H1N1 2009 Pandemic Influenza
Last updated December 16, 2010. At the current time, this content is considered historical and will not be updated until further notice.
- Influenza A viruses are negative-sense single-stranded RNA viruses and belong to the family Orthomyxoviridae and the genus Influenzavirus A.
- 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 virus envelope glycoproteins (hemagglutinin [HA] and neuraminidase [NA]) are distributed evenly over the virion surface, forming characteristic spike-shaped structures; antigenic variations in these proteins form the basis of the classification system for influenza A virus subtypes.
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).
- All of these subtypes have been found in birds, and birds are the primordial reservoir for influenza A viruses.
- Several subtypes have been found in pigs (see section below for more information).
- The pandemic H1N1 2009 influenza A virus (pH1N1 2009 virus) is antigenically unrelated to human seasonal influenza viruses but genetically related to viruses that have been circulating in swine for a number of years—North American H3N2 triple reassortment, classical swine H1N1 lineage, and the Eurasian avian-like swine H1N1 virus (Garten 2009).
- The NA and M gene segments are in the Eurasian swine genetic lineage; they were originally derived from a wholly avian influenza virus and likely entered the Eurasian swine population in 1979. Until emergence of the current novel H1N1 strain, these gene segments had not been identified outside Eurasia.
- The HA, NP, and NS gene segments are in the classical swine lineage which is common in North America; they likely entered the swine population around 1918 and can be traced to the 1918 H1N1 pandemic virus, which caused the "Spanish flu." The HA gene, which codes for the surface protein most important for immune response, is related most closely to the HA found in contemporary influenza viruses circulating among swine.
- The PB1, PB2, and PA gene segments are from the North American H3N2 triple reassortment lineage, which was first isolated from swine around 1998. Viruses that seeded this lineage were originally of avian origin.
Several unusual features of the pH1N1 2009 virus include the following (Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic H1N1 2009 Influenza):
- The virus shows increased ex vivo replication in human bronchial epithelium at 33°C compared with seasonal influenza strains.
- The virus shows increased replication in ex vivo human lung tissue.
- The virus targets type I and type II pneumocytes (which line the alveoli of the lungs).
Early changes include vascular congestion; alveolar hemorrhage also can occur.
A report of autopsy tissue samples from 100 fatal cases of pH1N1 2009 virus infection showed the following major findings (Shieh 2010):
- The most prominent histopathological feature observed was viral pneumonia associated with diffuse alveolar damage.
- Alveolar lining cells, including type I and type II pneumocytes, were the primary infected cells.
- Bacterial co-infections were identified in >25% of the patients.
Another study of autopsy findings from 21 Brazilian patients with confirmed pH1N1 2009 infection showed (Mauad 2010):
- Diffuse alveolar damage was present in 20 patients.
- Diffuse alveolar damage was associated with necrotizing bronchiolitis in six patients and extensive hemorrhage in five patients.
- A cytopathic effect was noted in the bronchial and alveolar epithelial cells, as well as necrosis, epithelial hyperplasia, and squamous metaplasia of the large airways.
Investigators in Norway found that a specific mutation in the viral HA (D222G) of pH1N1 2009 was associated with increased frequency in severe fatal cases; this mutation was not found in clinically mild cases (Kilander 2010).
A 2007 report identified 37 civilian swine-origin influenza cases reported in the medical literature from 1958 through 2005 (Myers 2007). Of these cases, 19 occurred in the United States, 6 in Czechoslovakia, 4 in the Netherlands, 3 in Russia, 3 in Switzerland, 1 in Canada, and 1 in Hong Kong. Twenty-two of the 36 for whom data were available (61%) reported recent exposure to pigs. The overall case-fatality rate was 17%. Limited human-to-human transmission was reported in several situations.
From December 2005 to February2009, 11 sporadiccases of infection in humans with triple-reassortant swine influenzaA H1 viruses were reported to the Centers for Disease Control and Prevention (CDC) (Newman 2008, Shinde 2009).
- Ten of the infections were caused by triple reassortant H1N1 viruses and one by triple reassortant H1N2 virus.
- Seven cases involved either direct exposure to pigs or close proximity to pigs (ie, within 6 feet) shortly before illness onset. In two other cases the patients were in the general vicinity of pigs before illness onset, one was epidemiologically linked to a possible case, and one had no pig exposure.
- Among the 10 patients with known clinical symptoms,nine reported fever, all had cough, six had a headache, and three reported diarrhea. All patients survived the illness, although four were hospitalized and two required mechanical ventilation.
An outbreak of swine-origin influenza was recognized in early 1976 among military personnel at Fort Dix, New Jersey. Thirteen clinical cases occurred with one death; the cause of the outbreak remains unknown, and no exposure to pigs was identified (Gaydos 2006). Retrospective serologic testing subsequently demonstrated that up to 230 soldiers had been infected with the novel virus, which was an H1N1 strain. The outbreak did not spread beyond Fort Dix.
Following the Fort Dix outbreak, the federal government embarked upon a universal vaccination campaign aimed at vaccinating the United States population against the H1N1 swine-origin influenza strain because of concerns that it could cause a pandemic (Sencer 2006). A vaccine was developed and vaccinations began in the fall of 1976. By late in the year, more than 40 million Americans had been vaccinated. Soon after vaccinations began, however, reports of Guillain-Barre syndrome (GBS) associated with vaccination began to surface. By December 1976, the federal government decided to halt the vaccination campaign since no evidence of H1N1 transmission had been detected during the course of the year and there was concern regarding an association between GBS and the H1N1 vaccine. A subsequent epidemiologic study demonstrated a slightly elevated risk for acquiring GBS among persons who received the H1N1 swine-origin influenza vaccine (Schonberger 1979).
Cases of pH1N1 2009 influenza were first identified in mid-April 2009 in California and soon thereafter in Texas and Mexico (CDC 2009: Swine influenza A [H1N1] infection in two children—southern California, March-April 2009; CDC 2009:Update: swine influenza A [H1N1] infections—California and Texas). The earliest recognized case occurred in Mexico with illness onset on Mar 17, 2009 (CDC 2009: Outbreak of swine-origin influenza A (H1N1) virus infection—Mexico, March-April 2009).
- Following initial recognition, the virus quickly spread around the globe, and on Jun 11, 2009, the World Health Organization (WHO) declared the onset of an influenza pandemic.
- An interactive map showing the timeline of events is available on the WHO Web site (WHO 2009: Timeline of influenza A [H1N1] cases).
- An analysis of global air traffic patterns illustrates how the virus spread via air travel from its likely source in Mexico to other areas of the world, most notably the United States (Khan 2009).
The WHO declared the onset of an influenza pandemic in June 2009 for the following reasons:
- Once the first human infections with the new H1N1 virus were confirmed in April 2009, analysis of samples showed that this new virus had not circulated in humans previously. This virus was genetically distinct from other H1N1 viruses causing disease since 1977.
- Epidemiologic patterns of disease occurrence were seen that were not typical during seasonal epidemics of influenza.
- The new H1N1 pattern of illness and death differed significantly from the patterns seen with seasonal influenza. Seasonal influenza typically affects the frail elderly, but this virus targeted a younger population. In addition, a frequent cause of death was viral pneumonia caused directly by the virus. In seasonal viruses, most cases of pneumonia result from secondary bacterial infections.
- The new virus crowded out other circulating influenza viruses and appeared to have shifted the old H1N1 out of circulation. This occurrence is a feature of pandemic activity.
- Early findings suggested that antibodies from seasonal influenza did not protect against the new virus. (Later findings showed that about a third of the elderly had some protection but the younger population was unprotected.)
During the first influenza season following recognition of the pandemic strain, five WHO National Influenza Centers (NICs) in the Southern Hemisphere collected data to examine circulation of pandemic and seasonal influenza strains (Blyth 2010).
- The overall proportion of influenza A–positive specimens from May to October 2009 subtyped as the pH1N1 2009 virus ranged from 53% in Johannesburg, South Africa, to 85% in Melbourne, Australia.
- For specimens received from August to October 2009, the proportion of influenza viruses typed as pH1N1 2009 ranged from 92% to 96%.
- The pH1N1 2009 virus significantly displaced seasonal influenza A H1N1, and to a lesser extent A H3N2 viruses, circulating in the Southern Hemisphere. Complete replacement of seasonal influenza A strains, however, was not observed.
From the start of the pandemic in April 2009 through late July 2010, the total number of specimens reported positive for influenza by NIC laboratories around the globe was 652,849. Of those, 491,766 (75.3%) were of the pH1N1 2009 strain (WHO 2010: Pandemic (H1N1) 2009—update 110). The cumulative number of deaths from pandemic H1N1 influenza reported to WHO regional offices as of July 18, 2010, was at least 18,366.
The CDC estimated the burden of the H1N1 pandemic in the United States as follows (CDC 2010: Updated CDC estimates of 2009 H1N1 influenza cases, hospitalizations and deaths in the United States, April 2009 – April 10, 2010):
- Between 43 million and 89 million cases of 2009 H1N1 occurred in the United States between April 2009 and April 10, 2010. The mid-level in this range is about 61 million people infected with pH1N1 2009.
- Between about 195,000 and 403,000 pH1N1-related hospitalizations occurred between April 2009 and April 10, 2010. The mid-level in this range is about 274,000 hospitalizations related to pH1N1 infection.
- Between about 8,870 and 18,300 pH1N1-related deaths occurred between April 2009 and April 10, 2010. The mid-level in this range is about 12,470 pH1N1-related deaths.
The overall case-fatality rate for persons infected with pH1N1 2009 appears to be slightly less than 0.5%, although estimates have varied somewhat (Vaillant 2009, Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic H1N1 2009 Influenza). Approximately half of the patients who died had underlying medical conditions, most notably pregnancy and obesity (Vaillant 2009). In addition, most deaths occurred in younger populations.
One recent report estimated the mortality and years of potential life lost (YLL) attributable to the pH1N1 2009 influenza in the United States (Viboud 2010). Estimates were based on pneumonia and influenza mortality surveillance data from 122 US cities, and the age distribution of laboratory-confirmed pandemic deaths, which had a mean of 37 years.
- The authors estimated that between 7,500 and 44,100 deaths in the United States were attributable to the pandemic strain between May and December 2009.
- The authors also estimated that between 334,000 and 1,973,000 years of life were lost during that time. The upper range of YLL estimates for 2009 exceeded the burden of the 1968 pandemic adjusted to the year 2000 population. The high estimates of YLL for the 2009 pandemic are reflective of the mean age at death (ie, 37 years), which is substantially younger than the 1957 and 1968 pandemics (mean ages at death of 64.6 and 62.2 years, respectively).
On Aug 10, 2010, the WHO declared that the H1N1 situation had moved into the post-pandemic period.
- During the summer months of 2010, pH1N1 2009 activity continued at low levels in a number of areas of the world, with more intense activity in India and New Zealand.
- Also during summer 2010, a number of different influenza strains (including pH1N1 2009, influenza A H3N2, and influenza B viruses) were circulating in the Southern Hemisphere.
- The pH1N1 2009 virus is expected to continue to circulate in the coming years and follow a typical seasonal pattern.
At the beginning of the pandemic, the CDC indicated that adults appeared to have some degree of preexisting immunity to the pandemic strain, especially those 60 years of age or older. The CDC postulated that some adults in this age-group may have had previous exposure (through either prior infection or remote vaccination) to an influenza A H1N1 virus genetically and antigenically more closely related to the pH1N1 2009 virus than contemporary seasonal H1N1 strains (CDC 2009: Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine).
Several additional studies in Europe also suggested that the elderly had some pre-pandemic immunological protection (Ikonen 2010, Miller 2010, Rizzo 2010). For example, in a study of 1,000 elderly individuals in Finland, investigators found that 96% of persons born from 1909 to 1919 had cross-reactive antibodies against the pH1N1 2009 virus and that persons born from 1920 to 1944 had a varying prevalence of such antibodies (14% to 77%); however, most persons born after 1944 lacked cross-reactive antibodies to the pandemic strain (Ikonen 2010).
- The pH1N1 2009 virus is transmitted in ways similar to other influenza viruses, including large-particle respiratory droplet transmission (eg, when an infected person coughs or sneezes near a susceptible person). Transmission via aerosols also may be important, although animal studies using a ferret model are somewhat conflicting on this issue (Maines 2009, Munster 2009). The relative contributions of small-particle aerosols, large droplets, and fomites remain uncertain.
- According to the WHO, the estimated reproduction number or R0 (which is the number of secondary cases generated by each primary case) during the pandemic ranged from 1.3 to 1.7 in most populations (Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic H1N1 2009 Influenza). This number is similar to or slightly higher than estimates for seasonal influenza. Other studies have found a range in R0 from 1.4 to 2.3 (Boelle 2009, Fraser 2009, Nishiura 2010, White 2009).
- For more information on transmission, see the section on Infection Control Considerations.
Several studies have examined transmissibility of pH1N1 2009 virus in households.
- One study found that the transmissibility of the pH1N1 2009 influenza virus in households was lower than that seen in past pandemics (Cauchemez 2009). The proportion of household contacts in whom acute respiratory illness developed decreased with the size of the household (28% in two-member households, 9% in six-member households) (Cauchemez 2009).).
- Another study found that the secondary attack rates (as confirmed on reverse-transcriptase polymerase-chain-reaction [RT-PCR] assay) among household contacts of index patients were similar for the pandemic influenza virus (8%) and seasonal influenza viruses (9%) (Cowling 2010). The patterns of viral shedding and the course of illness among index patients were also similar for the pandemic and seasonal influenza viruses.
- In another study, 77 households were investigated to assess household transmission of pH1N1 2009 in San Antonio , Texas, from Apr 15 through May 8, 2009. Secondary attack rates were highest in children <5 years of age and were higher in children 5 to 18 years of age than in adults. Secondary attack rates were highest in households with 2 to 3 persons and were lowest in households with 7 to 9 persons (Morgan 2010: Household transmission).
- The effect of oseltamivir treatment on the household and individual secondary attack rates was assessed in 135 households in Milwaukee (Goldstein 2010). Oseltamivir treatment on the day of onset or the following day of the index case was associated with a 42% reduction in the odds of one or more secondary infections in a household and a 50% reduction in the odds of a secondary infection in individual contacts.
Several studies have examined viral shedding following infection with pH1N1 2009 virus. Examples include the following:
- One prospective study showed that the proportion of infected persons still shedding replicating virus 8 days after illness onset varied from 8% to 13%, with no difference between children and adults (De Serres 2010). None of the subjects were shedding virus on day 11.
- Another study conducted during an outbreak at the US Air Force Academy showed that 24% of 29 swabs collected on day 7 and 13% of the 16 swabs collected on day 8 of illness were culture positive, despite the large proportion of patients prescribed antiviral drugs (Witkop 2010).
- A study in Singapore showed that the mean duration of viral shedding from illness onset was 6 days (plus or minus 2 days). Viral shedding persisted beyond 7 days, however, in 37% of patients. When prescribed during the first 3 days of illness, oseltamivir shortened the duration of viral shedding (Ling 2010).
Since viral shedding drops substantially after the first few days of influenza illness, the CDC recommends that persons with influenza-like illness should remain away from others until 24 hours after fever has resolved. In healthcare settings, the exclusion period should be continued for 7 days from symptom onset or until the resolution of symptoms, whichever is longer (CDC 2009: CDC recommendations for the amount of time persons with influenza-like illness should be away from others). More stringent guidelines and longer periods of exclusion may be necessary in some situations, if exposure to persons at high risk of complications is anticipated.
The groups at risk for complications related to seasonal influenza also have been shown to be at increased risk for complications following pH1N1 2009 influenza (Carcione 2010, Louie 2009, Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic H1N1 2009 Influenza):
- Pregnant women (especially those in the second or third trimester); pregnant women represent approximately 1% of the US population, but they accounted for 5% of deaths in the United States from pH1N1 2009 influenza reported to the CDC during the primary pandemic period (Siston 2010)
- Persons aged 65 or older (the risk of infection in this group has been lower than for other age-groups, but if infection occurs, people of this age-group are at increased risk of complications)
- Children <5 years old (Libster 2010)
- Adults and children who have chronic pulmonary, cardiovascular, renal, hepatic, hematological, neurologic, or metabolic disorders
- Adults and children who have immunosuppression (associated with HIV infection, organ transplantation, chemotherapy, corticosteroid use, or malnutrition)
- Children and adolescents (age 6 months to 18 years) who are receiving long-term aspirin therapy and who might be at risk for experiencing Reye's syndrome after influenza virus infection
In addition, severe or morbid obesity (ie, a body mass index of 40 or more) has been found to be an important risk factor for complications or severe illness related to pH1N1 2009 infection (Kumar 2009, Louie 2009, Morgan 2010: Morbid obesity as a risk factor). This finding had not been noted previously with seasonal influenza.
The incubation period is generally 1.5 to 3 days but can extend to 7 days (Writing Committee of the WHO).
Most patients who presented for care during the primary pandemic period had typical influenza-like illness with fever, cough, sore throat, and rhinorrhea; however, gastrointestinal symptoms (including nausea, vomiting, and diarrhea) were reported more frequently among pH1N1 cases than among patients with seasonal influenza (Writing Committee of the WHO).
Observational studies have shown that pH1N1 2009 infection can cause a broad range of clinical syndromes, from afebrile upper respiratory illness to fulminate viral pneumonia.
Complications include the following (Writing Committee of the WHO):
- Diffuse viral pneumonitis (can be associated with severe hypoxia and acute respiratory distress syndrome [ARDS])
- Shock and renal failure among some patients with ARDS
- Prolonged exacerbation of chronic obstructive pulmonary disease (COPD)
- Secondary bacterial pneumonia
- Neurologic manifestations (eg, altered mental status, seizures, encephalopathy, encephalitis)
The overall case-fatality rate during the pandemic period was estimated to be somewhat less than 0.5% (Writing Committee of the WHO). Most deaths occurred in younger populations.
Laboratory Testing for Influenza
A variety of tests are available for confirming influenza infection (CDC: Rapid diagnostic testing for influenza). These are outlined in the table below.
Features of Common Influenza Tests
Influenza Virus Types Detected
A and B
NP swab/aspirate, nasal swab/aspirate/wash, throat swab, bronchioalveolar lavage
A and B
NP swab/aspirate, nasal swab/aspirate/wash, throat swab,
A and B
NP swab/aspirate, nasal swab/aspirate/wash, throat swab, bronchioalveolar lavage, sputum
A and B
paired acute and convalescent serum samples
2 weeks or more
A and B
NP swab/aspirate, nasal swab/aspirate/wash, throat swab
Rapid diagnostic tests
Dependent on the specific test used
Dependent on the specific test used
Viral RNA detection by conventional or real-time RT-PCR assay remains the best method for diagnosis of pH1N1 2009 influenza (Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic H1N1 2009 Influenza).
- Nasopharyngeal aspirates or swabs are recommended for patients who have typical influenza-like illness.
- For those with lower respiratory infection, endotracheal or bronchoscopic aspirates have higher yields.
- Negative results, however, do not rule out pH1N1 2009 infection.
Commercially available rapid influenza diagnostic tests (RIDTs) have poor clinical sensitivity (11% to 70%) for detection of pH1N1 2009 virus in clinical specimens; therefore, negative test results should not be used to make decisions regarding clinical management or appropriate infection control. Furthermore, RIDTs cannot distinguish between influenza A subtypes. Other points regarding use of RIDTs include the following:
- False-positive (and true-negative) results are more likely to occur when influenza is uncommon in the community, which is generally at the beginning and end of an outbreak.
- False-negative (and true-positive) results are more likely to occur when influenza is common in the community, which is typically at the height of an outbreak.
- Test sensitivity may vary depending on collection timing. Respiratory specimens for testing should be collected in the first 4 to 5 days after illness onset, when viral shedding is greatest.
Several studies suggest that direct fluorescent antibody (DFA) staining performs better than RIDTs for diagnosis of pH1N1 2009 influenza, particularly for patients who have high levels of virus replication (Pollock 2009). However, if DFA testing is negative, the diagnosis of pH1N1 influenza cannot be ruled out and RT-PCR testing should be considered if diagnostic confirmation is needed.
- Nasopharyngeal swab/aspirate or nasal wash/aspirates are the most appropriate for testing; if these specimens cannot be collected, a nasal swab or throat swab is acceptable.
- Ideally, swab specimens should be collected using swabs with a synthetic tip (eg, polyester or Dacron) and an aluminum or plastic shaft. Swabs with cotton tips or wooden shafts are not recommended. Specimens collected with swabs made of calcium alginate are not acceptable.
- The swab specimen collection vials should contain 1 to 3 mL of viral transport medium (eg, containing protein stabilizer, antibiotics to discourage bacterial and fungal growth, and buffer solution).
Storing Clinical Specimens
- All respiratory specimens should be kept at 4°C for no longer than 4 days.
Shipping Clinical Specimens
- Clinical specimens should be shipped on wet ice or cold packs in appropriate packaging.
- All specimens should be labeled clearly and include information requested by the appropriate state public health laboratory.
The CDC recommends that people with influenza-like illness (fever with either cough or sore throat) remain at home until at least 24 hours after they are free of fever (100°F [37.8°C]) or signs of fever without the use of fever-reducing medications (CDC 2009: CDC recommendations for the amount of time persons with influenza-like illness should be away from others.) This recommendation does not apply to healthcare settings, where the exclusion period should be continued for 7 days from symptom onset or until the resolution of symptoms, whichever is longer.
- Epidemiologic data indicate that most people with the pH1N1 2009 influenza who were not hospitalized had a fever that lasted 2 to 4 days; this would require an exclusion period of 3 to 5 days in most cases. Those with more severe illness are likely to have a fever for a longer period.
- The CDC recommends this exclusion period regardless of whether or not antiviral medications are used.
- More stringent guidelines and longer periods of exclusion—for example, until complete resolution of all symptoms—may be considered for people returning to a setting where large numbers of high-risk people may be exposed, such as a camp for children with asthma or a child-care facility for children younger than 5 years old.
Several outbreak control strategies have been reported.
- A quarantine approach was used to control an outbreak of pH1N1 2009 influenza among students at a university in northern China in September 2009 (Chu 2010). Once the outbreak was recognized, 202 contacts were identified and immediately quarantined in a separate dormitory on September 1. Oropharyngeal swabs from all contacts were collected and tested on the first day of quarantine. One or two contacts were assigned to each bedroom. The attack rate of subsequent suspect cases among pH1N1 2009 virus-negative contacts increased significantly when students were quarantined in the same room or used the same bathroom as a virus-positive contact. However, quarantining virus-negative contacts alone or two per room was effective in preventing illness.
- A nosocomial outbreak of pH1N1 2009 occurred in a pediatric oncology hospital ward in Italy in October and November 2009 (Chironna 2010). Eight laboratory-confirmed cases were identified. All confirmed patients were treated with 75 mg oseltamivir daily for five days and were lodged in a separate area of the ward until 48 hours after symptoms had resolved. Contact with other hospitalized children was prohibited and external visits were strictly limited. All healthcare workers used masks, gowns, and gloves until 48 hours after the patients' symptoms had resolved. Once these measures were implemented, additional cases did not occur.
- A "ring chemoprophylaxis" strategy (geographically targeted containment via prophylaxis) using oseltamivir was used to control four outbreaks involving military personnel in Singapore (Lee 2010). Each outbreak was in a different location: one in each of three military units and one at a military camp medical center. All personnel with suspected infection were tested and isolated in the hospital if the test was positive. Ring prophylaxis with oseltamivir was then given to all members of each unit. Subsequent follow-up found that the rate of infection was reduced in the affected units. The authors concluded that oseltamivir ring chemoprophylaxis, together with prompt identification and isolation of infected personnel, was effective in reducing the impact of outbreaks of pH1N1 2009 in these semi-closed settings.
- Mass treatment and prophylaxis with oseltamivir, along with school closure, was used to control an outbreak of pandemic influenza in a primary school in Sheffield, United Kingdom (Strong 2010). In all, 273 students (92%) and 53 staff (91%) took oseltamivir for treatment or prophylaxis; 14% of students and 20% of staff did not complete the course of treatment owing to adverse side effects. Nausea, abdominal pain, and headache were the most common reported side effects. Daily reported pH1N1 2009 cases dropped from 11 to 4 and then continued to decline after school closure and oseltamivir treatment were initiated.
On September 15, 2009, the FDA announced approval of four pH1N1 2009 influenza vaccines, and in November 2009 approved a fifth one. By October 9, 2009, all states had placed orders for the vaccine. Initially, the CDC's Advisory Committee on Immunization Practices (ACIP) recommended that vaccination efforts focus on five target groups of persons at high risk for influenza. These groups included:
- Pregnant women
- Persons who live with or provide care for infants younger than 6 months (eg, parents, siblings, and day-care providers)
- Healthcare and emergency medical services personnel
- Persons aged 6 months to 24 years
- Persons aged 25 to 64 who have medical conditions that put them at higher risk for influenza-related complications
As vaccine supply increased, restrictions to target groups were eased, and by late December 2009, vaccination became available to the general public (CDC: The 2009 H1N1 pandemic: summary highlights). By the end of 2009, approximately 61 million persons had been vaccinated in the United States, and by January 29, 2010, 124 million doses had been distributed.
To estimate state-specific vaccination coverage for the 2009-2010 influenza season, the CDC analyzed results from the Behavioral Risk Factor Surveillance System and the National 2009 H1N1 Flu Survey for the period November 2009 through February 2010. Estimated state vaccination rates among persons 6 months of age and older ranged from 12.9% in Mississippi to 38.8% in Rhode Island. Median coverage was 36.8% for children 6 months to 17 years, 20.1% for adults 18 and over, and 33.2% for persons in the ACIP target groups (CDC 2010:Interim results: state-specific influenza A (H1N1) 2009 monovalent vaccination coverage).
Clinical studies of the 2009 H1N1 monovalent vaccines indicate that this vaccine antigen is immunogenic and response rates are similar to those observed after immunization with influenza A antigens found in typical seasonal influenza vaccines.
- Among children aged 6 to 35 months, 19% to 92% responded with a hemagglutination inhibition (HI) titer ≥40 at ≥21 days after one dose, and >90% responded with an HI titer ≥40 after two doses separated by ≥21 days (ACIP 2010, Nolan 2010).
- Among children aged 3 to 9 years, 44% to 93% responded with an HI titer ≥40 at 21 or more days after one dose, and >90% responded with an HI titer ≥40 after two doses separated by ≥21 days (ACIP 2010).
- In a study in the Republic of Korea, 118 subjects aged 6 months to <9 years and 130 subjects 9 years to <18 years were enrolled in a multicenter open label clinical trial. Subjects received either 7.5 mcg (subjects 6 months to <3 years of age) or 15 mcg (subjects 3 years to <18 years of age). By day 21 after the first dose, HI titers of >40 were observed in 6% of subjects 6 months to <3 years of age, 35% of subjects 3 to <9 years of age, and 81% of subjects 9 to 18 years of age. By day 21 after the second dose, the titers of >40 had been achieved by 56%, 70%, and 91% of the respective groups. The authors concluded that a single 15-mcg dose of vaccine was immunogenic in subjects 9 years of age or older. However, a two-dose regimen was needed to produce potentially protective antibody titers in younger children (Oh 2010).
- In a Taiwanese study, 183 healthy children and adolescents aged 1 year to 17 years received two doses of a monovalent, unadjuvanted, inactivated, split-virus vaccine. Three weeks after the first dose, 36% of children age 1 to 2, 53% of children age 3 to 5, 57% of children age 6 to 9, and 90% of children age 10 to 17 generated protective antibodies. A second vaccination given 3 weeks later induced protective antibodies in 89% of all age-groups (Lu 2010).
- In a multicenter, randomized laboratory-blinded clinical trial in Taiwan, 107 subjects aged 60 years or older (range 61 to 86 years), were randomized to receive 15 mcg or 30 mcg of hemagglutinin antigen (Kao 2010). At 3 weeks post-vaccination, an HI titer ³40 was observed in 76% in the 15-mcg group and 81% in the group receiving 30 mcg. This study indicated that one dose of 15 mcg of hemagglutinin antigen without adjuvant induced a protective immune response in the majority of elderly subjects.
- Among older children and adults, response rates after one dose of vaccine exceeded 90% (Greenberg 2009, Plennevaux 2010), although geometric mean titers were substantially lower among adults aged ≥50 years in one study (Greenberg 2009) and among adults aged ≥65 years (Plennevaux 2010).
The first commercially available pandemic influenza vaccines were registered for use in September of 2009, 5 months after identification of the pandemic H1N1 virus. The goal of the WHO's Global Pandemic Influenza Action Plan was to have enough vaccine to vaccinate two billion people with one dose within 6 months after industry had the vaccine prototype (WHO 2006).
The actual global production of pandemic vaccine by December 1, 2009, was 534 million doses, and the forecasted production of pandemic vaccine 12 months after the availability of the vaccine virus (ie, June 2010) was approximately 1.37 billion doses, which is only 28% of the annual global production capacity of 4.9 billion doses estimated from a WHO survey conducted in May 2009. Reasons cited for decreased production were (Partridge 2010):
- Lower-than-expected vaccine virus yields
- Inability of manufacturers to use their most dose-sparing formulations
- Reluctance of certain regulatory agencies to register adjuvanted low-antigen dose vaccine formulations
- Shrinking vaccine demand (due to the bulk of vaccine delivery coming after the fall wave had peaked and in the face of a pandemic of moderate severity)
- Stopping of pandemic vaccine production by some manufacturers in late 2009 and by almost all manufacturers in early 2010 to switch to Southern and Northern Hemisphere seasonal vaccine production, respectively
The vaccine for the 2010-2011 season protects against three influenza viruses, including the 2009 pandemic H1N1 virus. Virus strains in the 2010-2011 vaccine include:
- A/California/7/09 (H1N1)-like virus (pH1N1 2009 influenza virus)
- A/Perth/16/2009 (H3N2)-like virus
- B/Brisbane/60/2008-like virus
The CDC currently recommends annual seasonal influenza vaccination for all persons age 6 months and older (ACIP 2010).
When vaccine supply is limited, the CDC recommends that vaccination efforts should focus on delivering vaccination to (ACIP 2010):
- Children aged 6 months to 4 years (59 months)
- Adults aged ≥50 years
- Persons with chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, neurologic, hematologic, or metabolic disorders (including diabetes mellitus)
- Immunosuppressed persons (including immunosuppression caused by medications or by human immunodeficiency virus [HIV])
- Pregnant women
- Persons aged 6 months to 18 years and receiving long-term aspirin therapy and who therefore might be at risk for experiencing Reye's syndrome after influenza virus infection
- Residents of nursing homes and other chronic-care facilities
- American Indians/Alaska Natives
- Persons who are morbidly obese (body mass index ≥40)
- Healthcare personnel
- Household contacts and caregivers of children aged <5 years and adults aged ≥50 years, with particular emphasis on vaccinating contacts of children aged <6 months
- Household contacts and caregivers of persons with medical conditions that put them at higher risk for severe complications from influenza
According to 2010-11 recommendations from the CDC (CDC 2010: Interim guidance on the use of influenza antiviral agents during the 2010-2011 influenza season), antiviral treatment is recommended as early as possible for any patient with confirmed or suspected influenza who:
- Has severe, complicated, or progressive illness
- Is hospitalized
- Is at higher risk for influenza complications as follows:
- Children younger than 2 years old (Note: neuraminidase inhibitors are not licensed for treatment of children <1 year of age [oseltamivir] or <7 years of age [zanamivir]. Oseltamivir was used for treatment of pH1N1 2009 influenza virus infection in children <1 year of age under an Emergency Use Authorization [EUA], but this EUA has expired. However, the CDC recommends that clinicians who treat children aged 3 to11 months administer 3 mg/kg body weight/dose twice per day for treatment, and 3 mg/kg body weight/dose once per day for chemoprophylaxis. Infants aged <3 months are recommended to receive 3 mg/kg body weight /dose twice per day for treatment. However, chemoprophylaxis for infants aged <3 months is not recommended unless the exposure situation is judged to be critical, because of a lack of data on use of oseltamivir in this age-group.)
- Adults 65 years of age and older
- Persons with the following conditions: chronic pulmonary (including asthma), cardiovascular (except hypertension), renal, hepatic, hematological (including sickle cell disease), neurological, neuromuscular, or metabolic disorders (including diabetes mellitus)
- Persons with immunosuppression, including that caused by medications or by HIV infection
- Women who are pregnant or postpartum (within 2 weeks after delivery)
- Persons younger than 19 years of age who are receiving long-term aspirin therapy
- American Indians and Alaskan Natives
- Persons who are morbidly obese (body mass index ≥40)
- Residents of nursing homes and other chronic-care facilities
Clinical judgment, based on the patient's disease severity and progression, age, underlying medical conditions, likelihood of influenza, and time since onset of symptoms, should be considered when making antiviral treatment decisions for high-risk outpatients. When indicated, antiviral treatment should be started as soon as possible after illness onset.
- The greatest benefit is when antiviral treatment is started within 48 hours of influenza illness onset.
- Antiviral treatment may still be beneficial in patients with severe, complicated, or progressive illness, and in hospitalized patients when administered >48 hours from illness onset.
Antiviral treatment also can be considered for any previously healthy, non–high-risk, symptomatic outpatient with confirmed or suspected influenza based on clinical judgment, if treatment can be initiated within 48 hours of illness onset.
In areas with limited antiviral medication availability, local public health authorities might provide additional guidance about prioritizing treatment within groups at higher risk for complications.
Dosing recommendations are outlined in the table below.
Oseltamivir and Zanamivir Prescribing Information
75-mg capsule twice per day for 5 days
75-mg capsule once per day
Children (age >12 mo), weight
30 mg twice daily
30 mg once per day
45 mg twice daily
45 mg once per day
60 mg twice daily
60 mg once per day
75 mg twice daily
75 mg once per day
Two 5-mg inhalations (10 mg total) twice per day
Two 5-mg inhalations (10 mg total) once per day
Two 5-mg inhalations (10 mg total) twice per day (age, 7 years or older)
Two 5-mg inhalations (10 mg total) once per day (age, 5 years or older)
An increased dose of the drug (150 mg twice daily in adults) and an increased duration of therapy (a total of 10 days) with no treatment interruptions has been used in patients with pneumonia or evidence of clinical progression (Writing Committee of the WHO Consultation on Clinical Aspects of Pandemic H1N1 2009 Influenza).
- Pregnancy should not be considered a contraindication to oseltamivir or zanamivir use. Pregnant women are known to be at higher risk for complications from infection with seasonal influenza viruses. Furthermore, pregnant women are at higher risk for influenza complications from pH1N1 2009.
- Oseltamivir, zanamivir, rimantadine, and amantadine are "Pregnancy Category C" medications, indicating that data from clinical studies are not adequate to fully assess the safety of these medications for pregnant women. Although a few adverse effects have been occasionally reported in pregnant women who took these medications, no causal relation between the use of these medications and those adverse events has been established. One retrospective cohort study found no evidence of an association between oseltamivir use during pregnancy and a variety of adverse events, including preterm birth, premature rupture of membranes, increased duration of hospital stay for mother or neonate, malformations, or fetal weight (Greer 2010).
- The California Department of Public Health reviewed data from 94 pregnant, 8 postpartum, and 137 non-pregnant women of reproductive age who were hospitalized with pH1N1 2009 influenza. In total, 18 pregnant women and 4 postpartum women (22/102 [22%]) required intensive care, and 8 (8%) died. Late antiviral treatment (³2 days after symptom onset) was associated with admission to the intensive care unit (ICU) or death (Louie 2010).
- A multicenter cohort study of adults and children who had received solid-organ transplants and had confirmed influenza A infection showed that antiviral treatment initiated within 48 hours of symptom onset was associated with a decrease in admission to the hospital and ICU, a need for mechanical ventilation, and death (Kumar 2010).
- In a study of 45 immunocompromised patients with either cancer or hematopoietic stem-cell transplantation who developed pH1N1 2009 infection, all received antiviral therapy, and no patients died (Redelman-Sidi 2010).
To date, most isolates of the pH1N1 2009 virus generally have been susceptible to the neuraminidase inhibitors oseltamivir and zanamivir, although sporadic instances or small clusters of resistant isolates have been reported.
As of August 2010, more than 300 cases of oseltamivir-resistant pH1N1 2009 influenza had been reported to the WHO (WHO 2010: Weekly update on oseltamivir resistance to influenza A (H1N1) 2009 viruses). All of these oseltamivir-resistant isolates except one had the same mutation in the neuraminidase gene (H275Y), conferring resistance to oseltamivir but not to zanamivir.
Resistant isolates predominantly have been obtained from treated patients and immunosuppressed patients receiving prolonged therapy (Harvala 2010, Tramontana 2010), although in some instances, resistant isolates have been found in patients who had no exposure to oseltamivir.
Recommendations on infection control practices are based on available data regarding the modes of transmission of influenza viruses. 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 systematic 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).
- A recent study showed that influenza patients who are coughing often emit aerosol particles that contain influenza virus RNA, and a high proportion of patients produce aerosol particles that are <5 mcm in size (Lindsley 2010). The results support the idea that the airborne route may be a pathway for influenza transmission, especially in the immediate vicinity of an influenza patient. However, further research is needed on the viability of airborne influenza viruses and the risk of transmission.
- Available data suggest that airborne transmission does not play a major role in the 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.
- 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 tuberculosis and certain other viral agents.
The CDC has recently updated infection control guidance for the care of patients who have influenza infection (CDC:Prevention strategies for seasonal influenza in healthcare settings). Recommendations from the guidance are summarized below; the full guidance can be accessed at CDC 2010:Prevention strategies for seasonal influenza in healthcare settings.
- Promote and administer seasonal influenza vaccine for healthcare providers and patients.
- Take steps to minimize potential exposures before patients arrive at a healthcare setting, upon entry, and during visits to a healthcare setting.
- Monitor and manage ill healthcare personnel.
- Adhere to standard precautions.
- Adhere to droplet precautions.
- Use caution when performing aerosol-generating procedures.
- These include some procedures that are usually planned ahead of time, such as bronchoscopy, sputum induction, elective intubation and extubation, and autopsies, as well as some procedures that often occur in unplanned, emergent settings and can be life-saving, such as cardiopulmonary resuscitation, emergent intubation, and open suctioning of airways.
- Precautions for aerosol-generating procedures include several actions:
- Perform these procedures only on patients with suspected or confirmed influenza if they are medically necessary and cannot be postponed.
- Limit the number of healthcare providers present during the procedure to only those essential for patient care and support.
- Conduct the procedures in an airborne infection isolation room (AIIR) when feasible.
- Consider use of portable HEPA filtration units to further reduce the concentration of contaminants in the air.
- Healthcare providers should adhere to standard precautions, including wearing gloves, a gown, and either a face shield that fully covers the front and sides of the face or goggles.
- Healthcare providers should wear respiratory protection equivalent to a fitted N-95 filtering facepiece respirator or equivalent N-95 respirator (eg, powered air purifying respirator, elastomeric) during aerosol-generating procedures.
- Unprotected healthcare providers should not be allowed in a room where an aerosol-generating procedure has been conducted until sufficient time has elapsed to remove potentially infectious particles.
- Conduct environmental surface cleaning following procedures (see section on environmental infection control).
- Manage visitor access and movement within the facility.
- Monitor influenza activity in the community and the facility.
- Implement environmental infection control.
- Standard cleaning and disinfection procedures (eg, using cleaners and water to preclean surfaces prior to applying disinfectants to frequently touched surfaces or objects for indicated contact times) are adequate.
- Management of laundry, food service utensils, and medical waste should also be performed in accordance with standard procedures.
- Implement engineering controls.
- Examples of engineering controls include installing physical barriers such as partitions in triage areas or curtains that are drawn between patients in shared areas.
- Another important engineering control is ensuring that appropriate air-handling systems are installed and maintained in healthcare facilities.
- Train and educate healthcare personnel.
- Healthcare administrators should ensure that all healthcare providers receive during orientation job- or task-specific education and training on preventing transmission of infectious agents, including influenza, in the healthcare setting.
- Competency should be documented initially and repeatedly, as appropriate, for the specific staff positions.
- Key aspects of influenza and its prevention that should be emphasized to all healthcare providers include:
- Influenza signs, symptoms, complications, and risk factors for complications
- Awareness among healthcare providers that, if they have conditions that place them at higher risk of complications, they should inform their healthcare provider immediately if they become ill with an influenza-like illness so they can receive early treatment if indicated
- Central role of administrative controls such as vaccination, respiratory hygiene and cough etiquette, sick policies, and precautions during aerosol-generating procedures
- Appropriate use of personal protective equipment, including respirator fit testing and fit checks
- Use of engineering controls and work practices, including infection control procedures to reduce exposure
- Administer antiviral treatment and chemoprophylaxis of patients and healthcare personnel when appropriate.
- Underscore considerations for healthcare personnel at higher risk for complications of influenza:
- Healthcare providers at risk for complications from influenza include pregnant women and women up to 2 weeks postpartum, persons 65 years old and older, and persons with chronic diseases such as asthma, heart disease, diabetes, diseases that suppress the immune system, certain other chronic medical conditions, and morbid obesity.
- Provide vaccination and early treatment with antiviral medications.
- Healthcare providers at higher risk for complications should check with their healthcare provider if they become ill so that they can receive early treatment.
The WHO declared the end of the H1N1 pandemic on August 10, 2010. The 2009 H1N1 virus is expected to continue to circulate as a seasonal virus during the years to come and is now included in seasonal influenza vaccinations.
In the post-pandemic period, the WHO recommends the following to health authorities (WHO 2010: WHO recommendations for the post-pandemic period):
- Monitoring of respiratory disease activity
- Unusual events, clustering, or outbreaks should be investigated. In addition, appropriate channels for communication and data transmission should be used, such as FluID, FluNet and EUROFlu.
- The WHO should be notified immediately if sustained transmission of antiviral-resistant H1N1 is detected, human cases of any influenza virus not currently circulating are detected, or if any notable changes in the severity or other epidemiologic or clinical characteristics of the pH1N1 2009 virus are detected.
- Key aspects of influenza and its prevention that should be emphasized to all healthcare providers include:
- The pH1N1 2009 virus should be monitored for important genetic, antigenic, or functional changes such as altered antiviral drug sensitivity.
- Vaccination of high-risk individuals
- pH1N1 2009 will continue to circulate in some parts of the world. In some countries, trivalent vaccines that cover pH1N1 2009 virus are available. However, in some countries seasonal influenza vaccine is not available. The WHO advises using the monovalent H1N1 vaccine where available to immunize high-risk persons, especially when trivalent seasonal influenza vaccine is not available.
- The 2010-11 seasonal influenza vaccine will contain an influenza A (H1N1) California/7/2009-like strain, which was also the strain used for the 2009 pandemic H1N1 monovalent vaccines.
Influenza A was first recognized as a clinical illness in swine in 1918, which coincided with the 1918-19 influenza pandemic in humans. H1N1 influenza A virus was first isolated from pigs in the United States in 1930.
Swine influenza is considered endemic in swine in the United States, and animal outbreaks occur with regular frequency (usually in the fall and winter months). Key information about swine influenza viral subtypes in North America includes the following (Olsen 2002):
- From 1930 through 1998 swine influenza in North America was primarily caused by viruses of the classical H1N1 lineage.
- 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.
- H1N2 viruses that resulted from reassortment between the triple reassortant H3N2 viruses and classical H1N1 swine viruses also have been isolated in swine in the United States.
- Avian H4N6 virus was recognized in swine in Canada in 1999, but no spread beyond the original farm of detection was identified.
- A novel H3N1 influenza virus was isolated from swine in the United States in the mid 2000s; this virus may have risen from reassortment of an H3N2 turkey isolate, a human H1N1 isolate, and currently circulating swine influenza viruses (Lekcharoensuk 2006).
Influenza viruses also have been identified in swine in South America, Europe (including the United Kingdom, Sweden, and Italy), Africa (Kenya), and in parts of eastern Asia.
Swine influenza is an upper respiratory disease that causes outbreaks in herds. The incubation period in swine is usually 1 to 3 days. Clinical signs include fever, loss of appetite, weight loss, lethargy, coughing, sneezing, nasal discharge, labored breathing, conjunctivitis, and spontaneous abortion. The mortality rate is relatively low (1% to 3%), and most affected animals recover within 5 to 7 days after illness onset. Some pigs exhibit severe viral pneumonia, which is the major cause of death. Secondary bacterial or viral infections also can occur. Pigs begin excreting the virus within 24 hours after infection, and may shed the virus for 7 to 10 days. A carrier state can exist for up to 3 months.
After being identified in humans, the pH1N1 2009 strain was subsequently found in swine herds in a number of countries around the globe during 2009 and early 2010 (Pasma 2010, Sreta 2010). The virus presumably was introduced into the herds from ill or recovering workers who were harboring the virus. Following identification of the virus in a herd, the accepted practice is to monitor the herd to verify that infected animals recover before they are sent to slaughter (CFIA 2009, Pasma 2010). There is no need to quarantine or destroy infected herds, since recovered animals pose no risk to humans.
In August 2009, the pH1N1 2009 strain was isolated from domestic turkeys on two farms in Chile (Mathieu 2010). A temporary quarantine was established and the birds were allowed to recover before going to market (rather than being culled). Since that time, the virus has been found in several additional turkey farms, including farms located in California and Canada. These incidents raise the possibility that other poultry flocks around the globe could become infected with pH1N1. The major concern is the potential for the novel pH1N1 virus and the highly pathogenic H5N1 virus to co-infect poultry, which could produce a new reassortant strain that could be much more lethal to humans than the current H1N1 pandemic strain.
According to the WHO, the Food and Animal Health Organization (FAO) of the United Nations, and the World Organization for Animal Health (OIE), influenza viruses are not known to be transmissible to people through eating processed pork or other food products derived from pigs (WHO 2009).
- Heat treatments commonly used in cooking meat (eg, 70°C/160°F core temperature) will readily inactivate any viruses potentially present in raw meat products.
- Pork and pork products, handled in accordance with good hygienic practices recommended by the WHO, Codex Alimentarius Commission, and the OIE, will not be a source of infection
- Authorities and consumers should ensure that meat from sick pigs or pigs found dead is not processed or used for human consumption under any circumstances.
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