INTRODUCTION — In late March and early April 2009, an outbreak of H1N1 influenza A virus infection was detected in Mexico, with subsequent cases observed in many other countries including the United States [1,2]. On June 11, 2009, the World Health Organization raised its pandemic alert level to the highest level, phase 6, indicating widespread community transmission on at least two continents [3].

The pandemic that began in March 2009 was caused by an H1N1 influenza A virus that represents a quadruple reassortment of two swine strains, one human strain, and one avian strain of influenza. (See 'Genetic and antigenic characterization' below.)

The epidemiology, clinical manifestations, and diagnosis of pandemic H1N1 influenza A virus infection will be reviewed here. The treatment and prevention of pandemic H1N1 influenza A virus infection are discussed separately; seasonal and avian (H5N1) influenza viruses are also reviewed elsewhere. (See "Treatment of pandemic H1N1 influenza ('swine influenza')" and "Prevention of pandemic H1N1 influenza ('swine influenza')" and "Epidemiology of influenza" and "Epidemiology, transmission, and pathogenesis of avian influenza" and "Clinical manifestations and diagnosis of seasonal influenza in adults" and "Clinical features and diagnosis of influenza in children" and "Clinical manifestations and diagnosis of avian influenza".)

EPIDEMIOLOGY

Historical perspective — The pandemic that began in March 2009 was caused by an H1N1 influenza A virus that represents a quadruple reassortment of two swine strains, one human strain, and one avian strain of influenza; the largest proportion of genes comes from swine influenza viruses. (See 'Genetic and antigenic characterization' below.)

Illness with influenza in pigs was first recognized during the influenza pandemic of 1918 to 1919, and a swine influenza virus was first isolated from a human in 1974 [4-6]. In 1976, swine influenza virus caused a respiratory illness with one fatality among 13 soldiers in Fort Dix, New Jersey [7]. No exposure to pigs was found. A subsequent epidemiologic study showed that up to 230 soldiers had been infected with the virus [4,8].

Between 1958 and 2005, 37 cases of swine influenza among civilians were reported [4]. Six cases (17 percent) resulted in death. Forty-four percent of infected individuals had known exposure to pigs. Cases were reported in the United States, former Czechoslovakia, the Netherlands, Russia, Switzerland, and Hong Kong. (See 'Mortality' below.)

2009 pandemic — In March and April 2009, an outbreak of respiratory illnesses was first noted in Mexico, which was eventually identified as being related to H1N1 influenza A [1]. The outbreak spread rapidly to the United States, Canada, and throughout the world as a result of airline travel [9].

Reported cases — Since early July 2009, the World Health Organization has ceased closely tracking the number of cases, since it has become difficult for countries to continue such monitoring in the setting of widespread community transmission [10]. Furthermore, even with close tracking, the true numbers of cases are many fold higher than the numbers of confirmed cases [11]. The focus has shifted to following trends of illness rather than individual cases in countries with widespread disease, and to close monitoring of cases only in newly affected countries.

As of November 1, 2009, over 482,000 laboratory-confirmed cases had been reported in numerous countries [2]. Intense and persistent influenza activity has continued to occur in North America, and continues to increase in many countries in Europe as well as Central and Western Asia. High numbers of cases have been reported from Ukraine [12]. Although most countries in the tropical regions of Central and South America have reported decreasing influenza activity, increasing activity continues to occur in parts of the Caribbean including Cuba and Haiti. Overall transmission has been declining in most parts of tropical South and Southeast Asia, with the exception of Nepal, Sri Lanka, and Cambodia.

In the United States, as of July 24, 2009, over 43,000 confirmed cases had been reported from 55 states and territories, but reporting of case counts has since been discontinued [13]. However, a modeling study showed that during the same time period, the number of individuals infected with pandemic H1N1 influenza in the United States may have been up to 140 times greater than the reported number of confirmed cases; 1.8 to 5.7 million cases, including 9000 to 21,000 hospitalizations, may have occurred [11].

Updated information can be found at the websites of the World Health Organization (http://www.who.int/csr/disease/swineflu/en/index.html) and the United States Centers for Disease Control and Prevention (http://www.cdc.gov/h1n1flu/update.htm).

Age distribution — The rate of infection in the United States has been highest among individuals ≤24 years of age [14-16]. In the US between April 15 and July 24, 2009, 43,771 probable and confirmed cases of pandemic H1N1 influenza A were reported to the Centers of Disease Control and Prevention [14]. The rate of reported cases was highest among individuals aged 5 to 24 years followed by individuals aged 0 to 4 years. The rates of reported cases per 100,000 population in various age groups were (graph 1):

• 0 to 4 years — 22.9
• 5 to 24 years — 26.7
• 25 to 49 years — 6.97
• 50 to 64 years — 3.9
• ≥65 years — 1.3

Although elderly patients are considered to be at an increased risk for complications of influenza, pandemic H1N1 influenza A infections in such individuals have been uncommon to date possibly as a result of preexisting immunity against antigenically similar influenza viruses that circulated prior to 1957 [17]. In one study, 39 of 115 (34 percent) of individuals born before 1950 had preexisting microneutralization titers ≥80 against pandemic H1N1 influenza, whereas only 4 of 107 (4 percent) of individuals born after 1980 had titers ≥40 [18]. Microneutralization titers ≥80 to 160 in adults and ≥40 in children often correlate with at least a 50 percent decrease in risk for influenza infection or disease, but whether these titers offer partial protection against pandemic H1N1 influenza A virus infection or disease is unclear [19]. (See "Seasonal influenza vaccination in adults".)

In a surveillance study of probable or confirmed pandemic H1N1 influenza A infections resulting in hospitalization or death in California, the median age was 27 [20]. The highest hospitalization rates were observed in infants younger than 1 year of age, and were particularly high among the youngest individuals; hospitalization rates per 100,000 population were 36 among 1 month olds, 21 among 2 months olds, and ranged from 4 to 13 among 3 to 12 month olds. Individuals ≥50 years of age had the highest mortality rates once hospitalized.

Between August 30 and October 10, 2009, 4958 hospitalizations due to laboratory-confirmed pandemic H1N1 influenza A infection were reported in the US [17]. The percentages of individuals hospitalized in various age groups follow:

• 0 to 4 years — 19 percent
• 5 to 24 years — 25 percent
• 25 to 49 years — 24 percent
• 50 to 64 years — 15 percent
• ≥65 years — 7 percent

During the same time period, 292 deaths in patients with laboratory-confirmed pandemic H1N1 influenza A infection were reported in the US [17]. The percentages of deaths among various age groups follow:

• 0 to 4 years — 3 percent
• 5 to 18 years — 14 percent
• 19 to 24 years — 7 percent
• 25 to 49 years — 33 percent
• 50 to 64 years — 32 percent
• ≥65 years — 12 percent

Pandemic alert level — On June 11, 2009, the World Health Organization raised its pandemic alert level to the highest level, phase 6, indicating widespread community transmission on at least two continents [3].

VIROLOGY

Influenza subtypes — Clinical influenza can be caused by several different influenza subtypes, although H1N1 is the most common subtype implicated in both swine and human infections [21]. Human cases of swine H3N2 influenza A virus infection have been reported rarely [4]. Other subtypes that have circulated in pigs include H1N2, H3N1, and H3N2.

Genetic and antigenic characterization — The pandemic that began in March 2009 was caused by an H1N1 influenza A virus that had not been recognized previously in pigs or humans, although six of its eight gene segments were similar to ones previously detected in triple reassortant swine influenza viruses in pigs in North America [22]. This strain represents a quadruple reassortment of two swine strains, one human strain, and one avian strain of influenza (figure 1) [15,23-25]. The largest proportion of genes comes from swine influenza viruses (30.6 percent from North American swine influenza strains, 17.5 percent from Eurasian swine influenza strains), followed by North American avian influenza strains (34.4 percent) and human influenza strains (17.5 percent) [26].

Analysis of the antigenic and genetic characteristics of the pandemic H1N1 influenza A virus demonstrated that its gene segments have been circulating for many years, suggesting that lack of surveillance in swine is the reason that this strain had not been recognized previously [23,24,27]. One of the swine influenza viruses that contributed gene segments to the strain causing the 2009 pandemic is thought to have derived from the strain that caused the 1918 influenza pandemic [23,28].

Among the 2009 pandemic H1N1 influenza A viruses sequenced, each gene segment had high sequence identity (99.9 percent), suggesting that introduction into humans was either a single event or multiple events of genetically similar viruses [23]. Furthermore, the H1N1 influenza A viruses causing the 2009 pandemic were found to be antigenically homogeneous. Phylogenetic analysis has suggested that initial transmission to humans occurred several months before the outbreak was recognized [27].

Sequence analysis of isolates from the United States and Mexico did not identify molecular features known to confer increased transmissibility or virulence [23].

TRANSMISSION

Person-to-person transmission — Influenza virus is present in respiratory secretions of infected persons. As a result, influenza virus can be transmitted through sneezing and coughing via large-particle droplets [29,30]. Transmission via contact with surfaces that have been contaminated with respiratory droplets or by aerosolized small-particle droplets may also occur, although these modes of transmission have not been proven [29]. In addition to respiratory secretions, certain other bodily fluids (eg, diarrheal stool) should also be considered potentially infectious [29]. (See "Clinical manifestations and diagnosis of seasonal influenza in adults", section on 'Transmission'.)

In contrast to previous outbreaks of swine influenza viruses described above, the pandemic of H1N1 influenza A infection that began in March 2009 appears to involve sustained human-to-human transmission, as suggested by the large numbers of patients with respiratory illnesses identified within a short period of time at various locations around the world [31]. Several of the isolates causing disease in the United States have been found to be nearly genetically identical to isolates in Mexico, supportive of person-to-person transmission [22,32].

Based on analysis by the World Health Organization using early data from the outbreak in Mexico and other countries, transmissibility appears substantially higher compared with seasonal influenza [33]. In one study, the secondary attack rate of the strain causing this pandemic was estimated to be 22 to 33 percent, compared with 5 to 15 percent for seasonal influenza [34]. In another study, the secondary attack rate in households was estimated to be 27 percent, and an infected school child was estimated to infect 2.4 other children within the school [35]. In contrast to the two studies cited above [34,35], the United States Centers for Disease Control and Prevention has reported that the attack rate observed in the US is similar to that in seasonal influenza [36]. Similarly, the rate of secondary household transmission of laboratory-confirmed H1N1 influenza infection in Kenya between June and July 2009, prior to the use of antiviral drugs, was 26 percent, which is comparable to that of seasonal influenza [18].

Infection control and social distancing measures are discussed in detail separately. (See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on Infection control in healthcare settings.) (See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on Community social distancing measures.)

Incubation period — Although the precise incubation period has not been established for pandemic H1N1 influenza A infection, it could range from one to seven days, and most likely from one to four days [30].

Shedding — Since the duration of shedding of pandemic H1N1 influenza A virus is currently unclear, the estimated duration of shedding is based upon what is known for seasonal influenza virus [37]. (See "Clinical manifestations and diagnosis of seasonal influenza in adults", section on 'Transmission'.)

It is thought that immunocompetent patients with pandemic H1N1 influenza A virus infection are likely to be contagious from one day prior to the development of signs and symptoms until resolution of fever [37]. However, in a study of US air force academy cadets with confirmed or suspected pandemic H1N1 influenza infection, 31 of 106 samples (29 percent) from individuals with temperature <100ºF and 11 of 58 samples (19 percent) from individuals reporting no symptoms for ≥24 hours contained viable H1N1 influenza virus as detected by viral culture [38]. Of 29 samples that were obtained seven days following illness onset, seven (24 percent) contained viable H1N1 influenza virus. Longer periods of shedding may occur in children (especially young infants), elderly adults, patients with chronic illnesses, and immunocompromised hosts [37].

Recommendations for the duration of home isolation for ill individuals in the community and for isolation precautions in hospitalized individuals are discussed separately. (See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Home isolation' and "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Precautions'.)

Role of pigs — Pigs play an important role in interspecies transmission of influenza virus. Susceptible pig cells possess receptors for both avian (alpha 2-3-linked sialic acids) and human influenza strains (alpha 2-6-linked sialic acids), which allow for the reassortment of influenza virus genes from different species if a pig cell is infected with more than one strain [4,39-41]. (See "Epidemiology, transmission, and pathogenesis of avian influenza", section on 'Pathogenesis'.)

Since the late 1990s, triple reassortant swine influenza A viruses containing genes from swine, human, and avian strains of influenza have been detected among swine herds in North America [42-44]. Eleven sporadic cases of triple reassortant swine H1 influenza A viruses were detected in the United States between December 2005 and February 2009 [42]. Nine patients had exposure to pigs.

It is not clear yet how this virus arose or was initially transmitted to humans. On May 2, 2009, the Canadian government reported the identification of pandemic H1N1 influenza A from a swine herd in Alberta, Canada [45]. It is suspected that the pigs became infected following exposure to a farm worker who had recently visited Mexico and had developed an influenza-like illness.

There is no risk of becoming infected with influenza virus from eating pork [45].

CLINICAL MANIFESTATIONS — The signs and symptoms of influenza caused by pandemic H1N1 influenza A virus are similar to those of seasonal influenza, although gastrointestinal manifestations appear to be more common with pandemic H1N1 influenza A [15,30,31,46]. The severity has been less than what was observed during the influenza pandemic of 1918 to 1919 [34]. (See "Epidemiology of influenza".)

Signs and symptoms — The most common clinical findings of the 2009 H1N1 influenza A pandemic have been fever, cough, sore throat, malaise, and headache; vomiting and diarrhea have also been common, both of which are unusual features of seasonal influenza [15,21,31,46]. Other frequent findings have included chills, myalgias, and arthralgias [15,31]. Rhabdomyolysis has been reported rarely [47].

During the spring of 2009 in New York City, 95 percent of patients with pandemic H1N1 influenza A met the case definition for influenza-like illness (subjective fever plus cough and/or sore throat) [31]. In contrast, approximately one third of patients seen at two hospitals in Mexico had no fever at presentation [48]. (See "Clinical manifestations and diagnosis of seasonal influenza in adults".)

Certain groups, such as infants, elderly individuals, and immunocompromised hosts, may have atypical presentations. In addition, subclinical infection has been reported rarely [49], although further study is required to determine how common this is.

Among 268 patients in the United States requiring hospitalization for pandemic H1N1 influenza A infection, clinical findings included fever (93 percent), cough (83 percent), shortness of breath (54 percent), fatigue or weakness (40 percent), chills (37 percent), myalgias (36 percent), rhinorrhea (36 percent), sore throat (31 percent), headache (31 percent), vomiting (29 percent), wheezing (24 percent), and diarrhea (24 percent) [50].

Complications of pandemic H1N1 influenza A infection are discussed below. (See 'Complications' below.)

Children — Young children are less likely to have the usual influenza signs and symptoms, such as fever and cough [51]. Infants may present with fever and lethargy, and may not have cough or other respiratory symptoms. Symptoms of severe disease in infants and young children may include apnea, tachypnea, dyspnea, cyanosis, dehydration, altered mental status, and extreme irritability. (See "Clinical features and diagnosis of influenza in children".)

Young children ( <5 years of age, and especially <2 years of age) are at increased risk for influenza complications [51,52]. (See 'Complications' below and "Treatment of pandemic H1N1 influenza ('swine influenza')", section on 'High risk groups'.)

Complications

Underlying conditions — Among 553 patients with confirmed or probable pandemic H1N1 influenza A in California, the most common risk factors for influenza complications were chronic lung disease (asthma or chronic obstructive pulmonary disease, 37 percent), immunosuppressive conditions (17 percent), cardiac disease (17 percent), pregnancy (17 percent), diabetes mellitus (13 percent), and obesity (13 percent) [53]. (See "Treatment of pandemic H1N1 influenza ('swine influenza')", section on 'High risk groups' and 'Pregnant women' below.)

Among patients requiring hospitalization in the United States, approximately 70 percent have had at least one underlying condition known to increase the risk of influenza complications [20,21]. The prevalence of certain underlying conditions has been higher among patients requiring hospitalization for pandemic H1N1 influenza A in the United States than in the general population [17,50]. As an example, 32 percent of these patients had asthma compared with only 8 percent of the US population [50]. In a cohort study of patients in Australia and New Zealand admitted to the ICU with confirmed pandemic H1N1 influenza A infection between June and August 2009, the proportion of patients requiring ICU admission who were pregnant, had chronic lung disease, had a body-mass index >35, or were indigenous to Australia or New Zealand were all higher compared with the general population [54]. One third of the patients were young or middle-aged and did not have an identifiable risk factor for severe disease.

Similar to what has been observed among the indigenous populations of Australia and New Zealand, a disproportionately high percentage of the indigenous population of Canada has been affected by severe pandemic H1N1 influenza infection [55].

Range of complications — Approximately 2 to 5 percent of confirmed cases in the United States and Canada have required hospitalization compared with 6 percent in Mexico [46,53,56]. However, since the number of cases of mild illness is almost certainly under-reported, the true percentage of cases requiring hospitalization is much lower; it has been estimated to be 0.3 percent of cases in the United States [57]. The most common reasons for admission were pneumonia and dehydration [53].

Of 1088 patients in California with suspected or confirmed pandemic H1N1 influenza A resulting in hospitalization or death, 31 percent were admitted to the intensive care unit and 11 percent died [21].

During the 2009 pandemic, rapidly progressive pneumonia, respiratory failure, acute respiratory distress syndrome, and multisystem organ failure have been reported in some cases [20,21,46,55,58-61]. In Mexico, between late March and late April 2009, 2155 cases of severe pneumonia, including 821 hospitalizations and 100 deaths, were reported to the epidemiologic surveillance network [58]. Pneumonia has been less common among patients with pandemic H1N1 influenza A in the United States [15].

Some patients with respiratory failure have had profound hypoxemia that has been refractory to routine mechanical ventilation; these patients have required such measures as neuromuscular blockade, inhaled nitric oxide, high-frequency oscillatory ventilation, extracorporeal membrane oxygenation, and/or prone positioning ventilation [55,61].

Bacterial coinfections of the lung were detected in 46 of 1088 (4 percent) of cases that resulted in hospitalization or death in California [21], but in 22 of 77 (29 percent) of fatal cases of pandemic H1N1 influenza A infection in the United States [62]. One hundred and forty of 689 patients (20 percent) requiring ICU admission for pandemic H1N1 influenza A infection in Australia and New Zealand were found to have secondary bacterial pneumonia [54]. Among the fatal cases described in the US, 10 were caused by Streptococcus pneumoniae, six by Streptococcus pyogenes, seven by Staphylococcus aureus, two by Streptococcus mitis, and one by Haemophilus influenzae; four cases involved multiple pathogens [62].

Four children in Texas with pandemic H1N1 influenza A have had seizures, three of whom also had abnormal electroencephalograms [63]. All four recovered fully. Another reported complication among patients with severe pandemic H1N1 influenza A pneumonia and ARDS has been multiple pulmonary emboli [57].

The complications of seasonal influenza are discussed in detail separately. (See "Clinical manifestations and diagnosis of seasonal influenza in adults" and "Clinical features and diagnosis of influenza in children".)

Pregnant women — During prior influenza epidemics and pandemics, as well as during the current pandemic, pregnant women have had increased morbidity and mortality [52,64,65]. In the United States during the 2009 H1N1 influenza A pandemic, increased rates of hospitalization have been observed among pregnant women compared with the general population [66]. Other countries have also reported an increased risk of severe influenza among pregnant women during the 2009 pandemic, particularly during the second and third trimesters [57,67].

As of late August 2009, 100 pregnant women in the US have required intensive care unit admission and 28 have died [65]. The mortality rate from the current H1N1 influenza A pandemic among pregnant women is higher than among the general population. (See 'Mortality' below.)

During previous influenza pandemics, increased rates of spontaneous abortion and preterm birth have been reported among pregnant women, especially those with pneumonia [52]. Of five pregnant women requiring hospitalization for pandemic H1N1 influenza A, two developed complications including spontaneous abortion (at 13 weeks of gestation) and premature rupture of membranes (at 35 weeks of gestation) [53].

Laboratory findings — In a study of 272 patients requiring hospitalization in the United States for pandemic H1N1 influenza A, the following laboratory abnormalities were observed [20]:

• Elevated alanine aminotransferase — 58 of 130 (45 percent)
• Elevated aspartate aminotransferase — 57 of 131 (44 percent)
• Anemia — 87 of 238 (37 percent)
• Leukopenia — 50 of 246 (20 percent)
• Leukocytosis — 44 of 246 (18 percent)
• Thrombocytopenia — 33 of 234 (14 percent)
• Thrombocytosis — 20 of 234 (9 percent)
• Elevated total bilirubin — 6 of 121 (5 percent)

In a study of individuals with probable pandemic H1N1 influenza A infection, relative lymphopenia (≤21 percent of white blood cells) without leukopenia was observed in 23 of 25 adults, but in only 3 of 16 children [68].

Mild to moderate elevations of creatine kinase levels have been reported in some patients with severe illness [59]; one case of a patient with a creatine kinase level of 27,820 U/L resulting in rhabdomyolysis has been reported [47]. Lactate dehydrogenase was elevated in all 16 patients with severe illness in one study [59].

Radiographic findings — Of 833 hospitalized patients with probable or confirmed pandemic H1N1 influenza A infection, 547 (66 percent) had infiltrates suggestive of pneumonia or acute respiratory distress syndrome [21].

In a study that included 66 patients with pandemic H1N1 influenza A infection who underwent chest imaging, the most common findings on chest radiography were patchy consolidation in 14 of 28 patients (50 percent), which occurred most commonly in the lower (in 71 percent) and central (in 71 percent) lung zones [69]. Ground glass opacities with or without consolidation was observed in 7 of 28 (25 percent) of patients. Of the 14 critically ill patients who required intensive care unit admission and mechanical ventilation, extensive disease involving ≥3 lung zones was observed in 13.

Of the 10 critically ill patients who underwent chest computed tomography (CT), nine had a combination of ground glass opacities and consolidation and one had a predominance of ground glass opacities. Seven of these patients had diffuse lung involvement and three had lower lung predominance. Among 15 patients who underwent CT (including both critically ill patients and non-critically ill patients), nodular opacities were detected on CT in six.

An unexpected finding was that pulmonary emboli were detected by CT in 5 of 14 critically ill patients.

Mortality — Seasonal influenza results in higher mortality rates among patients with certain chronic medical conditions, as well as in pregnant women and those at the extremes of age. During the current H1N1 influenza A pandemic there have been higher mortality rates among patients with certain underlying medical conditions and in pregnant women. Since April 2009, 129 children in the US have died from laboratory-confirmed H1N1 influenza infection, and another 15 children have died with laboratory-confirmed influenza infection that was not subtyped [70].

Few elderly individuals have been infected, which may be due to some degree of preexisting immunity in older individuals against antigenically similar influenza viruses. However, based on past experience, elderly individuals who are infected are still thought to be at increased risk for complications. In a surveillance study of 1088 probable or confirmed cases of pandemic H1N1 influenza A resulting in hospitalization or death in California, individuals ≥50 years of age had the highest mortality rates; this may have been the result of comorbidities, since 80 percent of patients in this age group had underlying medical conditions [21]. One-third of deaths have occurred in individuals aged 25 to 49 in the US, which is a higher percentage than occurs with seasonal influenza. (See 'Age distribution' above and 'Pregnant women' above and "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Preexisting antibodies'.)

As of November 1, 2009, there have been over 482,300 laboratory-confirmed cases of pandemic H1N1 influenza A worldwide, including at least 6071 deaths [2]. Most deaths have been related to respiratory failure resulting from severe pneumonia with multifocal infiltrates and acute respiratory distress syndrome [21,46]. In the surveillance study of probable or confirmed cases of pandemic H1N1 influenza A resulting in hospitalization or death described above, 11 percent were fatal [21].

Of 45 fatal cases in Mexico, 24 (54 percent) occurred in previously healthy individuals [46]. In contrast, most of the deaths outside of Mexico occurred in individuals with underlying health problems [15,20,21,56,57,71,72]. Approximately 6 percent of deaths caused by pandemic H1N1 influenza A virus in the US have occurred in pregnant women, although only 1 percent of the population is pregnant at any given time [73]. In a cohort study of patients in Australia and New Zealand admitted to the ICU with confirmed pandemic H1N1 influenza A infection, older age, the presence of preexisting conditions, and a requirement for mechanical ventilation were independently associated with mortality [54].

Variable severity of human infections with swine influenza viruses isolated before the 2009 pandemic has been reported in several studies, as illustrated by the following findings [30]:

• In a review of 37 cases of human infections with swine influenza virus reported between 1958 and 2005, six cases (17 percent) resulted in death, all of which were due to pneumonia. Influenza virus was the only pathogen identified from the lungs in four patients; in one individual, Streptococcus viridans, Neisseria spp, and Klebsiella spp were also identified in addition to influenza virus [5,74-77].
• Between 2005 and January 2009, 12 cases of human infection with swine influenza virus were detected in the United States with no fatalities [30].
• An outbreak occurred among soldiers in Fort Dix, New Jersey in 1976, which involved up to 230 individuals but resulted in only one death [4,7,8,30].
• A fatal human infection with swine influenza virus complicated by pneumonia was also reported in a previously healthy pregnant woman in 1988 [30].

DIAGNOSIS — Guidelines for the diagnosis of pandemic H1N1 influenza A virus have been released by the United States Centers for Disease Control and Prevention (CDC) [78]. Updated recommendations can be found at the CDC's website (http://www.cdc.gov/swineflu/). Clinicians in other countries should consult their individual health ministries for information about recommended diagnostic testing.

Whom to test — Most patients with an uncomplicated influenza-like illness who reside in areas where influenza viruses are known to be circulating do not need to be tested for influenza infection [78]. Recommendations regarding whom to test may differ by state or community.

Patients in whom influenza testing should be considered include [78]:

• Hospitalized patients with suspected influenza infection
• Patients for whom a diagnosis of influenza will affect decisions regarding clinical care, infection control, or management of close contacts

In addition, influenza testing should be considered when conducting autopsies of individuals who died of acute illness in whom influenza was suspected [78].

Specimens — To establish the diagnosis of pandemic H1N1 influenza A, an upper or lower respiratory sample should be collected [78]. Appropriate specimens include:

• Nasopharyngeal swab
• Nasal aspirate, wash, or swab
• Endotracheal aspirate (in intubated patients)
• Bronchoalveolar lavage (BAL) fluid
• Combined nasopharyngeal or nasal swab with oropharyngeal swab

In patients with severe pneumonia who are suspected of being infected with influenza and who are intubated or undergoing bronchoscopy, lower respiratory samples (endotracheal aspirate or BAL fluid) should be obtained and tested for influenza infection.

For proper specimen collection, instructions in the test's package insert should be followed. Furthermore, specimens should be obtained as soon as possible following the onset of symptoms.

Swabs with a synthetic tip (eg, polyester or Dacron) and an aluminum or plastic shaft should be used. Swabs with cotton tips and wooden shafts are not recommended. Swabs made of calcium alginate are not acceptable. The collection vial in which the swab is placed should contain 1 to 3 mL of viral transport media.

Specimens should be placed in viral transport media and placed on ice (4ºC) or refrigerated immediately for transportation to the laboratory. Once the samples arrive in the laboratory, they should be stored either in a refrigerator at 4ºC or in a -70ºC freezer. If a -70ºC freezer is not available, they should be kept refrigerated. Refrigerated samples should ideally be processed within 24 hours, and should not be stored for >72 hours.

Diagnostic tests — Real-time reverse transcriptase (rRT)-PCR is the most sensitive and specific test for the diagnosis of pandemic H1N1 influenza A virus infection [78]. Isolation of pandemic H1N1 influenza A virus using culture is also diagnostic, but culture is usually too slow to help guide clinical management. A negative viral culture does not exclude pandemic H1N1 influenza A infection.

Several rapid antigen and immunofluorescent antibody tests are available for the diagnosis of influenza virus infection. However, the sensitivity of these tests varies widely, and although some assays are able to distinguish between influenza A and B viruses, they are not able to distinguish between pandemic and seasonal strains of H1N1 influenza A.

Polymerase chain reaction — Nucleic acid amplification tests, such as real-time reverse transcriptase (rRT)-PCR, are the most sensitive and specific tests for the diagnosis of influenza virus infection [78]. However, they may not be readily available and/or may require several days for processing since many hospitals and clinics must send samples to be processed at public health or commercial laboratories. Test performance depends on the individual rRT-PCR assay used.

The United States Food and Drug Administration has authorized several rRT-PCR assays for the diagnosis of pandemic H1N1 influenza A infection under an Emergency Use Authorization [79].

Rapid antigen tests — Clinicians may consider using rapid influenza antigen tests as part of their evaluation of patients suspected of having pandemic H1N1 influenza A, but results should be interpreted with caution [78,80]. Certain rapid influenza antigen tests that are commercially available can distinguish between influenza A and B viruses, but cannot distinguish among different subtypes of influenza A (eg, pandemic H1N1 influenza A versus seasonal H1N1 or H3N2 influenza A). Confirmation of pandemic H1N1 influenza A infection can only be made by real-time reverse-transcriptase (rRT)-PCR or culture. (See 'Choice of test' below.)

The sensitivity of rapid antigen testing for pandemic H1N1 influenza A virus infection has ranged from 10 to 70 percent compared with rRT-PCR [78,80-85]. Thus, a negative result does not rule out infection. The specificity of rapid antigen testing has generally been >95 percent [78], although in one study it was only 86 percent [84].

Among 39 patients with pandemic H1N1 influenza A confirmed by rRT-PCR, 20 had a positive rapid antigen test using the QuickVue Influenza A+B (Quidel) assay (sensitivity 51 percent) [81]. Twelve of 19 patients who had seasonal H1N1 influenza confirmed by rRT-PCR had a positive rapid antigen test (sensitivity 63 percent). In the same study, the specificity of rapid antigen testing was 99 percent for patients with either the pandemic strain or a seasonal strain of H1N1 influenza A. (See "Clinical manifestations and diagnosis of seasonal influenza in adults".)

Immunofluorescent antibody testing — Direct or indirect immunofluorescent antibody testing (DFA or IFA) can distinguish between influenza A and B, but does not distinguish among different influenza A subtypes [78]. In one study, among 42 samples that were positive for pandemic H1N1 influenza A by real-time reverse-transcriptase polymerase chain reaction, 39 were positive by direct fluorescent antibody testing [86]. However, a negative DFA or IFA does not exclude pandemic H1N1 influenza A infection since larger studies are required to define the sensitivity to detect this virus.

Choice of test — As discussed above, most patients with an uncomplicated influenza-like illness who reside in areas where influenza viruses are known to be circulating do not need to be tested for influenza infection [78]. (See 'Whom to test' above.)

However, among patients for whom a diagnosis of influenza will affect decisions regarding clinical care, infection control, or management of close contacts, it is reasonable to use a rapid antigen or immunofluorescence antibody test. In regions where the majority of circulating influenza viruses are known to be pandemic H1N1 influenza A, a positive result using one of these assays can be presumed to indicate infection with pandemic H1N1 influenza A.

If identification of pandemic H1N1 influenza A is required, such as in pregnant patients and those with severe immunosuppression, then real-time reverse transcriptase polymerase chain reaction (rRT-PCR) testing should be performed. In addition, rRT-PCR testing should be performed in hospitalized patients with suspected influenza infection who have a negative rapid antigen or immunofluorescence antibody test. Influenza subtype testing with rRT-PCR or viral culture should also be prioritized for use in individuals who have died from suspected or confirmed influenza infection.

The diagnostic tests for influenza are discussed in greater detail separately. (See "Clinical manifestations and diagnosis of seasonal influenza in adults" and "Clinical features and diagnosis of influenza in children".)

DEFINITIONS

Case definitions — The following case definitions have been provided by the United States Centers for Disease Control and Prevention [87]:

• Influenza-like illness (ILI) is defined as fever (temperature of 100ºF [37.8ºC] or greater) with cough or sore throat in the absence of a known cause other than influenza.
• A confirmed case of pandemic H1N1 influenza A is defined as an individual with an ILI with laboratory-confirmed H1N1 influenza A virus detection by real-time reverse transcriptase (rRT)-PCR or culture.

Pandemic H1N1 influenza A may be suspected in an individual who does not meet the definition of confirmed pandemic H1N1 influenza A, but has an ILI and an epidemiologic link. Full case definitions can be found at the CDC's website (http://www.cdc.gov/swineflu/).

High risk groups — Individuals with certain medical conditions, those at the extremes of age, and pregnant women are at increased risk of influenza complications. (See 'Complications' above and "Treatment of pandemic H1N1 influenza ('swine influenza')", section on 'High risk groups'.)

Close contacts — The definitions of close contacts are presented separately. (See "Treatment of pandemic H1N1 influenza ('swine influenza')", section on 'Close contacts'.)

SUMMARY AND RECOMMENDATIONS

Pandemic in 2009

• In March and April 2009, an outbreak of H1N1 influenza A virus infection was detected in Mexico, with subsequent cases observed in many other countries including the United States. On June 11, 2009, the World Health Organization raised its pandemic alert level to the highest level, phase 6, indicating widespread community transmission on at least two continents. (See 'INTRODUCTION' above and 'EPIDEMIOLOGY' above.)

• The 2009 H1N1 influenza A pandemic was caused by an H1N1 virus that had not been recognized previously in pigs or humans. This strain represents a genetic reassortment of swine, human, and avian strains of influenza. (See 'Genetic and antigenic characterization' above.)

• Influenza virus can be transmitted through sneezing and coughing via large-particle aerosols, as well as by contact with surfaces that have been contaminated with respiratory droplets. (See 'Person-to-person transmission' above.)

• Although the incubation period has not been established for pandemic H1N1 influenza A infection, it could range from one to seven days, and most likely from one to four days. (See 'Incubation period' above.)

• Immunocompetent patients with pandemic H1N1 influenza A virus infection are likely to be contagious from one day prior to the development of signs and symptoms until resolution of fever. Longer periods of shedding may occur in children (especially young infants), elderly adults, patients with chronic illnesses, and immunocompromised hosts. (See 'Shedding' above.)

• Infection control and social distancing measures help to limit transmission of influenza viruses. Recommendations for the duration of home isolation for ill individuals in the community and isolation precautions in hospitalized individuals are discussed separately. (See "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Home isolation' and "Prevention of pandemic H1N1 influenza ('swine influenza')", section on 'Precautions'.)

Clinical findings

• Typical clinical manifestations include fever, headache, cough, sore throat, myalgias, chills, and fatigue; vomiting and diarrhea have also been common, both of which are unusual features of seasonal influenza. During the 2009 pandemic, rapidly progressive pneumonia, respiratory failure, and acute respiratory distress syndrome have been reported in some cases. (See 'CLINICAL MANIFESTATIONS' above.)

Diagnostic testing — Guidelines for the diagnosis of pandemic H1N1 influenza A virus have been released by the United States Centers for Disease Control and Prevention (CDC). Updated recommendations can be found at the CDC's website (http://www.cdc.gov/swineflu/).

• Most patients with an uncomplicated influenza-like illness who reside in areas where influenza viruses are known to be circulating do not need to be tested for influenza infection. (See 'Whom to test' above.)

• Patients in whom influenza testing should be considered include:

• - Hospitalized patients with suspected influenza infection
• - Patients for whom a diagnosis of influenza will affect decisions regarding clinical care, infection control, or management of close contacts.
• - Individuals who died of acute illness in whom influenza was suspected. (See 'Whom to test' above.)

• Among patients for whom a diagnosis of influenza will affect decisions regarding clinical care, infection control, or management of close contacts, it is reasonable to use a rapid antigen or immunofluorescence antibody test. If identification of pandemic H1N1 influenza A is required, then real-time reverse transcriptase polymerase chain reaction testing should be performed. (See 'Choice of test' above.)

• To establish the diagnosis of pandemic H1N1 influenza A, an upper or lower respiratory sample should be collected. Appropriate swabs must be used and conditions observed for optimal specimen collection. (See 'Specimens' above.)

Case definitions of pandemic H1N1 influenza A

• Case definitions of suspected and confirmed pandemic H1N1 influenza A virus infection are based on symptoms, signs, and epidemiologic information. (See 'Case definitions' above.)