection. 28, 43, 45 A recent study reported non-neutralizing rhinovirus-specific IgG and IgA in nasal secretions by the third day of rhinovirus illness. 46 There is evidence that the cellular immune response may play a role in rhinovirus pathogenesis. The peripheral white blood cell count increases in infected, ill subjects during the first two to three days after virus challenge. 47 This increase in the WBC count is the result of an increase in the concentration of neutrophils. Infected non-ill subjects have no change in the WBC count. A polymorphonuclear leukocyte response to rhinovirus infection is also seen in the nasal mucosa and nasal secretions. 39, 48 As with the changes in peripheral neutrophil count the increase in polymorphonuclear leukocytes is seen in infected symptomatic subjects but not in asymptomatically infected individuals. 48 The correlation between lymphocytic response to rhinovirus infection and symptomatic illness is less clearly characterized. There are conflicting data about the effect of rhinovirus infection on the peripheral lymphocyte count. 47, 49, 50 Modest increases in T-lymphocyte concentrations have been reported in both the nasal mucosa and in nasal secretions during rhinovirus infection. 51, 52 Few B-lymphocytes were noted in the nasal mucosa.

The role of inflammatory mediators has been the focus of several recent studies of rhinovirus pathogenesis. The similarity between the clinical manifestations of allergic rhinitis and the common cold has prompted repeated attempts to establish the role of hista-mine in the common cold. Several studies have reported no detectable increase in histamine in nasal secretions during rhinovirus infection. 48, 53, 54 A recent study reported increases in histamine levels in 4/15 normal subjects and 13/17 subjects with a history of allergic rhinitis following rhinovirus inoculation. 38 Prostaglandin D 2 , another mast cell derived mediator, cannot be detected in the nasal secretions of rhinovirus-infected subjects. 38, 48 These studies suggest that it is unlikely that histamine or other mast cell mediators make an important contribution to the pathogenesis of rhinovirus colds.

The kinins, bradykinin and lysyl bradykinin, have been found in the nasal secretions of volunteers with rhinovirus colds, both experimentally induced and naturally acquired. 48, 55 The concentration and time course of the production of kinins were roughly correlated with the severity and time course of symptoms in these subjects. Subjects who were infected with rhinovirus but who did not develop symptoms did not have an increase in nasal secretion kinin concentration. Intranasal challenge of uninfected volunteers with increasing concentrations of bradykinin resulted in symptoms of nasal obstruction, rhinorrhea, and sore throat. 56 The role of kinins in the pathogenesis of common cold symptoms is less clear, however, in light of the failure of a bradykinin antagonist to alleviate common cold symptoms. 57 Similarly, in a more recent study, steroid therapy significantly reduced the concentration of kinins in nasal washes but had no effect on symptoms. 58 The interleukins IL-1␤, IL-6, and IL-8 have also recently been reported in the nasal secretions of symptomatic subjects with experimental rhinovirus colds. 34, 59, 60 As with the kinins, the concentration of these proteins increases and then decreases as symptom severity is increasing and then decreasing. The concentrations of IL-6 and IL-8 in nasal secretions appear to be directly correlated with the severity of the common cold symptoms. 60, 61 Intranasal challenge of normal volunteers with interleukin-8 produces an influx of neutrophils, a transient increase in nasal resistance to airflow, and a significant increase in nasal symptom scores compared with placebo-challenged subjects. 62 In spite of these data demonstrating an association between symptoms and inflammatory mediators, the role of these mediators in pathogenesis will not be clear until specific inhibitors are available for use in clinical trials.

The neurologic response of the host may also play a role in the pathogenesis of rhinovirus colds. Studies of nasal secretions have shown that glandular secretions in the nose, under the control of cholinergic neurologic pathways, contribute to rhinorrhea especially in the later stages of the illness. 38 Neurologic pathways also appear to be involved in the reactive airway disease associated with rhinovirus infection. 63, 64 Inflammatory neuropeptides, such as substance P, play a role in some forms of non-infectious rhinitis however the role of these agents in the common cold remains to be examined.

A variety of antiviral agents have been studied for the treatment of rhinovirus infections. Several drugs have been identified which have significant in vitro anti-rhinoviral activity. [65] [66] [67] [68] [69] [70] [71] [72] When tested in vivo, however, these agents have been ineffective for treatment of rhinovirus infection. In 1984, Abraham and Colonno reported that different rhinovirus serotypes shared the same cellular receptor. 73 Subsequent studies have shown that all rhinoviruses but one attach to cells via only two different receptors. 73, 74 The majority of serotypes bind by a single receptor that has subsequently been identified as intercellular adhesion molecule 1 (ICAM-1). 75, 76 Blockade of the receptor site on the cells with antibody to ICAM-1 or of the receptor binding site on the virus with soluble ICAM-1 have both been shown to inhibit viral infection in vitro and are potential treatments for the common cold. 74, [77] [78] [79] [80] The logistics of maintaining an appropriate concentration of either of these proteins in the nasal cavity present formidable obsta-cles to effective use of these agents, however. Studies of the effect of these agents for treatment of the common cold are in progress.

In the mid-1970s, it was reported that zinc ions inhibit rhinovirus replication. 81 As a result of this observation there have been numerous studies of the efficacy of zinc, given as oral lozenges, for the treatment of common cold symptoms. In spite of the in vitro effect of zinc on virus replication, there has been no detectable effect of zinc lozenges on virus replication in vivo. 82, 83 The effect of zinc on symptoms has been inconsistent with some studies reporting dramatic effects on the duration of cold symptoms and other studies finding no effect. [82] [83] [84] [85] [86] These studies may not be directly comparable since different formulations of zinc were used in the various studies, however, there is not a direct correlation between the dose of zinc given and the clinical efficacy. A major problem with the interpretation of these studies is the very high frequency (50% to 90%) of side effects in subjects who receive zinc and the difficulty in producing a placebo that is as distasteful and astringent as the active preparation.

Symptomatic therapy remains the mainstay of treatment for the common cold. The use of symptomatic therapies available over-the-counter and directed at specific symptoms of rhinovirus colds has been the subject of some controversy. 87 Although some of these medications have been found to be effective in adults, studies in children have been limited by an inability to accurately measure common cold symptoms in noncompliant subjects. It is reasonable to conclude that the effects of these various preparations should be similar in adults and children. The use of these medications in children, however, must be balanced against the potential side effects of each drug.

Both topical and oral adrenergic agents are effective nasal decongestants. 88 -90 Comparative studies have not been done in the common cold; however, it is generally accepted that the topical agents are more potent than the oral drugs. 91 Prolonged use of the topical adrenergic agents should be avoided to prevent the development of rhinitis medicamentosa, an apparent rebound effect when the drug is discontinued. Systemic absorption of the imidazolines (eg, oxymetazoline and xylometazoline) has rarely been associated with bradycardia, hypotension, and coma. The systemic side effects of the oral adrenergic agents are central nervous system stimulation, hypertension, and palpitations. The antihistamines have no effect on nasal congestion.

The treatment of rhinorrhea is primarily by blockade of cholinergic stimulation of glandular secretion. Atropine or ipratropium bromide treatment of experimental rhinovirus colds produced a small decrease in rhinorrhea or nasal mucus weights that was not statistically significant. 92, 93 In larger studies of subjects with natural colds, ipratropium produced a 22% to 31% decrease in rhinorrhea compared with placebo. 94 -96 Ipratropium has been approved for use for the treatment of rhinorrhea in the common cold. The most common side effects of intranasal ipratropium are nasal irritation and bleeding.

The first generation antihistamines have been used for many years for treatment of rhinorrhea associated with the common cold. A modest but statistically significant effect on rhinorrhea has been found in several small studies in adults, although other studies have failed to detect any therapeutic effect. 97-100 A recent, large study in experimental colds disclosed that clemastine fumarate reduced rhinorrhea by approximately 27% compared with placebo. 101 This observation was subsequently confirmed in a natural cold trial. 102 The second generation or "nonsedating" antihistamines have had no effect on common cold symptoms in a limited number of studies. 103, 104 This observation, the absence of histamine in the secretions of most subjects with colds, and the similarity of the response to ipratropium and the antihistamines suggest that the effect of the antihistamines on rhinorrhea is related to the anticholinergic rather than the antihistaminic properties of these drugs. The major side-effects associated with the use of the antihistamines are sedation and drying of the eyes, mouth, and nose.

Sneezing is frequently reported as a symptom during the common cold, however, it is rarely considered the most bothersome symptom by the patient. Antihistamines are effective for treatment of sneezing. 100 -102 The mechanism of the effect of antihistamines on sneezing in colds is not known.

Sore throat is a common symptom early in the course of the cold and is frequently the first symptom noticed by the patient. The sore throat associated with colds is generally not severe and is often described as a "scratchy throat." Treatment with mild analgesics is occasionally indicated, particularly if there is associated myalgia or headache.

Cough during colds is produced by several different mechanisms and treatment should be directed at the most likely underlying cause. Cough in some patients appears to be due to nasal obstruction or postnasal drip. Cough in these patients is most prominent during the time of greatest nasal symptoms and responds to treatment with an antihistamine/decongestant combination. 105 In other patients, cough may be a result of virus-induced reactive airway disease. 63 These patients may have cough that persists for days to weeks after the acute illness and may benefit from bronchodilator therapy. Cough that persists after the resolution of other cold symptoms or that persists in association with unremitting rhinorrhea may be due to sinusitis and may respond to antibiotic therapy. 106 Nonspecific cough suppression with either codeine or dextro-methorphan hydrobromide is frequently used; however, the efficacy of these agents has not been demonstrated in the common cold. 107,108 A single study has described a modest effect of nonsteroidal antiinflammatory agents on the acute cough of colds. 109 Expectorants such as guaifenesin are not effective antitussive agents. 110 A new approach that examined the effect of combining anti-inflammatory and antiviral compounds was reported recently. Gwaltney, reported effective treatment of established rhinovirus infections with a combination of naproxen, ipratropium bromide, and interferon-␣2b. 111 The effect of this combination appeared to be greater than the effects usually seen with available common cold therapies.

The recognition that direct contact was an important mechanism of transmission of rhinovirus led to efforts to prevent contamination of the hands of infected or susceptible individuals. A variety of chemical compounds have been evaluated for efficacy for inactivation of rhinovirus on environmental surfaces or on skin. [112] [113] [114] Although some of these agents were found to have activity, a practical and effective hand treatment has not been developed. Facial tissues treated with a combination of citric acid, malic acid, and sodium lauryl sulfate were found to readily inactivate a number of different rhinovirus serotypes and there was some evidence that these tissues would reduce or prevent transmission of virus. [115] [116] [117] In spite of the potential utility of this product, it was never made available commercially.

The large number of rhinovirus serotypes has long been recognized as an obstacle to the development of vaccines for protection against rhinovirus infections. The recent observation that most rhinoviruses attach to cells via only two different receptors suggests the potential for preventing infection by receptor blockade. 73, 74 Prophylaxis of experimental rhinovirus colds with monoclonal antibody to ICAM-1, the major cellular receptor, delayed but did not prevent infection. 118 Prevention of rhinovirus infections also has been attempted with a variety of antiviral agents. Pirodavir, a virus capsid binding agent, appears to have some efficacy for prevention of rhinovirus infection although there is no detectable effect on treatment of established infections. 119, 120 Similarly, ␣-interferon is an effective agent for prevention of rhinovirus infections but has no effect on established infection. [121] [122] [123] [124] [125] [126] The cost and the side effects of ␣-interferon preclude its use as an agent for the prevention of rhinovirus colds. 126 -130 

The relatively mild symptoms and short duration of the common cold have presented a challenge to attempts to provide effective treatment. Currently available treatments that are targeted primarily at reversing the observed effects of the viral infection have limited efficacy. Newer efforts seem likely to result in therapies targeted at key steps in the pathogenesis of the upper respiratory symptoms. These efforts may prove beneficial not only for treatment of the common cold but also for treatment of other viral respiratory syndromes and their complications. 

Illness in the home: a study of 25,000 illnesses in a group of Cleveland families

Rhinovirus infections in an industrial population. I. The occurrence of illness

HHS: Vital Health Statistics 10

Expense of physician care spurs OTC, self-care market

Over-the-counter medication use among US preschool-age children

Transmission of experimental rhinovirus colds in volunteer married couples

A model for obtaining predictable natural transmission of rhinoviruses in human volunteers

Short-duration exposure and the transmission of rhinoviral colds

Aerosol transmission of rhinovirus colds

Hand-to-hand transmission of rhinovirus colds

Mechanisms of transmission of rhinovirus infections

Modes of transmission of respiratory syncytial virus

The influenza viruses and influenza

An outbreak of influenza aboard a commercial airliner

Relation between naturally acquired immunity and infectivity of two rhinoviruses in volunteers

Transmission of rhinovirus colds by self-inoculation

Sites of virus recovery and antigen detection in epithelial cells during experimental rhinovirus infection

Localization of human rhinovirus replication in the upper respiratory tract by in situ hybridization

Shedding of infected ciliated epithelial cells in rhinovirus colds

Computed tomographic study of the common cold

Elaboration of interleukin 8 from fibroblast cells and human nasal epithelium in response to rhinovirus challenge

Pathogenesis of lower respiratory tract symptoms in experimental rhinovirus infection

A common cold virus, rhinovirus 16, potentiates airway inflammation after segmental antigen bronchoprovocation in allergic subjects

Pathogenesis of rhinovirus common colds in human volunteers

Analysis of nasal secretions during experimental rhinovirus upper respiratory infections

Histopathologic examination and enumeration of polymorphonuclear leukocytes in the nasal mucosa during experimental rhinovirus colds

Light and scanning electron microscopy of nasal biopsy material from patients with naturally acquired common colds

Respiratory virus infection of monolayer cultures of human nasal epithelial cells

Studies with rhinovirus in volunteers: Production of illness, effect of naturally acquired antibody, and demonstration of a protective effect not associated with serum antibody

The role of nasal secretion and serum antibody in the rhinovirus common cold

The secretory immune system: Its relation to respiratory viral infection

Comparison of protective effect of neutralizing antibody in serum and nasal secretions in experimental rhinovirus type 13 illness

An ELISA for the detection of rhinovirus specific antibody in serum and nasal secretions

The leukocyte response during viral respiratory illness in man

Kinins are generated during experimental rhinovirus colds

Acute-phase decrease of T lymphocyte subsets in rhinovirus infection

Effect of rhinovirus 39 infection on cellular immune parameters in allergic and nonallergic subjects

Effects on the nasal mucosa of upper respiratory viruses (common cold)

Jackson GG. Nasal-secretion leukocyte populations determined by flow cytometry during acute rhinovirus infection

Histamine in nasal secretions

Mediators of immediate hypersensitivity in nasal secretions during natural colds and rhinovirus infection

Kinins are generated in nasal secretions during natural rhinovirus colds

Nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat

A study of the efficacy of the bradykinin antagonist, NPC 567, in rhinovirus infections in human volunteers

Oral prednisone therapy in experimental rhinovirus infections

Increased levels of interleukin-1 are detected in nasal secretions of volunteers during experimental rhinovirus colds

Rhinovirus stimulation of interleukin-6 in vivo and in vitro: evidence for nuclear factor kB-dependent transcriptional activation

Association between interleukin-8 (IL-8) and symptom severity in rhinovirus colds [Abstract H48

Influence of interleukin-8 challenge in the nasal mucosa in atopic and nonatopic subjects

Airway reactivity in subjects with viral upper respiratory tract infections: the effects of exercise and cold air

Mechanisms of bronchial hyperreactivity in normal subjects after upper respiratory infection

Studies on 44 081 R.P., a new antirhinovirus compound, in cell cultures and in volunteers

In vitro and in vivo activities of WIN 54954, a new broad-spectrum antipicornavirus drug

SCH 38057: a picornavirus capsid-binding molecule with antiviral activity after the initial stage of viral uncoating

In vitro and in vivo antipicornavirus activity of some phenoxypyridinecarbonitriles

Direct and specific inactivation of rhinovirus by chalcone Ro 09-0410

Inhibition of rhinovirus replication in organ culture by a potential antiviral drug

Sensitivity of rhinoviruses to human leukocyte and fibroblast interferons

In vitro activity of Pirodavir (R 77975), a substituted phenoxypyridazinamine with broad-spectrum antipicornaviral activity

Many rhinovirus serotypes share the same cellular receptor

Isolation of a monoclonal antibody that blocks attachment of the major group of human rhinoviruses

The major human rhinovirus receptor is ICAM-1

A cell adhesion molecule, ICAM-1 is the major surface receptor for rhinoviruses

A soluble form of intercellular adhesion molecule-1 inhibits rhinovirus infection

In vitro inhibitory activity of soluble ICAM-1 for the numbered serotypes of human rhinovirus

Bacterial expression of antibody fragments that block human rhinovirus infection of cultured cells

In vitro studies of the antirhinovirus activity of soluble intercellular adhesion molecule-1

Zinc ions inhibit replication of rhinoviruses

Prophylaxis and treatment of rhinovirus colds with zinc gluconate lozenges

Two randomized controlled trials of zinc gluconate lozenge therapy of experimentally induced rhinovirus colds

Failure of zinc gluconate in treatment of acute upper respiratory tract infections

Zinc gluconate lozenges for treating the common cold: a randomized, double-blind, placebo-controlled study

Reduction in duration of common colds by zinc gluconate lozenges in a double-blind study

Over-thecounter cold medications. A critical review of clinical trials between 1950 and 1991

Nasal decongestant effect of oxymetazoline in the common cold: a objective dose-response study in 106 patients

Therapeutic effects of an anticholinergic-sympathomimetic combination in induced rhinovirus colds

Evaluation of an alpha agonist alone and in combination with a nonsteroidal antiinflammatory agent in the treatment of experimental rhinovirus colds

Comparison of nasal airway patency changes after treatment with oxymetazoline and pseudoephedrine

Intranasally administered atropine methonitrate treatment of experimental rhinovirus colds

Ipratropium bromide treatment of experimental rhinovirus secretion

A double-blind, placebo-controlled study of the safety and efficacy of ipratropium bromide nasal spray versus placebo in patients with the common cold

A dose-response study of the efficacy and safety of ipratropium bromide nasal spray in the treatment of the common cold

Effectiveness and safety of intranasal ipratropium bromide in common colds: a randomized, doubleblind, placebo-controlled trial

Effectiveness of antihistamines in common cold

Effectiveness of antihistamines in the symptomatic management of the common cold

Intranasally and orally administered antihistamine treatment of experimental rhinovirus colds

A double-blind, placebo-controlled clinical trial of the effect of chlorpheniramine on the response of the nasal airway, middle ear and eustachian tube to provocative rhinovirus challenge

Randomized controlled trial of clemastine fumarate for treatment of experimental rhinovirus colds

Effectiveness of clemastine fumarate for treatment of rhinorrhea and sneezing associated with the common cold

Ineffectiveness of oral terfenadine in natural colds: evidence against histamine as a mediator of common cold symptoms

Evaluation of oral terfenadine for treatment of the common cold

Cough and the common cold

Treatment of acute maxillary sinusitis in childhood: a comparative study of amoxicillin and cefaclor

Antitussives in the treatment of acute transient cough in children

The treatment of acute transient cough: a placebo-controlled comparison of dextromethorphan and dextromethorphan-beta2-sympathomimetic combination

Effects of naproxen on experimental rhinovirus colds. A randomized, double-blind, controlled trial

Antitussive effect of guaifenesin in young adults with natural colds. Objective and subjective assessment

Combined antiviral and antimediator treatment of rhinovirus colds

Chemical disinfection to interrupt transfer of rhinovirus type 14 from environmental surfaces to hands

Evaluation of virucidal compounds for inactivation of rhinovirus on hands

Inactivation of rhinovirus on human fingers by virucidal activity of glutaric acid

Interruption of transmission of rhinovirus colds among human volunteers using virucidal paper handkerchiefs

The effect of placebo and virucidal paper handkerchiefs on viral contamination of the hand and transmission of experimental rhinoviral infection

Rhinovirus inactivation by nasal tissues treated with virucide

Modification of experimental rhinovirus colds by receptor blockade

An appraisal of the efficacy of the antiviral R 61837 in rhinovirus infections in human volunteers

Safety and efficacy of intranasal pirodavir (R77975) in experimental rhinovirus infection

Prophylactic efficacy of intranasal alpha 2-interferon against rhinovirus infections in the family setting

Intranasal interferon alpha 2 for prevention of rhinovirus infection and illness

Intranasal interferon-alpha 2 treatment of experimental rhinovirus colds

Prevention of natural colds by contact prophylaxis with intranasal alpha2-interferon

Interferon-beta ser as prophylaxis against experimental rhinovirus infection in volunteers

Intranasal interferon-␣2b for seasonal prophylaxis of respiratory infection

Human tolerance and histopathologic effects of long-term administration of intranasal interferon-␣2

Efficacy and tolerance of intranasally applied recombinant leukocyte A interferon in normal volunteers

Intranasally applied recombinant leukocyte A interferon in normal volunteers. II. Determination of minimal effective and tolerable dose

Tolerance of one-month intranasal interferon