Understanding the Risk to Healthcare Personnel
Interest in the transmission of influenza viruses has increased in recent years due to the ongoing zoonotic infection of humans with avian H5N1 influenza viruses and the pandemic spread of a swine-like H1N1 strain in 2009. In particular, the recognition that person-to-person transmission is a major criterion that must be met for pandemic infection has stimulated research into the mechanisms by which influenza viruses are transmitted and what factors enhance or interfere with this transmission. In considering preventive efforts to avoid viral respiratory disease transmission, the committee emphasizes the importance of the use of a range of hazard controls, including vaccination, to protect healthcare personnel.
This chapter provides a synopsis of the discussion in the 2008 report regarding influenza transmission followed by an overview of recent (2007 to mid-2010) research on viral respiratory disease transmission. Studies on personal protective equipment (PPE) use to prevent viral respiratory disease transmission are also reviewed. The chapter concludes with the committee’s thoughts on immediate research needs and long-term research opportunities.
BACKGROUND AND CONTEXT FROM THE 2008 REPORT
The prior Institute of Medicine report examined research studies conducted through 2007 on the modes of influenza transmission and highlighted the paucity of data on the relative contributions of each to the risk of illness in the community or clinical setting. A major challenge in research on this issue has been the lack of consistency in the use of terms
to describe particle size and to describe potential transmission routes (Box 2-1). As research efforts move forward, agreement is needed on terminology to be used so that studies can be compared. Box 2-1 provides the definitions used by the committee throughout the report, including in describing earlier studies. The terms and definitions of the transmission routes were developed at a recent Centers for Disease Control and Prevention (CDC) workshop (David Weissman, personal communication, CDC, November 2010) and are provided as a starting point. These are operational
Terminology—Particle Size and Transmission Routes
As noted above, the terms and definitions here are used to frame the discussion, and efforts are needed to reach consensus agreement among the many relevant areas of research and clinical care.
NOTE: da= aerodynamic diameter. Terminology regarding particles with da > 100 μm is needed.
SOURCES: Nicas and Jones (2009); Personal communication, D. Weissman, November 2010.
definitions and are not CDC policy. The definitions of particle size are adapted from a set of definitions described by Nicas and Jones (2009). Further work is needed on standardization of terminology. A common set of definitions accepted by the industrial hygiene, infectious disease, and healthcare communities would be most helpful in discussing future research and policy.
Much of the discussion regarding influenza transmission has focused on the continuum between droplet spray and aerosol transmission, as well as on the role of contact transmission and the potential for transmission through inoculation of the conjunctivae. Aerosol transmission, an issue in healthcare settings where patients have diseases such as tuberculosis and measles, can occur at a short range between persons but can also involve infectious agents carried for longer distances by air currents. Fabian and colleagues (2008) collected exhaled breath of patients with active influenza. In 4 of 12 subjects, exhaled breath contained influenza, and more than 87 percent of exhaled particles were < 1 μm.
One of the main reasons why there is no clear understanding of long-range transmission is because aerosol transmission of influenza and other respiratory viruses is difficult to study in human populations. To study long-range aerosol transmission properly, the background prevalence of the disease would need to be low in the community, and many other factors would need to be controlled to rule out other transmission routes, such as droplet spray and contact (Tellier, 2009). Production of aerosols also varies by individual; some individuals produce large amounts of bioaerosols in coughs, sneezes, and even tidal breathing, while others do not. Therefore, some individuals may be more or less likely to transmit influenza infection or other viral respiratory diseases via aerosols.
Context is likely to play an important role in shaping the importance of these transmission pathways in relation to illness occurrence. Researchers have shown that contextual factors may include environment, humidity, temperature, number and types of fomites, air flow, age of susceptible and infected populations, and number of individuals and their interactions within space. Biological factors that may influence transmission include virus strain characteristics, human physiology, immune status, and genetic susceptibility of the host.
Modifications to the living environment have the potential to reduce the transmission of influenza virus or other respiratory viral agents. These modifications include increasing the rate of air exchange, using non-recirculated air, irradiating air prior to recirculation, and changing absolute humidity (Lowen et al., 2007; Shaman et al., 2010). Increased
air exchange is expected to affect transmission by an aerosol route through a reduction in the concentration of infectious particles in the air. Because both temperature and humidity are known to impact the stability of influenza viruses in an aerosol (Harper, 1961, 1963; Hemmes et al., 1960; Schaffer et al., 1976), interventions to reduce transmission by altering these environmental conditions may be useful.
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 possible role of aerosol transmission. Experiments performed in the 1930s demonstrated that influenza virus–naïve, asymptomatic ferrets that were caged with influenza virus–infected ferrets would subsequently develop disease and that, even in the absence of experimental infection, ferrets occasionally displayed an influenza-like illness, after which they became immune to subsequent virus inoculation (Francis and Magill, 1935; Smith et al., 1933). Andrewes and Glover (1941) demonstrated transmission using an experimental design in which air flowed from infected to naïve ferrets through a tube containing S- and U-shaped bends, which would be expected to allow the transfer of only small (< 5 μm) respirable particles. In hamsters, by contrast, transmission of influenza viruses appeared to depend on contact between infected and exposed animals (Ali et al., 1982). A series of experiments with mice in the 1960s also provided some evidence suggesting aerosol transmission (Schulman, 1968; Schulman and Kilbourne, 1962). More recently, the guinea pig has been successfully used to study influenza transmission (Lowen et al., 2006).
Transmission among humans has been studied less. Early volunteer studies found that infection via inhalation of respirable particles requires considerably less virus than infection via droplets placed on the nasal membranes (Alford et al., 1966; Couch et al., 1971, 1974; Douglas, 1975). Several observational studies of naturally occurring influenza provided insights into the challenges of studying transmission modes. One of the most well-known incidents of an influenza A outbreak happened among passengers on a grounded airplane (Gregg, 1980; Moser et al., 1979). An observational study of 49 passengers delayed on a 737 jet for 3 hours and exposed to an index case with influenza suggested aerosol transmission. Within 72 hours, 72 percent of the passengers became ill. Specimens from 31 of the 38 cases were cultured and found to have similar isolates. A second airline travel–associated outbreak also suggested aerosol transmission with a 37 percent attack rate and wide seat-
ing distribution of secondary cases throughout the aircraft (Klontz et al., 1989). More recent studies of airline travel indicate close-proximity transmission (Baker et al., 2010; Han et al., 2009; Ooi et al., 2010), which could occur via one or more routes. Newer airplanes have more laminar air flow and improved filters over older planes, which may reduce long-range aerosol transmission. Studies examining how air flow may help prevent transmission of viral respiratory diseases in closed and crowded settings, such as an airplane, are warranted.
Wong and colleagues (2010) recently reported a nosocomial outbreak of seasonal influenza in an acute-ward setting that appeared to be attributed to aerosol transmission. An aerosol-generating device was used on the influenza index case patient. At the same time, the authors identified an imbalance in the indoor airflow that likely created a directional dispersion of air and potentially carried influenza aerosols to other areas of the ward. Other patients were infected following a temporal and spatial pattern of air flow originating from the index patient. Two of the staff also became ill even though they were required to adhere to strict hand hygiene and medical mask use.
Additional observational studies of human influenza have provided further descriptions of influenza outbreaks, but the findings do not clarify potential mechanisms of transmission (discussed in IOM, 2008). For example, Drinka and colleagues (1996, 2004) compared influenza rates in several buildings of a long-term care facility during several seasons of influenza. Their initial study found that persons working in buildings with ventilation systems that provided outside air had much lower infection rates than those working in buildings with partially recirculated air (Drinka et al., 1996). However, an update of this study found similar infection rates (Drinka et al., 2004). Reviews of other reported influenza outbreaks suggest droplet spray and contact transmission routes based on temporal and spatial patterns (Brankston et al., 2007; Cunney et al., 2000; Drinka et al., 1996; Morens and Rash, 1995).
Studies of the clinical effectiveness of PPE have had mixed results in preventing severe acute respiratory syndrome (SARS) or respiratory syncytial virus (RSV) infections (see Appendix C). Challenges in studies of this type include difficulties in retrospectively separating the effects of PPE from the effects of other infection control measures.
Specific issues regarding respiratory disease transmission to healthcare personnel have focused on medical procedures that have a potential for creating aerosols, and data are primarily available for SARS, not influenza. Fowler and colleagues (2004) observed a greater risk of devel-
oping SARS for physicians and nurses performing endotracheal intubation. Similarly, in a retrospective study of 43 nurses who worked in Toronto with SARS patients, Loeb and colleagues (2004) found that assisting during intubation, suctioning before intubation, and manipulating the oxygen mask were high-risk activities for acquiring SARS; wearing a face mask or N95 respirator was protective.
As stated throughout the 2008 report, establishing how influenza is transmitted and understanding the contribution of each mode of transmission is critical to preventing its spread and reducing morbidity and mortality due to influenza infection, especially in healthcare settings. The 2008 report outlined a number of questions that remained to be addressed regarding influenza transmission (IOM, 2008):
Questions regarding transmission mode, including: What are the major modes of transmission? How much does each mode of transmission contribute individually or with other modes of transmission? What is the size distribution of particles expelled by infectious individuals, and how does that continuum of sizes affect transmission? Is the virus viable and infectious on fomites, and for how long? Are fomites a means of transmission, and are some more able to transmit than others?
Questions regarding infectivity, including: Can infection take place through mucous membranes or conjunctiva exposure? What is the time sequence of infectivity?
Questions specific to transmission in healthcare settings, including: What activities in the healthcare setting are associated with minimal or increased transmission? How distinct is transmission in different venues including health care, schools, and households?
Questions specific to the role of PPE in preventing or reducing transmission, including: How effective is each type of PPE in reducing the risk of influenza transmission? How effective are face masks? What innovations regarding PPE are needed to enhance effectiveness? What is the impact on transmission risk when patients wear face masks?
Questions specific to other potential forms of prevention, including: What is the role of ultraviolet (UV) light, humidity, temperature, pressure differentials, air flow and exchange, and ventilation in preventing transmission?
The 2008 report concluded its discussion regarding research on influenza transmission with a recommendation that a Global Influenza Research Network should be initiated and supported. This network would facilitate an understanding of the transmission and prevention of seasonal and pandemic influenza, with priority funding given to short-term clinical and laboratory studies. Furthermore, the recommendation stressed the need to develop rigorous, evidence-based research protocols and implementation plans for clinical studies for use during an influenza pandemic (IOM, 2008).
UPDATE ON RECENT RESEARCH
In the 3 years since the writing of the prior report (IOM, 2008), research efforts continue to examine the various routes of transmission and explore approaches to preventing transmission. The following section provides an overview of recent research (2007 to mid-2010) and describes animal studies, environmental monitoring and persistence studies, transmission modeling studies, and human studies. The literature searches on disease transmission conducted by the committee focused on influenza. Searches of bibliographic databases for studies on PPE use and transmission were broader and incorporated other viral respiratory diseases; only a few recent studies on other viral respiratory diseases were identified, however, and those are discussed and referenced in this report.
Animal models complement epidemiological approaches by allowing the examination of influenza virus transmission from an infected to a susceptible host under well-controlled conditions. The ferret and guinea pig models are the current models of choice in influenza studies. Ferrets are naturally susceptible to infection with human influenza viruses, and these viruses transmit among them, making the ferret the current gold-standard animal model for the study of influenza. Prompted by the need for a more convenient animal model than the ferret in which to study transmission, the guinea pig was recently developed as such a model host (Lowen et al., 2006). Although signs of disease are generally not observed in influenza virus–infected guinea pigs, these animals are highly
susceptible to infection with human strains, and human influenza viruses transmit efficiently from one guinea pig to another.
Animal Models on Modes of Transmission
The relative contributions of the various modes by which influenza viruses transmit is currently a subject of debate in the field. In the context of experimental studies using animals, transmission by the contact route is normally modeled by placing infected and naïve animals into the same cage together. It is important to note, however, that this set-up does not allow one to distinguish transmission by a contact route from short-range spread mediated by an aerosol. To study transmission specifically by inspirable or respirable aerosols, animals are placed into separate cages so that air exchange can occur among them, but they cannot touch. Although this arrangement rules out contact-based transmission, when cages are placed in close proximity (as is usually the case), transmission may proceed via the droplet spray or aerosol modes.
Transmission of human seasonal and 2009 H1N1 pandemic strains among either ferrets or guinea pigs occurs efficiently using both experimental designs, indicating that transmission among ferrets and guinea pigs can proceed in the absence of direct or indirect contact among animals (recent studies include Lowen et al., 2006, 2007, 2008; Maines et al., 2009; Munster et al., 2009; Steel et al., 2010; Tumpey et al., 2007). In addition, evidence for transmission of influenza viruses by the aerosol route has been obtained in the ferret and guinea pig models; early work in ferrets (Andrewes and Glover, 1941) and recent experiments performed in guinea pigs (Mubareka et al., 2009) demonstrate transmission over a distance of up to 3.5 feet.
Recent attempts to model influenza virus transmission in BALB/c mice have been unsuccessful (Lowen et al., 2006); nevertheless, a mouse model was used by Schulman and Kilbourne to study transmission in the 1960s (Schulman, 1968; Schulman and Kilbourne, 1962). Because of the inefficiency of transmission and the low susceptibility of mice to human influenza viruses that have not been serially adapted in this host, currently the mouse model is not used widely for research on influenza virus transmission. Hamsters are also not in widespread use as a model for influenza virus infection, but Ali and colleagues (1982) showed that certain human influenza isolates transmitted well when infected and naïve ham-
sters were housed in the same cage; transmission in the absence of contact was not, however, observed.
The potential for contact with contaminated surfaces to mediate influenza virus transmission among guinea pigs was examined by Mubareka and colleagues (2009). Naïve guinea pigs were placed in cages that either had previously housed an acutely infected animal or had been contaminated with high titers of influenza virus through direct application onto non-porous cage surfaces. In the former case, approximately 20 percent of exposed animals contracted infection, while with the latter design, no exposed animals became infected (Mubareka et al., 2009). When these results are compared to the high efficiency of transmission of the same virus by the aerosol route, they suggest that—at least in the guinea pig model—spread via fomites makes a minor contribution to the overall transmission of influenza viruses.
Relationships Between Transmission and Symptoms, Timing Post-Infection, and Shedding Titers
Because of their potential to produce infectious aerosols, coughing and sneezing are generally thought to promote transmission (Tumpey et al., 2007). Evidence against a critical role for sneezing and coughing arises from the guinea pig model: Although these animals do not sneeze or cough following influenza virus infection, viral spread is efficient among guinea pigs (Lowen et al., 2007). Influenza viruses have been isolated from the air surrounding infected guinea pigs (Mubareka et al., 2009) and even mice (Schulman, 1967); this virus is most likely expelled into the environment through normal breathing (Fabian et al., 2008).
The timing of transmission events relative to initial infection of donor animals has not been examined closely (through the use of defined exposure periods) in the ferret or guinea pig models; the serial collection of nasal wash samples over the course of exposure does, however, allow an estimate of the time of transmission to be made. In the guinea pig model after exposure by contact and aerosol routes, virus was detected initially in the nasal washings of exposed animals at 1–3 days and 3–5 days, respectively (Lowen et al., 2006, 2007, 2008, 2009; Steel et al., 2009). The infection of exposed ferrets occurs with similar timing by contact and aerosol routes: Initial detection of virus in the nasal passages of exposed animals usually occurs between 1 and 3 days post-exposure (Itoh et al., 2009; Maines et al., 2006, 2009; Tumpey et al., 2007). Varia-
tions in transmissibility among differing strains of influenza viruses do not show a strong correlation with differences in peak shedding titers (Maines et al., 2006, 2009; Mubareka et al., 2009; Steel et al., 2009; Tumpey et al., 2007), suggesting that, although efficient growth in the upper respiratory tract is most likely required for an influenza virus to transmit, additional criteria must be met for transmission to proceed.
Relative Transmissibility of Influenza Viruses Derived from Different Host Species
Viral strain and subtype specific differences in influenza virus transmission have been observed in recent studies of animal models. One strength of both the ferret and guinea pig models is that influenza viruses adapted to human hosts generally transmit more efficiently than avian-, swine-, or mouse-adapted strains. Thus, the low pathogenic avian strains A/duck/Alberta/35/1976 (H1N1) and A/duck/Ukraine/1963 (H3N8) did not transmit among guinea pigs, while certain highly pathogenic H5N1 influenza viruses have been observed to transmit among co-caged guinea pigs to a limited extent (Gao et al., 2009; Steel et al., 2009). Swine influenza isolates of the H3 subtypes transmitted with 25 percent efficiency by the aerosol route among guinea pigs (Steel et al., 2010). By contrast, human H3N2 subtype viruses, as well as the H1N1 pandemic strain, generally transmit to all exposed guinea pigs by either contact or aerosol routes (Lowen et al., 2006; Steel et al., 2010). Overall, seasonal H1N1 subtype viruses have been found to transmit less efficiently among guinea pigs than epidemic strains of the H3N2 subtype (Mubareka et al., 2009). A similar pattern of transmissibility is observed in the ferret model: Avian influenza viruses do not transmit to exposed animals by an aerosol route (Tumpey et al., 2007; Van Hoeven et al., 2009), but some low and highly pathogenic strains do transmit by contact to a limited extent (Belser et al., 2008; Maines et al., 2006; Sorrell et al., 2009; Van Hoeven et al., 2009; Wan et al., 2008). Human seasonal strains of both H3N2 and H1N1 subtypes transmit readily among ferrets (Itoh et al., 2009; Maines et al., 2006, 2009; Wan et al., 2008), and the pandemic H1N1 strain has been observed to transmit with similar efficiency (Itoh et al., 2009; Munster et al., 2009) or somewhat lower efficiency (Maines et al., 2009) by an aerosol route than seasonal influenza viruses.
Interventions: Blocking Influenza Virus Transmission in Animal Models
Interventions that offer the potential to limit transmission of influenza viruses in healthcare settings include vaccination; the prophylactic and therapeutic use of antiviral drugs; non-pharmaceutical interventions, such as the use of good hand hygiene and PPE; use of source control; cohorting the patients; and modifications to the indoor environment. Changes in transmission achieved through vaccination were studied in the guinea pig model, and it was found that transmission could be abrogated through vaccination. This was the case whether the vaccinated animals were the donors or recipients in the transmission experiment. Vaccination was particularly effective in blocking spread if sterilizing immunity was achieved (as was seen using a live attenuated vaccine), but transmission was also reduced following suboptimal vaccination1 (Lowen et al., 2009). Also in guinea pigs, twice-daily treatment with oseltamivir reduced titers shed from the upper respiratory tract of treated donor guinea pigs and, in turn, prevented transmission to untreated aerosol contacts. This is similar to recent and past studies of prophylactic treatment of household contacts of infected persons that has been found to be very effective (Halloran et al., 2007; Hayden et al., 2000, 2004; Monto et al., 2002; Welliver et al., 2001).
Research in the past several years has demonstrated in the guinea pig model that transmission between animals in separate cages occurs with lower frequency (or not at all) when the surrounding air is warm (30°C) or maintained at high (80 percent) or intermediate (50 percent) relative humidities (Lowen et al., 2007, 2008). Although field studies are required to translate these findings to the human situation, they suggest that the modification of relative humidity in healthcare settings may be a means of controlling the spread of influenza virus infection. The impact of UV treatment of air on influenza viral spread has not been assessed in an animal model; if transmission proceeds at least in part by an aerosol route, however, such treatment is expected to be effective.
Environmental Monitoring and Persistence Studies
To learn more about the distribution of aerosol influenza virus in an urgent care setting, two studies have recently been conducted. A study by Blachere and colleagues (2009) of real-time polymerase chain reaction (RT-PCR) identified the presence of aerosolized influenza in several areas of an emergency department, including a waiting room, a reception area, and personal samplers placed on physicians. On 3 of 6 separate days, aerosolized influenza A virus was detected. Half of the influenza particles were found to be in the respirable size range. The follow-up study by Lindsley and colleagues (2010a) looked at both influenza and RSV. Seventeen percent of the stationary samplers contained influenza A ribonucleic acid (RNA), and 32 percent contained RSV. Nineteen percent and 38 percent of clinical staff samplers contained influenza A and RSV RNA, respectively. A correlation was found between samplers that contained influenza and presence of patients who were positive for influenza (r = 0.77). A slightly smaller proportion of the influenza A RNA was in particles ≤ 4.1 μm in aerodynamic diameter (42 percent) compared with the earlier study by Blachere and colleagues (2009) (53 percent). These studies indicate that aerosolized particles exist in this specific urgent care setting. However, the viability of the influenza viruses was not ascertained, and therefore it is not possible to quantify the importance of the identified aerosol particles to transmission in the hospital setting.
A recent study by Lindsley and colleagues (2010b) showed that 84 percent (32/38) of influenza-positive patients had influenza viral RNA in their cough aerosols as identified by a National Institute for Occupational Safety and Health two-stage bioaerosol cyclone sampler or an SKC BioSampler. Of the influenza viral RNA detected, 65 percent was contained in particles in the respirable range (< 4 μm), suggesting that these particles could be inhaled and deposited in the alveolar region of the lungs. Viable virus was detected in the cough aerosols of some infected patients. A limitation of the collection system was the inability to collect larger particles. Therefore, this study was unable to quantify the proportion of small versus large particles or the total amount of viral material contained in the cough of an influenza-infected patient.
Studies examining fomite contamination have focused largely on virus survivability on environmental surfaces. The type of fomite surface appears to play a significant role in influenza virus survival with low survival times on porous materials, such as paper and cloth, ranging from 8 to 12 hours and on non-porous materials, such as stainless steel and plastic, ranging from 24 to 72 hours (Boone and Gerba, 2007). Other factors likely to affect survival of influenza on fomites include cleanliness and moisture. In experimental studies reviewed by Boone and Gerba, transfer of influenza virus to the hands occurred up to 24 hours after contaminating stainless steel fomites with influenza virus. Hands appear not to be a very hospitable environment for influenza, with viral decay occurring within the first 5 minutes of fomite-to-hand transfer. Nonetheless, if hands are continually inoculated by a touch to contaminated fomites, direct infection is likely. In the case of commonly touched fomites, influenza virus may be transferred from the fomite to the hands of a human host through consistent contact. As noted in an earlier study, among clinicians, 1 in 3 healthcare professionals rubbed their eyes and 42 percent picked their nose per 1-hour observation, suggesting that self-inoculation of influenza virus among these healthcare personnel would be likely if hands became contaminated in the hospital environment (Boone and Gerba, 2007; Hendley et al., 1973).
The significance of fomites in the spread of respiratory disease has been assessed through experimental seeding studies and assessments of inactivation rates (Boone and Gerba, 2007). Of the inactivation rates reviewed across a range of respiratory viruses (rhinovirus, RSV, coronaviruses, parainfluenza virus, avian influenza, and influenza A and B viruses), avian influenza and influenza A viruses had the lowest log10 reductions per hour. The log10 reduction per hour on non-porous fomites were 22 and 45 times lower for avian influenza and influenza A virus, respectively, compared to RSV, which had the highest log10 reduction per hour on surfaces. The only other respiratory virus with similar survivability as influenza on non-porous surfaces was rhinovirus, which can also survive for more than 24 hours. Avian influenza virus, in particular, was shown to have high survival rates on both porous and non-porous surfaces, including stainless steel, latex gloves, and cotton—as long as 144 hours. Survival on fomites, therefore, is much longer than what has been observed for human influenza survival in artificially produced aero-
sols, where rates ranged from 6 to 16 hours (Brankston et al., 2007; Mitchell and Guerin, 1972; Mitchell et al., 1968).
In a recent experimental study, coronavirus was detected on PPE at a minimum of 4 hours following initial exposure (Casanova et al., 2010). N95 respirators, contact isolation gowns, and latex gloves all had detectable virus 24 hours after exposure. The authors concluded that coronaviruses were able to survive on hospital PPE longer than the duration of contact with an infected patient. Far fewer observational studies have been done on influenza and other respiratory viruses on surfaces and PPE in the clinical setting. There are some developments in antimicrobial masks, but the utility and risks associated with these embedded materials are unclear. For example, Li and colleagues (2006) examined the antimicrobial activity of nanoparticle material with a mixture of silver nitrate and titanium dioxide for reducing bacteria on N95 respirators. There were large reductions in S. aureus and E. coli after 48 hours of incubation, but whether this material would have any activity against influenza was unclear because no respiratory viruses were tested in the study (Li et al., 2006). Macias and colleagues (2009) examined the extent of 2009 H1N1 contamination on the hands of healthcare personnel and patients and on environmental surfaces in a hospital in Mexico. The computer mouse, hands, and bed rails were all found to be positive for the influenza virus, but viability of the virus was not assessed. Studies have also examined the role of the contact transmission route in the transfer of rhinovirus and RSV (Gwaltney et al., 1978; Hall et al., 1980, 1981). Taken together, these experimental and observational studies support a role for the contaminated environment and PPE as a potential source of viable respiratory viruses, such as influenza. Nonetheless, no recent studies identified by the committee have examined whether infection can be transmitted directly from contact with a contaminated fomite.
Inactivation of Influenza A Viruses
A review by Weber and Stilianakis (2008) examined studies on the inactivation of influenza A viruses in the environment and the impact on modes of transmission. Currently little is known about inactivation of influenza virus. Experimental studies indicate that low relative humidity in heated indoor areas promotes influenza survival in the closed environment. However, the converse relationship has been observed outside of the United States, where outbreaks have occurred in tropical regions
during hot and rainy months. Relative humidity does not independently predict virus survivability. Because of the variability in global outbreak patterns by relative humidity, some have argued that contact transmission may predominate in tropical climates whereas aerosol transmission is more common in temperate climates (Lowen and Palese, 2009). Modeling studies support a role of humidity in predicting disease outbreaks. Shaman and colleagues (2010) report that absolute humidity provided a robust correlate for seasonal variation in temperate climates.
Although empirical studies have shown that influenza transmission is feasible by aerosol, droplet spray, and contact routes, the results of these studies have not provided a comprehensive understanding of the relative contribution of each mode in causing outbreaks. Mathematical models can be used as a method for testing hypotheses about the spread of respiratory infections (Brauer, 2009). Not all components of disease spread are measured in these models, but important parameters can be identified and estimated. Unfortunately, the lack of basic scientific data on transmission and survivability of influenza makes it very difficult to accurately determine the parameters for these models or to assess the fit of these models with available data. Many transmission models looking at the spread of influenza and other respiratory diseases include simulations that provide varying estimates on different modes of transmission, including the case reproductive number (R0), social patterning, susceptibility, and influenza strain characteristics. The following summary of recent research in this area focuses on the key findings and assumptions inherent in these models in a way that may apply to healthcare personnel.
Multiple modes of influenza transmission have been explored using modeling information. Potential sources of influenza transmission to healthcare personnel through community and nosocomial exposures have also been modeled.
Models of the Dynamics of Influenza Transmission
Nicas and Jones (2009) examined the contribution of four modes of influenza transmission: hand contact; respirable particles (cough particles < 10 μm in diameter); inspirable particles (cough particles 10–100 μm in
diameter); and droplet spray (> 100 μm in diameter). This study used two very different assumptions regarding infectivity: (1) the ratio of infectivity was 3,200:1 for influenza virus deposited in the lower respiratory tract compared to the upper respiratory tract, and (2) the ratio of infectivity was 1:1 for influenza virus deposited in the lower respiratory tract versus the upper respiratory tract. The infectivity ratio assumptions played a major role in determining which method of transmission was most likely to cause disease. Assuming a 3,200:1 infectivity ratio for influenza virus deposited in the lower respiratory tract compared with the upper respiratory tract, droplet spray accounted for 58 percent of the infection risk at low salivary viral concentrations, compared to 27 percent of the risk for fomite or hand contact and 14 percent of risk from respirable particles. Little is known about virus saliva concentrations in humans, which may vary widely.
As the salivary viral concentration increased, the risk of infection from droplet spray decreased, while the importance of hand contact in spreading disease increased. However, with a 1:1 ratio of infectivity in the lower versus upper respiratory tract, hand contact was the major driver of infection across all viral salivary concentrations (Nicas and Jones, 2009). The main measures assessed for reducing the risk of influenza transmission in the healthcare setting included hand washing, disposable gloves, and face masks to reduce touching the face. Measures for preventing infection caused by droplet spray included fluid-resistant masks and eye goggles or face shields. Besides social distancing, the model found that the most effective way to reduce respirable and inspirable particles included the use of an N95 filtering respirator and/or increasing the room ventilation. When the model used an infectivity ratio of 1:1, the research found that if influenza-positive individuals have a low concentration of salivary virus, healthcare personnel can significantly decrease the risk of transmission through simple methods, such as hand washing, standard surgical face masks with goggles, or face shields. At an infectivity ratio of 3,200:1, respirable particles would make up a substantial part of the risks, and respirators would be required.
Chen and colleagues (2009a) specifically assessed the dynamics of aerosol influenza transmission and found the volume of particles released from a sneeze were approximately three-fold higher than for a cough. Using an equation to estimate the total volume of particles had the following results: with cough, the highest volume occurred with a particle sized 5.8 μm (which would be classified as respirable particles by Nicas and Jones ), leading to a volume of virus of 500 × 10–10 mL, and
26 μm for sneeze (classified as inspirable particles by Nicas and Jones), with a volume of virus of 3 × 10–7 mL. The predicted tissue culture infective dose50 (TCID50) for influenza was estimated to be 0.57 at 5.5 μm per cough 2.6 days after infection, and 264 per sneeze at 10 μm after 2.6 days. This model suggests that the TCID50 produced by a sneeze is higher than that emanating from a cough.
A model of the risk of aerosol transmission was examined in the setting of a commuter train. Assuming the inhalation of aerosol infectious agents during a commute, the estimated R0 was found to be 2.22 (geometric standard deviation [SD] = 1.53), with a specified number of air ventilation cycles per hour (Furuya, 2007). An exposure time of less than 30 minutes was found to reduce the likelihood of transmission, as were surgical masks to reduce droplet spray transmission (assuming a reduction in the risk of contaminated air inhaled by 40 percent), and high-efficiency particulate air masks (assuming a reduction in contaminated air inhaled by 97 percent) to reduce smaller particulate transmission. Of significance for healthcare personnel, doubling the number of air ventilation cycles per hour was found to reduce the risk of infection to R0 = 1. Although not all healthcare settings are comparable to the close and extended proximity found on a commuter train, the effectiveness of increasing the number of air ventilation cycles per hour may be useful for reducing the likelihood of inhalation exposure to aerosol particles in the clinical setting. Other factors to consider in addition to ventilation would be the number of windows, number of stops, opening and closing of doors, and movement of people.
Models of Household Transmission
Household transmission models may be useful as a proxy for transmission within the healthcare setting. A single household model with two bedrooms and a common living quarter was used to assess the likelihood of influenza infection (Atkinson and Wein, 2008). The model included one infected individual, one primary caregiver, and two other household residents. The authors assumed that the death rate (rate of viral inactivation) on porous surfaces was more than one magnitude higher than the death rate on non-porous surfaces (0.12 per hour versus 1.78 per hour). The death rate of virus in the air was estimated to be 0.36 per hour. The authors assumed viral transmission occurred from the infected individual to the caregiver only within the infected individual’s room, through un-
protected aerosol transmission with no deposition on surrounding surfaces. Transmission was assumed through close contact at the time of the infected individual’s emission, and that aerosol virus would be deposited on either porous or non-porous surfaces. The authors then compared total influenza virus shed, infectious dose likely to infect half of the population, and death rate of the viruses on different surfaces between influenza virus and the rhinovirus. They found a higher total shed virus (1.93 × 105 TCID50compared to 1.57 × 105 TCID50), higher TCID50required for respiratory epithelium (0.671 TCID50compared to 0.216 TCID50), and much higher TCID50 for nose and eyes (500 TCID50compared to 0.032 TCID50) for influenza compared to rhinovirus. Although the death rate on hands was much higher for the influenza virus (55.3 per hour) compared to rhinovirus (0.61 per hour), the death rate on porous and non-porous surfaces was lower for influenza than rhinovirus. Atkinson and Wein (2008) concluded that aerosol transfer was the most likely mode of infection in the described setting.
Models of Healthcare-Associated Infection
The committee was unable to identify any studies since 2007 that modeled transmission of influenza within the hospital setting among healthcare personnel. Earlier, Nicas and Sun (2006) modeled the risk of transmissible respiratory diseases in a healthcare setting. The authors provided an integrated method of examining transmission between infected individuals, contaminated environments, and direct patient-to-healthcare worker exposure, which could be used as a template for an influenza-specific model in the healthcare setting.
Models of Asymptomatic Carriers
The role of asymptomatic carriers in spreading influenza was examined using a Susceptible Exposed Infective Recovered model, with two additional categories: asymptomatic and hospitalized (Hsu and Hsieh, 2008). The model assumed that exposed individuals could either become infectious, and then move toward a hospital or recover without hospitalization, or become asymptomatic, and spread disease before recovering. Building on previous literature that up to a third of all influenza cases are asymptomatic, the authors assumed that asymptomatic
individuals contributed less to viral shedding as a result of a decrease in symptoms, such as coughing, that may spread disease. The authors found that the way that the public responds to information about an outbreak can reduce the number of influenza infections. However, due to asymptomatic influenza infections, community response alone cannot affect the basic dynamics of the model without additional steps, such as quarantine or other intervention measures, which were not included in the model because of additional complexities in their basic model. Therefore, with an asymptomatic subpopulation that is shedding virus, influenza can continue to persist within the community even with an R0 of less than 1.
Human Challenge, Observational, and Clinical Studies
Infectivity, Viral Shedding, and Symptoms
The timing of infection and quantity of viral shedding obviously play a role in the spread of influenza. A meta-analysis of 56 volunteer challenge studies attempted to quantify the time of peak viral shedding among healthy human volunteers (Carrat et al., 2008b). Two different strains of virus were examined: influenza A/H1N1 strains (recovered earlier than 2009 H1N1) and influenza A/H3N2. In human volunteers, viral shedding showed a quick increase the first day following inoculation, with a maximum value reached after 2 days, and a return to baseline, on average, 8 days following inoculation. The first signs of shedding were observed in 83 percent of subjects 1 day after inoculation, 14 percent of subjects 2 days after inoculation, and 3 percent of subjects 3 days after inoculation, with an average duration of 1.1 days until viral shedding occurred. The mean duration of viral shedding was 4.80 days (95% confidence interval [CI] = 4.31, 5.29), with no significant difference in duration between H1N1 and H3N2 strains. One dose-varying study included in the meta-analysis found that shedding duration was dependent upon the initial inoculation dose.
Consistent with previous findings, Carrat and colleagues (2008b) determined that an average of 66.9 percent of influenza-inoculated participants showed clinical symptoms. Total symptom scores peaked 2 to 3 days after inoculation, and returned to baseline after 8 days. The mean duration of illness was 4.4 days (SD = 1.8 days). The curves plotted for influenza viral shedding and symptom severity were similar, with viral
shedding peaking 1 day prior to clinical symptoms. However, limited information across the studies was provided on the participants who did not develop clinical illness. The authors concluded that viral shedding peaked rapidly and that symptoms for influenza-like illness varied widely, making an influenza-like illness case definition unreliable for identifying infectious individuals to implement control measures. Moreover, the study populations were adults and generally healthy. Thus, variability in age, immune status, and underlying health conditions may have profound effects on these estimates, as has been observed recently for 2009 H1N1 (Goodman, 2009). For example, children under age 9 infected with 2009 H1N1 shed virus for a median duration of 6 days after fever was detected, 1 day longer than overall median duration for all age groups, and some children showed signs of shedding for up to 13 days (Goodman, 2009).
Historically, controlled viral challenge studies have provided key insights on respiratory virus transmission (Carrat et al., 2008a). Current preliminary efforts to develop influenza voluntary challenge studies are under way in the United Kingdom and may provide an opportunity to better understand the relative contribution of differing transmission modes of influenza (Van-Tam, 2010).
A household model of transmission of pandemic 2009 H1N1 virus found an average time between symptom onset of the primary case and secondary cases to be 2.6 days (95% CI = 2.2–3.5 days), similar to previous reports of time of disease spread between household members, but shorter than the secondary infections reported below (Cauchemez et al., 2009). Another study that recruited index patients to study the serial interval of influenza leading to a secondary infection within the household found the period to be longer than previously reported: an average of 3.6 days (95% CI = 2.9–4.3 days). The interval measured time from symptom onset in a laboratory-confirmed case of influenza to the time of symptom onset in a corresponding household contact (Cowling et al., 2009b). More recently, Lau and colleagues (2010) used a community-based study of households to show that the bulk of viral shedding happened during the first 2 to 3 days after illness onset and only 1 to 8 percent of infectiousness occurs prior to symptom onset. Moreover, only 14 percent of cases that had RT-PCR–detectable influenza virus RNA were asymptomatic, and the quantity of viral particles was low among these cases, suggesting that asymptomatic cases are unlikely to play a large role in transmission.
An observational study examined influenza and rhinovirus infections among healthcare personnel. Bellei and colleagues (2007) collected both acute respiratory illness reports and laboratory samples among healthcare personnel. Nearly 50 percent of staff reporting influenza-like illnesses had rhinovirus rather than influenza. Thus, surveillance by symptoms may not accurately predict influenza viral activity among healthcare personnel. Influenza vaccination in this study population was low (19.7 percent), and varied by the department where hospital personnel were assigned. Of the 203 personnel recruited with any acute respiratory illness symptom, 48.3 percent reported direct contact with a patient, and 39.4 percent had preschool children exposure either at the hospital or at home.
In a recent study in an infant ward, of 122 susceptible patients with single rooms, only 6 (5 percent) acquired influenza in the ward, while 17 percent (13/77) of infants in a multiple-crib room acquired nosocomial infection (Hall, 2007). Overall, children with one or two roommates were nearly 4 times more likely to acquire influenza in the hospital (odds ratio = 3.90, 95% CI 2.88–4.92). The author notes that one to three separate influenza cases occurred before peak influenza activity began over the two influenza seasons that were studied, and that neither of these cases was followed by a quick outbreak in the ward. Similarly, novel data examining outbreaks of 2009 H1N1 in airplanes, buses, and schools primarily implicate close proximity transmission (Baker et al., 2010; Han et al., 2009; Kar-Purkayastha et al., 2009; Ooi et al., 2010).
In a review by Chen and colleagues (2008), transmission routes of SARS were examined. Major transmission modes that have been demonstrated include close contact via droplet spray or contaminated fomites with respiratory excretion. In addition, diarrhea accompanied infection and SARS virus was found in the greatest quantities in feces compared to nasopharyngeal and urine samples 14 days after first onset of symptoms.
Avian influenza H5N1 virus has been studied in several family clusters, and both droplet spray and contact with stool have been hypothesized as important transmission routes. In a household cluster study by Wang and colleagues (2008), an index case (the son) transmitted the infection to his father while his father cared for him in the hospital. The index case had large amounts of sputum, frequent coughing, and watery
diarrhea with H5N1 infection. His father had no known exposure to poultry or other ill individuals. Neither the index case’s mother nor girlfriend, both of whom also had close contact, became infected. Transmission to the father may have occurred through inhalation of respirable or inspirable particles or contact with feces-contaminated clothes. Of note, 2009 H1N1 illness symptoms also included vomiting and diarrhea (Bryant et al., 2010; Riquelme et al., 2009). Research on the potential for fecal oral transmission of 2009 H1N1 influenza is warranted.
PPE Use to Prevent Respiratory Disease Transmission
Models on the Use of PPE
The effectiveness of surgical masks and N95 respirators in reducing the spread of influenza were directly modeled as a method of preventing the 2009 H1N1 (Tracht et al., 2010). Considering that the likelihood of wearing a surgical mask or respirator can vary by many factors, including age and marital status, the authors assumed that compliance with the recommended intervention would only occur in the closed population when a minimal level of susceptible individuals became infected, and that individuals within the population could switch between wearing and not wearing masks or respirators. Several scenarios were explored, with the following results:
when neither masks nor respirators were used, the total percentage of the population infected was estimated at 75 percent (in a population of 1 million people);
if 10 percent of the population wore surgical masks (assumed in this scenario to be 2 percent effective in reducing susceptibility and infectivity), the total number of cases would be only minimally reduced (to approximately 73 percent);
increasing the percentage of the population wearing surgical masks to 50 percent (assumed in this scenario to be 5 percent effective in reducing susceptibility and infectivity) reduced the infected population to approximately 69 percent;
if 10 percent of the population wore N95 respirators (assumed in this scenario to be 20 percent effective in reducing susceptibility and infectivity), the total number of cases would be reduced to
approximately 55 percent (a reduction of approximately 19 percent from not wearing masks or respirators); and
increasing the percentage of the population wearing N95 respirators to 50 percent (assumed in this scenario to be 50 percent effective in reducing susceptibility and infectivity) dropped the total number of cases drastically to approximately 0.1 percent.
The authors concluded that surgical masks were unlikely to impact the epidemic because of low effectiveness at reducing the spread of influenza among susceptible and infected individuals, while N95 respirators could reduce the impact of the epidemic, though they could not reduce the R0 below 1. The authors acknowledge that the effectiveness of the interventions are time dependent and that delays in mask-use initiation can have strong effects on the findings. The results from the model suggest that healthcare personnel would benefit from widespread use of properly fitting N95 respirators among susceptible and infected individuals.
Community Studies of PPE Use
Several recent studies have looked at community use of PPE. Results of these studies have been inconsistent because of differences in study design, setting, intervention type, and ability to control for confounding factors. MacIntyre and colleagues (2009) conducted a study on the use of face masks in households in Australia during the winters of 2006 and 2007. The participating 145 households included adults with known exposure to a child with fever and other respiratory symptoms. The households were randomized to one of three arms of the trial: (1) surgical masks that were to be worn when in the same room as the ill child; (2) P2 masks (equivalent to N95 respirators), also to be worn when in the same room; and (3) a control group with no masks used. Adherence to the use of masks was found to be low (less than 50 percent). Of those who used the masks, a reduction in the risk of acquiring a respiratory infection was noted in the range of 60 to 80 percent, and no differences were seen between surgical masks and P2 masks, but the study was underpowered to determine differences between these two interventions. In addition, the authors noted that some adults may have already been in the incubation period for infection because enrollment occurred in conjunction with a sick child visit to a healthcare facility. Thus, the mask intervention may
have been applied too late in the course of illness transmission within the household.
Hand hygiene has been demonstrated to provide a reduction in respiratory infections in the community setting (Aiello et al., 2008), but the role of face masks in combination with hand hygiene (i.e., layered interventions) had not been studied in a controlled intervention trial until recently. Several recent randomized community intervention studies have attempted to compare face-mask use and hand hygiene or a combination of both interventions during seasonal influenza seasons. In one study, researchers randomized university residence halls housing 1,297 student participants to use of face masks, face masks with hand hygiene, or a control group for a 6-week period during the influenza season (Aiello et al., 2010). Significant reductions in influenza-like illnesses were seen in the group using face masks and hand hygiene as compared with the control group (reductions of 35 to 51 percent after adjusting for vaccination and other factors). Compliance data were difficult to ascertain, and the mild influenza season may have impacted the results. This study provided some insights on primary prevention rather than secondary prevention of illness because the participants were asked to wear masks before influenza-like illness was observed on campus.
Larson and colleagues (2010) conducted a study examining secondary transmission of influenza infection (i.e., other than the index case) by providing one of three interventions to urban households. The 509 households were randomized to receive one of the following: (1) education on the prevention and treatment of upper respiratory infections and influenza, (2) the same educational component plus alcohol-based hand sanitizer, or (3) the educational component plus hand sanitizer and face masks (Larson et al., 2010). Compliance with wearing the face masks was low; half of the households provided with face masks reported using the face masks when they had a household member with an influenza-like illness. In multivariate analyses no differences were observed in the rate of infection.
A study by Cowling and colleagues (2009a) assessed several interventions in 259 households and used secondary transmission of laboratory-confirmed influenza infection in family members as the outcome measure. Households were identified through household members presenting to outpatient clinics with influenza-like illness confirmed as influenza A or B by rapid testing. An education intervention was provided to the 134 households in the control group, hand hygiene supplies were provided to 136 households, and 137 households received face masks and hand hy-
giene supplies. Data for all the households in the study found that someone in the household developed confirmed influenza in 19 percent of the households. A significant reduction in confirmed influenza was seen for households receiving an intervention within 36 hours of the onset of symptoms in the index patient; no differences were seen in a comparison of the hand hygiene and the hand hygiene plus face masks groups.
Challenges in studies of interventions in the community setting include adherence, observations for compliance, and disentangling the contribution of layered interventions (i.e., face masks and hand hygiene together) when the effect estimate size between layered and non-layered interventions may be small. Moreover, in a light influenza season difficulties in identifying cases rapidly can impact the statistical power and effectiveness of the interventions, respectively. Last, these types of studies are unable to provide insights on the modes of transmission of influenza because face masks may block both droplet spray and direct contact inoculation from hands contaminated with influenza virus.
Clinical Studies of PPE Use by Healthcare Personnel
Although the benefits of vaccination are clear (Fiore et al., 2009; Treanor et al., 1999), much less is certain about what types of respiratory PPE are needed or the value of face masks worn by healthcare personnel. Few studies have been conducted of effective PPE interventions to reduce the transmission of influenza in hospitals or other healthcare facilities to guide policy makers seeking to ensure the health and safety of healthcare personnel. The relative value of face masks versus N95 respirators in preventing influenza transmission is especially debated, and recent reviews have concluded that there are insufficient data for recommending effective PPE approaches for preventing influenza transmission (Cowling et al., 2010; Gralton and McLaws, 2010; Jefferson et al., 2010). The possible modes of transmission of influenza, the confounding variables that exist in testing alternative interventions, and the common issues inherent with study design (see Box 2-2) suggest the complexity of the problem facing both investigators and policy makers.
Several observational studies have looked at various aspects of PPE use, but usually in small numbers of healthcare personnel. Ng and colleagues (2009) performed a survey of 133 on-duty nurses, and then divided them into cases (nurses who contracted influenza-like illness during the study period) and compared them to nurses who did not. A
significant difference was noted between cases and controls in use of PPE, specifically the use of gloves, gowns, and face shields. No mention was made of respiratory protection. A significant difference between the cases and controls was that cases were less likely to be vaccinated and were also more likely to have been exposed to a sick colleague without using PPE. In a survey of healthcare personnel participating in a medical mission and treating patients in crowded conditions, fewer cases of acute respiratory illness were noted for personnel using hand sanitizer; however, use of face masks was not reported to make a difference (Al-Asmary et al., 2007). A study of 32 healthcare personnel (in which one group wore face masks and the other did not) found no differences in occurrence of the common cold, but the small number of study participants did not allow for adequate exploration of the study question (Jacobs et al., 2009). A retrospective study compared “frontline” healthcare personnel confirmed to have SARS with those who did not acquire the disease (Chen et al., 2009b). The risk of contracting SARS increased for those who performed tracheal intubations of SARS patients and for those who cared for “super-spreader” SARS patients. Risk decreased for those healthcare personnel wearing multiple pairs of gloves and for those who avoided face-to-face contact with SARS patients.
Observations during the 2009 H1N1 epidemic were reported from a Singapore hospital that documented the varying requirements for respirators or face masks based on different departments of the hospital or work tasks during three phases of the 2009 H1N1 epidemic (Ang et al., 2010). No difference was seen in the transmission of H1N1 to healthcare personnel. Many healthcare personnel who were confirmed to have H1N1 had not cared for H1N1 patients and may have acquired the disease in community settings. This hospital had worked with cases of SARS in 2003, and the authors stated that adherence to PPE, although not documented, was usually strict.
Recently, the first randomized trial assessing the value of face masks compared with N95 respirators in preventing influenza among healthcare personnel was published (Loeb et al., 2009). Among the 446 nurses from 8 tertiary care hospitals in Ontario who participated in the study, 225 were assigned to wear surgical masks (the brand used at their respective hospitals), and 221 were assigned to wear N95 respirators during the 2008–2009 winter influenza season. Study participants also wore gowns and gloves (as part of routine infection control practice) when caring for patients with febrile respiratory illnesses. Online questionnaires were
Confounding Issues for Understanding the Transmission of Influenza and Other Viral Respiratory Diseases
Confounding Variables in Testing Interventions
Issues with Study Design
used twice a week to assess symptoms of influenza. The primary outcome examined by the study was laboratory-confirmed influenza. Compliance with PPE use was determined through audits during several weeks in March and early April 2009 that were anticipated to be the peak of the influenza season. If the unit had patients with influenza or a febrile respiratory illness, auditors were sent to observe use of masks or respirators. The study stopped collecting data in late April 2009, with the reporting of novel H1N1 influenza A and the recommendation by the Ontario Ministry of Health and Long-Term Care that N95 respirators be used for caring for patients with febrile respiratory disease. Laboratory-confirmed influenza was documented in 50 of the 225 nurses allocated to wear surgical masks (23.6 percent) and in 48 of the 221 nurses allocated to wear N95 respirators (22.9 percent). The authors concluded that the similar results between groups indicated that surgical masks were noninferior to N95 respirators. Study limitations noted by the authors included challenges in assessing compliance with PPE use; lack of measurement on rates of hand hygiene or gown and glove use; and the source of infectious exposure (hospital or community exposure) could not be ascer-
tained. Several subsequent letters to the editor noted issues including that measures of exposure risk were missing and the value of triage procedures and the adherence to cough etiquette were not measured (Srinivasan and Perl, 2009), concerns about study power (Clynes, 2010), and concerns about the lack of eye-shield protection among nurses in the study (Finkelstein et al., 2010). This study has pointed out the many challenges in assessing the effectiveness of respirators and face masks in preventing influenza transmission, including the rates of correct use and fit of respirators and masks, the level of environmental contamination, the duration and intensity of exposure, and the susceptibility of healthcare personnel to H1N1. Similar to the community intervention studies, this type of study cannot provide information on the modes of transmission of influenza in the clinical setting. In future studies, the severity of infection might be an important secondary endpoint of interest because it may reflect infectious dose. Moreover, it will be important to add higher levels of monitoring for compliance and assessment of close contacts (such as household members) to better identify sources of infection in these types of studies.
Use of Face Masks and Respirators as Source Control
Face masks and respirators have also been used as source control, that is, placing a mask on patients with respiratory illnesses in clinics or emergency departments to reduce the potential for disease transmission to other patients, family members, or healthcare personnel. Johnson and colleagues (2009) studied nine patients with documented influenza and asked each to cough 5 times into a 90 mm diameter petri dish containing transport media. With no mask on, 7 of 9 patients had detectable virus. However, with either a surgical mask or N95 mask on, no virus was detected. The authors concluded that as a source control, masks were equally effective in preventing dissemination. Because this was not a study of transmission, however, one can only say that the concept of droplet spray dissemination being controlled with a surgical mask is plausible, but unconfirmed.
SUMMARY OF PROGRESS
Animal studies have found that the ferret and guinea pig models appear to be highly representative of humans in terms of their susceptibility to infection, the influenza viral strains that display a transmissible phenotype, and the kinetics with which transmission occurs. Experiments performed in both of these animal models suggest that transmission of influenza viruses can proceed by both droplet spray as well as aerosol modes, which would include respirable particles. Animal studies have also pointed to a number of environmental factors, including relative humidity and temperature that may influence transmission. Recent studies that have employed environmental monitoring of the air for influenza, as well as others that have examined contamination of fomites and hands with H1N1, have provided insights on the potential for influenza-virus contamination of the healthcare environment. Nonetheless, data on the viability of influenza in air samples and fomites in these settings are limited. Mathematical models have been developed to better characterize the relative contribution of influenza transmission modes. Available, well-specified parameters for these models are limited because information is lacking on the viability of influenza in aerosols, salivary virus concentrations, amounts of virus in respirable and inspirable particles, and the quantity and persistence of viability on various fomites in the healthcare setting. Taken together, progress has been made in understanding the modes of transmission, but the relative contributions of the modes are still unclear. Much remains to be learned about the effectiveness of control measures to prevent transmission.
Observational studies and controlled studies relevant to PPE use and transmission of influenza or other viral respiratory diseases are limited because study protocols were largely not in place for 2009 H1N1 or for recent seasonal flu periods, and studies have not provided adequate power to answer questions regarding the effectiveness of using PPE in reducing or preventing disease transmission.
FINDINGS AND RESEARCH NEEDS
As discussed throughout this chapter, much remains to be learned about the transmission of influenza and other viral respiratory diseases. The committee’s overall findings in this area (Box 2-3) highlight the current limitations on data regarding transmission that are needed to inform
decisions on the protection of healthcare personnel and patients. The committee heard about a number of ongoing research efforts at its June 2010 workshop (Appendix A). Sustained efforts will be critical, as prior research efforts from the 1940s to 1990s have largely ebbed between pandemics.
The committee has identified a range of research efforts, some of which can be addressed expeditiously (in the next 6 to 12 months) and have a significant impact on improving the nation’s readiness for pandemic influenza; long-term studies are also needed to more fully understand disease transmission and prevention strategies. As in the 2008 IOM report, the recommendations focus on a comprehensive research strategy to address critical questions in as expedited and coordinated manner as possible.
Animal studies Although data in ferrets and guinea pigs indicate that vaccination, antiviral treatment, and altered environmental conditions can each reduce or abrogate transmission, confirmatory and more in-depth experimentation would be valuable in determining which interventions are likely to be the most effective. In vivo studies on the impacts of increased air exchange and UV treatment of air would also be highly informative and relatively simple to execute in an animal model.
Environmental studies Future studies are needed to assess whether the identified influenza RNA in aerosol samplers (in multiple locations, e.g., schools, trains, healthcare facilities) are viable and reflect the extent to which individuals are exposed to aerosols of influenza within these environments. In addition, the impact of environmental factors, such as UV and humidity, on influenza transmission and infection should be examined in the community and healthcare setting.
Modeling studies Statistical and mathematical models need to be evaluated for their utility in prediction and inferences regarding the relative contributions of different transmission modes in varying environmental/community contexts. Collaborations between experimental or observational research and mathematical modelers are warranted so that the parameters used in mathematical models are based on rigorous data and provide evidence that would help narrow parameter estimates used in modeling.
Clinical studies Appropriately powered studies are needed that examine all possible modes of transmission, measure the rates of compliance with each intervention of interest, and define the pre-exposure influenza antibody titers of study subjects. Environmental levels of contamination need to be studied, including cultures from air sampling and swabs of hard surfaces. Serological studies of exposure to influenza virus in family members or roommates would be a reasonable marker of home exposure during the study period. Useful measures would also include the distribution of the size of respiratory particles of patients exposed to the healthcare personnel and some measure of the intensity of the exposure to patients that might include distance from, time in contact with, and specific procedures performed on the infected patients.
Studies on the role of PPE The potential role of face shields and face masks as PPE should be explored to determine the level of protection from droplet spray transmission. The role of fomites is unclear in the healthcare setting. Additional studies are needed to determine what role gowns, gloves, face masks, and respirators might play in influenza transmission. Further work on donning and doffing processes is also
needed. Studies should examine whether antiviral-coated PPE provides any additional protection and how maintenance and reuse are affected.
Recommendation: Develop Standardized Terms and Definitions
CDC and the Occupational Safety and Health Administration, in partnership with other relevant agencies and organizations, should work to develop standardized terms, definitions, and appropriate classifications to describe transmission routes and aerodynamic diameter of particles associated with viral respiratory disease transmission. This effort should involve a consensus from the industrial hygiene, infectious disease, and healthcare communities.
Recommendation: Develop and Implement a Comprehensive Research Strategy to Understand Viral Respiratory Disease Transmission
The National Institutes of Health, in collaboration with other research agencies and organizations, should develop and fund a comprehensive research strategy to improve the understanding of viral respiratory disease transmission, including, but not limited to, examining the characteristics of influenza transmission, animal models, human challenge studies, and intervention trials. This strategy should include
an expedited mechanism for funding these types of studies and
clinical research centers of excellence for studying influenza and other respiratory virus transmission.
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