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 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".)

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.

EPIDEMIOLOGY OF THE 2009 PANDEMIC — In March 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]. 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].

Reported cases — Over 99 percent of subtyped influenza A isolates in Europe and the US have been pandemic H1N1 influenza A [10,11]. Pandemic H1N1 influenza is also the predominant influenza virus circulating in northern and eastern Africa and in Australia [10,12]. In West Africa, both pandemic and seasonal influenza strains (H1N1 and H3N2) are circulating.

Influenza activity has peaked and is declining in North America and in parts of western, northern, and eastern Europe, but activity continues to increase in parts of central and southeastern Europe, as well as in central and South Asia [10]. In tropical parts of Central and South America and the Caribbean, there continues to be widespread influenza activity, although it is declining in most areas [10]. Little influenza activity has been reported from the temperate regions of the southern hemisphere. Further details regarding disease activity in specific regions can be found at: http://www.who.int/csr/don/2010_01_15/en/index.html.

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 [13]. Furthermore, even with close tracking, the true numbers of cases are many fold higher than the numbers of confirmed cases [14].

Since April 2009, 255 children in the US have died from laboratory-confirmed pandemic H1N1 influenza A infection [15].

Estimated cases — A modeling study suggested that by late July 2009, 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; an estimated 1.8 to 5.7 million cases, including 9000 to 21,000 hospitalizations, may have occurred [14]. A subsequent analysis by the US Centers for Disease Control and Prevention that used the same methodology has estimated that approximately 55 million cases, including 246,000 hospitalizations, occurred in the US between April and mid-December 2009 [16]. Clinic visits to doctors for an influenza-like illness have remained above baseline in the United States, but have declined from 4.3 percent in November to 2.6 percent in December [16].

Serologic surveys are being conducted in the United States, Vietnam, Britain and France to get a better estimate of morbidity and mortality rates and the extent of the pandemic [17].

Rates of infection by age — The rate of infection in the United States has been highest among individuals ≤24 years of age [16,18-20]. The rates of reported cases per 100,000 population in various age groups are shown below:

• 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

To date, pandemic H1N1 influenza A infections are uncommon in persons older than 65 years, possibly as a result of preexisting immunity against antigenically similar influenza viruses that circulated prior to 1957 [21]. For example, in one study of 222 stored serum samples, approximately one-third of individuals born before 1950 had evidence of preexisting cross-reactive antibodies to the 2009 pandemic H1N1 influenza virus; in contrast, only 4 percent of individuals born after 1980 had evidence of such cross-reactive antibodies [22].

MORBIDITY AND MORTALITY

General trends — As of January 10, 2010, there have been at least 13,500 deaths due to laboratory-confirmed cases of pandemic H1N1 influenza A worldwide [10].

Using mathematical modeling, the US Centers for Disease Control and Prevention has estimated that approximately 9800 fatal cases occurred in the US between April and mid-November 2009 [16]. In one surveillance study of 1088 probable or confirmed cases of pandemic H1N1 influenza A in California, 31 percent of patients were admitted to the intensive care unit and 11 percent died [23]. Most deaths have been related to respiratory failure resulting from severe pneumonia with multifocal infiltrates and acute respiratory distress syndrome [23,24].

Approximately 2 to 5 percent of confirmed cases in the United States and Canada have required hospitalization compared with 6 percent in Mexico [24-26]. However, since the number of cases of mild illness is almost certainly under-reported, the true percentage of cases requiring hospitalization is likely much lower and has been estimated to be 0.3 percent of cases in the United States [27]. The most common reasons for admission were pneumonia and dehydration [25].

Age — High rates of morbidity and mortality have been noted among children and young adults across the globe.

United States — Between August 30 and October 10, 2009, 4958 hospitalizations due to laboratory-confirmed pandemic H1N1 influenza A infection were reported in the US [28]. 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 [28]. 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

In a surveillance study based within California, rates of hospitalization and death were reviewed among individuals with probable or confirmed pandemic H1N1 influenza A infection [23]. The highest hospitalization rates were observed in infants younger than 1 year of age, particularly those ≤ 2 months of age. Once hospitalized, individuals ≥50 years of age had the highest mortality rates.

Laboratory-confirmed data on hospitalizations and deaths reported to CDC provide a likely underestimation of the true number that have occurred because of incomplete testing, inaccurate test results, or diagnoses that attribute hospitalizations and deaths to complications secondary to influenza (eg, exacerbation of congestive heart failure or bacterial superinfection) [16].

Outside of the United States — In a retrospective case study of Argentinian children with H1N1 respiratory infection, pediatric death rates were 10 times the rates for seasonal influenza in previous years; the most common cause of death in infants less than one year of age was refractory hypoxemia [29].

In one Australian study, 387 adults were admitted with viral pneumonitis secondary to H1N1 influenza; the median age of those who died was 53 years (as compared with 83 years in previous years 2005 through 2008) [12].

Risk groups

Patients without co-morbidity — The majority of reported deaths have occurred in individuals with underlying health problems [15,19,23,26,27,30,31], although up to one-third of hospitalized patients have had no underlying chronic illness [12,23,30,32].

Patients with co-morbidities — 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 [23,30,32,33].

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 (37 percent), immunosuppressive conditions (17 percent), cardiac disease (17 percent), pregnancy (17 percent), diabetes mellitus (13 percent), and obesity (13 percent) [25]. A history of asthma has also been overrepresented among both children and adults hospitalized with H1N1 influenza infection compared to rates within the community [18,34,35]. (See 'Pregnant women' below.)

Pregnant women — During the 2009 H1N1 influenza A pandemic, increased rates of hospitalization have been observed among pregnant women in the United States compared with the general population [36]. 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 [27,32,37-41].

The mortality rate from the current H1N1 influenza A pandemic among pregnant women is higher than among the general population. 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 [42]. As of late August 2009, 100 pregnant women in the US have required intensive care unit admission and 28 have died [40].

The impact of H1N1 influenza on disease severity in pregnant women is well-illustrated by the following study:

• A statewide surveillance study was performed in California among 94 pregnant women, eight postpartum women, and 137 nonpregnant women of reproductive age who were hospitalized with laboratory-confirmed H1N1 influenza [37]. In all, 18 pregnant women and four postpartum women required intensive care. Six of eight women who died had underlying medical conditions including hypothyroidism, asthma, gestational diabetes, and a history of Hodgkin's lymphoma. The maternal mortality ratio (number of maternal deaths per 100,000 live births) attributed to H1N1 influenza in this study was 4.3.

During previous influenza pandemics, increased rates of spontaneous abortion and preterm birth have been reported among pregnant women, especially those with pneumonia [38]. In the California surveillance study noted above, 11 of 13 infants were delivered prematurely; none had evidence of influenza and all survived. In a report issued from the Centers for Disease Control and Prevention, of five pregnant women who required 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) [25].

Indigenous populations — A disproportionately high percentage of the indigenous population of Canada, Australia, and New Zealand have been affected by severe pandemic H1N1 influenza infection [43]. Native Americans in the continental US and Alaska have had a fourfold increase in mortality compared with non-Native Americans [44].

Older populations — 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 [23].

Obesity — In one study of hospitalized patients in New Zealand and Australia, of 722 patients with confirmed H1N1 influenza infection, 172 (29 percent) had a body-mass index greater than 35 [32]. Whether obesity is a risk factor for more severe disease is unclear.

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 [45]. 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 [2]. This strain represents a quadruple reassortment of two swine strains, one human strain, and one avian strain of influenza (figure 1) [19,46-48]. 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) [49].

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 [46,47,50]. 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 [46,51,52].

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 [46]. 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 [50].

Sequence analysis of isolates from the United States and Mexico did not identify molecular features known to confer increased transmissibility or virulence [46].

TRANSMISSION

Person-to-person transmission — Influenza virus can be transmitted through sneezing and coughing via large-particle droplets [53]. In addition to respiratory secretions, certain other bodily fluids (eg, diarrheal stool) should also be considered potentially infectious. (See "Clinical manifestations and diagnosis of seasonal influenza in adults", section on 'Transmission' and "Prevention of pandemic H1N1 influenza ('swine influenza')".)

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 [54]. 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 [2,55].

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.)

Viral shedding — Influenza shedding begins the day prior to symptom onset and can persist for five to seven days in immunocompetent individuals [53]. Longer periods of shedding may occur in children (especially young infants), elderly adults, patients with chronic illnesses, and immunocompromised hosts. The amount of virus shed is greatest during the first two to three days of illness.

Although 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, longer periods of shedding were detected in a study of US air force academy cadets with confirmed or suspected pandemic H1N1 influenza infection [56]. Of 29 samples that were obtained seven days following illness onset, seven (24 percent) contained viable H1N1 influenza virus.

In a study that included 426 patients in China who were quarantined with pandemic H1N1 influenza A virus infection, the average duration of viral shedding was 6 days based upon real-time reverse transcriptase PCR (rRT-PCR) [57]. The median interval from resolution of fever to a negative rRT-PCR result was 3 days, with negative results occurring within 5 days in 88 percent of patients and within 7 days in 96 percent of patients. However, PCR techniques detect viral RNA, and not infectious virus, and may continue to be positive after viral cultures become negative.

Studies of shedding of seasonal influenza viruses are reviewed separately. (See "Clinical manifestations and diagnosis of seasonal influenza in adults", section on 'Transmission'.)

Incubation period — The estimated median incubation period appears to be approximately two days [57,58].

Secondary attack rates — There are conflicting data regarding whether secondary attack rates are higher with H1N1 influenza infection compared to seasonal influenza [59-64]. One study in Mexico estimated that the secondary attack rates of the pandemic strain were 22 to 33 percent, compared with 5 to 15 percent for seasonal influenza [60]. In contrast, studies from the United States and Kenya suggest that secondary attack rates are similar to those for seasonal influenza [62-64].

One US-based study investigated household transmission of infection from 216 index patients with confirmed or probable H1N1 influenza to their household contacts [64]. An acute respiratory illness developed in 78 of 600 household contacts (13 percent). Contacts who were 18 years of age or younger were twice as susceptible as those who were 19 to 50 years of age while individuals 50 years of age or older were significantly less susceptible than individuals 19 to 50. However, transmission from the index patient did not vary with age.

The mean time between the onset of symptoms in a case patient and the onset of symptoms in the household contacts infected by that patient (eg, the generation time) was 2.6 days (rage 2.2 to 3.5 days) [64]. Similar estimates were observed in an outbreak among students in one New York City high school [58].

Environmental transmission — Transmission via contact with surfaces that have been contaminated with respiratory droplets or by aerosolized small-particle droplets may also occur.

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 [4,65-67]. (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 [68-70]. Eleven sporadic cases of triple reassortant swine H1 influenza A viruses were detected in the United States between December 2005 and February 2009 [68]. Nine patients had exposure to pigs.

It is not clear how this virus arose or was initially transmitted to humans. There is no risk of becoming infected with influenza virus from eating pork [71].

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 [19,24]. The overall severity has been less than what was observed during the influenza pandemic of 1918 to 1919 [42]. (See "Epidemiology of influenza".)

Signs and symptoms — The signs and symptoms of H1N1 influenza have varied in adults and children.

Adults and adolescents — 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 [19,23,24,64,72-74]. Other frequent findings have included chills, myalgias, and arthralgias [19,73]. Rhabdomyolysis has been reported rarely [75].

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) [73]. In contrast, approximately one third of patients seen at two hospitals in Mexico had no fever at presentation [76]. Similarly, one third of patients in a multicenter study from China did not have a fever at presentation [72]. When fever was present, it usually lasted for three days (range 1 to 11 days). (See "Clinical manifestations and diagnosis of seasonal influenza in adults".)

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) [18].

Certain groups, such as elderly individuals and immunocompromised hosts, may have atypical presentations. In addition, subclinical infection has been reported rarely [77], although further study is required to determine how common this is.

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 [78]. 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 [78]. (See 'Complications' below and "Treatment of pandemic H1N1 influenza ('swine influenza')", section on 'High risk groups'.)

Definitions of illness severity — The United States Centers for Disease Control and Prevention has categorized the severity of illness from influenza as follows [79]:

• Mild or uncomplicated illness is characterized by fever, cough, sore throat, rhinorrhea, muscle pain, headache, chills, malaise, and sometimes diarrhea and vomiting, but no shortness of breath and little change in chronic health conditions.
• Progressive illness is characterized by typical symptoms plus signs or symptoms such as chest pain, poor oxygenation (eg, tachypnea, hypoxia, labored breathing in children), cardiopulmonary insufficiency (eg, hypotension), CNS impairment (eg, confusion, altered mental status), severe dehydration, or exacerbations of chronic conditions (eg, asthma, chronic obstructive pulmonary disease, chronic renal failure, diabetes or other cardiovascular conditions).
• Severe or complicated illness is characterized by signs of lower respiratory tract disease (eg, hypoxia requiring supplemental oxygen, abnormal chest radiograph, mechanical ventilation), CNS findings (encephalitis, encephalopathy), complications of hypotension (shock, organ failure), myocarditis or rhabdomyolisis, or invasive secondary bacterial infection based on laboratory testing or clinical signs (eg, persistent high fever and other symptoms beyond three days).

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 [30]:

• 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)

Among 426 patients with confirmed pandemic H1N1 infection in China, lymphopenia occurred in 68 percent of adults and 92 percent of children [72]. 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 [80].

Mild to moderate elevations of creatine kinase levels have been reported in some patients with severe illness [81]; one case of a patient with a creatine kinase level of 27,820 U/L resulting in rhabdomyolysis has been reported [75]. Lactate dehydrogenase was elevated in all 16 patients with severe illness in one study [81].

IMAGING

Chest radiography — 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 [23]. In a smaller study, common findings included patchy consolidation in lower or central lung zones or ground glass opacities with or without consolidation [82]. Of 14 critically ill patients who required intensive care unit admission and mechanical ventilation, extensive disease involving ≥3 lung zones was observed in 13.

CT imaging — Nodular opacities and pulmonary emboli have been reported in critically ill patients with H1N1 influenza who underwent CT chest imaging [82].

COMPLICATIONS

Respiratory complications — Rapidly progressive pneumonia, respiratory failure, acute respiratory distress syndrome, and multisystem organ failure have been reported [23,24,30,43,81,83-85].

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 (ECMO), and/or prone positioning ventilation [12,43,85].

Bacterial superinfection — Bacterial superinfection of the lung has been reported in 4 to 29 percent of cases that resulted in hospitalization or death in the United States, Argentina, Australia, and New Zealand [23,32,86,87]. Among the fatal cases described in the US, the following pathogens were identified: Streptococcus pneumoniae, Streptococcus pyogenes, Staphylococcus aureus, Streptococcus mitis, and Haemophilus influenzae [86].

An increase in the incidence of invasive pneumococcal disease has been detected in Denver, Colorado, which is one of the CDC's Active Bacterial Core surveillance sites [88]. The majority of cases have occurred in individuals between 20 and 59 years of age, whereas during non-pandemic years, most cases of invasive pneumococcal disease occur in individuals ≥65 years of age. Coinfection with S. pneumococcus was correlated with an increased case fatality ratio among patients with H1N1 influenza infection in Argentina [87].

Neurologic complications — Four children in Texas with pandemic H1N1 influenza A have had seizures, three of whom also had abnormal electroencephalograms [89]. All four recovered fully.

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".)

PATHOLOGY — Autopsy findings from the lungs of patients who died from pandemic H1N1 influenza A infection have included both upper and lower respiratory tract abnormalities, as illustrated in the following studies:

• Among 21 patients who died from pandemic H1N1 influenza A infection, 20 had diffuse alveolar damage [90]. Of the 20 patients with diffuse alveolar damage, six also had necrotizing bronchiolitis and five had extensive pulmonary hemorrhage. Other findings included cytopathic effects in the bronchial and alveolar epithelial cells and necrosis, epithelial hyperplasia, and squamous metaplasia of the large airways.
• In another autopsy study, four out of five patients had edema, hemorrhage, or necrosis in the upper respiratory tract [91]. Four patients had evidence of diffuse alveolar damage (hyaline membranes, alveolar septal edema), hyperplasia of type II pneumocytes, fibrin thrombus in the vascular lumen, and necrosis of bronchiolar walls. Three patients had inflammatory infiltrates below the endothelium and partial loss and adherence of the endothelium in the medium and small intrapulmonary blood vessels.
• Of 34 patients who died from pandemic H1N1 influenza A, most had tracheitis, bronchiolitis, and diffuse alveolar damage [92]. Influenza viral antigen was detected most commonly in the epithelium of the tracheobronchial tree, but also in alveolar epithelial cells and macrophages. Histologic and microbiologic evidence of bacterial pneumonia was present in 55 percent of cases.

PREDICTORS OF OUTCOME — 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 [32].

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) [93]. 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 [93]. Recommendations regarding whom to test may differ by state or community.

Patients in whom influenza testing should be considered include [93]:

Hospitalized patients, including pregnant women in labor, with suspected influenza infection (see "Prevention of pandemic H1N1 influenza ('swine influenza')" section on Newborns.)

• 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 [93].

Specimens — To establish the diagnosis of pandemic H1N1 influenza A, an upper or lower respiratory sample should be collected [93]. 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. A video showing the proper technique for nasopharyngeal specimen collection can be found at: http://content.nejm.org/cgi/content/full/NEJMe0903992/DC1.

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 [93]. 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 [93]. 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, as well as the quality of the sample obtained.

Among 21 critically ill patients with pandemic H1N1 influenza infection, lower respiratory tract specimens were positive by rRT-PCR in all patients, but upper respiratory tract specimens were positive in only 17 of 21 patients (81 percent) [94]. In a multicenter study from China, the median length of time during which patients had a positive rRT-PCR was six days (range 1 to 17 days) [72]. Independent risk factors for prolonged rRT-PCR positivity included age <14 years, male gender, and a delay from onset of symptoms to treatment with oseltamivir of >48 hours.

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 [95].

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 [93,96]. 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 [74,93,96-102]. Thus, a negative result does not rule out infection. The specificity of rapid antigen testing has generally been >95 percent [93], although in one study it was only 86 percent [100].

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) [97]. 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".)

Of 21 critically ill patients with pandemic H1N1 influenza infection, upper respiratory tract specimens were positive in 17 of 21 patients (81 percent) using rRT-PCR, but in only 5 of 20 patients (25 percent) using rapid antigen testing [94].

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 [93]. In one study, among 42 samples that were positive for pandemic H1N1 influenza A by real-time reverse-transcriptase polymerase chain reaction (rRT-PCR), 39 (93 percent) were positive by direct fluorescent antibody testing [103]. However, in another study, among 21 critically ill patients with pandemic H1N1 influenza, lower respiratory tract specimens were positive in all patients when tested by rRT-PCR, but in only 5 of 20 patients (25 percent) tested by immunofluorescence [94].

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 [93]. (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 [104]:

• 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 of the 2009 pandemic' 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.)

• Preliminary data suggest that the incubation period of pandemic H1N1 influenza A infection is approximately 2 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 'Viral 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.)