sharon sanders
Editor-in-Chief & President
Influenza Team, European Centre for Disease Prevention and Control (influenza@ecdc.europa.eu)
The recent attention devoted to human influenza in the context of a possible pandemic has identified a surprising number of research gaps [1,2], some of which concern issues of fundamental importance for preventing or reducing transmission. Important unresolved questions include:
The evidence supporting these methods for transmitting influenza includes data from two sources. Firstly, experimental and observational studies of viral excretion usually find that infected people start excreting influenza viruses at low levels from their respiratory tract a short while before they develop symptoms [8]. Secondly, serological studies of levels of population immunity to influenza often find people who show antibodies from prior infection but have no recollection of symptoms. Other surveys suggest that many more people have been infected during annual epidemics than can be explained by the number of cases observed [9,10]. However, as there are few field reports of infections from asymptomatic or pre-symptomatic persons, the public health importance of such transmission remains unclear. One systematic review found very few convincing reports of transmission from a pre-symptomatic patient [2,8]. Reports of asymptomatic or pre-symptomatic patients excreting high levels of virus are rare and it is possible that any infections resulting from such transmission are mild or asymptomatic, although they could be of importance in maintaining chains of transmission [8,11].
Indirect transmission
There are studies showing that influenza viruses can survive for hours or days on non-porous surfaces [12]. However, a careful systematic review found that human-to-human transmission through this route had not been well studied and hardly ever documented [3, 10]. Similarly while there have been trials showing that hand-washing reduces respiratory infections in general, there has never been a trial regarding its effect on influenza transmission [2,8].
Contact transmission
This category includes direct and indirect contact via large droplets as modes of transmission (Table 1). How influenza transmits through the air has been an area of controversy recently. It is known that influenza transmits by coughing and sneezing, which produce large droplets (>=5?m). Large droplets do not stay in the air long but usually quickly fall onto surfaces so that the risk of acquiring infection from such droplets declines quickly beyond one metre from the symptomatic person [2, 3].
What is much less certain is whether there is transmission of influenza viruses through the air-borne route and small aerosolized particles (<5?m). If this were the case, infectious influenza viruses could travel long distances, and penetrate the incomplete defenses provided by surgical or home-made masks. Some microorganisms e.g. measles and varicella [3], transmit through aerosols and the air-borne route. However, these are infections where one person may infect many others, while even during a pandemic the average symptomatic influenza patient usually infects less than two other people [13].
Two review articles on this topic were recently published by Tellier [4] and Brankston et al [3]. The article by Tellier implied that aerosol transmission was of considerable importance, while the more extensive review with a specific search procedure by Brankston et al concluded there was little evidence that aerosol transmission was of importance, except in unusual hospital circumstances where some higher-risk medical procedures (intubation, bronchopulmonary lavage etc) could generate aerosols [3].
Comparison of the two reviews shows more common ground than differences, and the articles essentially answer distinct questions. Tellier considered a simple question about whether aerosol transmission of influenza occurs at all and specifically states that he only reviewed studies that supported the existence of such transmission [4]. The review by Brankston et al. looks more at the balance of different types of transmission (Table 1) and concludes that, except in the circumstances mentioned above, aerosol transmission contributes little to the overall transmission of influenza [3].
Table 1. Modes of influenza transmission ? implications for control <table border="1"> <tbody><tr> <td bgcolor="#ffffcc">Direct Contact Transmission occurs when the transfer of influenza results from direct physical contact between an infected individual and a susceptible host
Indirect Contact Transmission occurs by the passive transfer of microorganisms to a susceptible host via an intermediate object such as contaminated hands that are not washed between contact, or other inanimate objects in the infected person?s environment
Control Measures ? Early self-isolation of the person with suspected influenza, good respiratory hygiene (use of disposable tissues), hand-washing; possibly enhanced cleaning of non-porous surfaces where practicable.
</td> </tr> <tr> <td bgcolor="#ccffff">Large Droplet Transmission occurs via droplets of >=5?m diameter produced from the respiratory tract of an infected person during coughing and sneezing, talking or, in health care settings during medical procedures on the respiratory tract (examination of the throat etc.). These large droplets travel through the air and may be deposited on the respiratory mucosa on a new susceptible host or onto their immediate environment. The large droplets do not remain suspended in the air and are usually only propelled for a metre from the infected person.
Control Measures ? Simple masks worn by the infectious person when they have to be in close contact with others and by those caring for them, notably in the health care setting.
NB Direct, Indirect contact and Droplet Transmission may be referred to collectively as Contact Transmission ? all cause influenza transmission but the relative importance between the three is currently undetermined </td> </tr> <tr> <td bgcolor="#ffffcc">Airborne (Aerosol) Transmission can occur through the aerosolisation of microorganisms where viruses are contained in small droplets (=< 5?m diameter) or on dust particles small enough to remain suspended in the air for some time. These can then be carried long distances in air-currents. There is little evidence that airborne transmission is common in natural transmission of human influenza, although it is important in the transmission of some other respiratory viruses. However, it is thought to be likely to happen during medical procedures that generate aerosols (e.g. bronchoscopy and intubation).
Implications for control measures ? Special precautions, such as the use of negative pressure rooms and staff wearing respirators, should be taken when undertaking these medical procedures. They can also be considered when dealing with infections of more highly pathogenic viruses such as A/H5N1.</td> </tr> </tbody></table> Adapted from Reference 3.
Prevention and infection control strategies for health-care settings
Currently there seem to be two strategies for health-care settings to prevent the spread of influenza (Table 1), which can be characterised as the Precautionary and Pragmatic approaches. The Precautionary approach aims to stop all transmission, especially to those occupationally exposed in a health-care setting (which includes care at home by relatives) so applying this includes mechanisms to protect against aerosols. Inevitably, this leads to approaches that include the wide-spread use of respirators* that can trap and protect against very small air-borne particlesThe Precautionary approach aims to stop all transmission, especially to those occupationally exposed in a health-care setting (which includes care at home by relatives) so applying this includes mechanisms to protect against aerosols [5, 6]
Those taking the Pragmatic approach point out that while reasonable in theory, respirators are hard to use properly and make performing normal tasks difficult. In practice, they are rarely used properly outside of high-risk situations and/or dealing with a few patients where special procedures can be reasonably expected [7,14,15]. Hence in health care settings, supporters of the Pragmatic approach will insist on the use of respirators in high-risk settings or with exceptionally dangerous highly pathogenic organisms (such as avian influenza A/H5N1) but will only expect surgical masks to be used when dealing with patients with human seasonal or pandemic influenza [14,15].
In community settings, it is difficult to advocate unequivocally for or against the use of masks [16]. However, it is consistent with the approach in hospitals that surgical-type masks should be worn when close contact (less than one metre) with symptomatic influenza patients in the home or clinic setting is unavoidable, for example by family members caring for ill patients or by doctors and nurses seeing patients [14,15].
In summary, the scientific basis of knowledge of how human influenza transmits and can be controlled remains poor. Table 2 lists higher order and some more detailed questions that need to be urgently answered and provides a number of suggestions for approaches, including experimental and observational strategies and trials. Fortunately, there will be no lack of research opportunities as these arise annually during epidemics of seasonal influenza.
Table 2. Research questions concerning influenza transmission and infection control <table border="1"> <tbody><tr> <td bgcolor="#ccffff">Higher Level Questions</td> </tr> <tr> <td bgcolor="#ffffcc">1. What are the contributions to influenza transmission and disease from pre-symptomatic and asymptomatic spread?</td> </tr> <tr> <td bgcolor="#ffffcc">2. How important in influenza transmission are indirect and aerosol transmission?</td> </tr> <tr> <td bgcolor="#ffffcc">3. How practical, acceptable and cost-effective are the more stringent mechanisms proposed for infection control for influenza in settings providing health care for patients (such as wide-spread use of respirators)</td> </tr> <tr> <td bgcolor="#ccffff">Detailed Questions</td> </tr> <tr> <td bgcolor="#ffffcc">4. What are the relative contributions of large droplets versus small particles and droplet nuclei to disease transmission? </td> </tr> <tr> <td bgcolor="#ffffcc">5. What is the role of localized airborne transmission of small particles and droplet nuclei in the spread of human influenza viruses? </td> </tr> <tr> <td bgcolor="#ffffcc">6. What is the efficacy and effectiveness of respirators and surgical masks in preventing influenza infection? </td> </tr> <tr> <td bgcolor="#ffffcc">7. How much occupational risk of influenza infection can be additionally prevented through the use of respirators compared with surgical masks?</td> </tr> <tr> <td bgcolor="#ffffcc">8. What is the relative benefit, efficacy, or effectiveness of contact versus droplet versus airborne precautions in preventing influenza infection and/or outbreaks in healthcare settings?</td> </tr> <tr> <td bgcolor="#ffffcc">9. What strategies are most effective in promoting adherence to infection control measures during a pandemic?</td> </tr> <tr> <td bgcolor="#ffffcc">10. Is there a risk to users from potentially contaminated surgical masks and respirators (e.g., does influenza virus persist in surgical mask/respirator materials)? </td> </tr> <tr> <td bgcolor="#ffffcc">11. How long does influenza virus remain infective on environmental surfaces? </td> </tr> <tr> <td bgcolor="#ffffcc">12. What is the efficacy of various decontamination techniques for environmental surfaces, including respirators?</td> </tr> <tr> <td bgcolor="#ffffcc">13. Which medical procedures produce aerosols capable of transmitting influenza? </td> </tr> <tr> <td bgcolor="#ffffcc">14. Can influenza infection occur via deposition of virus on the conjunctiva which in turn could lead to infection of the respiratory tract via spread through the lacrimal duct? </td> </tr> <tr> <td bgcolor="#ffffcc">15. How frequently and through what mechanisms can transmission of influenza virus occur from asymptomatic or pre-symptomatic persons? </td> </tr> </tbody></table>
Mary Chamberland (Centers for Disease Control and Prevention, Atlanta, United States), Arlene King (Public Health Agency, Ottawa, Canada) and Jonathan Van Tam (Health Protection Agency, London, United Kingdom) for their input into Table 2.
References:
The recent attention devoted to human influenza in the context of a possible pandemic has identified a surprising number of research gaps [1,2], some of which concern issues of fundamental importance for preventing or reducing transmission. Important unresolved questions include:
- Is there significant pre-symptomatic (transmission from people who will become sick with influenza before they develop symptoms) and/or asymptomatic spread (transmission from people who are infected but never develop symptoms)?
- How is influenza transmitted? E.g. how much transmission takes place through indirect contact (Table 1) and what is the relative contribution of aerosol transmission under normal conditions [3,4]?
- How effective, practical and acceptable are some of the more stringent measures suggested by some authorities for infection control in high-risk and lower-risk settings, especially in places where people with influenza are being cared for [5]? In health-care settings in particular, will people follow the stricter recommended measures, and will they be able to do their jobs whilst adhering to the more demanding recommendations [5-7]?
The evidence supporting these methods for transmitting influenza includes data from two sources. Firstly, experimental and observational studies of viral excretion usually find that infected people start excreting influenza viruses at low levels from their respiratory tract a short while before they develop symptoms [8]. Secondly, serological studies of levels of population immunity to influenza often find people who show antibodies from prior infection but have no recollection of symptoms. Other surveys suggest that many more people have been infected during annual epidemics than can be explained by the number of cases observed [9,10]. However, as there are few field reports of infections from asymptomatic or pre-symptomatic persons, the public health importance of such transmission remains unclear. One systematic review found very few convincing reports of transmission from a pre-symptomatic patient [2,8]. Reports of asymptomatic or pre-symptomatic patients excreting high levels of virus are rare and it is possible that any infections resulting from such transmission are mild or asymptomatic, although they could be of importance in maintaining chains of transmission [8,11].
Indirect transmission
There are studies showing that influenza viruses can survive for hours or days on non-porous surfaces [12]. However, a careful systematic review found that human-to-human transmission through this route had not been well studied and hardly ever documented [3, 10]. Similarly while there have been trials showing that hand-washing reduces respiratory infections in general, there has never been a trial regarding its effect on influenza transmission [2,8].
Contact transmission
This category includes direct and indirect contact via large droplets as modes of transmission (Table 1). How influenza transmits through the air has been an area of controversy recently. It is known that influenza transmits by coughing and sneezing, which produce large droplets (>=5?m). Large droplets do not stay in the air long but usually quickly fall onto surfaces so that the risk of acquiring infection from such droplets declines quickly beyond one metre from the symptomatic person [2, 3].
What is much less certain is whether there is transmission of influenza viruses through the air-borne route and small aerosolized particles (<5?m). If this were the case, infectious influenza viruses could travel long distances, and penetrate the incomplete defenses provided by surgical or home-made masks. Some microorganisms e.g. measles and varicella [3], transmit through aerosols and the air-borne route. However, these are infections where one person may infect many others, while even during a pandemic the average symptomatic influenza patient usually infects less than two other people [13].
Two review articles on this topic were recently published by Tellier [4] and Brankston et al [3]. The article by Tellier implied that aerosol transmission was of considerable importance, while the more extensive review with a specific search procedure by Brankston et al concluded there was little evidence that aerosol transmission was of importance, except in unusual hospital circumstances where some higher-risk medical procedures (intubation, bronchopulmonary lavage etc) could generate aerosols [3].
Comparison of the two reviews shows more common ground than differences, and the articles essentially answer distinct questions. Tellier considered a simple question about whether aerosol transmission of influenza occurs at all and specifically states that he only reviewed studies that supported the existence of such transmission [4]. The review by Brankston et al. looks more at the balance of different types of transmission (Table 1) and concludes that, except in the circumstances mentioned above, aerosol transmission contributes little to the overall transmission of influenza [3].
Table 1. Modes of influenza transmission ? implications for control <table border="1"> <tbody><tr> <td bgcolor="#ffffcc">Direct Contact Transmission occurs when the transfer of influenza results from direct physical contact between an infected individual and a susceptible host
Indirect Contact Transmission occurs by the passive transfer of microorganisms to a susceptible host via an intermediate object such as contaminated hands that are not washed between contact, or other inanimate objects in the infected person?s environment
Control Measures ? Early self-isolation of the person with suspected influenza, good respiratory hygiene (use of disposable tissues), hand-washing; possibly enhanced cleaning of non-porous surfaces where practicable.
</td> </tr> <tr> <td bgcolor="#ccffff">Large Droplet Transmission occurs via droplets of >=5?m diameter produced from the respiratory tract of an infected person during coughing and sneezing, talking or, in health care settings during medical procedures on the respiratory tract (examination of the throat etc.). These large droplets travel through the air and may be deposited on the respiratory mucosa on a new susceptible host or onto their immediate environment. The large droplets do not remain suspended in the air and are usually only propelled for a metre from the infected person.
Control Measures ? Simple masks worn by the infectious person when they have to be in close contact with others and by those caring for them, notably in the health care setting.
NB Direct, Indirect contact and Droplet Transmission may be referred to collectively as Contact Transmission ? all cause influenza transmission but the relative importance between the three is currently undetermined </td> </tr> <tr> <td bgcolor="#ffffcc">Airborne (Aerosol) Transmission can occur through the aerosolisation of microorganisms where viruses are contained in small droplets (=< 5?m diameter) or on dust particles small enough to remain suspended in the air for some time. These can then be carried long distances in air-currents. There is little evidence that airborne transmission is common in natural transmission of human influenza, although it is important in the transmission of some other respiratory viruses. However, it is thought to be likely to happen during medical procedures that generate aerosols (e.g. bronchoscopy and intubation).
Implications for control measures ? Special precautions, such as the use of negative pressure rooms and staff wearing respirators, should be taken when undertaking these medical procedures. They can also be considered when dealing with infections of more highly pathogenic viruses such as A/H5N1.</td> </tr> </tbody></table> Adapted from Reference 3.
Prevention and infection control strategies for health-care settings
Currently there seem to be two strategies for health-care settings to prevent the spread of influenza (Table 1), which can be characterised as the Precautionary and Pragmatic approaches. The Precautionary approach aims to stop all transmission, especially to those occupationally exposed in a health-care setting (which includes care at home by relatives) so applying this includes mechanisms to protect against aerosols. Inevitably, this leads to approaches that include the wide-spread use of respirators* that can trap and protect against very small air-borne particlesThe Precautionary approach aims to stop all transmission, especially to those occupationally exposed in a health-care setting (which includes care at home by relatives) so applying this includes mechanisms to protect against aerosols [5, 6]
Those taking the Pragmatic approach point out that while reasonable in theory, respirators are hard to use properly and make performing normal tasks difficult. In practice, they are rarely used properly outside of high-risk situations and/or dealing with a few patients where special procedures can be reasonably expected [7,14,15]. Hence in health care settings, supporters of the Pragmatic approach will insist on the use of respirators in high-risk settings or with exceptionally dangerous highly pathogenic organisms (such as avian influenza A/H5N1) but will only expect surgical masks to be used when dealing with patients with human seasonal or pandemic influenza [14,15].
In community settings, it is difficult to advocate unequivocally for or against the use of masks [16]. However, it is consistent with the approach in hospitals that surgical-type masks should be worn when close contact (less than one metre) with symptomatic influenza patients in the home or clinic setting is unavoidable, for example by family members caring for ill patients or by doctors and nurses seeing patients [14,15].
In summary, the scientific basis of knowledge of how human influenza transmits and can be controlled remains poor. Table 2 lists higher order and some more detailed questions that need to be urgently answered and provides a number of suggestions for approaches, including experimental and observational strategies and trials. Fortunately, there will be no lack of research opportunities as these arise annually during epidemics of seasonal influenza.
Table 2. Research questions concerning influenza transmission and infection control <table border="1"> <tbody><tr> <td bgcolor="#ccffff">Higher Level Questions</td> </tr> <tr> <td bgcolor="#ffffcc">1. What are the contributions to influenza transmission and disease from pre-symptomatic and asymptomatic spread?</td> </tr> <tr> <td bgcolor="#ffffcc">2. How important in influenza transmission are indirect and aerosol transmission?</td> </tr> <tr> <td bgcolor="#ffffcc">3. How practical, acceptable and cost-effective are the more stringent mechanisms proposed for infection control for influenza in settings providing health care for patients (such as wide-spread use of respirators)</td> </tr> <tr> <td bgcolor="#ccffff">Detailed Questions</td> </tr> <tr> <td bgcolor="#ffffcc">4. What are the relative contributions of large droplets versus small particles and droplet nuclei to disease transmission? </td> </tr> <tr> <td bgcolor="#ffffcc">5. What is the role of localized airborne transmission of small particles and droplet nuclei in the spread of human influenza viruses? </td> </tr> <tr> <td bgcolor="#ffffcc">6. What is the efficacy and effectiveness of respirators and surgical masks in preventing influenza infection? </td> </tr> <tr> <td bgcolor="#ffffcc">7. How much occupational risk of influenza infection can be additionally prevented through the use of respirators compared with surgical masks?</td> </tr> <tr> <td bgcolor="#ffffcc">8. What is the relative benefit, efficacy, or effectiveness of contact versus droplet versus airborne precautions in preventing influenza infection and/or outbreaks in healthcare settings?</td> </tr> <tr> <td bgcolor="#ffffcc">9. What strategies are most effective in promoting adherence to infection control measures during a pandemic?</td> </tr> <tr> <td bgcolor="#ffffcc">10. Is there a risk to users from potentially contaminated surgical masks and respirators (e.g., does influenza virus persist in surgical mask/respirator materials)? </td> </tr> <tr> <td bgcolor="#ffffcc">11. How long does influenza virus remain infective on environmental surfaces? </td> </tr> <tr> <td bgcolor="#ffffcc">12. What is the efficacy of various decontamination techniques for environmental surfaces, including respirators?</td> </tr> <tr> <td bgcolor="#ffffcc">13. Which medical procedures produce aerosols capable of transmitting influenza? </td> </tr> <tr> <td bgcolor="#ffffcc">14. Can influenza infection occur via deposition of virus on the conjunctiva which in turn could lead to infection of the respiratory tract via spread through the lacrimal duct? </td> </tr> <tr> <td bgcolor="#ffffcc">15. How frequently and through what mechanisms can transmission of influenza virus occur from asymptomatic or pre-symptomatic persons? </td> </tr> </tbody></table>
*Interim Guidance on Planning for the Use of Surgical Masks and Respirators in Health Care Settings during an Influenza Pandemic (Ref 6) Appendix B Types of Surgical Masks and Respirators Used in Health Care Settings. Available from: http://www.pandemicflu.gov/plan/healthcare/maskguidancehc.html#appB
AcknowledgementsMary Chamberland (Centers for Disease Control and Prevention, Atlanta, United States), Arlene King (Public Health Agency, Ottawa, Canada) and Jonathan Van Tam (Health Protection Agency, London, United Kingdom) for their input into Table 2.
References:
- Stohr K. Avian influenza and pandemics, research needs and opportunities. NEJM 2005 Jan 27;352(4):405-7. Epub 2005 Jan 24.
- World Health Organization Writing Group. Nonpharmaceutical interventions for pandemic influenza, national and community measures. Emerg Infect Dis [serial on the Internet]. 2006 Jan [date cited]. Available from: http://www.cdc.gov/ncidod/EID/vol12no01/05-1371.htm
- Brankston G, Gitterman G, Hirji J, Lemieux C, Gardam M. Transmission of influenza A in human beings. Lancet Infectious Diseases 2007; 7 (4):257 -265.
- Tellier R. Review of aerosol transmission of influenza A virus. Emerg Infectious Diseases 2006; 12: 1657-62.
- US Interim Public Health Guidance for the Use of Facemasks and Respirators in Non-Occupational Community Settings during an Influenza Pandemic. HHS USA May 2007. Available from: http://www.pandemicflu.gov/vaccine/maskguidance.html
- US Interim Guidance on Planning for the Use of Surgical Masks and Respirators in Health Care Settings during an Influenza Pandemic. Oct 2006. Available from: http://www.pandemicflu.gov/plan/healthcare/maskguidancehc.html
- Cummings KJ, Cox-Ganser J, Riggs MA, Edwards N, Kreiss K. Respirator donning in post-hurricane New Orleans. Emerg Infect Dis [serial on the Internet]. 2007 May [date cited]. Available from: http://www.cdc.gov/EID/content/13/5/700.htm
- World Health Organization Writing Group. Nonpharmaceutical interventions for pandemic influenza, international measures. Emerg Infect Dis [serial on the Internet]. 2006 Jan [date cited]. Available from: http://www.cdc.gov/ncidod/EID/vol12no01/05-1370.htm
- Elder AG, O'Donnell B, McCruden EA, Symington IS, Carman WF. Incidence and recall of influenza in a cohort of Glasgow healthcare workers during the 1993-4 epidemic: results of serum testing and questionnaire. BMJ 1996; 313:1241-1242.
- Glezen WP, Keitel WA, Taber LH, Piedra PA, Clover RD, Couch RB. Age distribution of patients with medically-attended illnesses caused by sequential variants of influenza A/H1N1: comparison to age-specific infection rates, 1978-1989. Am J Epidemiol 1991; 133:296-304.
- Hayden FG, Fritz RS, Lobo MC, Alvord WG, Strober W, Straus SE. Local and systemic cytokine responses during experimental human influenza A virus infection. Relation to symptom formation and host defense. J Clin Invest 1998;101:643-9.
- Bean B, Moore BM. Sterner B, Peterson LR, Gerding DN, Balfour HH. Survival of influenza viruses on environmental surfaces. J. Infect Dis 1982; 146: 47-51.
- Hall IM, Gani R, Hughes HE, Leach S. Real-time epidemic forecasting for pandemic influenza. Epidemiol Inf 2006.
- Department of Health England & Health Protection Agency Guidance for pandemic influenza: Infection control in hospitals and primary care settings Oct 2005. Available from: http://www.dh.gov.uk/en/Publication...ions/PublicationsPolicyAndGuidance/DH_4121752
- Canadian Pandemic Plan 2006 Guidance Infection Control and Occupational Health Guidelines During Pandemic Influenza in Traditional and Non-traditional Health Care. Available from: http://www.phac-aspc.gc.ca/cpip-pclcpi/pdf-e/15-CPIP-Appendix-F-Infection-Control_e.pdf
- ECDC Interim Recommendations Personal (non-Pharmaceutical) Protective Measures for Reducing Transmission of Human Influenza October 2006. Available from: http://ecdc.europa.eu/documents/pdf/PPHM_Recommendations.pdf