Symptomatic treatment

Symptomatic treatment with analgesics, decongestants, antihistamines, and antitussives is currently the mainstay of therapy. These over-the-counter (OTC) preparations are likely to benefit older children and adolescents [85] but should be avoided for children younger than 6 years (see below). [81] In 2004-2005, an estimated 1500 children younger than 2 years were treated in US emergency departments (EDs) for adverse events (including overdoses) associated with cough and cold medications. [86] In adults, antihistamines improve overall symptoms and rhinorrhea only in the short term (first two days of therapy), but not on the long term, according to a 2015 Cochrane review. [87]

Antibacterial therapy

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 within which to have a positive effect on infection. In addition, the common cold is not always caused by rhinovirus. Therefore, rapid and accurate diagnostic tests would be needed if a specific antiviral therapy were to be developed.

Zinc therapy

Zinc has been studied extensively as a treatment for the common cold. The exact mechanism of zinc’s antiviral effect remains uncertain, although in vitro studies have demonstrated that zinc can inhibit viral replication and has activity against respiratory viruses including rhinovirus and respiratory syncytial virus (RSV). [88] Ionic zinc reduces the level of intracellular adhesion molecule-1 (ICAM-1), increases IFN-γ levels by 10-fold, and assists in the protection of cell plasma membranes, which is thought to explain its therapeutic effectiveness for common colds. [89] In addition, zinc seems to inhibit rhinovirus from binding to ICAM-1 in the nasal mucosa while also inhibiting viral replication by preventing the formation of rhinovirus capsid proteins. Zinc also reduces symptoms by inhibiting proteolysis during the rhinovirus cell cycle, blocking facial nerve and trigeminal nerve conduction and decreasing nasal congestion and sneezing. It also stabilizes cell membranes and prevents the release of histamine. Lastly, zinc is able to inhibit prostaglandin metabolism. [90, 91, 92]

Multiple meta-analyses have investigated the role of zinc in the treatment and prevention of the common cold. A 2013 Cochrane review assessed 13 therapeutic trials involving 966 patients. Oral zinc taken within 24 hours of onset of common cold symptoms reduced duration of illness in adults when high doses (at least 75 mg of elemental zinc per day) were used. Unfortunately, the same benefit was not seen in the subgroup analysis among children, nor in trials that used low doses of zinc. In addition, zinc has also been associated with faster resolution of nasal congestion, nasal drainage, and sore throat, as well as improvement of cough (in terms of cough score). [92] Although heterogeneity was high among the trials included in the review, the findings were consistent with those reported in another systematic review of 17 trials involving 2121 participants. [88] Overlap of included studies was noted and methodological limitations have been raised against the two reviews. Still, in an illness that is considered a high-burden disease (with children experiencing 6-12 colds a year and adults having 2-4 episodes annually, accounting for 40% of time lost from work), [92, 91] "even an only partially effective medication could markedly reduce morbidity and economic losses." [93]

Multiple zinc preparations are available; 75 mg of elemental zinc per day should be used to treat the common cold in adult patients so that the benefits of reduction of symptom duration and severity can be achieved. Zinc acetate is composed of 30% elemental zinc; zinc gluconate, 14.3%; zinc sulfate, 23%; and zinc oxide, 80%. [94]

When administered for at least 5 months, zinc reduces the incidence of colds. However, zinc may have side effects, and the recommended dosing, formulations, and duration are difficult to establish without further studies. For most pediatric patients, zinc lozenges are not practical, because of their metallic taste.

Because of the large number of rhinovirus serotypes 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.

Steroid therapy

Steroids have been examined as a therapeutic modality in rhinovirus infection but have not been shown to confer a substantial benefit. In one study, children who experienced wheezing during infection and were treated with prednisolone experienced fewer wheezing episodes than untreated individuals in the subsequent 2 months; however, time to discharge was unchanged. [95] A Cochrane review of three poor-quality trials also did not recommend the use of intranasal steroid for the relief of common colds symptoms. [96]

Investigational agents

Numerous agents have been investigated or are being investigated for the treatment of viral infections. These include the following:

Capsid-binding agents (eg, pleconaril)

Pirodavir

WIN 54954

Intranasal interferon (IFN)

Virus receptor blockers

Antireceptor antibodies

Soluble intercellular adhesion molecule-1 (ICAM-1)

3C protease inhibitors

Protein kinase D (PKD) inhibitors

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 given orally 3 times daily for 5 days, initiated within 24 hours of symptom onset, resulted in a decrease in the duration of symptoms by 1 day. [97] However, safety concerns, which included menstrual disorders in women taking pleconaril and oral contraceptives and the report that two women became pregnant while taking pleconaril and oral contraceptives, prompted the FDA advisory committee to reject the manufacturer’s application. [98]

Pirodavir, a substituted phenoxypyridazinamine, possesses broad antipicornavirus activity. Clinical studies demonstrate no decrease in viral shedding or symptoms.

Overall, although capsid binders are attractive and potent early-stage inhibitors of rhinovirus replication in vitro, problems in pharmacodynamics, in vivo efficacy, and resistance development were reported.

WIN 54954, a methylisoxazole derivative, has not been found to have any significant antiviral or clinical effects.

Interferon (IFN)–alfa is effective for cold prevention but has limited efficacy against for established symptomatic illness. [99] When administered via nasal spray (typically at dosages of 5 million U/day or higher), it can prevent as many as 80% of secondary rhinovirus colds. It has also been given in conjunction with ipratropium, chlorpheniramine, and ibuprofen. Unfortunately, IFN-alfa is not cost-effective, and significant adverse effects have been reported.

On the other hand, IFN-beta (but not IFN-gamma) has been shown to counter the permissiveness of mast cells for rhinovirus replication and release. This may be a novel mechanism by which rhinovirus-associated asthma exacerbations can be prevented in the future. [100] However, other bench researchers have also noted that IFN-gamma antagonizes type 2 innate lymphoid cells expansion and gene expression. This blocks the development of an asthma phenotype in baby mice. [101]

Virus receptor blockers are believed to prevent replication by blocking virus internalization. Tests of antireceptor antibodies have not demonstrated any decreases in infection frequency.

Tremacamra, a recombinant soluble ICAM-1 administered intranasally 6 times per day either 7 hours before or 12 hours after rhinovirus challenge was analyzed in a randomized, double-blinded study; neither timing strategy affected the incidence of infection, but combining the results from the 2 treatment groups demonstrated a 23% decrease in clinical colds, a 45% decrease in total symptom score, and a 56% decrease in total nasal secretion weight. [102]

3C protease inhibitors (eg, rupintrivir) are being evaluated in human trials. In a phase II study, rupintrivir delivered as a nasal spray was well tolerated, decreased positive viral culture results, and improved symptom scores; however, it did not decrease the frequency of colds. [103] 3C protease inhibitors act by interfering with the cleaving of a single large polyprotein that produces individual structures and enzymatic proteins of the virus.

Rhinoviruses are sensitive to low pH. In one study, citrate/phosphate buffers were administered intranasally, decreasing viral shedding but failing to decrease symptomatology. [104]

Protein kinase D (PKD) inhibitors are being studied for their novel antiviral action, since PKD appears to regulate viral replication. The specific mechanism of action of PKD inhibitors is still unknown. [105]

Bench research on alpha-1 antitrypsin has shown that it appears to prevent cigarette smoke–induced increases in rhinovirus infection incidence and may be an area of continued research that may be beneficial in smokers who are infected. [106]

When compared with itraconazole suspension, itraconazole microemulsion formulation delivered intranasally was considered a promising candidate for the treatment of rhinovirus infection, since the latter led to significantly less inflammatory markers in the lungs in mouse models, which may be related to the significant increase in drug released in the microemulsion formulation group. [107] Similar results in a murine model study also showed that itraconazole reduced virus replication and reduced immune cells (granulocytes and monocytes) in bronchoalveolar lavage fluid, which seemed to be related to the decreased pro-inflammatory cytokine and chemokine levels in the bronchoalveolar lavage fluid. In addition, the same study also noted that intranasal itraconazole may also be effective in the prevention of infection. [108]

Liposomes of phosphatidylserine have also been studied as a potential prototype treatment modality to reduce rhinovirus-associated inflammation. The liposomes did not induce cell death but appeared to markedly reduce inflammation as a response to infection, despite a nonsignificant increase in replication. [109]

The bark extract Ficus religiosa L, considered a "sacred tree" in South Asia, is another material that has been shown to possess antiviral activity in human rhinovirus (and respiratory syncytial virus) in vitro but will need further studies with regard to in vivo activity. [110]

Special considerations in children

Remind parents that treatment of rhinovirus infection in children younger than 6 years should be supervised by a physician. These children should receive analgesics, cough suppressants, decongestants, and antihistamines only on the advice of a physician.

The US Food and Drug Administration (FDA) does not recommend the use of cough and cold medications in very young children (age < 2 years). In January 2008, the FDA completed its review of information regarding the safety of OTC cough and cold medicines in children younger than 2 years. This review resulted in a new recommendation that these drugs should not be used to treat children in this age group, because serious and potentially life-threatening adverse effects can occur.

In October 2008, the pharmaceutical industry voluntarily changed the labeling for OTC pediatric cough and cold drugs to include that a statement these drugs should not be used in children younger than 4 years. This action was in response to dosing errors, misuse, and overuse of OTC pediatric cough and cold medications. Each year, nearly 7000 visits to EDs in the United States by children younger than 11 years are associated with cough and cold medicines.

Healthcare providers should emphasize to parents and caregivers that although OTC medications are available without a prescription, that does not mean that they are harmless. Providers should discuss the merits of hydration, rest, and humidification as initial treatment options. Most important, parents should seek specific instructions from their child’s physician if cough or cold medications are warranted and should give only the exact amount of medication that is prescribed.

To prevent overdose, it is vital that parents and caregivers be carefully instructed not to add other cough and cold medications to the regimen. Adverse effects, including deaths, have occurred as a consequence of unintentional overdose when different OTC or prescription medications that contain the same ingredients (eg, pseudoephedrine, dextromethorphan, an antihistamine, or an analgesic or antipyretic) have been combined.

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