Virucidal hand treatments for prevention of rhinovirus infection

Ronald B. Turner* and J. Owen Hendley

Department of Pediatrics, University of Virginia School of Medicine, PO Box 800386, Charlottesville, VA 22908, USA


* Corresponding author. Tel: +1-434-243-9864; Fax: +1-434-982-4246; E-mail: rbt2n{at}virginia.edu


    Abstract
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
Rhinovirus infections are associated with substantial morbidity and economic cost. The available common cold remedies are of limited utility and specific antiviral approaches have been unsuccessful. Viral contamination of the hands appears to play an important role in the transmission of rhinovirus from person-to-person. Interruption of this step in transmission presents a potential target for intervention. Initial studies demonstrated that the common cold could be prevented by treatment of hands with iodine. Inactivation of the rhinoviruses by acid is well known and a survey of organic acids considered safe for consumer use revealed that salicylic acid and pyroglutamic acid have potent virucidal activity for the rhinoviruses that persists for several hours after application to the hands. A subsequent evaluation in human volunteers confirmed the prevention of rhinovirus infections by these acids and suggested that these agents have promise as cosmetically acceptable virucidal agents for interruption of the transmission of these infections.

Keywords: common cold , hand disinfection , antiviral


    Introduction
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
Rhinovirus infections are the most frequent cause of common cold illnesses. These upper respiratory infections are generally mild and self-limited in the normal host, but they are associated with an enormous economic burden both in lost productivity and in expenditures for treatment. In addition, rhinovirus infection is frequently associated with medical complications that have substantial morbidity. Rhinovirus infection has been detected in up to 30% of children who seek medical care for acute otitis media and also appears to exacerbate underlying lower respiratory tract illnesses. Rhinovirus infection may also be associated with substantial morbidity in the elderly. Prevention or treatment of rhinovirus infections with resulting avoidance of these complications would have an enormous societal impact with regard to both medical morbidity and economic cost.


    Treatment of rhinovirus infections
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
Treatment options for rhinovirus colds are unsatisfactory. The available common cold remedies have only modest effects on specific symptoms and have no effect on the development of otitis media or exacerbations of lower respiratory tract disease. There are ongoing attempts to develop antiviral treatments for rhinovirus colds. Substantial challenges remain, however, and it is not clear that this approach will ultimately result in effective treatment (reviewed in ref. 1). Pleconaril, an antiviral with good activity against the rhinoviruses, had only modest effects on the symptoms of the common cold in healthy adults.2 The effect of pleconaril on the morbidity associated with rhinovirus infections in high-risk patients has not been carefully evaluated. An alternative to antiviral treatment—prevention of rhinovirus infection by interruption of person-to-person transmission—appears to be technologically and economically feasible.


    Person-to-person transmission of rhinovirus
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
During a rhinovirus cold, virus replicates primarily in the epithelium of the nasal cavity and posterior nasopharynx. Potential mechanisms of spread of virus from the upper respiratory tract to a susceptible contact include small particle aerosols, large particle aerosols and contact spread either directly or via a fomite. Spread by direct contact implies that the infected individual contaminates themselves and/or the environment with rhinovirus that can be transferred to a susceptible ‘recipient’ by casual contact. The recipient then inoculates the virus onto the nasal mucosa by self-inoculation. The steps in these different modes of person-to-person transmission of rhinovirus infection have been studied in some detail. Aerosols generated by coughs and sneezes infrequently contain infectious virus. Virus was recovered in 1/13 sneezes and 0/8 coughs generated by adults with natural rhinovirus infections.3 In contrast, virus can be recovered from the hands of ~40% of adults with rhinovirus colds.3,4 The quantity of virus recovered from the hands is also generally greater than that recovered in coughs and sneezes and virus can readily be transferred to the hands of a ‘recipient’ by direct contact.3,57


    Transmission of rhinovirus by contact
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
Early observations suggesting that hand-to-hand contact was an important mode of transmission of rhinovirus prompted a search for compounds that would inactivate the virus on the hands. Of the disinfectants evaluated, only aqueous iodine was found to reliably eliminate virus on human skin.8,9 Ethanol (70%) and combinations of ethanol with benzalkonium chloride or hexachlorophene were less active. A study in human volunteers demonstrated that 2% aqueous iodine could prevent the transmission of rhinovirus by direct contact.7 The effect of hand treatment with 2% iodine on transmission of rhinovirus infection and common colds was then evaluated in the natural setting.10 For this evaluation, the mothers in 206 families with at least one child were randomized to use either iodine or placebo hand treatment whenever respiratory symptoms appeared in another family member. The secondary attack rate of rhinovirus infection and common cold illness was then determined for mothers in the two treatment groups. Common cold illnesses developed after 16 (20%) of 79 exposures in the mothers in the control group for an attack rate of 40 illnesses/1000 days of exposure. In contrast, the iodine-treated mothers developed illness after four (7%) of 58 exposures for an attack rate of 13 illnesses/1000 days of exposure (P = 0.05). The attack rate for rhinovirus infection after exposure to a rhinovirus-positive contact was also examined in the two treatment groups. Rhinovirus transmission occurred in five (31%) of the 16 exposures in the control group compared with none of the 11 exposures in the iodine treatment group (P = 0.06). Although the power of this study was reduced by the insensitivity of standard cell culture isolation and serological techniques for detection of rhinovirus infections, the results support the concept that direct contact transmission of rhinovirus is an important mode of transmission in the natural setting and document that common cold illnesses can be prevented by the use of an effective virucidal hand treatment. Iodine is not acceptable for general use as a virucidal hand treatment because it discolours and dries the skin.


    Development of virucidal hand treatments
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
The inactivation of rhinovirus by acids is well known and has been used for many years to distinguish the rhinoviruses from other picornaviruses. The mechanism of this inactivation appears to involve changes in the virion structure that result in loss of VP4 with an associated loss of infectivity.11 Acid sensitivity has been used as the basis for attempts to develop effective virucidal agents against the rhinovirus.

Effective prevention of rhinovirus infection appears to require complete eradication of the virus from the hands. Previous studies have demonstrated that the ‘human infectious dose’ of rhinovirus for a susceptible individual is less than one tissue culture infectious dose.12 Glutaric acid, evaluated as a potential virucidal agent in the 1980s, reduced viral titre but did not reliably eradicate virus from the hands and was ineffective for prevention of infection.13 It should be noted that 62% ethanol, contained in many commercial hand sanitizers, is also ineffective for complete removal of rhinovirus from the hands and would be expected to be ineffective for the prevention of rhinovirus infection.

In vitro studies

Initial studies to screen a variety of organic acids approved for use in over-the-counter products revealed that salicylic acid, pyroglutamic acid and benzoic acid had potent virucidal activity that persisted for 3 h after application.14 In these experiments, all of the acids were standardized to 0.145 M in 1:1 water/ethanol and the pH of each solution was adjusted to 3.0. The water/ethanol vehicle was used as the negative control. All three acids reduced the rhinovirus titre by at least 2 logs, to concentrations undetectable in the assay, 3 h after application to the skin. The log reduction in titre with each of these three acids was greater than that of 2% iodine at both the 1 h and 3 h time points.

In vivo studies

The efficacy of salicylic and pyroglutamic acid for prevention of experimental rhinovirus infection in human volunteers was examined in two randomized, double-blinded clinical studies.14 Volunteers susceptible to rhinovirus type 39 applied a measured amount of a hand cleanser containing organic acid to both hands. The vehicle, 62% ethanol, was used as the negative control. At specified time points after application of the study material, the fingers of each hand were contaminated with 100 TCID50 of rhinovirus type 39. After contamination with virus the hands were allowed to air dry for 10 min before the volunteers attempted to intentionally inoculate the virus on the right hand by making contact with both the conjunctiva and the nasal mucosa. Following the self-inoculation, the amount of virus contaminating the fingers of the left hand was determined by elution into 2 mL of viral collecting broth for quantitative culture. In the interval between the hand treatment and the virus challenge the volunteers remained at the study site and were not allowed to use or wash their hands.

The first study examined the effect of 3.5% salicylic acid, and a combination of 1% salicylic acid with 3.5% pyroglutamic acid at a single time point (15 min) after application. Both of the organic acids significantly reduced recovery of virus from the hands and the rhinovirus infection rate (Table 1). In the second clinical trial, a formulation of 4% pyroglutamic acid was tested by challenging with virus 15 min, 1 h and 3 h after application. In this experiment, recovery of virus from the hands was significantly reduced at all time points but the infection rate in the volunteers was not significantly different (Table 1).


View this table:
[in this window]
[in a new window]
 
Table 1. Effect of virucidal hand treatment on recovery of virus from the hands and infection of volunteers

 

    Comment
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
The persistence of the virucidal effect of the organic acids for up to 3 h after application is an attractive feature of this approach. It is not clear, however, whether this persistence will be retained when studies are conducted under natural conditions. In these preliminary studies, volunteers were not permitted to use their hands in the interval between application of the acids and the challenge with virus. A limited evaluation found no effect of using the hands on virucidal activity in these studies,14 but previous work suggests that the virucidal effect of the organic acids may be diminished by normal usage.13

In summary, there is substantial evidence that direct contact followed by self-inoculation of the respiratory mucosa is an important mechanism of transmission for the rhinoviruses. In light of this evidence, treatment of the hands with virucidal agents appears to be a rational approach to prevention of rhinovirus infection. These early studies suggest that the organic acids have potent virucidal activity against the rhinoviruses and may be suitable agents for this use. Ultimately, however, studies in the natural setting will be required to establish the effectiveness of this intervention.


    References
 Top
 Abstract
 Introduction
 Treatment of rhinovirus...
 Person-to-person transmission of...
 Transmission of rhinovirus by...
 Development of virucidal hand...
 Comment
 References
 
1. Turner RB. The treatment of rhinovirus infections: progress and potential. Antiviral Res 2001; 49: 1–14.[CrossRef][ISI][Medline]

2. Hayden FG, Herrington DT, Coats TL. et al. Efficacy and safety of oral pleconaril for treatment of colds due to picornaviruses in adults: results of 2 double-blind, randomized, placebo-controlled trials. Clin Infect Dis 2003; 36: 1523–32.[CrossRef][ISI][Medline]

3. Hendley JO, Wenzel RP, Gwaltney JM Jr. Transmission of rhinovirus colds by self-inoculation. N Engl J Med 1973; 288: 1361–4.[ISI][Medline]

4. Reed SE. An investigation of the possible transmission of rhinovirus colds through indirect contact. J Hyg 1975; 75: 249–58.[ISI]

5. Gwaltney JM Jr, Moskalski PB, Hendley JO. Hand-to-hand transmission of rhinovirus colds. Ann Intern Med 1978; 88: 463–7.[ISI][Medline]

6. Hayden GF, Hendley JO, Gwaltney JM Jr. The effect of placebo and virucidal paper handkerchiefs on viral contamination of the hand and transmission of experimental rhinoviral infection. J Infect Dis 1985; 152: 403–7.[ISI][Medline]

7. Gwaltney JM Jr, Moskalski PB, Hendley JO. Interruption of experimental rhinovirus transmission. J Infect Dis 1980; 142: 811–15.[ISI][Medline]

8. Carter CH, Hendley JO, Mika LA et al. Rhinovirus inactivation by aqueous iodine in vitro and on skin. Proc Soc Exp Biol Med 1980; 165: 380–3.

9. Hendley JO, Mika LA, Gwaltney JM Jr. Evaluation of virucidal compounds for inactivation of rhinovirus on hands. Antimicrobial Agents and Chemotherapy 1978; 14: 690–4.[ISI][Medline]

10. Hendley JO, Gwaltney JM Jr. Mechanisms of transmission of rhinovirus infections. Epidemiol Rev 1988; 10: 243–58.[Medline]

11. Giranda VL, Heinz BA, Oliveira MA et al. Acid-induced structural changes in human rhinovirus 14: possible role in uncoating. Proc Natl Acad Sci USA 1992; 89: 10213–17.[Abstract/Free Full Text]

12. Hendley JO, Edmonson P Jr, Gwaltney JM Jr. Relation between naturally acquired immunity and infectivity of two rhinoviruses in volunteers. J Infect Dis 1972; 125: 243–8.[ISI][Medline]

13. Hayden GF, DeForest D, Hendley JO et al. Inactivation of rhinovirus on human fingers by virucidal activity of glutaric acid. Antimicrob Agents Chemother 1984; 26: 928–9.[ISI][Medline]

14. Turner RB, Biedermann KA, Morgan JM et al. Efficacy of organic acids in hand cleansers for prevention of rhinovirus infections. Antimicrob Agents Chemother 2004; 48: 2595–8.[Abstract/Free Full Text]





This Article
Abstract
FREE Full Text (PDF)
All Versions of this Article:
56/5/805    most recent
dki329v1
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Disclaimer
Request Permissions
Google Scholar
Articles by Turner, R. B.
Articles by Hendley, J. O.
PubMed
PubMed Citation
Articles by Turner, R. B.
Articles by Hendley, J. O.