Last updated June 12, 2013
All past influenza pandemics in humans have been caused by influenza A viruses. General information about influenza A viruses (not specific to pandemic strains) is presented in the bullet points below.
- Family: Orthomyxoviridae
- Enveloped virions are 80 to 120 nm in diameter, are 200 to 300 nm long, and may be filamentous.
- They consist of spike-shaped surface proteins, a partially host-derived lipid-rich envelope, and matrix (M) proteins surrounding a helical segmented nucleocapsid (6 to 8 segments).
- The family contains five genera, classified by variations in nucleoprotein (NP and M) antigens: influenza A, influenza B, influenza C, thogotovirus, and isavirus.
- Genus: Influenzavirus A
- The genus consists of a single species: influenzaA virus.
- Influenza A viruses are a major cause of influenza in humans.
- The multipartite genome is encapsidated, with each segment in a separate nucleocapsid. Eight different segments of negative-sense single-stranded RNA are present; this allows for genetic reassortment in single cells infected with more than one virus and may result in multiple strains that are different from the initial ones (Voyles 2002).
- The genome consists of 10 genes encoding for different proteins (eight structural proteins and two nonstructural proteins). These include the following: three transcriptases (PB2, PB1, and PA), two surface glycoproteins (hemagglutinin [HA] and neuraminidase [NA]), two matrix proteins (M1 and M2), one nucleocapsid protein (NP), and two nonstructural proteins (NS1 and NS2).
- The virus envelope glycoproteins (HA and NA) are distributed evenly over the virion surface, forming characteristic spike-shaped structures. Antigenic variation in these proteins is used as part of the influenza A virus subtype definition (but not used for influenza B or C viruses).
- Influenza A virus subtypes
- There are 16 different HA antigens (H1 to H16) and nine different NA antigens (N1 to N9) for influenza A.
- Human disease historically has been caused by three subtypes of HA (H1, H2, and H3) and two subtypes of NA (N1 and N2).
- More recently, human disease has been recognized to be caused by additional HA subtypes, including H5, H7, and H9 (all from avian origin). A recent report suggests that human infections with H9N2 viruses may be more common than previously recognized (Wan 2008). The authors also concluded that H9N2 viruses can evolve extensively and reassort, suggesting that they may be capable of undergoing further adaptation for more efficient transmission among mammals and humans.
- Classification of influenza A strains by pandemic potential
- Strains from past pandemics: "Noncontemporary" strains are those from previous pandemics that pose some degree of risk to the public owing to decreased immunity in the current population. The term is currently used to describe strains from the Asian flu (H2N2).
- Nonpandemic strains: These include strains that have recently circulated or are currently circulating in the human population (ie, those belonging to H1N1, H3N2, and H1N2 subtypes).
- Potential pandemic strains: Potential pandemic strains must have the following features: (1) an antigenic makeup to which the population is immunologically naive, (2) ability to replicate in humans, and (3) capability to transmit efficiently from human to human. Because of homosubtypic immunity (see below), new pandemic strains are most likely to be of subtypes not previously recognized in human populations. Currently, strains of H5 and H7 subtypes are of greatest concern.
- Animal pandemic strains (including avian influenza strains): Animal strains such as H5N1 avian influenza are not considered human pandemic strains unless the above criteria are met, but they have significant potential to evolve into new human pandemic strains through the process of genetic reassortment (see below) or through gradual adaptation to the human host. Most avian strains are not of concern as potential pandemic strains.
The following general considerations apply to laboratory testing of novel or pandemic influenza strains.
- Tests for influenza virus include viral culture, polymerase chain reaction (PCR), rapid antigen testing, and immunofluorescence (IFA). Serologic tests are used to retrospectively diagnose infection.
- During a pandemic, recommendations for laboratory testing may be unique and depend on factors such as: (1) availability of reagents and laboratory surge capacity, (2) presence or absence of other influenza strains in the community, (3) level of influenza activity in the community, and (4) treatment considerations.
- The sensitivity and specificity of laboratory tests appear to vary with the involved strain, which has implications for emerging variants (Weinberg 2005).
- Laboratory tests are required for specific identification of pandemic strains. The most likely ways that a pandemic strain would be detected initially are:
- Outbreak investigations or investigation of unexplained death in a previously healthy individual
- Influenza surveillance with laboratory testing and characterization of unusual strains
- Investigation of unusual laboratory findings
- Testing of persons with influenza-like symptoms who meet certain exposure criteria
- State and local health departments should be prepared to process or test for the following (if they have the capability, as described below) (HHS 2005: Pandemic influenza plan).
- Avian influenza A (H5N1) and other avian influenza viruses
- Other animal influenza viruses
- New or re-emergent human influenza viruses (such as H2 strains)
- Testing during a pandemic (HHS 2005: Pandemic influenza plan):
- The Centers for Disease Control and Prevention (CDC) will update protocols and distribute reagents as necessary.
- The need for confirmatory testing will diminish as the pandemic progresses. Some level of continued monitoring will be necessary to monitor changes in antigenicity and antiviral susceptibility. The CDC will provide appropriate guidance in such situations.
- Reporting and referral (HHS 2005: Pandemic influenza plan)
- Clinical laboratories should contact their state or local health departments if they receive specimens from patients with possible novel influenza suspected on the basis of clinical and epidemiologic criteria.
- Public health laboratories should send specimens to the CDC if the patient meets clinical and epidemiologic criteria and (1) tests positive for influenza A by reverse transcriptase PCR (RT-PCR) or rapid testing or (2) tests negative for influenza A by rapid testing and RT-PCR is not available. Laboratories without capacity for testing avian strains by indirect IFA or RT-PCR should send untypable influenza isolates to the CDC.
- Any unusual subtype should be reported to the CDC through its emergency response hotline (770-488-7100).
- Laboratory-based influenza surveillance networks
Laboratory values that may trigger concern for human pandemic influenza include the following:
- Positive test for influenza from a patient with risk factors for avian influenza
- Culture: CPE positive or negative; HAd positive; HAI titer low or negative and no other hemagglutinating viruses identified
- RT-PCR positive for H5 or H7
- RT-PCR positive for influenza A from a conserved target, such as matrix protein, and negative for H1-H3
- A four-fold rise in H5-specific antibody titer (acute and convalescent serum samples)
Detailed information about laboratory testing for avian influenza in humans is available in the overview "Avian Influenza (Bird Flu): Implications for Human Disease" on this site. Topics included in that overview are: specimen collection, biosafety and biosecurity, direct detection methodology, serology, virus isolation by cell culture, and viral susceptibility testing.
In general, the degree of immunity induced by one strain of influenza virus to a second challenge with another influenza virus is related to the taxonomic distance between the two strains (Epstein 2003). Several terms that characterize the type of immunity are identified below.
- Heterologous immunity:Immunization with one type of influenza virus (eg, A, B, or C) does not offer protection from challenge with a different type.
- Heterosubtypic immunity (also referred to as "heterotypic immunity"):Immunization with one influenza A virus subtype (eg, H1N1) may offer some protection from challenge with a second influenza A subtype (eg, H5N2). The degree of protection, or lack of protection, is important to the discussion of pandemic influenza and vaccine development.
- Homosubtypic immunity:Immunization with one strain within a subtype (eg, A/Hong Kong/03/68[H3N2]) will frequently offer some protection against challenge with a second strain within the same subtype (eg, A/Fujian/447/2003[H3N2]).
Homologous immunity: Immunization with one strain of influenza A virus (eg, A/Fujian/447/2003[H3N2]) offers protection from a second challenge with the same strain.
- "Antigenic drift" refers to the process of small genetic changes that influenza viruses continuously undergo from year to year, which necessitates the development of new vaccines annually. Partial immunologic cross-reactivity between new strains and those they are replacing (ie, homosubtypic immunity) limits morbidity, mortality, and spread in the population.
- "Antigenic shift" refers to substantial genetic changes caused by the process of genetic reassortment. Relatively few lineages of influenza A are circulating among humans at any one time, which reduces the likelihood of significant genetic reassortments. However, antigenic shift can occur between human and animal strains, which is what happened with the pandemic strains of 1957 and 1968. It is important to note that not all pandemic strains arise from genetic reassortment. For example, the 1918 pandemic strain apparently did not originate through a reassortment event; rather, it is likely that an avian strain initially infected humans and then adapted gradually to the human population over time to become a pandemic strain (Taubenberger 2005).
Pandemics occur when a novel influenza strain emerges that has the following features:
- Highly pathogenic for humans
- Easily transmitted between humans
- Genetically unique (ie, lack of preexisting immunity in the human population)
In reviewing the public health implications of a pandemic, it is useful to understand the current framework of phases that a pandemic will likely go through. These are outlined in the following table. (Note: In 1999, the WHO developed a set of pandemic phases; these were first revised in April 2005 and then revised again in April 2009). The current pandemic phase is phase 5, in response to swine influenza H1N1 activity, which was first recognized in April 2009 in the United States and Mexico.
WHO Pandemic Phases
No viruses circulating among animals have been reported to cause infections in humans.
An animal influenza virus circulating among domesticated or wild animals is known to have caused infection in humans, and is therefore considered a potential pandemic threat.
An animal or human-animal influenza reassortant virus has caused sporadic cases or small clusters of disease in people, but has not resulted in human-to-human transmission sufficient to sustain community-level outbreaks. Limited human-to-human transmission may occur under some circumstances, for example, when there is close contact between an infected person and an unprotected caregiver. However, limited transmission under such restricted circumstances does not indicate that the virus has gained the level of transmissibility among humans necessary to cause a pandemic.
This phase is characterized by verified human-to-human transmission of an animal or human-animal influenza reassortant virus able to cause “community-level outbreaks.” The ability to cause sustained disease outbreaks in a community marks a significant upwards shift in the risk for a pandemic. Any country that suspects or has verified such an event should urgently consult with WHO so that the situation can be jointly assessed and a decision made by the affected country if implementation of a rapid pandemic containment operation is warranted. Phase 4 indicates a significant increase in risk of a pandemic but does not necessarily mean that a pandemic is a forgone conclusion.
This phase is characterized by human-to-human spread of the virus into at least two countries in one WHO region. While most countries will not be affected at this stage, the declaration of phase 5 is a strong signal that a pandemic is imminent and that the time to finalize the organization, communication, and implementation of the planned mitigation measures is short.
This pandemic phase is characterized by community-level outbreaks in at least one other country in a different WHO region in addition to the criteria defined in phase 5. Designation of this phase will indicate that a global pandemic is under way.
During the post-peak period, pandemic disease levels in most countries with adequate surveillance will have dropped below peak observed levels. The post-peak period signifies that pandemic activity appears to be decreasing; however, it is uncertain if additional waves will occur, and countries will need to be prepared for a second wave. Previous pandemics have been characterized by waves of activity spread over months. Once the level of disease activity drops, a critical communications task will be to balance this information with the possibility of another wave. Pandemic waves can be separated by months, and an immediate “at-ease” signal may be premature.
In the post-pandemic period, influenza disease activity will have returned to levels normally seen for seasonal influenza. It is expected that the pandemic virus will behave as a seasonal influenza A virus. At this stage, it is important to maintain surveillance and update pandemic preparedness and response plans accordingly. An intensive phase of recovery and evaluation may be required.
Earliest reports of influenza epidemics date back to 412 BC and were recorded by Hippocrates. A number of epidemics that likely were influenza were described in the Middle Ages, and one that was probably a true pandemic took place in 1510 (Beveridge 1978). Other key historical facts include the following:
- One of the earliest recorded pandemics occurred in 1580. Like the 1918 pandemic, this one was particularly severe. It started in Asia and spread to Africa, Europe, and the Americas. In 6 weeks it afflicted all of Europe. Death rates were high; 9,000 of 80,000 people died in Rome, and some Spanish cities were described as "nearly entirely depopulated" by the disease (Beveridge 1978, Patterson 1986).
- Ten pandemics have been recorded in the past 300 years (Osterholm 2007: The fog of pandemic preparedness). The time between starting points of these pandemics has ranged from 10 to 49 years, with an average of 24 years.
- During the 17th century, localized epidemics were reported, and in the 18th century at least two pandemics occurred (1732-33, and 1781-82).
- Five influenza pandemics occurred during the 19th century (1800-02, 1830-33, 1847-48, 1857-58, and 1889-90) (Osterholm 2007: The fog of pandemic preparedness). The 1889 pandemic, known as the Russian Flu, began in Russia and spread rapidly throughout Europe. It reached North America in December 1889 and spread to Latin America and Asia in February 1890. About 1 million people died in this pandemic.
Global influenza surveillance was established in 1947 by the WHO to better understand the epidemiology of influenza and to obtain isolates in a systematic fashion for annual vaccine development (Hampson 1997).
Three pandemics occurred during the 20th century, caused by an H1, an H2, and an H3 strain. These are outlined in the table below and then briefly summarized. Currently, H1 and H3 influenza strains are circulating in the human population. Scientists have raised concern about the possibility of H2N2 reemerging (also referred to as recycling) in humans, particularly through accidental release of a laboratory strain (Dowdle 2006).
Influenza Pandemics of the 20th Century: Impact in the United States*
Estimated No. of Deaths in US
1918-19 (Spanish Flu)
Global mortality may have been as high as 100 million. The virus likely originated in the US and then spread to Europe.
The virus was first identified in China; approximately 1 million people died globally during this pandemic.
The death rate from this pandemic may have been lower because the strain had a shift in the hemagglutinin (HA) antigen only and not in the neuraminidase (NA) antigen.
This pandemic was caused by an influenza A (H1N1) strain. Worldwide, about one third of the world's population was infected and had clinically apparent illness (about 500 million people) and an estimated 50 to 100 million died (Johnson 2002, Taubenberger 2006). Earlier estimates implied that the death toll was 20 to 40 million, but more recent evidence supports the higher figures. Adjusting for today's population, a similar pandemic would yield a modern death toll of 175 to 350 million.
- One study projected 51 to 81 million deaths using 2004 population estimates; however, the authors assumed wide variability in death rates by country based on per-capita income and other factors (see Dec 22, 2006, CIDRAP News Story and see Murray 2006).
- Another report suggests that if a 1918-like pandemic were to occur with increased deaths in the elderly population, over 142.2 million people would die and there would be a gross domestic product loss of US $4.4 trillion worldwide (Osterholm 2007: Unprepared for a pandemic).
- Some have suggested that the death toll from a similar pandemic occurring in modern times would be lower owing to improved medical care and public health infrastructure (Morens 2007); however, if attack rates were high, medical and public health systems could quickly become overwhelmed.
The 1918 pandemic began with a relatively mild "herald" wave in the spring of 1918. During that time, outbreaks were reported in Europe and in the United States (particularly in military training camps for new recruits headed to the war in Europe) (Reid 2001, Glezen 1996).
- Many investigators believe that the strain originated in the United States (perhaps in rural Kansas) and then migrated initially to France before spreading throughout Europe (Barry 2004). However, others believe that the strain may have been circulating in the Mid-Atlantic states as early as February of 1918 (Simonsen 2004). Furthermore, an outbreak of severe respiratory disease occurred in an army camp in France in 1916-17 (Oxford 2000). A significant clinical feature of this disease was cyanosis, which also was a predominant finding among those who acquired the pandemic strain of influenza. It is possible that this outbreak represented H1N1 infection and was an early precursor to the pandemic. At any rate, it is clear that the 1918-19 pandemic did not begin in Asia, although the origin of the implicated H1N1 strain still remains a mystery.
- This first wave was followed by two additional waves in the fall and winter of 1918-19 that were much more severe (Taubenberger 2006). The second, highly virulent, wave spread rapidly around the world in the fall of 1918; it took only 2 months for the pandemic to circle the globe at that time.
- Recorded case-fatality rates (CFRs) varied around the globe. In the US military, death rates ranged from 5% to 10% (Barry 2004). Higher rates were reported in some areas.
- A recent study examined cross-protection between successive waves of the 1918-1919 pandemic by looking at hospitalization data for repeated illnesses and mortality rates (Barry 2008). The authors concluded that the first wave provided 35% to 94% protection against clinical illness during the second wave and 56% to 89% protection against death.
- Additional waves that were not as severe occurred in 1919 and 1920.
An unusual feature of the pandemic was the age-related mortality; the pandemic strain killed a disproportionate number of healthy young adults. This led to the observation of a "W" shaped age-related mortality curve in the United States, with high rates of mortality among very young children, persons 15 to 45 years of age, and the elderly (Reid 2001, Glezen 1996, Morens 2007). Usually the curve associated with influenza mortality follows a "U" shape, with excess deaths occurring only among the very young and the elderly. One striking feature of the pandemic was its impact on pregnant women; a summary of 13 studies involving pregnant women demonstrated that CFRs ranged from 23% to 71% (Barry 2004).
The excess influenza deaths appear to have involved two overlapping clinical-pathologic syndromes (Morens 2007). One pattern was aggressive bronchopneumonia, most likely caused by a secondary bacterial pneumonia. The second pattern was a rapidly evolving severe acute respiratory distress-like syndrome (ARDS). A recent report suggests that secondary bacterial pneumonia was the major cause of death during the1918-1919 pandemic (Morens 2008). The authors state that most deaths resulted from poorly understood interactions between the infecting virus and secondary infections caused by bacteria that colonize the upper respiratory tract. The findings of this study may not be generalizable, however, because the population studied included only patients who had an autopsy performed (see Aug 22, 2008, CIDRAP News story).
In October 2005, the CDC reported that scientists had reconstructed the 1918 pandemic H1N1 strain and tested it in mice (Tumpey 2005). They found that mice infected with the 1918 strain died in as little as 3 days, and mice that survived as long as 4 days had 39,000 times as many virus particles in their lungs as did mice infected with a control influenza virus, a Texas strain of H1N1 from 1991. All the mice infected with the 1918 virus died, while those exposed to the Texas strain survived. Further, the 1918 virus was at least 100 times as lethal as an engineered virus that contained five 1918 genes and three genes from the Texas H1N1 strain. The researchers found that the mice had severe inflammation in their lungs and bronchial passages, findings very similar to those in people who died of the 1918 virus.
Earlier studies in mice using genetically engineered influenza strains similar to the H1N1 1918 pandemic strain suggest that macrophage activation with high levels of cytokine production may have been a key factor in lung damage caused by the pandemic strain (Kobasa 2004). Investigators have postulated that an overly robust immune response inducing a "cytokine storm" may have contributed to the high CFRs seen in younger populations during the 1918 pandemic. Another study recently found that cynomolgus macaques had an atypical host response to infection with the 1918 virus (characterized by dysregulation of the antiviral response), suggesting that the 1918 virus was able to modulate the host immune response (Kobasa 2007).
Recent genetic sequencing of the 1918 strain indicates that the strain was of avian origin and that the strain did not reassort with a human strain (unlike later pandemics), but rather gradually adapted to humans until it could be efficiently transmitted person to person (Taubenberger 2005). Current evidence indicates that the 1918 virus was an avian-like virus derived in toto from an unknown source (Taubenberger 2006). A two-amino acid change in the HA of the 1918 virus was recently shown to abolish transmission among ferrets, confirming the essential role of HA receptor specificity for the transmission of influenza viruses in mammals (Tumpey 2007).
The Asian flu was caused by an H2N2 strain and originated in China. The virus was initially isolated in Singapore in February 1957 and in Hong Kong in April of that year. The pandemic spread to the Southern Hemisphere during the summer of 1957 and reached the United States in June 1957 (Glezen 1996). The pandemic strain acquired three genes from the avian influenza gene pool in wild ducks by genetic reassortment and obtained five other genes from the then-circulating human strain.
About 69,800 people in the United States died and mortality was spread over three seasons. Overall, the highest mortality rates occurred among the elderly; however, during the initial season in 1957, nearly 40% of the influenza deaths occurred among persons less than 65 years of age (Simonsen 2004). The high CFR in this age-group declined in subsequent years. Globally, approximately 1 million people died during this pandemic.
The Hong Kong flu was caused by an H3N2 strain. The strain acquired two genes from the duck reservoir by reassortment and kept six genes from the virus circulating at the time in humans.
During the pandemic, about 33,800 people died in the United States. The death rate from this pandemic may have been lower because the strain had a shift in the HA antigen only and not in the NA antigen. Although antibodies to NA antigen do not prevent infection, they may modify the severity of disease (Glezen 1996). Also, an H3 strain had apparently circulated in the United States around the turn of the century, so elderly persons may have had some protective antibody from past exposure to an H3 strain (Simonsen 2004). This could have caused a lower fatality rate in the elderly.
In a report issued in January 2005, WHO officials identified key lessons from the three pandemics of the past century (WHO 2005: Avian influenza: assessing the pandemic threat). These lessons are summarized as follows.
- Pandemics behave as unpredictably as the viruses that cause them. During the previous century, great variations were seen in mortality, severity of illness, and patterns of spread.
- One consistent feature important for pandemic preparedness planning is the rapid surge in the number of cases and their exponential increase over a very brief time, often measured in weeks.
- Apart from the inherent lethality of the virus, its capacity to cause severe disease in non-traditional age groups, namely young adults, is a major determinant of a pandemic's overall impact.
- The epidemiologic potential of a virus tends to unfold in waves. Subsequent waves have tended to be more severe.
- Virologic surveillance, as conducted by the WHO Laboratory Network, has performed a vital function in rapidly confirming the onset of pandemics.
- Most pandemics have originated in parts of Asia where dense populations of humans live in close proximity to ducks and pigs.
- Some public health interventions may have delayed the international spread of past pandemics, but could not stop them.
- Delaying spread is desirable, as it can flatten the epidemiological peak, thus distributing cases over a longer period.
- The impact of vaccines on a pandemic, though potentially great, remains to be demonstrated. In 1957 and 1968, vaccine manufacturers responded rapidly, but limited production capacity resulted in the arrival of inadequate quantities too late to have an impact.
- Countries with domestic manufacturing capacity will be the first to receive vaccines.
- The tendency of pandemics to be most severe in later waves may extend the time before large supplies of vaccine are needed to prevent severe disease in high-risk populations.
- In the best-case scenario, a pandemic will cause excess mortality at the extremes of the lifespan and in persons with underlying chronic disease. Countries with good programs for yearly influenza vaccinations will have experience with the logistics of vaccinations for these populations.
In February 2007, HHS released the "pandemic severity index," or PSI, as a way to grade pandemics (CDC/HHS 2007). The severity level is initially based on CFR, a single criterion that will likely be known even early in a pandemic when small clusters and outbreaks are occurring. The pandemic severity index levels are:
- Category 1, CFR <0.1%
- Category 2, CFR 0.1% to 0.5%
- Category 3, CFR 0.5% to 1%
- Category 4, CFR 1% to 2%
- Category 5, CFR >2%
According to this index, the pandemics of 1957 and 1968 both fit into category 2, whereas the 1918 pandemic qualified as a category 5.
Influenza A was first recognized as a clinical illness in pigs in 1918, which coincided with the 1918-1919 influenza pandemic in humans (although as noted earlier in this document, the H1N1 virus that caused the global pandemic was a virus of avian origin and did not emerge from the swine reservoir). H1N1 influenza A virus was first isolated from pigs in the United States in 1930 and since that time, swine influenza H1N1 has become endemic in pigs in the United States, with animal outbreaks occurring at regular frequencies (usually in the fall and winter months). Swine influenza also has been recognized in a number of other countries throughout the world.
The influenza A subtypes that have been shown to cause swine influenza include H1N1, H1N2, H3N1, and H3N2. Since 1998, H3N2 viruses with genes derived from human, swine, and avian viruses (triple reassortant viruses) have become an important cause of swine influenza in North America, along with classical H1N1 (Olsen 2002).
Occasionally, humans have acquired swine influenza, often following contact with pigs. Human-to-human transmission of swine influenza strains, however, has historically been limited, although an outbreak of H1N1 swine influenza occurred in military personnel at Fort Dix, New Jersey, in 1976, which sparked a swine influenza vaccination campaign in the United States during that year (Gaydos 2006).
On April 17, 2009, the CDC determined, through a sentinel surveillance program, that two unrelated children in California had infections with a swine-origin influenza H1N1 virus. Ongoing surveillance efforts and case investigations demonstrated additional cases in other states, and in Mexico, Canada, and other countries around the globe. The virus appears to have emerged initially in Mexico in March 2009, with subsequent spread into the United States and other countries through international travel.
In late April, the WHO raised the pandemic alert level to phase 4 and then to phase 5-6 (widespread human infection). By the time the situation was recognized, early containment was not possible, since the virus had already spread to a number of countries around the globe. WHO ceased regular reporting of specific case counts Jul 16, 2009, saying many countries were having difficulty tracking individual numbers and that their time would be better spent on investigating severe cases and other exceptional events (WHO 2009: Changes in reporting requirements for pandemic [H1N1] 2009 virus infection.). The cumulative total number of deaths from pandemic H1N1 influenza reported to WHO regional offices by the end of February 2010 was well over 16,000, a number WHO acknowledges significantly understates the actual number. Additional background information and information on the current swine influenza situation is available in the document on this Web site, "Swine Influenza."
Of the avian influenza subtypes, currently the H5N1 subtype is of greatest pandemic concern for the following reasons (WHO: Avian influenza fact sheet; WHO 2005: Influenza pandemic preparedness and response):
- Since 2003, H5N1 viruses have spread across Asia and into Europe, the Middle East, India, and Africa, with outbreaks occurring in bird populations in more than 60 countries.
- In early 2008, the United Nations Food and Agriculture Organization (FAO) reported that the greatest areas of ongoing concern are Indonesia, Bangladesh, and Egypt, where the virus has become "deeply entrenched" (FAO 2008). The potential of exposure and infection of humans is likely to be ongoing in rural areas of these countries, which could enhance the likelihood that a pandemic strain will emerge (Stohr 2005).
- H5N1 strains cause severe disease in humans; worldwide, cases confirmed by the WHO total 630, with a CFR of about 60%.
Detailed information about H5N1 influenza in human populations can be found in the document on this Web site, "Avian Influenza (Bird Flu): Implications for Human Disease."
Limited Production Capacity
Production Capability in Only a Few Countries
Technological Challenges to Vaccine Development
Interpandemic Steps to Facilitate Vaccine Production
Current Status of H5N1 Candidate Vaccines
Stockpiling H5N1 Vaccines and Vaccination Strategies
Development of an effective vaccine is considered the cornerstone for controlling a global influenza pandemic. In general, if a novel strain occurs without adequate warning, the WHO has indicated that it will take at least 4 months to develop a vaccine (WHO 2005: WHO global influenza preparedness plan). In addition, there are several major obstacles in producing an adequate vaccine supply during a pandemic:
- Limited production capacity
- Production capability in only a few countries, which will yield an inequitable distribution
- Technological challenges to vaccine development
Limited global vaccine production capacity exists at this time. A 2009 report prepared in collaboration with the WHO and the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA) has concluded that if a pandemic emerged during 2009, the most likely case is that manufacturers could produce 2.5 billion doses globally in the first 12 months after they received the production strain. It would take 4 years to produce enough vaccine to meet total global demand (at two doses for 6.7 billion people) (IFPMA 2009). In the best-case scenario, the industry could produce 7.7 billion doses in the first 12 months of a pandemic and could meet global demand in 1.5 years. The authors of the report predicted that annual pandemic vaccine production capacity will rise to somewhere between 5 billion and 14.5 billion doses over the next 5 years.
Developing an effective pandemic vaccine will likely require having the specific pandemic strain in hand, which will mean that a vaccine cannot be produced until the onset of the pandemic. Once a virus is identified, it will take approximately 19 weeks to develop the appropriate reagents for an inactivated pandemic vaccine (WHO 2007: A description of the process).
Most of the world's influenza vaccine is produced in a few countries. These countries are likely to reserve scarce supplies for their own populations during a pandemic, thus leading to an inequitable distribution of vaccine, particularly to developing countries. This issue has relevance for the United States as well, where current domestic vaccine production falls far short of producing adequate vaccine supplies to vaccinate the entire US population. Moreover, the US plan does not address the issue of distributing vaccine to other countries.
Nine companies, located in the following nine developed countries, currently produce influenza vaccine:
- The Netherlands
- The United Kingdom
- The United States
One of the goals of the WHO Global Vaccine Action Plan is to establish new vaccine production facilities, particularly in developing countries (such as Indonesia) (WHO 2006: Global pandemic influenza action plan).
The manufacture of vaccines derived from pathogenic avian strains poses a number of technological challenges. For example, highly pathogenic avian strains cannot be grown in large quantities in eggs because they are lethal to chick embryos. These strains also pose significant safety issues and would require extensive biocontainment procedures during the manufacturing process.
- Reverse genetics provides several advantages in influenza vaccine development (Luke 2006: Vaccines for pandemic influenza; Palese 2006): (1) it allows creation of engineered viruses that are modified to be less virulent, thus eliminating the need for high-level containment, (2) with reverse genetics, a selection system is not needed to derive appropriate reassortant viruses from background parental viruses, (3) it dramatically shortens the timeframe for production of seed strains, (4) it allows for standardization of seed strains to be used in vaccine development, and (5) the process may eliminate the potential for any adventitious agents to enter the manufacturing process.
- Viruses representative of the newly emerging H5N1 clades continue to be identified for development of candidate vaccine viruses through reverse genetics. As of February 2009, more than 10 vaccine virus H5N1 strains had been produced and made available (WHO 2009: Antigenic and genetic characteristics).
Cell-based vaccines can shorten the time between the identification of a pandemic virus and full-scale production of the vaccine. In place of eggs, cell-based vaccine production uses laboratory-grown cell lines that can host a growing virus. A cell-based vaccine can be produced in a matter of weeks (HHS 2009: Pandemic planning update VI). In January 2009, the US government awarded a contract to Novartis to support building a vaccine manufacturing plant that will be capable of producing 150 million doses of cell-based pandemic influenza vaccine within 6 months of the start of a pandemic (HHS 2009: HHS awards $487 million contract).
Another option is development of recombinant DNA–based vaccines. The US government is pursuing this approach as well through issuing contracts to various companies (HHS 2009: Pandemic planning update VI).
In September 2006, the WHO released an action plan to increase pandemic influenza vaccine production capacity (WHO 2006: Global pandemic influenza action plan). The plan outlines the following strategies:
- Develop an immunization policy to increase demand for seasonal vaccines.
- Mobilize resources for the implementation of seasonal influenza vaccination programs.
- Increase influenza vaccine production capacity.
- Increase capacity for inactivated influenza vaccines.
- Improve production yield of H5N1 viruses and immunogenicity of prototype H5N1 inactivated vaccine.
- Build new production facilities in developing and/or industrialized countries.
- Assess formulations of influenza vaccine other than those commonly used for seasonal vaccine.
- Conduct clinical trials of adjuvanted vaccines.
- Explore the possibility to scale-up production of live, attenuated influenza vaccines.
- Further evaluate whole-cell vaccines.
- Assess alternative vaccine delivery routes (such as intradermal administration).
- Promote research and development of new influenza vaccines.
- Enhance protective efficacy and immunogenicity of existing vaccine types.
- Develop novel vaccines that induce broad-spectrum and long-lasting immune responses.
- Improve evaluation of vaccine performance.
- Develop regional and national plans for seasonal influenza vaccination programs.
According to the WHO, as of June 2008 more than 70 clinical trials involving prototype pandemic influenza vaccines have been completed or are ongoing (WHO 2008: Tables on the clinical trials).
Additional information about H5N1 influenza vaccine development can be found in the document on this Web site, "Avian Influenza (Bird Flu): Implications for Human Disease."
As of April 2009, four H5N1 influenza vaccines had been licensed:
- In April 2007, a Sanofi Pasteur vaccine was licensed by the FDA; this vaccine is currently being stockpiled in the United States.
- In May 2008, a vaccine produced by GlaxoSmithKline (GSK) was approved by the European Union (GlaxoSmithKline 2008).
- In June 2008, Australian authorities approved an H5N1 influenza vaccine made by the Australian-based pharmaceutical company, CSL (CSL 2008).
- In March 2009, a Sanofi Pasteur vaccine (Emerflu) was granted marketing authorization from the Australian Therapeutic Goods Administration (TGA). Emerfluvaccine is now approved for the prevention of pandemic influenza in Australia upon official declaration of a pandemic (Sanofi Pasteur 2009).
A universal vaccine that would be effective against all types of influenza, including emerging pandemic strains, is being developed by the British company Acambis (Acambis 2005) and is being researched by others as well. Such a vaccine would not have to be reengineered each year. One possible target for a universal vaccine is the relatively conserved M2 homotetramer (Haque 2007).
Researchers also are working on developing vaccines against other influenza A strains that may pose a pandemic risk (such as H9 and H7 strains).
As of January 2009, the US government had a stockpile of 2.2 million vaccination courses (each course provides full vaccination for one person) of H5N1 pre-pandemic influenza vaccine (HHS 2009: Pandemic planning update VI). The stockpile is available to support clinical trials and to protect healthcare workers, first responders, and other critical workers in the early stages of a pandemic. The government plans to continue to stockpile additional doses of pre-pandemic vaccine.
By 2011, HHS intends to expand US-based vaccine production capacity to the point that it can generate 600 million doses of a pandemic influenza vaccine (two doses for every American) within 6 months of the time that a reference strain of the actual pandemic virus is developed.
The WHO also has developed a pre-pandemic vaccine stockpile. In June 2007, GSK pledged to give 50 million doses of H5N1 vaccine to the WHO, and in June 2008, Sanofi Pasteur pledged an additional 60 million doses of vaccine over 3 years (see Jun 16, 2008, CIDRAP News story). A variety of issues are currently under discussion, such as developing consensus on policy options for use of H5 vaccines in an international stockpile; rules and procedures for the geographical placement, operation (including prioritization of release of vaccine), management, and oversight of a stockpile; and resources needed to maintain the stockpile (WHO 2007: Reports by the Director General).
In July 2008, HHS issued a guidance document on allocating vaccine during a pandemic (HHS 2008: Guidance on allocating and targeting pandemic influenza vaccine). The vaccination target groups and level of priority within each group (as identified by the tier according to the severity of a pandemic) are outlined in the table below.
Target Group (Estimated Number)
Severity of Pandemic
Homeland and national security
Deployed and mission critical personnel (700,000)
Essential support and sustainment personnel (650,000)
Intelligence services (150,000)
Border protection personnel (100,000)
National Guard personnel (500,000)
Other domestic national security personnel (50,000)
Other active duty and essential support (1,500,000)
Healthcare and community support services
Public health personnel (300,000)
Inpatient healthcare providers (3,200,000)
Outpatient and home healthcare providers (2,500,000)
Healthcare providers in long-term care facilities (1,600,000)
Community support services and emergency management personnel (600,000)
Mortuary services personnel (50,000)
Other important healthcare personnel (300,000)
Emergency medical services personnel (EMS, law enforcement, and fire services) (2,000,000)
Manufacturers of pandemic vaccine and antivirals (50,000)
Communications/IT, Electricity, Nuclear, Oil and Gas, and Water sector personnel (2,150,000)
Financial clearing and settlement personnel
Critical operational and regulatory government personnel
Banking and Finance, Chemical, Food and Agriculture, Pharmaceutical, Postal and Shipping, and Transportation sector personnel (3,400,000)
Other critical government personnel
Pregnant women (3,100,000)
Infants and toddlers, 6 – 35 months old (10,300,000)
Household contacts of infants under 6 months old (4,300,000)
Children 3 – 18 years old with high-risk medical conditions (6,500,000)
Children 3 – 18 years old without high-risk medical conditions (58,500,000)
Persons 19 – 64 years old with high-risk conditions (36,000,000)
Persons 65 years and older (38,000,000)
Healthy adults, 19 – 64 years old (123,350,000)
Given the current production capability for influenza vaccines, it is clear that, in a pandemic setting, there will be a vaccine shortage for some time before enough vaccine can be produced to vaccinate large segments of the population.
One modeling study suggests that the optimal vaccination strategy depends upon the transmission rate of the virus involved (Bansal 2006). If the transmission rate is high, a vaccination strategy that targets school-aged children and school staff (and thereby aims to reduce mortality through herd immunity) may be the most effective approach for limiting morbidity and mortality. If the transmission rate is moderate, then a vaccination strategy targeted to those at highest risk of serious complications and death (the elderly, infants, and the caregivers for these groups) would likely be most effective.
Two groups of antiviral agents are available for treatment and prophylaxis of influenza: M2 ion-channel inhibitors (the adamantanes [amantadine and rimantadine]) and the neuraminidase inhibitors (NIs) (oseltamivir [Tamiflu] and zanamivir [Relenza]). A review of these agents was published recently (De Clercq 2006).
Use of adamantanes during a pandemic is considered to be limited owing to the potential for development of resistance and high rates of side effects. Because influenza viruses are less likely to develop resistance to the NIs (at least based on current experience), they are considered the major class of antiviral agents to be used during a pandemic.
- NIs can reduce the duration of illness for both influenza A and B if given early in the clinical course (ie, within 48 hours after illness onset).
- Oseltamivir (given orally in capsule form) is approved for treatment and prevention of influenza in adults and children more than 1 year of age (Moscona 2005 and see Dec 27, 2005, CIDRAP News Story). In November 2006, Roche (maker of Tamiflu) changed the product information sheet for Tamiflu to include information about neuropsychiatric events (eg, self injury and delirium) following use of the product (Roche 2006: Tamiflu: Product information).
- Zanamivir (a powder that is inhaled by mouth) is approved for treatment of influenza in adults and children more than 7 years of age (Moscona 2005). In March 2006, the FDA approved the use of zanamivir for prevention of influenza in adults and children aged 5 and older (see Mar 29, 2006, CIDRAP News Story).
In May 2006, the WHO released guidelines on use of antiviral agents for H5N1 influenza treatment and prophylaxis (Schunemann 2007, WHO 2006: Rapid Advice Guidelines on pharmacological management of humans infected with avian influenza A [H5N1] virus). These guidelines are summarized below.
Recommendations for treatment:
- Where NIs are available:
- Clinicians should administer oseltamivir treatment (strong recommendation); zanamivir might be used as an alternative (weak recommendation). (According to the WHO, the quality of evidence if considered on a continuum is lower for the use of zanamivir compared with oseltamivir.)
- Clinicians should not administer amantadine or rimantadine alone as a first-line treatment (strong recommendation).
- Clinicians might administer a combination of an NI and an M2 inhibitor if local surveillance data show that the circulating H5N1 virus is known or likely to be susceptible (weak recommendation), but this should only be done in the context of prospective data collection.
- Where NIs are not available:
- Clinicians might administer amantadine or rimantadine as a first-line treatment if local surveillance data show that the H5N1 virus is known or likely to be susceptible to these drugs (weak recommendation).
Recommendations for chemoprophylaxis:
- Where NIs are available:
- In high-risk exposure groups, including pregnant women, oseltamivir should be administered as chemoprophylaxis, continuing for 7 to 10 days after the last exposure (strong recommendation); zanamivir could be used in the same way (strong recommendation) as an alternative.
- In moderate-risk exposure groups, including pregnant women, oseltamivir might be administered as chemoprophylaxis, continuing for 7 to 10 days after the last exposure (weak recommendation); zanamivir might be used in the same way (weak recommendation).
- In low-risk exposure groups, oseltamivir or zanamivir should probably not be administered for chemoprophylaxis (weak recommendation). Pregnant women in the low-risk group should not receive oseltamivir or zanamivir for chemoprophylaxis (strong recommendation).
- Amantadine or rimantadine should not be administered as chemoprophylaxis (strong recommendation).
- Where NIs are not available:
- In high- or moderate-risk exposure groups, amantadine or rimantadine might be administered for chemoprophylaxis if local surveillance data show that the virus is known or likely to be susceptible to these drugs (weak recommendation).
- In low-risk exposure groups, amantadine and rimantadine should not be administered for chemoprophylaxis (weak recommendation).
- In pregnant women, amantadine and rimantadine should not be administered for chemoprophylaxis (strong recommendation).
- In the elderly, people with impaired renal function, and individuals receiving neuropsychiatric medication or with neuropsychiatric or seizure disorders, amantadine should not be administered for chemoprophylaxis (strong recommendation).
Limited data suggest that current antiviral agents may be effective against a reconstructed 1918 H1N1 pandemic strain (Tumpey 2002). Researchers have shown that recombinant viruses possessing the HA and NA genes of the 1918 strain were inhibited effectively in both tissue culture and mice by oseltamivir and zanamivir. A recombinant virus possessing the M segment of the 1918 strains was inhibited effectively both in tissue culture and in vivo by the M2 ion-channel inhibitors amantadine and rimantadine.
Stockpiling NIs is considered by many experts to be an important strategy for limiting the impact of an influenza pandemic.
- One report, which analyzed several models of different stockpile sizes of NIs, estimated that having a stockpile to cover 20% to 25% of the population would be sufficient to treat most of the clinical cases and could lead to a 50% to 77% reduction in hospitalizations (Gani 2005).
- Two other reports have looked at the cost-benefit of stockpiling oseltamivir in defined geographic locations (Israel and Singapore). The Israeli study suggested that stockpiling oseltamivir could be cost-saving to the economy of Israel in the event of an influenza pandemic (Balicer 2005). In the Singapore study, a decision-based model was used to perform cost-benefit and cost-effectiveness analyses for stockpiling antiviral agents. The model compared three strategies: supportive management, early treatment of clinical influenza with oseltamivir, and prophylaxis in addition to early treatment. The authors found that stockpiles of antiviral agents for 40% of the population would save an estimated 418 lives and $414 million, at a cost of $52.6 million per shelf-life cycle of the stockpile. Prophylaxis was found to be economically beneficial in high-risk subpopulations (Lee 2006).
The WHO has stockpiled five million treatment courses of Tamiflu (donated by Roche) for initial pandemic response (Roche 2006: Roche update on Tamiflu for pandemic influenza preparedness). In addition, a number of countries around the globe have developed national antiviral stockpiles (Roche 2006: Roche update on Tamiflu for pandemic influenza preparedness).
- In May 2006, the WHO updated its pandemic influenza draft protocol for rapid response and containment (WHO 2006: Pandemic influenza draft protocol for rapid response and containment). One of the cornerstones of the protocol is deployment of the Roche international antiviral stockpile to be used initially for targeted antiviral prophylaxis (for known case contacts) and for mass antiviral prophylaxis as needed (either by offering prophylaxis to the affected population within a radius of 5 to 10 km from each detected case or covering at-risk populations in defined administrative areas).
- Through a global production network, Roche is currently able to produce in excess of 400 million treatment courses of Tamiflu annually. This network includes eight Roche sites and 19 external manufacturing partners located in nine different countries around the world (Roche 2006: Roche update on Tamiflu for pandemic influenza preparedness).
HHS currently has stockpiled enough pandemic influenza antiviral treatment courses to cover 44 million people. Further, states have purchased 22 million treatment courses for their pandemic stockpiles through a 25% federal subsidy and by making use of federal "best price" contracts (HHS 2009: Pandemic planning update VI). In addition, the Roche supply chain is fully operational in the US, with an annual production capacity of 80 million treatment courses (Roche 2006: U.S.-based supply chain for Tamiflu fully operational).
Even though antiviral stockpiles are considered to be an important strategy for pandemic preparedness, a number of caveats exist regarding their successful use for treatment or prophylaxis during a pandemic (Democratis 2006).
- First, it is not clear that such agents would be effective against the emergent pandemic strain.
- Rapid delivery of antiviral agents to newly diagnosed cases or contacts poses substantial logistical challenges, particularly in developing countries.
- Second, even if antiviral agents are shown to be effective, the dose and duration of treatment may depend on the virulence of the pandemic strain. Current antiviral treatment recommendations for influenza are based on studies using circulating H3N2 strains and not on potentially more virulent pandemic strains. For example, since H5N1 strains can be highly virulent, higher doses of antiviral agents given for a longer period may be necessary for effective treatment. This was demonstrated in a mouse model using and H5N1 strain from Vietnam (Yen 2005). Early treatment may also be critical for a successful outcome.
- Finally, even with the increased global capacity for production of oseltamivir, it is not clear whether enough Tamiflu will be available to meet the demand during a pandemic.
In December 2008, HHS released a guidance document on antiviral drug use during an influenza pandemic (HHS 2008: Guidance on antiviral use during an influenza pandemic). The guidance is based on the national pandemic response goals of slowing the spread of pandemic disease, reducing impacts on health, and minimizing societal and economic disruption. The guidance outlines the following strategies for antiviral use to meet these goals during a pandemic:
- Containing or suppressing initial pandemic outbreaks overseas and in the United States with treatment and postexposure prophylaxis among individuals identified as exposed to pandemic influenza and/or geographically targeted prophylaxis in areas where exposure may occur
- Reducing introduction of infection into the country early in an influenza pandemic as part of a risk-based policy at US borders
- Treatment of persons with pandemic illness who seek care early during their illness and would benefit from such treatment
- Prophylaxis of high-risk healthcare workers and emergency services personnel for the duration of community pandemic outbreaks
- Postexposure prophylaxis of workers in the healthcare and emergency services sectors who are not at high exposure risk, persons with compromised immune systems who are less likely to be protected by pandemic vaccination, and persons living in group settings such as nursing homes and prisons if a pandemic outbreak occurs at that facility
According to HHS, 195 million treatment courses are needed to fully implement the recommendations of the guidance. Since government stockpiles will only include approximately 80 million treatment courses, availability of antiviral agents for prophylaxis will depend largely on stockpiles in the private sector. To meet this need, HHS has suggested in a draft guidance document that employers consider stockpiling antiviral agents for their employees (HHS 2008: Proposed considerations for antiviral drug stockpiling by employers in preparation for an influenza pandemic).
A meta-analysis of studies on influenza patients during the 1918 pandemic found that patients with Spanish influenza pneumonia who received influenza-convalescent human blood products may have had a decreased risk of death (Luke 2006: Meta-analysis: convalescent blood products for Spanish influenza pneumonia). The authors suggest that convalescent human plasma could be a treatment option for patients with influenza pneumonia in a pandemic setting.
Several researchers have examined the potential of a new NI, peramivir, to protect against influenza (see Oct 2, 2006, CIDRAP News story). Clinical studies of this medication are ongoing.
M2 Ion-Channel Inhibitors
- Transmissible amantadine-resistant organisms are shed by about 30% of patients after 2 to 5 days of treatment. Mutations may confer resistance to both amantadine and rimantadine.
- Viral resistance to adamantanes can emerge rapidly because a single point mutation can confer resistance to both amantadine and rimantadine. For example, during the 2005-06 influenza season, the CDC found that more than 90% of isolates tested were resistant to both amantadine and rimantadine. As a result of these findings, the CDC issued a health alert in January 2006 recommending against the use of adamantanes during the 2005-06 influenza season (CDC 2006: CDC recommends against the use of amantadine and rimantadine).
- Despite the potential for resistance, a recent study of H5N1 isolates in Asia found that while more than 95% of the isolates from Vietnam and Cambodia were resistant to amantadine and rimantadine, those from Indonesia and China were much less likely to be resistant (6.3% and 8.9%, respectively) (Cheung 2006). These findings suggest that the adamantanes may be of use in curtailing spread of H5N1 during a pandemic situation.
Neuraminidase Inhibitors (McKimm-Breschkin 2003)
- Resistance to zanamivir: No resistance has been detected in previously healthy patients with influenza who have been treated with zanamivir. One influenza B isolate with reduced sensitivity was obtained from an immunocompromised (post bone marrow transplant) 18-month-old child after 12 days of treatment (Gubareva 1998).
- Resistance to oseltamivir:
- Oseltamivir-resistant H5N1 strains have been isolated from several patients in Vietnam. One was a Vietnamese child who received prophylactic treatment with the drug (Le 2005); another report involved two additional patients, both of whom died of H5N1 influenza (De Jong 2005).
- Clade 1 H5N1 viruses appear to be 15 to 30 times more sensitive to oseltamivir than clade 2 H5N1 isolates from Indonesia and Turkey (WHO Writing Committee 2008).
- A study of H5N1 influenza isolates from chickens, ducks, geese, and quailfrom Vietnam and Malaysia (2004), Cambodia (2004 and 2005), and Indonesia (2005) showed that sensitivities to oseltamivir fell into three groups when compared with a reference human H1N1 influenza strain (McKimm-Breschkin 2007).
- The clade 1 isolates from 2004 were all more sensitive to oseltamivir than the H1N1 influenza control.
- The 2005 Cambodian viruses showed a sixfold to sevenfold decrease in oseltamivir sensitivity compared with the 2004 Cambodian isolates.
- All of the clade 2 2005 Indonesian viruses demonstrated a 15- to 30-fold decrease in sensitivity to oseltamivir compared with clade 1 viruses.
- Genetic markers for reduced susceptibility to oseltamivir were noted in H5N1 isolates from two Egyptian patients who became ill and died in December 2006; both patients had been treated with oseltamivir for 2 days before the isolates were obtained (ECDC Influenza Team 2007; Cattoli 2009).
- A report suggested that natural variation in sensitivity to oseltamivir may exist among different H5N1 strains, indicating that ongoing surveillance and testing for sensitivity to NIs is essential for tracking trends (Rameix-Welti 2006).
In addition to vaccines and antiviral agents, a number of nonpharmaceutical interventions can be considered, although data assessing the effectiveness of these interventions are limited. Examples of such measures include isolation and quarantine, social distancing (such as school closures), use of masks by the general public (outside of healthcare settings), handwashing, and respiratory hygiene/cough etiquette.
In February 2007, the CDC and HHS released a document on nonpharmaceutical interventions (CDC/HHS 2007). In this guidance, community mitigation strategies are tied to the Pandemic Severity Index, as shown in the following table, which is included in the document. Additional details about community mitigation can be found in the guidance.
Summary of Community Mitigation Strategies by Pandemic Severity Index Level
Categories 2 and 3
Categories 4 and 5
Voluntary isolation of ill at home (adults and children); combine with use of antiviral treatment as available and indicated
Voluntary quarantine of household members in homes with ill persons§ (adults and children); combine with antiviral prophylaxis if effective, feasible and quantities sufficient
Generally not recommended
School: Child social distancing
Dismissal of students from schools and school-based activities, and closure of child care programs
Generally not recommended
Reduce out-of-school social contacts and community mixing
Generally not recommended
Workplace/Community: Adult social distancing
Decrease number of social contact (eg, encourage teleconferences, alternatives to face-to-face meetings)
Generally not recommended
Increase distances between persons (eg, reduce density of public transit, workplace)
Generally not recommended
Modify postpone, or cancel selected public gatherings to promote social distance (eg, postpone indoor stadium events, theater performances)
Generally not recommended
Modify workplace schedules and practices (eg, telework, staggered shifts)
Generally not recommended
In June 2008, HHS released interim guidance on the use and purchase of face masks and respirators by individuals and families for pandemic influenza preparedness (HHS 2008:Interim guidance on the use and purchase of facemasks and respirators). Settings for respirator or face masks use will depend on the potential for exposure to infectious persons; the following recommendations are outlined in the guidance:
- A face mask (ie, a disposable mask that covers the nose and mouth, such as a surgical mask) is recommended when exposure in a crowded setting (such as a bus or subway) occurs with persons not known to be ill.
- A face mask also is recommended for use by ill persons when they must be in close contact with others.
- An N-95 respirator is recommended for close contact (less than about 6 feet) with someone who has known or suspected influenza illness. In nonoccupational settings, the most common use for a respirator would be in the household of someone ill with influenza.
In 2006, the WHO published two reports on community interventions, one geared toward prevention of transmission internationally and one geared toward the national and local levels. These are briefly addressed below.
International level (WHO Writing Group 2006: Nonpharmaceutical interventions):
- Screening and quarantine of entering travelers have not been shown in previous pandemics to substantially delay virus introduction into countries where such measures were employed.
- Rather than instituting entry screening, the WHO recommends providing information to international travelers and possibly conducting exit screening (through health declarations and temperature measurement) for travelers departing from affected areas. It is important to note that exit screening is costly and disruptive and may not detect persons who are asymptomatic or in the preclinical stages of infection; however, exit screening may decrease transmission on conveyances (such as airplanes) and is a better use of resources than entry screening.
- Although generally not recommended, entry screening could be considered in the following situations: (1) where exit screening at the traveler's point of embarkation is suboptimal; (2) in geographically isolated areas, such as islands; and (3) when the host country's internal surveillance capacity is limited.
National and community levels (WHO Writing Group 2006: Nonpharmaceutical interventions):
- In general, isolation of patients in the community and quarantine of contacts are measures that have not been shown in past pandemics to be effective in preventing transmission outside of closed settings (such as dormitories or military barracks) and are not recommended once a pandemic is well established. However, the WHO recommends aggressive measures to detect and isolate cases and quarantine their contacts in situations where human-to-human transmission of a potential pandemic influenza strain is highly localized and limited (ie, during the pandemic alert period [WHO phases 4 and 5]).
- Social distancing measures, such as closing schools and other public gathering places and canceling sports events, have met with limited success during past pandemics, and the impact of such measures remains unclear. Social distancing measures and wearing masks in public apparently decreased influenza and other respiratory infections in Hong Kong during the 2003 SARS epidemic. About 76% of Hong Kong residents wore masks during that period.
- No controlled studies to date have specifically assessed mask use in preventing influenza transmission in community settings.
- Although data on these measures are limited, the WHO has made the following recommendations to decrease influenza transmission in community settings during a pandemic (phase 6).
- Ill persons should be advised to remain at home as soon as influenza-like symptoms develop.
- Measures to increase social distance should be considered, depending on the epidemiology of transmission, severity of disease, and risk groups affected.
- Mask use by the public should be based on risk, including frequency of exposure, and closeness of contact with potentially infectious persons. Routine mask use should be permitted but not required.
- Handwashing and respiratory hygiene/cough etiquette should be routine for all and strongly encouraged in public messages (although this recommendation is supported on the basis of plausible effectiveness rather than controlled studies or other supporting data).
- Despite the above guidance from the WHO, the potential efficacy of such measures in stemming the tide of a pandemic remains unclear. The value of implementing various community-based measures continues to be debated by experts in public health and epidemiology (Inglesby 2006).
A review of six US communities that reported relatively few, if any, cases of influenza during the 1918 pandemic found that these communities enacted "protective sequestration" to prevent healthy people from being exposed to the virus (Markel 2006). It is important to note that all six communities were relatively small and isolated. Also, the society of 1918 was much different than it is now. Protective sequestration involves the following features:
- Prohibitions on members of the community from leaving the site
- Prohibitions against visitors from entering a circumscribed perimeter
- Typically placing those visitors who are allowed to enter the community in quarantine for a period of time before they are admitted
- Taking advantage of geographic barriers, if available (eg, being on an island)
A historical review of nonpharmaceutical interventions implemented by US cities during the 1918 pandemic concluded that early, sustained, and layered application of nonpharmaceutical interventions was associated with mitigating the consequences of the pandemic (Markel 2007). However, a letter to the editor by historian John Barry called into question the validity of the data used in the review (Barry 2007). Another analysis of nonpharmaceutical interventions in 17 US cities during the 1918 pandemic also found that rapid implementation of multiple interventions resulted in lowered overall death rates (Hatchett 2007).
Several studies have used modeling methodology to assess influenza transmission and/or the impact of various nonpharmaceutical interventions; examples of published reports are outlined below. In addition, the IOM summarized available information from various modeling projects (IOM 2006: Modeling community containment). The IOM Committee on Modeling Community Containment for Pandemic Influenza concluded that community restrictions may play a role in reducing pandemic influenza virus transmission.
- A pandemic influenza simulation model using high-resolution population density data and data on travel patterns suggested that in the United States one third of transmission will occur in households, one third in workplaces and schools, and one third in the general community (Ferguson 2006). School closures could reduce peak attack rates but may have little impact on overall attack rates without other interventions. The authors advocate a combined strategy of targeted antiviral prophylaxis (to exposed persons, particularly household members) and school/business closures.
- Findings from another study involving mathematical modeling of influenza transmission within and between households showed that the combination of household-based quarantine, isolation of ill family members in a facility outside the household, and targeted use of antiviral prophylaxis of exposed household members could substantially reduce the impact of an influenza pandemic (Wu 2006).
- A third modeling study suggests that targeted social distancing (such as school closures and keeping children at home), to be implemented soon after cases begin occurring, could have a substantial impact in mitigating a pandemic at the local level (Glass 2006). However, for highly transmissible strains, social distancing would need to be widely practiced (for both adults and children) to be effective and may be impractical to implement.
Although pandemic planning has been ongoing for several years at the global level (through the WHO) and in a number of countries, the challenges for preparing for a pandemic are enormous. Even with the best planning efforts, there is no way to adequately prepare for a pandemic given the currently available resources. The challenges include these:
- If an influenza pandemic were to occur in the near future, vaccine for the pandemic strain would not be readily available for many months. Even though some developed countries have stockpiles of antiviral agents effective against influenza, supplies of these agents would be limited and inadequate to cover all of those in high-risk groups (Hayden 2004).
- The WHO has developed a protocol for rapid response and containment, which relies heavily on mass prophylaxis in the area where a pandemic strain arises (WHO 2006: Pandemic influenza draft protocol). Roche has developed a stockpile of oseltamivir that can be deployed to any area of the world where it is needed; however, the logistical challenges of implementing mass prophylaxis in many areas of the world are enormous, and such an effort would be extremely resource intensive.
- Once a vaccine is available, the current plans do not adequately address how the vaccine will be distributed globally. This is of great concern, since vaccine is only produced by a few countries and those countries are likely to not release vaccine until the needs of their populations are met.
- If the next pandemic strain is highly virulent (such as the 1918 strain) the global death toll could be dramatic. The current plans generally do not address the social, political, or economic issues that would likely be associated with an ongoing influenza pandemic (Osterholm 2005: A weapon the world needs; Osterholm 2005: Preparing for the next pandemic [N Engl J Med]; Osterholm 2005: Preparing for the next pandemic [Foreign Aff]).
- During a severe pandemic, substantial disruption of basic services (such as healthcare, food, clothing, provision of utilities [eg, water, electricity], and transportation) likely will occur. For example, a recent report has outlined the potential impact of an influenza pandemic on the US coal supply (Kelley 2008). The authors of the report provide convincing evidence that a severe pandemic would likely break major links in the coal supply chain, thus disrupting electrical generation across the United States. Furthermore, international trade will likely be affected, which could have serious global economic and societal consequences.
- A number of factors should be considered when every organization or individual approaches pandemic preparedness (Osterholm 2007: Unprepared for a pandemic). These include:
- The combination of the direct impact of influenza on the population
- The impact of a pandemic on the global just-in-time economy
- The lack comprehensive business continuity planning
- The inability of governments around the world to provide comprehensive and immediate relief based on inadequate supplies of antiviral agents, pandemic vaccine, and other critical medical supplies and equipment
To effectively manage a pandemic, additional information is urgently needed in a number of areas (Stohr 2005); if a pandemic occurs soon, we are unlikely to have complete answers to these complex issues (although progress is being made in a number of areas):
- Case management (including hospital surge capacity) and hospital infection control
- Immunogenicity of vaccines for pandemic influenza
- Early interventions to slow the spread of emerging pandemic viruses
- The role of various animal and bird species in the epidemiology of influenza viruses with pandemic potential
- Risk assessment
- Ethical issues related to distribution of scarce resources
The WHO has taken several steps toward global pandemic influenza planning, including development of a pandemic plan in 1999 and an updated plan in 2005 (WHO 2005: WHO global influenza preparedness plan). In addition, the WHO has issued a variety of additional guidance documents related to pandemic influenza planning (see WHO: Avian influenza home page).
In November 2005, the WHO held an international meeting on avian influenza and human pandemic influenza (see Nov 9, 2005, CIDRAP News story). The consultation was attended by more than 600 delegates from over 100 countries. Experts and officials set out key steps that must be taken in response to the threat of the H5N1 influenza virus that is currently circulating in animals in Asia and has been identified in parts of Europe:
Control Spread at the Source in Birds
- Improve veterinary services, emergency preparedness plans, and control campaigns including culling, vaccination, and compensation.
- Assist countries to control avian influenza in animal populations.
- Strengthen early detection and rapid-response systems for animal and human influenza.
- Build and strengthen laboratory capacity.
- Develop support and training for the investigation of animal and human cases and clusters, and carry out planning and testing of rapid containment activities.
- Build and test national pandemic preparedness plans.
- Conduct a global pandemic response exercise.
- Strengthen the capacity of health systems and training for clinicians and health managers.
Integrated Country Plans
- Develop integrated national plans across all sectors to provide the basis for coordinated technical and financial support.
- To support all of the above, factual and transparent communications, in particular risk communication, is vital.
HHS issued the final version of the US Pandemic Influenza Plan on November 2, 2005 (HHS 2005: Pandemic influenza plan), followed by an implementation plan on May 3, 2006 (HSC 2006). Since that time, the HHS Secretary has released six planning updates, with the most recent one being released in January 2009 (HHS 2009: Pandemic planning update VI).
The plan includes three main sections: (1) an overview (including executive summary), (2) a strategic plan (part 1), and (3) public health guidance (part 2).
Part 1, Strategic Plan, includes:
- The Pandemic Influenza Threat
- Planning Assumptions
- Doctrine for a Pandemic Influenza Response
- Key Pandemic Influenza Response Actions and Key Capabilities for Effective Implementation
- Roles and Responsibilities of HHS Agencies and Offices
- HHS Actions for Pandemic Influenza Preparedness and Response
A. Pandemic Influenza Background
B. WHO Pandemic Phases
C. National Response Plan
D. NVAC/ACIP Recommendations on Use of Vaccines and NVAC Recommendations on Pandemic Antiviral Drug Use
E. Legal Authorities
F. Current Key HHS Activities
G. HHS Research Activities
H. International Partnership on Avian and Pandemic Influenza
I. Acronym List
J. Internet Resources on Pandemic Influenza
Part 2, Public Health Guidance for State and Local Partners, includes:
- Overview of Planning by State and Local Governments
- Overview of Community-Wide Planning to Support Healthcare Facilities
- Appendix 1: Checklist for Legal Considerations for Pandemic Influenza in Your Community
- Appendix 2: Fact Sheet: Practical Steps for Legal Preparedness
- Public Health Guidance Supplements
- Pandemic Influenza Surveillance
- Laboratory Diagnostics
- Healthcare Planning
- Infection Control (this section was updated in October 2006 as noted in the section Infection Control Considerations)
- Clinical Guidelines
- Vaccine Distribution and Use
- Antiviral Drug Distribution and Use
- Community Disease Control and Prevention
- Managing Travel-Related Risk of Disease Transmission
- Public Health Communications
- Workforce Support: Psychosocial Considerations and Information Needs
The federal implementation plan addresses steps to achieve the strategy outlined in the federal plan (HSC 2006). The implementation plan divides planning and response efforts into eight areas, with corresponding chapters: federal government planning, federal government response, international efforts, transportation and borders, protecting human health, protecting animal health, law enforcement and public safety, and institutions. The plan also has an appendix with advice for schools, the business sector, families, and individuals.
In addition to the federal plan, pandemic influenza plans have been developed by state and local governments. Information on the state plans can be found on the HHS pandemic influenza Web site (HHS: PandemicFlu.gov). Guidance on pandemic planning for state and local health departments is provided in the federal plan as Part 2. In addition, the federal government released in March 2008 a strategic framework to help the 50 States, the District of Columbia (DC), and the five US territories improve and maintain their operating plans for responding to and sustaining functionality during an influenza pandemic (HHS 2008: Federal guidance to assist states). The plan outlines several strategic goals and a number of operating objectives that should be incorporated into state pandemic plans. These are outlined in the table below.
Strategic Goals and Operating Objectives That Should Be Included in State Pandemic Plans
Ensure continuity of operations of state agencies and continuity of state government
Sustain operations of state agencies and support and protect government workers
Ensure public COOP during each phase of a pandemic
Ensure continuity of food supply system
Ensure ability to respond to agricultural emergencies and maintain food safety net programs
Sustain transportation systems
Ensure surveillance and laboratory capability during each phase of a pandemic
Assist with controls at US ports of entry
Implement community mitigation interventions
Enhance state plans to enable community mitigation through student dismissal and school closures
Acquire and distribute medical countermeasures
Ensure mass vaccination capability during each phase of a pandemic
Manage mass casualties
Ensure communication capability during each phase of a pandemic
Mitigate the impact of an influenza pandemic on workers in the state
Understand official communication mechanisms for foreign mission, international organizations, and their members in the US
Integrates EMS and 9-1-1 into pandemic preparedness
Integrate public safety answering points into pandemic preparedness
Public safety and law enforcement
Sustain/support critical infrastructure sectors and key resource sectors
Define CIKR protection, planning, and preparedness roles and responsibilities
Build public private partnerships and support networks
Implement the NIPP risk management framework for a pandemic
Bolster CIKR information sharing and protection initiatives
Leverage emergency preparedness activities for CIKR protection, planning, and preparedness
Integrate federal and state CIKR protection, planning, and preparedness activities
Allocate scarce resources
National state-focused organizations also have issued various guidance documents on pandemic influenza planning; examples include the following:
- The Association of State and Territorial Health Officials (ASTHO) issued a guidance document for pandemic influenza planning in 2002 (ASTHO 2002).
- In July 2006, the National Governor's Association (NGA) released a pandemic planning guide for states titled "Preparing for a Pandemic Influenza: A Primer for Governors and Senior State Officials" (NGA 2006). According to the guide, states need to be self-reliant and should plan for maintaining essential services during a pandemic.
- In March 2009, the NGA released a document on protecting and managing state workers during an influenza pandemic to assure that essential government services are provided and that critical infrastructure can be maintained (NGA 2009).
Pandemic influenza planning at the hospital level has many similarities to overall hospital emergency preparedness planning, although an influenza pandemic has several unique features, outlined below:
- Unlike most disasters (which would likely be local or regional), an influenza pandemic would affect the whole country. As a result, federal assets or assets from surrounding areas likely would not be readily available.
- The first wave of an influenza pandemic would likely last 8 to 12 weeks, and multiple sequential waves could occur following the initial wave; therefore, a pandemic requires a prolonged response, which is different from most acute emergencies.
- An influenza pandemic would affect the healthcare workforce, likely leading to workforce shortages. There are several factors that would contribute to workforce shortages. First, a proportion of the workforce will become ill. Second, workers may need to care for ill family members or children who are at home because of school or day care closures. Finally, it is possible that some hospital and clinic workers will refuse to come to work for fear of acquiring influenza, particularly if the CFR is high and adequate supplies of antiviral agents and personal protective equipment (PPE) are not readily available (Irvin 2008).
- Shortages of critical supplies (such as ventilators, ventilator circuits, PPE, and essential medications) will likely occur. Two factors could contribute to shortages: (1) excess numbers of patients and (2) disruption of critical supply chains, which often operate on a just-in-time basis.
- Adequate supplies of antiviral agents and pandemic vaccine most likely will not be available; therefore, healthcare systems, in conjunction with state and local public health officials, will need to prioritize these resources.
According to a recent article, the US healthcare system is not currently able to respond to a pandemic effectively at the current time for the following reasons (Bartlett 2008):
- It consists of an uncoordinated, fragmented, and largely private system. It is “broke or nearly broke,” with one-third of hospitals operating at a deficit.
- There are severe manpower shortages, especially in nursing, with an estimated current need for approximately 100,000 nurses (representing roughly 8% of the nursing workforce).
- Approximately 48% of emergency departments operate at capacity or over capacity.
- The number of hospitals, emergency departments, and intensive care unit beds is decreasing.
- Approximately 80% of essential supplies, including drugs, come from offshore suppliers, which might not be functioning during a pandemic.
According to HHS, key issues that hospitals need to consider when planning for an influenza pandemic include (HHS 2005: Pandemic influenza plan [supplements 3 and 4]):
- Hospital surveillance
- Hospital communications
- Education and training
- Triage, clinical evaluation, and admission procedures (facilities may need to consider off-site triage)
- Facility access
- Occupational health (eg, monitoring employee health, managing ill workers)
- Surge capacity for beds, equipment, and supplies
- Surge capacity for staff (including plans for using volunteers)
- Mortuary issues
- Infection control issues, including isolation and PPE (see section below)
- Use and administration of antiviral agents and pandemic vaccine (once vaccine becomes available)
A perspective article published in 2006 identified the top priority areas for hospital planning as follows (Toner 2006):
- Comprehensive and realistic planning, including having a full-time disaster coordinator, creating a pandemic preparedness committee, participating in a regional hospital coordinating group, using modeling (such as FluSurge software available online from the CDC [CDC: FluSurge software]), planning for hospital bed surge capacity of 30% on a 1-week notice, and planning to create 200% bed capacity in the region on a 2-week notice.
- Limiting nosocomial spread of the virus through implementing respiratory etiquette (including use of surgical masks), providing appropriate PPE to staff (including fit-tested N-95 respirators if possible), limiting the number of staff members who are potentially exposed, and tracking staff illnesses.
- Maintaining, augmenting, and stretching the hospital workforce by using screened volunteers, providing medical day care for ill family members, shifting clinical staff to highest-need areas, using nontraditional personnel, and coordinating staff with other hospitals in the region.
- Allocating limited resources by deferring nonemergency care, instituting alternative patient care routines, planning for alternative care sites, creating criteria and clinical guidelines for use of resource-intensive services, and establishing a triage process for patients who are competing for limited resources.
As part of their planning efforts, hospital administrators will need to work with local and state public health and emergency management agencies to deal with additional issues, such as regional healthcare coordination, resource tracking across hospitals, plans for alternative care facilities, determining when standards of care in the community may need to be altered, and allocation of scarce resources such as ventilators.
- In 2005, the Agency for Healthcare Research and Quality (AHRQ) published a document on altering standards of care in mass casualty settings that outlines some of the issues on this topic (AHRQ 2005).
- In November 2006, AHRQ released another guide on providing mass care with scarce resources (AHRQ 2006). This guide deals with a number of community-wide strategies for managing a mass care event.
- Another report outlines a triage protocol for critical care during an influenza pandemic (Christian 2006). The protocol has four main components: inclusion criteria, exclusion criteria, minimum qualifications for survival, and a prioritization tool.
- A review article outlines potential models for alternative care in a pandemic setting (Lam 2006). Examples discussed include overflow hospitals that provide a full range of services, facilities dedicated to isolating influenza patients who are unable to be in their homes and need minimal medical care, expanded ambulatory care sites, care sites for recovering noninfluenza patients, limited noncritical supportive care sites for nonacute patients, primary triage and rapid patient screening sites, and quarantine sites (such as hotels or motels).
- Several documents have been published on allocating ventilators during emergencies (such as a pandemic) when demand outstrips availability. Most experts suggest that the SOFA (sequential organ failure assessment) score may be a valuable tool for predicting patient outcome in such situations (New York State 2007, Hick 2007), which could help providers determine which patients are most appropriate for ventilatory support.
- In April 2008, the American Nursing Association released a document titled "Adapting Standards of Care Under Extreme Conditions: Guidance for Professionals During Disasters, Pandemics, and Other Extreme Emergencies" (ANA 2008). This policy paper can be used as a basis for protocol development and refinement, especially with regard to ethics and standards that apply to decisions about care made during unusual or extreme circumstances such as a pandemic.
- In May 2008, a series of five articles was published on definitive care for the critically ill during a disaster (see May 13, 2008, CIDRAP News story). The articles represent the consensus opinions of a multidisciplinarypanel convened under the umbrella of the Critical Care CollaborativeInitiative. The five articles include an executive summary and individual papers on current capabilities, a framework to optimize surge capacity, medical resource guidance, and recommendations for allocating scarce critical care resources in a mass critical care setting (Devereaux 2008).
The Occupational Safety and Health Administration (OSHA) released guidance on preparing workplaces for an influenza pandemic (OSHA 2007). This guidance addresses a variety of work environments, including healthcare settings where the risk of potential exposure is considered high or very high.
For the past several years, the federal government has provided funds aimed at enhancing medical surge capacity at the state and local level; these funds were originally provided through the National Bioterrorism Hospital Preparedness Program (NBHPP) within the Health Resources and Services Administration (HRSA). The Pandemic and All Hazards Preparedness Act of 2006 transferred the NBHPP to the HHS Assistant Secretary for Preparedness and Response (HHS: The Hospital Preparedness Program). The focus of the HHS Hospital Preparedness Program (HPP) is now all-hazards preparedness and not solely bioterrorism. The HPP will continue to support capabilities-based planning by setting priorities that must be met by the end of the current budget period (August 2008). In an effort to continue strengthening healthcare medical surge capability across the nation, state and local governments are expected to focus on the following five areas:
- Interoperable communication system
- Bed tracking system
- Emergency System for the Advance Registration of Volunteer Health Professionals (ESAR-VHP)
- Fatality management plans
- Hospital evacuation plans
Funds also have been awarded through cooperative agreements from the CDC to state and big-city health departments to enhance pandemic preparedness; a number of the key issues that need to be addressed in the cooperative agreements involve the medical care delivery system.
The challenges that hospitals face in preparing for a pandemic are significant. According to the IOM, the US emergency medical system is seriously unprepared for a pandemic or other major public health crisis (IOM 2006: Hospital-based emergency care: at the breaking point). One of the biggest challenges is creating adequate surge capacity. Over the last 20 years, the number of hospital beds in the United States has steadily declined. Currently, only 4% to 6% of hospital beds are available at any given time (Bartlett 2006). According to the Trust for America's Health (TFAH), half of the states would run out of hospital beds within 2 weeks of a moderately severe pandemic influenza outbreak (TFAH 2006). In the situation of a severe pandemic similar to that in 1918, 47 states would run out of hospital bed capacity within 2 weeks.
Modes of Transmission for Influenza Viruses
Respiratory Hygiene/Cough Etiquette
Recommended Isolation Precautions to Prevent Transmission of Pandemic Influenza
Use of Surgical Masks and Respirators During an Influenza Pandemic
Use of Airborne Infection Isolation Rooms
Infection Control Guidelines Specific to H5N1 Avian Influenza
Infection control guidelines for pandemic influenza are provided in part 2, supplement 4 of the HHS Pandemic Influenza Plan (HHS 2005: Pandemic influenza plan). This part of the plan was updated in October 2006 with release of the document "Interim Guidance on Planning for the Use of Surgical Masks and Respirators in Health Care Settings during an Influenza Pandemic" (HHS 2006).
Recommendations on infection control practices are based on available data regarding the modes of transmission of influenza viruses in general. Influenza viruses potentially can be transmitted through droplet, contact, and airborne modes. Although existing data are limited regarding the contribution of each mode of transmission, a recent review concluded that influenza virus transmission occurs at close range rather than over long distances (Brankston 2007). Information on the modes of transmission for influenza viruses are outlined below.
- Influenza viruses are predominantly transmitted by large droplets (ie, >5 mcm).
- Droplets are expelled by coughing and sneezing and generally travel through the air no more than 3 feet from the infected person.
- Transmission via large droplets requires close contact between the source and recipient persons, permitting droplets, which do not remain suspended in the air, to come into direct contact with oral, nasal, or ocular mucosa.
- Special air handling and ventilation systems are not required to prevent droplet transmission.
Direct and Indirect Contact Transmission
- Direct contact transmission involves skin-to-skin contact (such as hand-to-hand) between an infected person and a susceptible person.
- The proportion of influenza virus transmission caused by direct or indirect contact remains unknown; however, transmission by these routes can occur.
- Influenza viruses can live for 24 to 48 hours on nonporous environmental surfaces and less than 12 hours on porous surfaces (Bean 1982), indicating that transmission can occur when hands that touch contaminated surfaces subsequently come into contact with oral, ocular, or nasal mucosa. Fomite transmission appears to be rare.
- Airborne transmission of influenza viruses (ie, transmission via droplet nuclei [<5 mcm], which remain suspended in the air and have the potential to travel farther than several feet) has been suggested in several reports, although evidence to conclusively support airborne transmission of influenza virus is limited (Bridges 2003). Furthermore, available data suggest that airborne transmission does not play a major role in spread of influenza viruses (Brankston 2007). However, airborne transmission of influenza viruses may occur, at least over short distances (Tellier 2006), and further study is needed to determine the importance of this mode of transmission in healthcare or other settings.
- One report describes the occurrence of an influenza outbreak following exposure to a person with influenza on board a commercial aircraft (Moser 1979). The aircraft was grounded for 3 hours with the ventilation system turned off and passengers on board. After the flight, 39 (72%) of the passengers reported having an influenza-like illness within 72 hours. These findings suggest that airborne transmission via droplet nuclei likely occurred for some passengers and may have been attributed to poor air circulation aboard the aircraft.
- Another observational study involved comparing rates of influenza among tuberculosis (TB) patients housed in a TB sanatorium during the 1957-58influenza pandemic (Riley 1974). TB patients inone building were housedin rooms with ultraviolet (UV)lights on the ceiling, whereas patients in other buildings did not haveUV lights in theirrooms. During an outbreakof influenza, the illnessrate was 19% amongthose in rooms withoutUV lights and only2% among those inrooms with UV lights.The fact that UV lights were protective suggests that airborne transmission of influenza was prevented in rooms with UV lights; however, the potential for exposure may not have been the same between patients in the different buildings and, therefore, no definitive conclusions about airborne transmission can be drawn.
- Several experimental studies involving humans have shown that influenza viruses can be transmitted via droplet nuclei, although these studies used masks to deliver the aerosols and did not involve person-to-person transmission (Alford 1966, Henle 1946).
- A 2009 report detected airborne influenza virus particles in a hospital emergency department through collection of size-fractioned aerosol samples that were analyzed by real-time PCR (Blachere 2009).
- Studies in mice also suggest the possibility of airborne transmission of influenza viruses.
- In one report, uninfected mice were as likely to become infected when housed in the same cage with infected mice asthey were if housed in an adjacent, separate cage that allowed droplet and droplet nuclei transmission between cages but no direct contact (Schulman 1967). In addition, a strong inverse correlation was found between the infection rate and the rate of air exchange, regardless of whether infected and uninfected mice were physically separated. Infectious particles of less than 10 mcm in diameter produced by infected mice were found by air sampling, suggesting that airborne transmission occurred between infected and uninfected mice held in separate cages.
- Another report showed that in an unventilated roomwith constantly agitated air held at a relative humidity of 17% to 24%, mice could become infected with influenza virus as late as 24 hoursafter the virus wasfirst aerosolized into theroom, although the proportionof animals infected decreasedover time (Loosli 1943).
- Aerosol-generating procedures (eg, intubation, bronchoscopy, nebulizer treatments) theoretically could promote dissemination of droplet nuclei from infected patients, although this has not been studied for influenza.
- There is no evidence to date that droplet nuclei containing influenza viruses can travel through ventilation systems or across long distances, such as can occur with TB and certain other viral agents.
The HHS Pandemic Influenza Plan indicates that respiratory hygiene/cough etiquette programs should be in place to decrease transmission of influenza. The CDC Web site outlines steps for implementing these programs (CDC: Respiratory hygiene/cough etiquette in healthcare settings). (Note: Although respiratory hygiene seems like a logical approach, its utility in preventing influenza virus transmission has not been scientifically validated.)
- The following measures to contain respiratory secretions are recommended for all individuals with signs and symptoms of a respiratory infection:
- Cover the nose and mouth when coughing or sneezing.
- Use tissues to contain respiratory secretions and dispose of them in the nearest waste receptacle after use.
- Perform hand hygiene (eg, hand washing with nonantimicrobial soap and water, alcohol-based hand rub, or antiseptic hand wash) after having contact with respiratory secretions and contaminated objects/materials.
- During periods of increased respiratory infection activity in the community (eg, when there is increased absenteeism in schools and work settings and an increased number of medical office visits by persons complaining of respiratory illness), healthcare facilities should offer masks to persons who are coughing.
- Either procedure masks (ie, with ear loops) or surgical masks (ie, with ties) may be used to contain respiratory secretions.
- Respirators such as N-95 or above are not necessary.
- When space and chair availability permit, coughing persons should be encouraged to sit at least 3 feet away from others in common waiting areas.
- When implementing respiratory hygiene programs, healthcare facilities should:
- Ensure the availability of materials for adhering to respiratory hygiene/cough etiquette in waiting areas for patients and visitors.
- Provide tissues and no-touch receptacles for used tissue disposal.
- Provide conveniently located dispensers of alcohol-based hand rub; where sinks are available, ensure that supplies for hand washing (eg, soap, disposable towels) are consistently available.
Since large droplets are the major mode of influenza transmission, the HHS Pandemic Influenza Plan recommends Droplet Precautions along with Standard Precautions for prevention of transmission in healthcare settings. In addition, N-95 respirators are recommended according to the guidance outlined below under Use of Surgical Masks and Respirators During an Influenza Pandemic. Airborne infection isolation rooms also are recommended in certain situations as outlined below under Use of Airborne Infection Isolation Rooms.
According to the 2007 CDC/HICPAC document, “Guideline for Isolation Precautions: Preventing Transmission of Infectious Agents in Healthcare Settings,” patients with influenza should be placed on Droplet Precautions for a minimum of 5 days from onset of symptoms (CDC/HICPAC 2007). Immunocompromised patients should be continued on Droplet Precautions for the duration of their illness. Specific features of Standard and Droplet Precautions as outlined in the federal pandemic plan are shown in the table below.
Components of Standard and Droplet Precautions
Perform hand hygiene after touching blood, body fluids, secretions, excretions, and contaminated items; after removing gloves; and between patient contacts. Hand hygiene includes both hand washing with either plain or antimicrobial soap and water or use of alcohol-based products (gels, rinses, or foams) that contain an emollient and do not require the use of water. If hands are visibly soiled or contaminated with respiratory secretions, they should be washed with soap (either nonantimicrobial or antimicrobial) and water. In the absence of visible soiling of hands, approved alcohol-based products for hand disinfection are preferred over soap and water because of the superior microbicidal activity, reduced drying of the skin, and convenience.
Use for touching blood, body fluids, secretions, excretions, and contaminated items; for touching mucous membranes and nonintact skin.
Use during procedures and patient-care activities in which contact of clothing/exposed skin containing blood/body fluids, secretions, and excretions is anticipated.
PPE: Face/eye protection (eg, surgical or procedure mask and goggles or face shield)
Use during procedures and patient-care activities likely to generate splashes or sprays of blood, body fluids, secretions, or excretions.
Safe work practices
Avoid touching eyes, nose, mouth, or exposed skin with contaminated hands (gloved or ungloved); avoid touching surfaces with contaminated gloves and other PPE that are not directly related to patient care (eg, door knobs, keys, light switches).
Soiled patient care equipment
Handle in a manner that prevents transfer of microorganisms to oneself, others, and environmental surfaces; wear gloves (gown if necessary) when handling and transporting soiled linen and laundry; and perform hand hygiene after handling equipment.
Soiled linen and laundry
Handle in a manner that prevents transfer of microorganisms to oneself, others and environmental surfaces; wear gloves if materials are visibly contaminated; perform hand hygiene after handling.
Needles and other sharps
Use devices with safety features when available; do not recap, bend, break, or hand-manipulate used needles; if recapping is necessary, use a one-handed scoop technique; place used sharps in a puncture-resistant container.
Environmental cleaning and disinfection
Use EPA-registered hospital detergent-disinfectant; follow standard facility procedures for cleaning and disinfection of environmental surfaces; emphasize cleaning/disinfection of frequently touched surfaces (eg, bed rails, phones, lavatory surfaces).
Disposal of solid waste
Contain and dispose of solid waste (medical and nonmedical) in accordance with facility procedures and/or local or state regulations; wear gloves when handling waste and waste containers; perform hand hygiene.
Respiratory hygiene/cough etiquette (source control measure for persons with symptoms of a respiratory infection; implement at first point of encounter [eg, triage/reception areas] within a healthcare setting.)
Cover the mouth/nose when sneezing/coughing; use tissues and dispose of in no-touch receptacles; perform hand hygiene after contact with respiratory secretions; wear a mask (procedure or surgical) if tolerated; sit or stand as far away as possible (more than 3 feet) from persons who are not ill.
Place patients with influenza in a private room or cohort with other patients with influenza. Keep door closed or slightly ajar, maintain room assignments of patients in nursing homes and other residential settings, and apply Droplet Precautions to all persons in the room.
Wear an appropriate mask or respirator for entry into patient room; wear other PPE as recommended for Standard Precautions.
Limit patient movement to medically necessary purposes; have patient wear a procedure or surgical mask when outside the room.
Follow Standard Precautions and facility procedures for handling linen and laundry and dishes and eating utensils, and for clearing/disinfection of environmental surfaces and patient care equipment, disposal of solid waste, and postmortem care.
During procedure that may generate small particles of respiratory secretions (eg, endotracheal intubation, bronchoscopy, nebulizer treatment, suctioning), healthcare personnel should wear gloves, gown, face/eye protection, and a fit-tested N-95 respirator or other appropriate particulate respirator.
In October 2006, the CDC revised the HHS Pandemic Influenza Plan to change the language regarding use of N-95 respirators. HHS now recommends that National Institute for Occupational Safety and Health (NIOSH)–certified N-95 respirators or higher be used when caring for patients with confirmed or suspected pandemic influenza during activities that have a high likelihood of generating infectious respiratory aerosols, including the following high-risk situations:
- Aerosol-generating procedures (eg, endotracheal intubation, nebulizer treatment, and bronchoscopy)
- Resuscitation (ie, emergency intubation or cardiac pulmonary resuscitation)
- Providing direct care for patients with influenza-associated pneumonia (as determined on the basis of clinical diagnosis or chest x-ray), who might produce larger-than-normal amounts of respirable infectious particles when they cough
Two documents related to use of masks and respirators can be found on the HHS Pandemic Influenza Web site: "Interim Guidance on Planning for the Use of Surgical Masks and Respirators in Health Care Settings During an Influenza Pandemic" (HHS) and "Interim Public Health Guidance for the Use of Facemasks and Respirators in Non-Occupational Community Settings During an Influenza Pandemic" (HHS).
The above recommendations are consistent with recommendations from the WHO (WHO 2005: Clarification: use of masks). However, the HHS guidance further states that "Use of N-95 respirators for other direct care activities involving patients with confirmed or suspected pandemic influenza is also prudent."
Respirator use should be in the context of a complete respiratory protection program in accordance with OSHA regulations. Detailed information on respiratory protection programs, including fit-test procedures, can be accessed on the OSHA Web site (OSHA: Respiratory Protection eTool).
Furthermore, measures should be considered to minimize the number of personnel required to come in contact with suspected or confirmed pandemic influenza patients, thereby reducing worker exposure and limiting the need for N-95 respirators. Such measures include:
- Establishing specific wards for patients with pandemic influenza
- Assigning dedicated staff (eg, healthcare, housekeeping, janitorial) to provide care for pandemic influenza patients and restricting those staff from working with noninfluenza patients
- Dedicating entrances and passageways for influenza patients
In the event of actual or anticipated shortages of N-95 respirators:
- Other NIOSH-certified N-, R-, or P-class respirators should be considered in lieu of the N-95 respirator.
- If reuseable elastomeric respirators are used, these respirators must be decontaminated according to the manufacturer's instructions after each use.
- Powered air purifying respirators (PAPRs) may be considered for certain workers and tasks (eg, high-risk activities). Loose-fitting PAPRs have the advantages of providing eye protection, being comfortable to wear, and not requiring fit-testing; however, hearing (eg, for auscultation) is impaired, limiting their utility for clinical care. Training is required to ensure proper use and care of PAPRs.
If supplies of N-95 (or higher) respirators are not available, surgical masks can provide benefits against large droplet exposure and should be worn for all healthcare activities for patients with confirmed or suspected pandemic influenza. A recent study using potassium chloride solution found that the protective performance of surgical masks may offer 95% filtration efficiency and N-95 respirators 97% filtration efficiency (Li 2006). The validity of these findings, however, has been questioned (see Feb 28, 2007, CIDRAP News story).
According to the HHS guidance, negative pressure isolation is not required for routine care of individuals with pandemic influenza. According to the guidance, "If possible, airborne infection isolation rooms should be used when performing high-risk aerosol-generating procedures. If work flow, timing, resources, availability, or other factors prevent the use of airborne infection isolation rooms, it is prudent to conduct these activities in a private room (with the door closed) or other enclosed area, if possible, and to limit personnel in the room to the minimum number necessary to perform the procedure properly."
N-95 respirators and isolation rooms may be in short supply during peak pandemic activity; hospitals and other healthcare settings should consider developing contingency plans that take this possibility into consideration(Osterholm 2005: Avian flu: addressing the global threat).
An IOM committee recently concluded that there is no good way to clean masks and respirators for reuse; however, consideration may be given to reusing these items (by the same user) to extend supplies (IOM 2006:Reusability of facemasks). According to the IOM report, a person who wants to reuse an N-95 respirator should wear a medical mask or a clear plastic face shield over it to protect it from surface contamination. The user should store the respirator carefully between uses and should wash his or her hands before and after handling it and the device used to shield it.
In May 2004, the CDC and the WHO issued infection control guidelines for prevention of transmission of H5N1 influenza in healthcare settings, and the WHO updated its guidance in April 2006 (CDC 2004: Interim recommendations for infection control; WHO 2006: Avian influenza, including influenza A (H5N1), in humans). Summaries of the recommended isolation precautions from the CDC and the WHO are outlined in the table below. Both agencies recommend that Airborne Precautions be implemented for patients with H5N1 influenza, if possible.
Isolation Precautions for Patients With H5N1 Avian Influenza
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Resources & Literature
CDC. CDC resources for pandemic flu. [Full text]
CDC. Cold versus flu [Full text]
HealthMap. HealthMap flu shot locator. [Interactive Map]
HHS. Flu 101. [Video]
HHS. Flu: children and infants. [Full text]
HHS. Public Service Announcements. [Full text]
HHS. The current flu situation. [Full text]
HHS. The next flu pandemic: what to expect. [Full text]
HHS. Seniors (adults 65 years and older) and the flu. [Full text]
HHS. Misconceptions about seasonal influenza and influenza vaccines. [Full text]
Ready America. Influenza pandemic page. [Web page]
Red Cross. Flu overview. [Full text]
WHO. WHO pandemic phase descriptions and main actions by phase. Apr 26, 2009. Describes new phase criteria [Full text]
Pandemic Planning for Families
Booth S, Hills-Evans K. Pandemic influenza preparation and response: a citizen's guide. A reference guide with information and essential lists [Full text]
FEMA. Are you ready? Basic preparedness. [Full text]
HHS. A guide for individuals and families. An overview of preparation activities [Full text]
HHS. Caring for someone with the flu. [Full text]
InSTEDD. Pandemic influenza preparation and response: a citizen's guide. [Full text]
Montgomery County Department of Health and Human Services (Maryland). Stay at home toolkit for influenza. [Full text]
Trust for America's Health. It's not flu as usual: what individuals and families need to know about pandemic flu. [Full text]
Ready America. Basic disaster supplies kit. [Full text]
Ready America. Family Emergency Plan. [Full text]
Ready America. Make a plan [Full text]
Readymom Alliance. College student flu kit. [Full text]
Readymom Alliance. Pandemic flu – children at risk. Fact sheet for parents & planners. [Full text]
Readymom Alliance. Pandemic parenting – are you prepared Are you prepared for the 3 most important challenges that may affect you and your family? [Full text]
Food and Water Storage
APHA. Get ready recipes: stockpile meals to make during an emergency. Recipes for six that don't require cooking [Full text]
APHA. Cheap stockpiling: how to be prepared on a budget. Preparing inexpensive emergency stockpiles [Full text]
Fluwiki. Planned nutrition. Information about nutritional value of foods and requirements for individuals [Full text]
HHS. Sample e-mail and checklist on stocking food and supplies. A short list of 2 weeks' worth of necessary supplies [Full text]
ReadyMoms Alliance. Food: getting started. [Full text]
ReadyMoms Alliance. Water: getting started. [Full text]
ReadyMoms Alliance. 2 weeks' food list for families. [Full text]
UCLA Center for Public Health and Disasters. The pandemic pantry: a quick and easy pandemic preparedness shopping guide for a family of four for two weeks.
Vermont Department of Health. Stock up to stay home - planning list. The cost, nutritional value, and calorie content of a two-week supply of food [Full text]
Family Healthcare Measures
American Red Cross. Home care for pandemic flu. [Full text]
APHA. Quarantine: scary scenario, or practical approach. [Full text]
CDC. Caring for someone sick at home. [Full text]
CDC. Inactivated influenza vaccine 2011-12: what you need to know. [Fact sheet]
CDC. Live, intranasal influenza vaccine 2011-12: what you need to know. [Fact sheet]
CDC. Preventing the flu: good health habits can help stop germs. Fact sheet Oct 6, 2006 [Full text]
CDC. Stopping the spread of germs at home, work and school. [Full text]
Childrens' Healthcare of Atlanta. Interactive flu assessment tool Decision tree for parents [Web site]
Dialysis Patient Citizens. Pandemic flu planning checklist for individuals with chronic kidney disease and their families. [Full text]
HHS. Family emergency health information sheet. Spreadsheet for creating a family record for emergency health information [Full text]
HHS. Home health care services pandemic influenza planning checklist. [Full text]
OSHA. How to protect yourself in the workplace during a pandemic. [Full text]
OSHA. Pandemic influenza preparedness and response guidance for healthcare workers and healthcare employers. OSHA 3328-05R 2009. Appendices D-1 and D-2 on pp 82-84 have information for individual, including flu symptom list, supplies needed for home care, home healthcare advice, self-triage algorithm, and sample home care log for individuals [Full text]
ReadyMoms Alliance. Homemade oral rehydration solution. [Full text]
Readymom Alliance. Do you have a flu buddy? [Full text]
Ready America. Basic disaster supplies kit [Full text]
Schwanberg SL, Renville MR. Pandemic flu home care: a detailed guide for caring for the ill at home. A downloadable booklet [Full text]
Vermont Department of Health. Home care shopping list. Suggested list of supplies for home health care [Full text]
Personal Protective Equipment
CDC. Interim guidance on the use and purchase of facemasks and respirators by individuals and families for pandemic influenza preparedness. Advice on using and purchasing masks for preventing disease [Full text]
ReadyMoms Alliance. N-95 Respirator instructions for general public model 8670F (3M). Instructions on how to use an N-95 mask [Full text]
ReadyMoms Alliance. How to make a homemade t-shirt mask. [Full text]
IOM. Reusability of facemasks during an influenza pandemic: facing the flu.[Full text]
OSHA. Respiratory infection control: respirators versus surgical masks. [Full text]
Utah Preppers. Pandemic Go-Kits. Instructions on making various home kits [Full text]
WHO. Advice on the use of masks in the community setting in influenza A (H1N1) outbreaks. [Full text]
WHO. How to put on and take off personal protective equipment. [Full text]
CDC. Cover your cough: stop the spread of germs that make you and others sick. [Full text]
CDC. CDC says "take 3" steps to fight the flu. [Full text]
CDC. Everyday preventive actions that can help fight germs, like flu. [Full text]
CDC. Stopping the spread of germs at home, work and school. [Full text]
EPA. Selected EPA-registered disinfectants. Contains list of disinfectants for many agents, including viruses [Full text]
HHS. HHS pandemic influenza plan. Supplement 4: infection control. [Full text]
HHS. Interim guidance on environmental management of pandemic influenza virus. Describes methods for disinfecting surfaces at home and in workplaces. [Full text]
OSHA. Respiratory infection control: respirators versus surgical masks. [Full text]
WHO. How to handwash. [Full text]
CDC. 2009 H1N1 and seasonal flu – what you should know about flu antiviral drugs. [Full text]
FDA. Influenza (flu) antiviral drugs and related information. Contains information about influenza drugs and vaccines for patients and healthcare providers [Full text]
FDA. Zanamivir [Relenza] summary fact sheet for patients and parents. [Full text]
FDA. Tamiflu fact sheet for patients and parents. [Full text]
Department of Homeland Security. Preparing your pets for emergencies makes sense: Get ready now. [Full text]
DHS/AKC/ASPCA/AVMA. Get pandemic ready. Preparing your pets for emergencies makes sense. A brief guide for stocking supplies for pets [Full text]
HHS. Information for travelers and people living abroad. [Full text]
InternationalSOS. Pandemic preparedness: preventive measures and travel recommendations. Lists worldwide influenza status, travel recommendations, and personal precautions [Full text]
Other Web Resources
APHA (American Public Health Association). Get ready for flu [Home page]
Flu.gov [Home page]
ReadyMoms Alliance. [Home page]
NCPA (National Citizens' Pandemic Alliance). Get pandemic ready [Home page]
Google. Google flu trends—explore flu trends around the world. [Map]