Introduction

Background
The common cold is an acute respiratory tract infection (ARTI) characterized by mild coryzal symptoms, rhinorrhea, nasal obstruction, and sneezing. Although the incidence of ARTI cannot be clearly defined because of seasonal and locational variability, it is estimated to vary from 3-6 cases per person per year in the United States. Children younger than 1 year have experienced an average of 6-8 episodes of ARTI. This figure decreases to 3-4 episodes per year by adulthood. Although the list of agents that cause the common cold is large, 66-75% of cases are due to 200 antigenically distinct viruses from 8 different genera. The most common of these are the rhinoviruses (25-80% of cases), followed by coronaviruses (10-20%), influenza viruses (1015%), and adenoviruses (5%). Rhinoviruses are members of the Picornaviridae family, which includes the human pathogens enteroviruses and hepadnaviruses (notably, hepatitis A). Rhinoviruses are small, nonenveloped, positive (sense) stranded RNA viruses. Their structure is an icosahedral capsid of 12 pentamers containing the 4 viral proteins. A deep cleft is involved in viral attachment. Attachment to cellular receptors can be blocked by a specific antibody. More than 100 different subtypes exist in 3 major groups and are categorized based on receptor specificity: intercellular adhesion molecule-1 (ICAM-1), low-density lipoprotein (LDL) receptors, and sialoprotein cell receptors. Rhinoviral infections are chiefly limited to the upper respiratory tract but may cause otitis media and sinusitis. Rhinoviral infections may exacerbate asthma, cystic fibrosis, chronic bronchitis, and serious lower respiratory tract illness in infants, elderly persons, and immunocompromised persons. Although infections occur year-round, the greatest incidence occurs in the fall and spring. Of persons exposed to the virus, 70-80% have symptomatic disease.

Pathophysiology
Rhinoviruses are transmitted to susceptible individuals by direct contact or by aerosol particles infecting both ciliated areas of the nose and nonciliated areas of the nasopharynx through receptors, most frequently ICAM-1 (found in high quantities in the posterior nasopharynx). Few cells are actually infected by the virus, and the infection involves only a small portion of the epithelium. Symptoms develop 1-2 days after viral infection, peaking 2-4 days after inoculation, although reports have described symptoms as early as 2 hours after inoculation with primary symptoms 8-16 hours later. Detectable histopathology that causes the associated nasal obstruction, rhinorrhea, and sneezing is lacking, which leads to the hypothesis that the host immune response plays a major role in rhinovirus pathogenesis. Infected cells release interleukin-8 (IL-8), which is a potent polymorphonuclear (PMN) chemoattractant. Concentrations of IL-8 in secretions correlate proportionally with the severity of common cold symptoms. Inflammatory mediators, such as kinins and prostaglandins, may cause vasodilatation, increased vascular permeability, and exocrine gland secretion. These, together with local parasympathetic nerve-ending stimulation, lead to cold symptoms.

Deficient interferon-beta production by asthmatic bronchial epithelial cells has been proposed as a mechanism for increased susceptibility to rhinoviral infections in individuals with asthma. Viral clearance is associated with the host response and is due, in part, to the local production of nitric oxide. Serotype-specific neutralizing antibodies are found 7-21 days after infection in 80% of patients. Although these antibodies persist for years, providing long-lasting immunity, recovery from illness is more likely related to cell-mediated immunity. Persistent protection from repeat infection by that serotype appears to be partially attributable to immunoglobulin A (IgA) antibodies in nasal secretions, serum immunoglobulin G (IgG), and, possibly, serum immunoglobulin M (IgM). The virus grows in a limited temperature range (33-35°C) and cannot tolerate an acidic environment. Thus, finding the virus outside of the nasopharynx is unlikely because of the acidic environment of the stomach and the increased temperature in both the lower respiratory and gastrointestinal tracts.

Frequency
United States The frequency of rhinoviral infection averages 1 episode every 1-2 years per person. Rhinoviruses cause up to 80% of colds during the autumn months in temperate climates. International Rhinoviruses have been found in all countries, even in remote areas such as the Kaluhi Islands and the Amazon. In Brazil, rhinoviruses reportedly cause 46% of ARTIs.

Mortality/Morbidity
Although not associated with fatal disease, rhinoviruses are associated with significant morbidity. ARTIs, predominantly rhinoviral infections, are estimated to cause 30-50% of time lost from work by adults and 60-80% of time lost from school by children. Complications of rhinoviral infections include otitis media, sinusitis, chronic bronchitis, and exacerbations of reactive airway disease in children and adults. These viruses are possibly involved in lower respiratory tract infections in elderly persons, infants, persons with cystic fibrosis, and immunosuppressed patients. The true impact of lower respiratory tract infection is not clear. Recovery of rhinovirus in these patients may be a marker of an underlying disease process or a precursor to a bacterial infection.

Race
No difference in susceptibility to infection or disease course has been described among different races.

Sex

Some reports indicate a male predominance of infection in children younger than 3 years, which switches to a female predominance in children older than 3 years. No difference in rates of infection in adults is apparent.

Age
Rhinoviral infection is most common in children, with decreasing incidence as they approach adulthood. Children are instrumental in transmission of infection, commonly passing infection to family members after contracting the virus in nurseries, daycare facilities, and schools.

Clinical
History
Rhinoviral infections are typically indistinguishable from colds of other viral etiologies. Individual patients exhibit a wide variety of signs and symptoms.
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The incubation period is 12-72 hours, averaging 8-16 hours after viral inoculation of the nose. Symptomatic complaints 2 hours after viral inoculation have been described. Illness initially begins with a sore throat, which is frequently the most bothersome of the early symptoms. This is followed by nasal discharge, nasal congestion, and sneezing, which intensify over the next 2-3 days. Other associated complaints include headache, facial and ear pressure, and loss of smell and taste. Thirty percent of infected individuals develop a cough, and 20% develop hoarseness, both of which may persist up to a week, although they seldom become bothersome until nasal symptoms improve. Systemic signs and symptoms, such as fever and malaise, are unusual. If they are present, consider an alternative diagnosis. Symptoms generally last 7-11 days, although they persist up to 2 weeks in a quarter of patients. Rarely, patients complain of lingering symptoms that last more than 30 days. Infants and toddlers may display only nasal discharge. However, Calvo et al recently reported that, among infants younger than 2 years with viral respiratory tract infection requiring hospitalization in Spain, rhinoviral infections are second only to respiratory syncytial virus infections in terms of frequency.46 School-aged children usually complain of nasal congestion, cough, and runny nose. These symptoms persist for an average of at least 10 days.45 Most patients have obstruction and mucosal abnormalities of sinuses, eustachian tubes, and middle ear, which causes a predisposition to secondary bacterial infection in up to 2% of patients. Infection may exacerbate underlying asthma and chronic pulmonary disease. People who smoke do not appear to have more frequent rhinoviral infections; however, their infections are more severe and their symptoms of longer duration.

Physical

The physical examination findings are typically less severe than those reported by the patient.
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Red nose with dripping nasal discharge may be present. Nasal mucous membranes have a glistening glassy appearance without obvious erythema or edema. Yellow or green nasal discharge does not indicate bacterial infection because a large number of white blood cells migrate to the site of viral infection. If marked erythema, edema, exudates, or small vesicles are observed in the oropharynx or if conjunctivitis or polyps in the nasal mucosa occur, consider other etiologies, including infection with adenovirus, herpes simplex virus, mononucleosis, diphtheria, coxsackievirus A, or group A streptococci (GAS). Auscultation of the chest may reveal rhonchi.

Causes

Rhinoviral transmission occurs with close exposure to infected respiratory secretions, including hand-to-hand, self-inoculation of eyes or nose, and, possibly, large- and smallparticle aerosolization. The virus has been cultured from the skin after up to 2 hours and after up to 4 days on inanimate objects in ideal conditions. Donors are typically symptomatic with a cold at the time of transmission, and virus is detected on their hands and nasal mucosa. One recent study assessed the transfer of virus to surfaces in 15 adults with rhinoviral infection. Each stayed overnight in a hotel room. Afterward, 10 commonly-touched sites in each room were tested for viral contaminants. They found that virus could be recovered from 35% of these sites. Furthermore, they found that virus could be transferred back from inanimate objects to fingertips in many cases.47 Higher rates occur in humid, crowded conditions, as found in nurseries, daycare centers, and schools, especially during cooler months in temperate regions and the rainy season in tropical regions. The likelihood of transmission does not appear to be related to exposure to cold temperatures, fatigue, or sleep deprivation.

Treatment
Medical Care
Rhinoviral infections are predominately mild and self-limited; thus, treatment is generally focused on symptomatic relief and prevention of person-to-person spread and complications. The mainstays of therapy include rest, hydration, antihistamines, and nasal decongestants. Antibacterial agents are not effective unless bacterial superinfection occurs. Development of effective antiviral medications has been hampered by the short course of these infections. Because peak symptom severity occurs at 24-36 hours after inoculation, antivirals have only a narrow window to positively affect a rhinoviral infection. In addition, the cause of the common cold is not always rhinoviral infection. Therefore, rapid and accurate diagnostic tests would be needed if a specific antiviral therapy were developed.

Because of the large number of rhinovirus immunotypes and the inaccessibility of the conserved region of the viral capsid (the most likely effective site for targeting a vaccine), no rhinovirus vaccine is on the horizon. Because infection is spread by hand-to-hand contact, autoinoculation, and, possibly, aerosol particles, emphasize appropriate hand washing, avoidance of finger-to-eyes or finger-to-nose contact, and use of nasal tissue. Heated humidified air has been used for decades for the alleviation of symptoms due to rhinoviral infections but has never been shown to improve objective outcome measures.34 Numerous agents are under investigation for the treatment of viral infections. o Pleconaril inhibits approximately 92% of rhinovirus serotypes. Susceptibility to pleconaril depends on the viral capsid surface protein VP1. A double-blind, randomized, placebo-controlled trial of pleconaril 400 mg PO tid for 5 days, initiated within 24 hours of symptom onset, resulted in a decrease in the duration of symptoms by 1 day.14 o Steroids have been examined as a therapeutic modality and have shown little effect with rhinoviruses. One recent article noted that children who experienced wheezing during a rhinoviral infection and were treated with prednisolone experienced fewer wheezing episodes than untreated individuals in the subsequent 2 months. However, no change in time to discharge was noted.18 o A blinded, placebo-controlled trial using intranasal interferon-alpha-2b and ipratropium with oral naproxen started within 24 hours of rhinovirus inoculation decreased viral shedding, geometric mean virus titers, and symptoms in the treatment group. Similar findings were reported with the use of intranasal interferon-alpha-2b, chlorpheniramine, and ibuprofen. Recombinant interferon-alpha-2b applied topically to the nose at 5 million U or more per day prevented experimental infections. Unfortunately, the effect of this agent on symptomatic illness was limited.11 o A recombinant soluble intercellular adhesion molecule-1 (ICAM-1) administered intranasally 6 times per day and beginning either 7 hours before or 12 hours after rhinovirus challenge was analyzed in a randomized, double-blinded study. Neither strategy affected the incidence of infection, but combining results from both treatment groups found a 23% decrease in clinical colds, a 45% decrease in total symptom score, and a 56% decrease in total nasal secretion weight.50 o 3C protease inhibitors are currently being evaluated in human trials, but no data are currently available. A phase II study found that ruprintrivir, a 3C protease inhibitor, delivered as a nasal spray was well tolerated and decreased positive viral culture results and improved symptom scores but did not decrease the frequency of colds.15 These drugs act by interfering with the cleaving of a single large polyprotein that produces individual structures and enzymatic proteins of the virus. o Rhinoviruses are sensitive to low pH. In one recent study, citrate/phosphate buffers were administered intranasally, decreasing viral shedding but failing to decrease symptomatology.48

Diet

Dietary supplements have been touted as possible therapeutic or preventive measures.

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Although large doses of vitamin C have been used for prevention and treatment of colds, controlled trials reveal minimal therapeutic benefit and no preventive qualities.33 Zinc has been found to inhibit rhinovirus replication in vitro, but no proven benefit has been shown in vivo on virus activity or immune modulation. The genus Echinacea consists of 3 species of plants used medicinally for their reported nonspecific stimulation of the immune system. o Echinacea purpurea has recently been studied and did not show any differences in rates of infection or severity of illness when compared with placebo. Although reports of improved symptoms have been described, validation and standardization of products is necessary.36 o Echinacea angustifolia has also been examined in the prophylaxis and treatment of experimental rhinoviral infection. Neither the rate of infection nor the severity of symptoms were found to be statistically significantly affected when E angustifolia was used either prophylactically or at the time of challenge.39 o In contrast, a recent meta-analysis of echinacea indicated that, in properly designed studies, patients receiving placebo were 55% more likely to experience cold symptoms than patients taking echinacea. The most striking part of this meta-analysis was that 231 of 234 articles identified were excluded because they did not control for the type of viruses causing the colds. Echinacea extracts will continue to be evaluated.32

Activity
Patients may limit their activity during the course of the infection, with clinical improvement occurring 48-72 hours after the prodrome of symptoms.

Medication
Drugs used in the symptomatic treatment include nonsteroidal anti-inflammatory drugs (NSAIDs), antihistamines, and anticholinergic nasal solutions. These agents have no preventive activity and appear to have no impact on complications. The combined effect of NSAIDs and antihistamines often relieves nasal obstruction; therefore, decongestion therapy is rarely needed. Oral (pseudoephedrine) and topical (oxymetazoline and phenylephrine) decongestants are commonly used for symptomatic relief. First-generation antihistamines reduce rhinorrhea by 25-35%, as do topical anticholinergics and ipratropium bromide. Second-generation or nonsedating antihistamines appear to have no effect on common cold symptoms. Corticosteroids may actually increase viral replication and have no impact on cold symptoms.

Antihistamines

These agents act by competitive inhibition of histamine at the H1 receptor.

Diphenhydramine (Benylin, Benadryl) Occasional drowsiness and is suitable for use on a day-to-day basis. Oral H1-blocker used in the treatment of allergic conjunctivitis and rhinitis, angioedema, pruritus, and urticaria.
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Dosing Interactions Contraindications Precautions

Adult

25-50 mg PO q6-8h prn; not to exceed 400 mg/d 10-50 mg IV/IM q6-8h prn; not to exceed 400 mg/d
Pediatric

12.5-25 mg PO tid/qid, or 5 mg/kg/d, or 150 mg/m2/d divided tid/qid; not to exceed 300 mg/d 5 mg/kg/d IV/IM or 150 mg/m2/d, divided qid; not to exceed 300 mg/d
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Dosing Interactions Contraindications Precautions

Potentiates effect of CNS depressants; because of alcohol content, do not administer syrup dosage form to patients taking medications that can cause disulfiram-like reactions
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Dosing Interactions Contraindications Precautions

Documented hypersensitivity; MAOIs
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Dosing Interactions Contraindications Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

May exacerbate angle-closure glaucoma, hyperthyroidism, peptic ulcer, or urinary tract obstruction; xerostomia may occur

Chlorpheniramine (Telachlor, Chlo-Amine, Chlor-Trimeton, Aller-Chlor) Competes with histamine or H1-receptor sites on effector cells in blood vessels and respiratory tract.
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Dosing Interactions Contraindications Precautions

Adult

10-20 mg IV/IM/SC once; not to exceed 40 mg/d 4 mg PO q4-6h; not to exceed 24 mg/d or 8-12 mg SR q8-12h; not to exceed 24 mg/d
Pediatric

<2 years: Not established 2-6 years: 1 mg PO divided q4-6h; not to exceed 6 mg/d 6-12 years: 2 mg PO q4-6h; not to exceed 12 mg/d or 8 mg SR PO hs >12 years: Administer as in adults
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Dosing Interactions Contraindications Precautions

CNS toxicity increases with coadministration of other CNS depressants, tricyclic antidepressants, MAOIs, and phenothiazines
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Dosing Interactions Contraindications Precautions

Documented hypersensitivity; asthma attacks; narrow-angle glaucoma; symptomatic prostate hypertrophy; bladder-neck obstruction; stenosing peptic ulcer
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Dosing Interactions Contraindications Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

May cause significant confusional symptoms; not for administration to premature or full-term neonates

Brompheniramine maleate (Bromphen, Nasahist B, Dimetane Extentabs) Does not tend to cause drowsiness and is suitable for use on a day-to-day basis. Oral H1-blocker used in the treatment of allergic conjunctivitis and rhinitis, angioedema, pruritus, and urticaria.
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Dosing Interactions Contraindications Precautions

Adult

Capsule/elixir: 4-8 mg PO q6-8h prn Extended-release form: 8 mg PO q8-12h or 12 mg PO q12h prn; not to exceed 24 mg/d
Pediatric

<2 years: Not established 2-5 years: 1 mg PO q4-6h prn; not to exceed 6 mg/d 6-11 years: 2-4 mg PO q6-8h prn; not to exceed 12 mg/d >12 years: Administer as in adults
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Dosing Interactions Contraindications Precautions

MAOIs and beta-blockers increase the effects of sympathomimetics; may reduce antihypertensive effects of methyldopa, mecamylamine, reserpine, veratrum alkaloids; alcohol and other CNS depressants may have an addictive effect
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Dosing Interactions Contraindications Precautions

Documented hypersensitivity; severe hypertension; severe coronary artery disease; current or within 14 days of MAOI use; narrow-angle glaucoma; urinary retention; peptic ulcer disease; during an asthma attack
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Dosing Interactions Contraindications Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions

Caution in patients with hypertension, heart disease, diabetes, or thyroid disease; antihistamines may cause drowsiness

Anticholinergics
These agents have antisecretory properties and, when applied locally, inhibit secretions from serous and seromucous glands lining the nasal mucosa.

Ipratropium intranasal (Atrovent) Two strengths of nasal spray: 0.03% for treatment of rhinorrhea associated with allergic and nonallergic perennial rhinitis and 0.06% for treatment of rhinorrhea associated with common cold. Chemically related to atropine.
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Dosing Interactions Contraindications Precautions

Adult

Rhinorrhea common cold 0.06% nasal solution: 2 sprays (42 mcg/spray) per nostril tid/qid Rhinorrhea allergic/nonallergic perennial rhinitis 0.03% nasal solution: 2 sprays (21 mcg/spray) per nostril bid/tid
Pediatric

Administer as in adults
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Dosing Interactions Contraindications Precautions

Drugs with anticholinergic properties, such as dronabinol, may increase toxicity; albuterol may increase effects
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Dosing Interactions Contraindications Precautions

Documented hypersensitivity
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Dosing Interactions Contraindications Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions

Caution in patients with narrow-angle glaucoma, prostatic hypertrophy, or bladder-neck obstruction

Nonsteroidal anti-inflammatory drugs (NSAIDs)
These agents have analgesic, anti-inflammatory, and antipyretic activities. Their mechanism of action is not known but may inhibit cyclooxygenase activity and prostaglandin synthesis. Other mechanisms also may exist (eg, inhibition of leukotriene synthesis, lysosomal enzyme release, lipoxygenase activity, neutrophil aggregation, various cell membrane functions).

Naproxen (Anaprox) For relief of mild to moderate pain and antipyretic action; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
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Dosing Interactions Contraindications Precautions

Adult

550 mg PO q12h or 275 mg PO q6-8h prn
Pediatric

<2 years: Not established >2 years: 2.5 mg/kg/dose PO; not to exceed 10 mg/kg/d
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Dosing Interactions Contraindications Precautions

Coadministration with aspirin increases risk of inducing serious NSAID-related adverse effects; probenecid may increase concentrations and, possibly, toxicity of NSAIDs; may decrease effect of hydralazine, captopril, and beta-blockers; may decrease diuretic effects of furosemide and thiazides; monitor PT closely (instruct patients to watch for signs of bleeding); may increase risk of methotrexate toxicity; phenytoin levels may be increased when administered concurrently
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Dosing Interactions Contraindications Precautions

Documented hypersensitivity; peptic ulcer disease; recent GI bleeding or perforation; renal insufficiency
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Dosing Interactions Contraindications Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions

Acute renal insufficiency, interstitial nephritis, hyperkalemia, hyponatremia, and renal papillary necrosis may occur; patients with preexisting renal disease or compromised renal perfusion risk acute renal failure; leukopenia occurs rarely, is transient, and usually returns to normal during therapy; persistent leukopenia, granulocytopenia, or thrombocytopenia warrants further evaluation and may require discontinuation of drug

Ibuprofen (Ibuprin, Motrin) For relief of mild to moderate pain and antipyretic action; inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which results in a decrease of prostaglandin synthesis.
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Dosing Interactions Contraindications Precautions

Adult

200-400 mg PO q4-6h while symptoms persist; not to exceed 3.2 g/d
Pediatric

<6 months: Not established 6 months to 12 years: 4-10 mg/kg/dose PO tid/qid >12 years: Administer as in adults