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2
Understanding the Risk of Influenza to Healthcare Workers
Although it has been 70 years since the influenza A virus was discovered and despite the recognition that it can cause yearly epidemics worldwide resulting in severe illness and death, little is known about the mechanisms by which influenza A is transmitted or its viability and infectivity outside the host. Debate continues about whether influenza transmission is primarily via the airborne or droplet routes and the extent of the contribution of the contact route (including contact with blood, fecal matter, or contaminated surfaces). Further, the aerosol-droplet continuum needs to be clarified as soon as possible in order to develop and implement effective prevention strategies.
Most of the research on influenza transmission was carried out prior to the 1970s, and there has only recently been a renewed focus on transmission, primarily as a result of new pandemic threats. The ongoing outbreak of H5N1 (avian) influenza among poultry and other birds with occasional transmission to human beings is of major concern because of intriguing parallels between the H5N1 strain and the highly virulent 1918 influenza strain. Should H5N1 or another novel influenza strain acquire the capability of easy human-to-human transmissibility, conservative estimates project several hundred million emergency and outpatient visits, more than 25 million hospital admissions, and several million deaths worldwide (WHO, 2005). The virulence of the strain will determine its impact on the healthcare system (Table 2-1). Healthcare workers are concerned about the risk of a new pandemic, especially in light of the recent outbreaks of severe acute respiratory syndrome (SARS) and the fact that many of the patients who developed SARS were healthcare workers (CDC, 2003a; Lee et al., 2003; Varia et al., 2003; Chen et al., 2006).
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TABLE 2-1 Estimated Aggregate Number of Episodes of Illness, Healthcare Utilization, and Death in the United States Associated with Moderate and Severe Pandemic Influenza Scenariosa
Characteristic
Moderate (such as 1958 and 1968)
Severe (such as 1918)
Illness
90 million (30%)
90 million (30%)
Outpatient medical care
45 million (50%)
45 million (50%)
Hospitalization
865,000
9,900,000
Intensive care unit care
128,750
1,485,000
Mechanical ventilation
64,875
745,500
Deaths
209,000
1,903,000
aEstimates based on extrapolation from past pandemics in the United States. Note that these estimates do not include the potential impact of interventions not available during the twentieth century.
SOURCE: DHHS, 2006.
This chapter provides a brief overview of the influenza virus and past pandemics and then focuses on understanding the risks to healthcare workers.
OVERVIEW OF INFLUENZA AND PANDEMICS
Influenza is a serious respiratory illness caused by infection with influenza type A or type B virus. Since the beginning of the twentieth century, only the influenza A virus has been associated with infection in humans. Cases of influenza peak during the winter months in each hemisphere. In addition to seasonal occurrences of influenza, outbreaks may result in a global pandemic. For seasonal influenza, the risk of serious illness and death is highest among persons over the age of 65 years, children under 2 years of age, and persons who have medical conditions that place them at increased risk of developing complications from influenza. Each year in the United States more than 35,000 deaths and 200,000 hospitalizations result from influenza and its complications, with most of the excess mortality in persons 65 years and older, often from pneumonia (Lewis, 2006; CDC, 2007). Vaccines and antiviral medications have been developed to prevent or mitigate the disease, although major challenges remain, particularly in determining the appropriate virus subtype to target. In a review of nine studies, Brankston and colleagues (2007) note that infections in individuals exposed to influenza ranged from 33 to 55 percent in unvaccinated and 0 to 37 percent in vaccinated cohorts.
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The influenza A virus is categorized by the subtypes of its major surface glycoproteins: hemagglutinin and neuraminidase.1 Of the 16 identified hemagglutinin subtypes (all of which are found in aquatic birds), only the H1, H2, and H3 subtypes are known to have resulted in global pandemics and ongoing epidemics in humans (Gillim-Ross and Subbarao, 2006). The influenza virus undergoes frequent changes in antigenicity due often to minor antigenic changes that result from the accumulation of point mutations (antigenic drift) or due to more major antigenic shifts with the introduction of novel subtypes into humans (Treanor, 2005; Gillim-Ross and Subbarao, 2006; Figure 2-1).
In contrast to seasonal influenza and frequent regional epidemics, pandemics occur more rarely, every 10 to 50 years (Kamps and Reyes-Terán, 2006). Within the past 400 years, at least 31 pandemics have been described, and most recently, during the twentieth century, pandemics occurred in 1918, 1957, and 1968 (Lazzari and Stohr, 2004). Of the three recent pandemics, the 1918 pandemic resulted in the highest mortality, causing an estimated 675,000 deaths in the United States and a total of 50 million or more deaths worldwide (Johnson and Mueller, 2002; Morens and Fauci, 2007).
The 1918-1919 pandemic, caused by an H1N1 virus of possible avian lineage, occurred in three waves across the globe (Morens and Fauci, 2007). In the first wave in the spring of 1918, illness rates were elevated, but death rates were near the annual normal rate as the pandemic spread through the United States, Europe, and possibly Asia (Taubenberger and Morens, 2006). The second and third waves, in the fall of 1918 and early 1919, occurred globally and with an increase in severity and fatality (Kilbourne, 2006; Taubenberger and Morens, 2006). Many deaths were the result of secondary bacterial pneumonia (Klugman and Madhi, 2007). Pandemic influenza has had its most consequential impact on younger age groups (Figure 2-2). Approximately half of the influenza-related deaths in the 1918 pandemic occurred in persons age 20-40 years; persons younger than 65 years of age constituted more than 99 percent of all excess influenza-related deaths in 1918-1919 (Taubenberger and Morens, 2006).
1
Hemagglutinin mediates the binding of influenza virus to the cells. Neuraminidase is involved in the release of virus from infected cells.
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FIGURE 2-1 Origins of pandemic influenza.
In 1918, an H1N1 virus closely related to avian viruses adapted to replicate efficiently in humans. In 1957 and 1968, reassortment events led to new viruses that resulted in pandemic influenza. The 1957 influenza virus (an H2N2 virus) acquired three genetic segments from an avian species, and the 1968 influenza virus (an H3N2 virus) acquired two genetic segments from an avian species. Future pandemic strains could arise through either mechanism.
SOURCE: Belshe, 2005. Reprinted with permission from Massachusetts Medical Society. Copyright 2005. All Rights Reserved.
The two pandemics that have occurred since 1918 appear to have resulted from natural reassortment events (Belshe, 2005; Figure 2-1). The 1957-1958 pandemic, resulting from an H2N2 virus, was clinically milder than the 1918-1919 pandemic, but was responsible for an estimated excess mortality of 1 million to 2 million deaths worldwide (Kamps and Reyes-Terán, 2006). Patients with chronic heart or lung disease and women in the third trimester of pregnancy were particularly at risk of developing pulmonary complications (Kilbourne, 2006).
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FIGURE 2-2 Combined influenza and pneumonia mortality, by age at death, per 100,000 persons, 1911-1917 and 1918. Influenza- and pneumonia-specific death rates are plotted for the interpandemic years 1911-1917 (dashed line) and for the pandemic year 1918 (solid line).
SOURCE: Taubenberger and Morens, 2006.
The global death toll of the 1968 H3N2 pandemic has been estimated at approximately 1 million individuals, with persons less than 65 years of age accounting for 48 percent of all influenza-related excess deaths (Simonsen et al., 1998).
The increased mortality of young adults in past pandemics may be particularly relevant to considerations of protecting healthcare workers, as young adults comprise a large proportion of the healthcare workforce and may be at higher risk depending on the pandemic influenza subtype.
The Next Pandemic Threat
The next pandemic may come from a human or an avian influenza strain. To date, human disease caused by transmission of avian influenza viruses has occurred with the H5, H7, and H9 subtypes (Katz, 2003; WHO, 2006), and there is serological evidence of exposure of poultry and bird market workers in Asia to other avian influenza virus subtypes (Gillim-Ross and Subbarao, 2006). Species barriers preventing animal-to-human spread of influenza include differences in cell surface recep-
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tors, intracellular environment, body temperature, and innate and adaptive antiviral immune responses (Parrish and Kawaoka, 2005).
At present, the avian influenza strain of greatest concern is H5N1 because although it remains primarily an avian disease, it has crossed the species barrier to humans. Through May 15, 2007, the World Health Organization had received reports of 291 confirmed human cases of H5N1 avian influenza and 172 deaths associated with the virus; 26.5 percent of the cases were in patients less than 10 years of age (WHO, 2007). To date most cases of human infection with an avian virus have well-documented exposure to sick or dying poultry. Recently, a few cases of human-to-human transmission of H5N1 have been reported, primarily in blood relatives who were primary caregivers and provided care without personal protective equipment (PPE; Ungchusak et al., 2005). Seroprevalence studies of healthcare workers and family members having close contact with an infected individual have found H5-specific antibodies indicating evidence of human-to-human transmission of the virus;2 severe disease has not occurred in those individuals following presumed human transmission (Buxton Bridges et al., 2000; Katz et al., 1999). In a study of a 2003 outbreak of H7N7 influenza in the Netherlands, 58.9 percent of household members of infected poultry workers (confirmed index cases) had detectable H7 antibodies (33 individuals of 56 providing blood samples; Du Ry van Beest Holle et al., 2005).
UNDERSTANDING TRANSMISSION OF INFLUENZA
Infectious respiratory diseases are transmitted from human to human primarily by three routes: (1) direct contact with an infected patient’s blood or secretions or a contaminated surface; (2) transmission via large droplets; or (3) transmission via small droplets (aerosolization) (Table 2-2). With most respiratory pathogens, including influenza, the relative contribution of each of these types of transmission has not been adequately studied. This paucity of definitive data on influenza transmission is a critical gap in the knowledge base needed to develop and implement
2
Comparisons were made between exposed and unexposed healthcare workers. Each individual’s history of poultry exposures was considered in both studies.
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TABLE 2-2 Possible Modes of Respiratory Virus Transmission
Direct contact
Physical contact between an infected and an uninfected individual
Indirect contact
Transmission occurs via contact with viruses that survive on intermediate surfaces such as contaminated hands, equipment, or other objects surrounding the patient
Droplet
Large droplets generated from the infected individual’s respiratory tract during activities such as talking, coughing, or sneezing, or during a procedure such as bronchoscopy or suctioning, can result in virus transmission. The droplets travel no further than 1 meter, collecting on a new host or the surrounding environment
Airborne
Droplets generated from the infected individual’s respiratory tract are small enough to remain airborne for an extended period of time. These aerosols are circulated by air currents and then inhaled by uninfected individuals who may be a substantial distance away—even in another room—from the infected individual
SOURCE: Adapted from Brankston et al., 2007.
effective prevention strategies. Without knowing the contributions of each of the possible route(s) of transmission, all routes must be considered probable and consequential, and the resources needed for prevention and control strategies cannot be rationally focused to maximize preparedness efforts.
Contact Transmission
Contact transmission of the influenza virus requires either direct transfer of the virus between persons or indirect transfer via contact with an influenza-contaminated object (fomite).3 In either case, transmission can result in infection only if the virus survives in an adequate infective
3
A fomite is an object (e.g., a dish, an article of clothing) that is contaminated with infectious organisms and may serve in the transmission (Boone and Gerba, 2007).
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dose. Data on both survivability and infectivity of the influenza virus are limited and more research is needed in both of these areas.
Virus survivability on surfaces depends on the complex interaction of a number of factors including humidity, pH, ambient temperature, ultraviolet light exposure, and the presence of other microorganisms (Boone and Gerba, 2007). In addition, the properties of the fomite—including its porous or nonporous nature, the presence of moisture, and cleanliness—contribute to the ability of a virus to survive. Finally, the type and strain of the virus and any suspending medium (inoculum) also contribute to its ability to survive on environmental surfaces (Boone and Gerba, 2007). When tested at room temperature (27.8 to 28.3°C) and 35 to 40 percent humidity, influenza A virus has been found to survive on hard, nonporous surfaces (stainless steel and plastic) for 24 to 28 hours, with reduced survivability (less than 8 to 12 hours) on more porous surfaces (cloth, paper, and tissues) (Bean et al., 1982). Inactivation rates of avian influenza, other influenza A strains, and other respiratory viruses (e.g., respiratory syncytial virus) vary significantly when tested on steel surfaces, leading to different log reductions hourly (Boone and Gerba, 2007). Although transmission from fomites to humans has been proven, contact transmission is generally considered of lesser importance (Hota, 2004).
Droplet and Airborne Transmission
Much of the discussion regarding influenza transmission has focused on the continuum between large-droplet and airborne transmission. Large-droplet transmission involves larger particles than those that can remain airborne. Because large droplets travel shorter distances before settling on a surface, prevention and protection strategies should focus on areas proximate to the infected patient. Airborne transmission is well described in healthcare settings with certain forms of tuberculosis and measles (Remington et al., 1985). It involves infectious agents carried for longer distances by air currents, with concerns for ventilation, and necessitates the protection of individuals at a greater distance from the infected person (Cole and Cook, 1998; CDC, 2003b).
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The aerosols generated by coughing, sneezing, talking, and other vocalizations vary widely in the number and size of particles expelled. Further, each particle from an infected patient may contain zero, one, or multiple viruses,4 and there is much to be learned about the nature and extent of infectivity. On average, a cough with a velocity of 10 meters per second contains hundreds to thousands of particles, while a sneeze can result in thousands to more than a million particles (Tang et al., 2006; Xie et al., 2007). As a result of evaporation or other changes in relative humidity, some of the expelled particles rapidly become even smaller; the droplet nuclei that remain after evaporation can easily be carried on air currents and remain suspended in the air for substantial lengths of time. The length of time that these particles remain airborne is determined by their size, their settling velocity, and air flow dynamics. When humans cough or sneeze, the exhaled aerosols commonly contain fluid from the respiratory tract that can also include infectious agents (Buckland and Tyrrell, 1964). Individuals exhibit a fair amount of variability in the volume and particle size of exhaled bioaerosol particles (Edwards et al., 2004). Persons generating (or who potentially generate) a large quantity of contaminated bioaerosols and who can transmit more virus than others have been labeled superspreaders, although the relevance to influenza transmission is not known.
Given the limited knowledge of the role of aerosols in the transmission of influenza, further research is needed to more fully define and characterize the nature, continuum, and infectivity of influenza-containing droplets and particle dispersion. Definitions of the size of the particles of concern vary widely (Nicas et al., 2005; Morawska, 2006). Differentiation of the route of transmission is based traditionally on a particle size of 5 μm; large-droplet transmission is considered the mechanism for particles greater than 5 μm and airborne transmission for small particles of less than 5 μm (Table 2-2; Garner and HICPAC, 1996; Brankston et al., 2007). Early classic studies of the evaporation of falling droplets considered 100 μm diameter as the approximate size to identify droplets that settle out and fall to the ground within 2 meters and would be responsible for droplet infection (Wells, 1934). Recent analyses have found that large droplets between 60 and 125 μm (depending on the relative humidity) can be carried approximately 6 meters by sneezing (veloc-
4
The size of the influenza virus is approximately 0.08 to 0.120 μm (Treanor, 2005), although the droplets containing the virus can vary widely in size.
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ity of 50 meters/second), more than 2 meters by coughing (velocity of 10 meters/second), and less than 1 meter by breathing (velocity of 1 meter/second) (Xie et al., 2007). Much remains to be learned about the continuum of infectious droplets and aerosols.
In addition to affecting the mode of transmission, particle sizes also affect where the particle can be deposited in the respiratory tract after inhalation (Figure 2-3). The smaller the particle, the deeper in the lung it is likely to be deposited. Large particles can be deposited in the nose and upper respiratory tract; 50 percent of particles with a diameter of 4 μm will penetrate the terminal bronchioles and deposit in the alveolar region. The rate of inspiration and expiration and the tidal volume can also affect the deposition of particles in the human host (Knight, 1980). Aerosols may also act as condensation nucleii, and increase in diameter as they are inhaled (lung relative humidity approximates 100 percent).
Further research is needed to understand the role of bioaerosols in the spread of infection, including the size and dispersion of the relevant continuum of droplets generated during breathing, speech, coughing, and sneezing; the infectivity and survival of microorganisms within droplets;
FIGURE 2-3 Deposition of particles in the respiratory tract.
Pathway from the source (A), in the air (B), to the recipient (C). The portion of the respiratory tract of a susceptible host in which inhaled particles are deposited is a function of the particles’ aerodynamic size.
SOURCE: Roy and Milton, 2004. Reprinted with permission from Massachusetts Medical Society. Copyright 2004 All Rights Reserved.
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and the detailed mechanisms of disease transmission under various conditions. These studies need to include nontraditional healthcare settings such as ambulances and long-term care and rehabilitation facilities (including the home environment) that would be involved in the care of patients during pandemic influenza. In addition, the role of medical equipment and procedures in altering aerosol behavior is critical to guide rational PPE recommendations. Less urgent, but equally important, is an understanding of the role of ultraviolet light and the ways in which processes such as hydrogen peroxide aerosolization alter aerosol behaviors (McLean, 1961; Boyce et al., 1997; French et al., 2004; Bates and Pearse, 2005).
Studies of Influenza A Transmission in Animals
Influenza A transmission has been studied in various animal species including mice, guinea pigs, monkeys, and ferrets with variable results. These studies show that animals develop influenza infection and most demonstrate the role of aerosols in transmission. Some of the earliest studies examined influenza A transmission in ferrets. After confirming contact transmission of influenza between animals, researchers then conducted experiments in which the cages were separated by varying distances and at different heights in the room (Andrewes and Glover, 1941). Because uninfected ferrets separated by more than 5 feet from the infected animals became infected (as did ferrets in cages at a higher level in the room), the authors suggested that airborne transmission was possible. It was noted that as ventilation improved, infection rates decreased: 10 of 18 (55 percent) ferrets separated by more than 5 feet developed influenza; 3 of 3 (100 percent) ferrets less than 3 feet apart developed influenza with an incubation period that ranged from 5 to 11 days. The authors subsequently separated infected and noninfected animals with barriers and fans, and no animal-to-animal transmission occurred. However when influenza virus was introduced into air ducts (including a U-shaped duct), infection occurred in previously well animals, indicating the possibility that airborne transmission was the primary route (Andrewes and Glover, 1941).
A series of experiments with mice in the 1960s also provided some evidence pointing toward airborne transmission. Schulman and Kilbourne (1962), using a chamber and aerosolized influenza A virus, found that the proportion of uninfected animals that subsequently developed disease
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demic. Some of the questions can be addressed fairly quickly (in the next 6 to 12 months) in sets of focused experiments; other questions may require work during several cycles of seasonal influenza to be able to conduct the natural experiments that are needed. What will be key is a coordinated and focused effort.
Moving forward toward the goal of developing effective strategies to prevent the transmission and spread of influenza will require substantial investment in research and dedicated efforts by investigators throughout the world. Since much of the research in this field was conducted 40 to 60 years ago, opportunities abound for building on prior research and applying new technologies including air particle size analyzers (e.g., impactors) and polymerase chain reaction assays, as well as advances in research fields such as aerobiology and mathematical modeling, to the study of seasonal influenza and avian influenza. Knowledge of influenza transmission can be furthered through a range of human studies including epidemiological analyses (e.g., Markel et al., 2007) and examination of natural experiments (e.g., workplace or school closures) involving seasonal influenza outbreaks as well as by a variety of research efforts including challenge studies and volunteer studies designed to meet institutional review board approvals.
Although there is the potential for differences between influenza strains in the details of the mechanisms of transmission, an accumulating body of knowledge on its transmission will provide insights that are needed to mitigate the impact of influenza and pave the way for responding quickly to unique differences between strains. A limited number of research efforts funded by CDC and other agencies are under way to examine prevention interventions, including the effectiveness of PPE and hand hygiene, as related to seasonal influenza. However, what is missing and needed is a concerted research effort that prioritizes research encompassing the continuum from basic science to epidemiologic investigations and is aimed at fully understanding influenza transmission and informing a wide range of prevention and intervention strategies.
Given the dearth of information on influenza transmission, it is critical to gather together the best minds in all related areas to identify and prioritize the most relevant research questions regarding the transmission of seasonal and possible pandemic influenza. The study of seasonal influenza is essential for the development of strategies to minimize the transmission of recognized human strains of influenza, while developing the technology and expertise to study pandemic influenza when it occurs. Further, it is vitally important to be ready for research during a pan-
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demic. Now is the time to develop the research plans and protocols that will be needed when a pandemic occurs. Timely, frontline measurements will be able to inform the evolving pandemic in the hope of reducing morbidity and mortality during its spread.
At the outset of the SARS outbreaks in March 2003, the World Health Organization (WHO) asked 11 laboratories in 9 countries to participate in a collaborative multicenter research network focused on identifying the causal agent and developing a diagnostic test (WHO, 2003). Using a secure website and daily teleconferences, information (including microscopy pictures, sequences of genetic material, testing protocols) was rapidly shared and disseminated. Daily assessment of research results allowed the investigators to immediately refine their strategies and focus their efforts. Within a month of the network’s inception, its objectives had been achieved (Drosten et al., 2003; WHO, 2003).
A similar global research effort is necessary for influenza transmission and prevention and could provide much needed answers in a relatively short time frame. The creation of an Influenza Study Network would allow for the identification and support of existing centers of excellence in influenza research worldwide and, as a result, could encourage their growth and development. The network could also be created so as to encourage the development of new centers of excellence, especially in areas that have unique opportunities to study various aspects of disease transmission.
In this time of preparation for an influenza pandemic, the realization of how little is known about critical aspects of the disease should prompt immediate action to coordinate multiple resources and a diversity of research expertise to address the unknowns regarding influenza transmission and prevention.
SUMMARY AND RECOMMENDATION
Although it has been 70 years since the influenza A virus was discovered and despite the annual toll that results from seasonal influenza and regional outbreaks, little is known about the mechanisms by which influenza is transmitted and its viability and infectivity outside the host. Most of the research on influenza transmission was conducted prior to the 1970s, and only recently has there has been a renewed focus on transmission, primarily as a result of new pandemic threats. Critical research questions regarding the many unknowns of influenza transmission
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and prevention need immediate attention. Current knowledge is fragmentary, and numerous gaps need to be filled in order to make rational and evidence-based recommendations on prevention efforts including PPE design, choice, and use.
Based on the paucity of data on influenza transmission and the importance of this knowledge in refining prevention and mitigation strategies, particularly for pandemic influenza, the committee makes the following recommendation.
Recommendation 1 Initiate and Support a Global Influenza Research Network
The Department of Health and Human Services in collaboration with U.S. and global partners through the WHO, should lead a multination, multicity, and multicenter focused research effort to facilitate understanding of the transmission and prevention of seasonal and pandemic influenza. A global research network of excellence should be developed and implemented that would
Identify and prioritize research questions with suggested possible study designs.
Provide priority funding to support short-term (1 to 3 years) laboratory and clinical studies of influenza transmission and prevention of seasonal influenza with particular focus on the effectiveness of types of PPE.
Develop rigorous evidence-based research protocols and implementation plans for clinical studies during an influenza pandemic.
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