First Season of 2009 H1N1 Influenza

Transcription

1 MOUNT SINAI JOURNAL OF MEDICINE 77: , SPECIAL FEATURE First Season of 2009 H1N1 Influenza Kristin A. Swedish, MD, Gina Conenello, and Stephanie H. Factor, MD, MPH Mount Sinai School of Medicine, New York, NY OUTLINE VIROLOGY OF INFLUENZA HISTORICAL PANDEMICS SWINE-ORIGIN INFLUENZAS PRIOR TO H1N1 INFLUENZA PANDEMIC CLINICAL DISEASE DIAGNOSIS AND TREATMENT EPIDEMIOLOGY PREVENTION CONCLUSION ABSTRACT The 2009 H1N1 influenza virus is responsible for the first influenza pandemic of the 21st century. Within 5 months after its emergence in Mexico, it had affected more than 290,000 patients and caused at least 3486 deaths on 6 continents. This report provides information about influenza viruses, previous pandemics, and the virology, clinical features, and epidemiology of 2009 H1N1 influenza in order to elucidate the current pandemic and outline the questions that remain. Mt Sinai J Med 77: , Mount Sinai School of Medicine Key Words: H1N1, influenza, pandemic, swine flu. Outbreaks of respiratory illnesses and an increased number of influenza-like illnesses were reported in Mexico throughout March On April 21, 2009, the Centers for Disease Control and Prevention (CDC) reported that 2 Americans were infected with a novel influenza A virus (H1N1) that was likely related. 2 On Address Correspondence to: Kristin A. Swedish Mount Sinai School of Medicine New York, NY kristin.swedish@mssm.edu April 26, 2009, after 20 Americans were infected, the presence of the novel influenza virus was declared an emergency by the US Department of Health and Human Services. 3 On June 11, 2009, the World Health Organization declared 2009 H1N1 influenza a phase 6 (global) pandemic after 74 countries had reported disease (Figure 1). 4 This report provides the background for the 2009 H1N1 influenza virus so that we can better understand the current pandemic and outline the questions that remain. VIROLOGY OF INFLUENZA Influenza A, from the family Orthomyxoviridae, is a single-stranded, enveloped RNA virus. The viral particle has 2 types of glycoprotein spikes that project from its surface: hemagglutinin (HA) and neuraminidase (NA). HA recognizes and binds to cell surface sialic acids, compounds found on the cells of many animal species. This leads to the fusion of the viral and cell membranes and allows the virus to enter the cell. After intracellular viral RNA transcription, replication, and translation in the host cell, NA enables newly formed viruses to leave by cleaving the HA sialic acid bond. 6,7 The surface glycoprotein spikes are 2 of the 11 proteins encoded in the 8-segment influenza A RNA viral genome (Table 1). HA is encoded by segment 4; NA is encoded by segment 6. Polymerase basic 1 frame 2 (PB1-F2) is a nonstructural protein encoded by segment 2 that may or may not be present in the virus. When present, it is a proapoptotic protein causing programmed cell death and increased virulence. 6 The human immune system specifically responds to the HA and NA glycoproteins. Influenza A viruses are subtyped according to the type of HA and NA glycoproteins that they possess. There are 16 different possible subtypes for HA and 9 for NA. Only 3 HA subtypes (H1, H2, and H3) and 2 NA subtypes (N1 and N2) have been found in human influenza viruses. Published online in Wiley InterScience ( DOI: /msj Mount Sinai School of Medicine

2 104 K. A. SWEDISH ET AL.: SPECIAL FEATURE FIRST SEASON OF 2009 H1N1 INFLUENZA Fig 1. Laboratory-confirmed cases of 2009 H1N1 influenza and number of deaths as reported to the World Health Organization (status as of September 27, 2009). Reprinted with permission from the World Health Organization. 5 Copyright 2009, World Health Organization. Table 1. Influenza A Viral Genome. Segment Protein Function 1 PB2 Messenger RNA cap recognition during RNA transcription 2 PB1 Polymerase activity PB1-F2 Accessory protein; proapoptotic 3 PA Endonuclease activity; necessary for RNA elongation 4 HA Receptor binding and fusion 5 NP RNA binding protein; regulates nuclear viral import 6 NA Virus release 7 M1 Matrix protein; regulates viral RNA export from host cell nucleus M2 Forms ion channel; assists with viral uncoating and assembly 8 NS1 Regulates host gene expression; interferon antagonist NS2 Nuclear export of RNA NOTE: This table was adapted from Bouvier and Palese 6 and Dias et al. 8 Abbreviations: HA, hemagglutinin; M1, matrix 1; M2, matrix 2; NA, neuraminidase; NP, nucleoprotein; NS1, nonstructural 1; NS2, nonstructural 2; PA, polymerase acidic; PB1, polymerase basic 1; PB1-F2, polymerase basic 1 frame 2; PB2, polymerase basic 2. Changes in these glycoproteins create new strains of influenza A. After recovering from an influenza infection, humans are still susceptible to subsequent influenza infections caused by viruses with different glycoprotein subtypes. 6,7 Changes in the glycoproteins occur via 2 main mechanisms. Antigenic drift occurs when errors in the viral genome occur during replication and cause small changes in the viral proteins. Antigenic shift occurs when 2 different influenza A subtypes exchange full RNA segments. Antigenic shift is possible when a cell is coinfected with multiple influenza A subtypes. 6,9 It is currently believed that all known pandemic influenzas have been caused by antigenic shift resulting in novel influenza viruses to which humans are both susceptible and immunologically naïve. 6,10,11 It is currently believed that all known pandemic influenzas have been caused by antigenic shift resulting in novel influenza viruses to which humans are both susceptible and immunologically naïve. Genetic analysis has demonstrated that all mammalian influenza viruses are originally derived from avian influenza viruses. Aquatic birds are the asymptomatic primary natural reservoir for all subtypes of influenza A. Influenza viruses replicate predominantly in avian intestinal tract cells and are excreted in high concentrations in feces. These viruses of avian origin are capable of infecting mammals, including seals, whales, horses, dogs, cats, pigs, and humans. Over time, viruses have evolved into host-specific lineages in horses, humans, and pigs. 12

3 MOUNT SINAI JOURNAL OF MEDICINE 105 Species have specific sialic acid configurations on their cell surfaces that are recognized by speciesspecific influenza viruses. Influenza viruses of avian origin preferentially recognize the avian-specific sialic acid configuration found predominantly on bird intestinal tract cells. Influenza viruses of human origin preferentially recognize the human-specific sialic acid configuration found on human respiratory tract cells. Both avian-type and human-type sialic acid configurations are found on swine respiratory tract cells. Swine respiratory tract cells, therefore, may be coinfected with avian and human influenza viruses in addition to influenza viruses also circulating in the pig population. Once coinfected, swine cells can act as mixing vessels and enable the reassortment of viral segments from these 3 different species, which causes antigenic shift. 6,10,11 HISTORICAL PANDEMICS The 1918 influenza pandemic (Spanish influenza) was caused by an H1N1 influenza virus. The first influenza cases occurred in March 1918 in both Europe and the United States with a high attack rate and a low case fatality rate (a rate of 1.1% was estimated in US Army camps 13 ). A second wave spread worldwide in the fall of 1918, and a third wave affected many countries in early The second and third waves were marked by a higher case fatality rate (a rate of 4.7% was estimated in US Army camps 13 ). Approximately 40 million people died worldwide between 1918 and 1919 for an overall case fatality rate of over 2.5%. Nearly 50% of the influenza-related deaths occurred among young adults (20 40 years old), and less than 1% occurred among adults over the age of 65 years. It is theorized that older adults had partial protection from exposure to a similar virus that had been circulating before In , swine were also infected with a respiratory illness that resembled human influenza, and this suggested that the 1918 H1N1 virus was able to infect pigs. Scientists believe that the 1918 H1N1 virus continued to circulate in the swine population for many decades after this introduction. 15 In 1931, Robert Shope, a veterinarian, demonstrated that human serum from adults who survived the 1918 pandemic was protective against infection with a swine influenza virus isolated in 1930, and this suggested a close antigenic similarity between the swine and human viruses. 16 Three subsequent influenza pandemics were also caused by antigenic shift. In 1957, H2N2 emerged and caused many deaths in the immunologically naïve population. Approximately 70,000 people died in the United States alone. In 1968, H3N2 emerged but had lower morbidity and mortality rates because of its antigenic similarity to the 1957 H2N2 strain: it differed in only 2 of its 11 viral proteins. In 1977, another H1N1 strain emerged, with a lower attack rate among people born before 1950, who had likely been exposed and developed protective immunity to earlier circulating H1N1 viruses. 7 Since 1977, H1N1 viruses have been circulating in the human population and causing seasonal influenza. For approximately the past 10 years, 3 influenza viruses have contributed to seasonal influenza: 2 influenza A viruses (H1N1 and H3N2) and 1 influenza B virus. These 3 viruses circulate between November and March in the Northern Hemisphere and between April and September in the Southern Hemisphere. 6 Typical seasonal influenza causes 250,000 to 500,000 deaths annually, 17 approximately 35,000 of which are in the United States. Approximately 200,000 people are hospitalized annually in the United States with seasonal flu. 18 SWINE-ORIGIN INFLUENZAS PRIOR TO 2009 Although swine-origin influenza A viruses typically do not infect humans, occasional infections have occurred in recent years, usually after direct exposure to pigs. The severity of swine-origin influenza infection in humans ranges from mild to severe. The first swine flu scare occurred at the Fort Dix Army base in New Jersey in 1976, when approximately 200 people were infected with a novel H1N1 swine influenza virus that caused several serious infections and 1 death. Fear of a pandemic prompted a mass immunization campaign. Despite the panic that it caused, the swine influenza pandemic never materialized. 19 The vaccination campaign was stopped after 532 cases of Guillain-Barré syndrome resulted in 32 deaths. 15 Since 1976, there have been scattered reports of swine influenza. According to the CDC, 1 swine influenza infection was reported in the United States every 1 to 2 years. However, between December 2005 and February 2009, 11 nonfatal cases of swine influenza infection were reported. The first case in December 2005 was identified as the first human infection with a triple-reassortment swine influenza, a combination of avian, human, and swine viral gene segments. As demonstrated in Figure 2, the proteins polymerase basic 2 (PB2) and polymerase acidic (PA; gene segments 1 and 3) were of

4 106 K. A. SWEDISH ET AL.: SPECIAL FEATURE FIRST SEASON OF 2009 H1N1 INFLUENZA Fig 2. Triple-reassortant swine influenza A isolated from 11 patients between December 2005 and February 2009 in the United States. It is common practice in the virology community to call these proteins by their abbreviations without describing what they stand for. Since we have done it once in text and in the previous Figure, we need to keep explaining the abbreviations. Reprinted with permission from the New England Journal of Medicine. 20 Copyright 2009, Massachusetts Medical Society. North American avian origin. The protein polymerase basic 1 (PB1; segment 2) was from human seasonal H3N2. The HA, nucleoprotein (NP), NA, matrix (M), and nonstructural (NS) proteins (segments 4 8) were of North American classic swine origin. All subsequent human infections of swine origin had this triple reassortment H1N1 INFLUENZA PANDEMIC The first confirmed case patient of 2009 H1N1 influenza in Mexico was a child in La Gloria, a village that is home to many industrial hog farms. Direct swine-to-human transmission in Mexico is the presumed source of the pandemic. The first 2 confirmed case patients of 2009 H1N1 influenza in the United States were children in Southern California who had not had any contact with pigs, and this suggested human-to-human transmission. Indeed, many of the initial American cases could not be linked to travel to Mexico or to exposure to another confirmed case patient. 21 The 2009 H1N1 influenza virus was identified in April 2009 as a previously unknown H1N1 virus. As demonstrated in Figure 3, the proteins PB2, PB1, PA, NA, NP, and NS (gene segments 1 5 and 8) were similar to those previously found in triplereassortment swine influenza viruses. The remaining 2 proteins, NA and M (segments 6 and 7), were from the Eurasian swine genetic lineage first noted in 1979 [the proteins HA, NP, and NS (gene segments 4, 5, and 8) had been in the classic swine lineage prior to triple reassortment 22 ]. Despite the novel genomic reassortment of the 2009 H1N1 influenza virus, 3 components of the virus s genome suggest that morbidity and mortality rates will be lower than originally feared. First, unlike the 1918, 1957, and 1968 viruses, the 2009 H1N1 influenza virus does not contain the proapoptotic PB1-F2 accessory protein. 19 Laboratory studies have shown that expression of PB1-F2 enhances inflammation during the primary viral infection of mice and increases both the frequency and severity of secondary bacterial pneumonia. 23 Second, although the 2009 H1N1 influenza virus

5 MOUNT SINAI JOURNAL OF MEDICINE 107 Fig 3. Host and lineage origins for the gene segments of the 2009 H1N1 influenza virus. Reprinted with permission from Science. 22 Copyright 2006, American Association for the Advancement of Science. Despite the novel genomic reassortment of the 2009 H1N1 influenza virus, 3 components of the virus s genome suggest that morbidity and mortality rates will be lower than originally feared. has demonstrated resistance to the adamantane M2 inhibitor class of influenza drugs (amantadine and rimantadine), it is sensitive to the NA inhibitors (oseltamivir and zanamivir). 19 Finally, its genome is sufficiently similar to those of previously circulating influenza viruses to allow a degree of protective immunity in portions of the human population. In microneutralization assays performed by the CDC, 33% of adults over 60 years demonstrated cross-reactive antibody levels associated with a 50% reduction in the risk for influenza infection. 24 CLINICAL DISEASE Clinically, the signs and symptoms of 2009 H1N1 influenza are similar to those of seasonal influenza. Patients have a febrile respiratory illness with cough, sore throat, myalgias, headache, chills, and/or fatigue. Case series have shown that 25% 25 to 40% 26 of confirmed case patients have also had diarrhea or vomiting, unlike seasonal influenza. The incubation period ranges from 2 to 7 days. Its infectious period, when viral shedding occurs, is presumed to be similar to that of seasonal flu. It ranges from 1 day before symptom onset to at least 5 to 7 days after symptom onset. 25 The majority of 2009 H1N1 influenza infections have been self-limited and mild in nature. 27 Some cases of severe illness, causing The majority of 2009 H1N1 influenza infections have been self-limited and mild in nature. respiratory failure requiring intensive care, have been reported. 28 DIAGNOSIS AND TREATMENT The CDC recommends 2009 H1N1 influenza laboratory testing for hospitalized patients with suspected influenza; patients for whom an influenza diagnosis will affect decision making regarding clinical care, infection control, or management of close contacts; and patients who died of suspected influenza. 29 Antiviral treatment is recommended for all hospitalized patients with confirmed or suspected 2009 H1N1 influenza and those at high risk for complications. Treatment with zanamivir or oseltamivir is best when initiated within 48 hours of illness onset. The treatment duration is 5 days. Some studies of hospitalized patients have shown a benefit

6 108 K. A. SWEDISH ET AL.: SPECIAL FEATURE FIRST SEASON OF 2009 H1N1 INFLUENZA from antiviral treatment when treatment was initiated more than 48 hours after the onset of illness. Therefore, patients at high risk for complications may initiate treatment more than 48 hours after illness onset. Antiviral prophylaxis with a 10-day course of oseltamivir or zanamivir is recommended for anyone at high risk for complications who has had close contact with cases of confirmed, probable, or suspected 2009 H1N1 influenza or seasonal influenza. The CDC also recommends prophylaxis for health care workers who have had unprotected close-contact exposure to a person with confirmed, probable, or suspected 2009 H1N1 influenza or seasonal influenza during that person s infectious period. Antiviral prophylaxis of healthcare workers should be initiated within 48 hours of contact with an infectious person. 30 There have been scattered reports of patients with oseltamivir-resistant strains of 2009 H1N1 influenza. Two unrelated immunosuppressed patients, both in Seattle, developed resistance to oseltamivir during the course of treatment for 2009 H1N1 influenza. 31 Oseltamivir-resistant 2009 H1N1 influenza was also reported in 2 adolescents who had received oseltamivir in a mass chemoprophylaxis program during a summer camp outbreak in North Carolina. 32 In Hong Kong, a previously healthy 16-year-old girl who had not received oseltamivir prophylactically or for treatment tested positive for oseltamivir-resistant 2009 H1N1 influenza. 33 EPIDEMIOLOGY Several epidemiological factors are unique to the 2009 H1N1 influenza pandemic. The typical influenza season in the Northern Hemisphere ends in March, yet 2009 H1N1 influenza cases were reported throughout the spring and summer and into the fall of This extension of the traditional influenza season in the Northern Hemisphere is unusual. The typical influenza season in the Southern Hemisphere ends in September, yet 2009 H1N1 influenza cases were reported through early October. 34 Second, the age distribution of morbidity and mortality due to 2009 H1N1 influenza is different from that due to seasonal influenza. Although seasonal influenza predominantly affects children under 5 years of age and adults over 64 years of age, the majority of morbidity and mortality from 2009 H1N1 influenza has occurred in persons younger than 45 years. Country-specific and state-specific data from the first season showed that for all laboratory-confirmed cases Although seasonal influenza predominantly affects children under 5 years of age and adults over 64 years of age, the majority of morbidity and mortality from 2009 H1N1 influenza has occurred in persons younger than 45 years. the median age of persons with clinical disease ranged from 12 to 19 years, the median age of persons hospitalized with 2009 H1N1 influenza ranged from 16 to 27.5 years, the median age of persons hospitalized with complications from 2009 H1N1 influenza ranged from 38 to 45 years, and the median age of persons deceased because of 2009 H1N1 influenza ranged from 26 to 45 years (Table 2). Epidemiological data collected during the first season have demonstrated that certain groups are at higher risk for complications of 2009 H1N1 influenza. These groups, which are similar to those who are at increased risk for complications of seasonal influenza, include children under the age of 2 years, pregnant women and women up to 2 weeks postpartum (including women who have suffered pregnancy loss), children and adults with chronic diseases (including pulmonary, cardiovascular, renal, hepatic, hematological, and metabolic disorders), children and adults with disorders that compromise respiratory function or increase the risk for aspiration, and children and adults who are immunosuppressed (including immunosuppression caused by medications or human immunodeficiency virus). Unlike seasonal influenza, adults over 65 years appear to have age-related protective immunity to 2009 H1N1 influenza. However, when they acquire 2009 H1N1 influenza, adults over 65 years are at increased risk for complications, and this mandates their inclusion in the list of groups at higher risk for complications. 30 Of patients hospitalized with 2009 H1N1 influenza during the first season, the proportion with underlying medical conditions ranged from 30% 38 to 76%. 42 The most common underlying medical conditions were chronic lung disease, including asthma and chronic obstructive pulmonary disease, immunosuppression, chronic cardiac disease, diabetes, and obesity. The same medical conditions were common among patients who died of 2009 H1N1 influenza. The proportion of patients with underlying medical conditions who died ranged from 33% 38 to 71%. 39 Like seasonal influenza, pregnancy appears to be an important risk factor for severe disease with

7 MOUNT SINAI JOURNAL OF MEDICINE 109 Table 2. State-Specific and Country-Specific Epidemiological Data for Confirmed Cases of 2009 H1N1 Influenza. Age Age at % with Affected Death Underlying Underlying Date of Number (Median, (Median, Medical Medical Authors Publication Location Study Period Setting Affected Range) CFR Range) Conditions Conditions Ciblak et al. 35 August 13, 2009 Turkey May 15 to July 17, 2009 CDC 36 May 22, 2009 California April 15 to May 17, 2009 CDC 37 June 5, 2009 Mexico March 1 to May 29, 2009 CDC 38 July 17, 2009 Michigan May 26 to June 18, 2009 CDC 39 August 28, 2009 Chicago, IL April 24 to July 25, 2009 Gilsdorf and August 27, 2009 Germany April 20 to Poggensee 40 August 10, 2009 Health Protection Agency et al. 41 Kingdom June 4, 2009 United New York City Department of Health and Mental Hygiene 42 April 27 to May 31, 2009 July 8, 2009 New York, NY April 25 to July 8, 2009 Confirmed H1N1 cases First 30 patients hospitalized with confirmed H1N1 Laboratoryconfirmed H1N1 cases 10 ICU patients with H1N1 and ARDS Laboratoryconfirmed H1N1 cases and hospitalized patients with confirmed H1N1 Confirmed H1N1 cases Confirmed H1N1 cases Hospitalized patients with confirmed H1N % between years years, 27 days to 89 years % <15 years 32.3% between years years, 21 to 53 years year, 24 days to 91 years 16 year, 24 days to 91 years % between 0 89 years 77% between years years, 0 to 73 years 0 N/A 0 N/A 64% Chronic lung disease (37%) Immunosuppression (20%) Chronic cardiac disease (17%) Diabetes (13%) Obesity (13%) 55.7% between 30 to 59 years 30% 43 years, 28 to 44 years 0.45% 32 years, 20 to 54 years years 4.95% 44 years, 2 months to 83 years 43% <18 years, 77% <50 years 30% (hospitalized) 33% (died) Asthma (20% hospitalized; 33% died) 71% (died) Asthma (21% hospitalized; 14% died) Immunosuppression (29% died) Pregnancy (7% hospitalized; 14% died) 3.3% Respiratory disease (45%) Cardiovascular disease (15%) Diabetes (9%) Obesity (6%) Pregnancy (5%) 0 N/A 76% (hospitalized) Asthma (30% hospitalized; 29% died) 70% (died) Diabetes (13% hospitalized; 31% died)

8 110 K. A. SWEDISH ET AL.: SPECIAL FEATURE FIRST SEASON OF 2009 H1N1 INFLUENZA Table 2. (Continued). Age % with Affected Underlying Underlying Date of Number (Median, Age at Medical Medical Authors Publication Location Study Period Setting Affected Range) CFR Death Conditions Conditions Jain et al. 26 October 8, 2009 United States May 1 to June 9, 2009 Munayco et al , 2009 August 13, 2009 Peru May 9 to July Perez-Padilla June 29, 2009 et al. 44 (online) Mexico March 24 to April 24, 2009 Vaillant etal. 45 August 20, 2009 Worldwide April 27 to July 16, 2009 First 272 patients hospitalized with confirmed H1N1 Confirmed H1N1 cases Hospitalized patients with confirmed H1N1 and pneumonia First 684 deaths of patients with confirmed H1N years, 21 days to 86 years years, 0 87 years years, 9 months to 61 years 6.99% 26 years, 1.3 to 57 years 73% (hospitalized) 68% (died) 0.33% 39% 45 years, 9 to 52 years 126,168 N/A 0.6% 37 years, 0 to 87 years 44.4% (hospitalized) 42.9% (died) Heart disease (12% hospitalized; 18% died) Immune deficiency (9% hospitalized; 22% died) Asthma or COPD (36% hospitalized; 16% died) Diabetes (15% hospitalized) Immunosuppression (15% hospitalized) Neurological disease (7% hospitalized; 21% died) Pregnancy (7% hospitalized; 16% died) Hypertension (17% hospitalized; 14% died) Diabetes (17% hospitalized) Asthma (11% hospitalized) Obstructive sleep apnea (6% hospitalized; 14% died) 53% (died) Diabetes and/or obesity (28%) Respiratory disease (19%) Heart disease (19%) Abbreviations: ARDS, acute respiratory distress syndrome; CDC, Centers for Disease Control and Prevention; CFR, case fatality rate; COPD, chronic obstructive pulmonary disease; ICU, intensive care unit; N/A, not applicable. Not discussed by the authors.

9 MOUNT SINAI JOURNAL OF MEDICINE 111 Table 3. Laboratory-Confirmed Cases of 2009 H1N1 Influenza Reported to the World Health Organization as of July 6, Country Cases Deaths CFR (%) Argentina 2, Uruguay Dominican Republic Colombia Mexico 10, Costa Rica Paraguay Honduras Guatemala United States 33, Thailand 2, Canada 7, New Zealand 1, Chile 7, Australia 5, Brazil Spain Philippines 1, United Kingdom 7, NOTE: This table was adapted from the World Health Organization Web site. 46 Abbreviation: CFR, case fatality rate. the acquisition of 2009 H1N1 influenza. In New York City, 16% of hospitalized women of childbearing age were pregnant. 42 Five of the first 30 patients (16.7%) hospitalized in California were pregnant, 2 of whom developed complications (spontaneous abortion and premature rupture of membranes). 36 Of the first 272 patients hospitalized in the United States, 18 (7%) were pregnant women, 6 of whom had another underlying medical condition. Nineteen of these hospitalized patients died, and 3 had been pregnant. 26 Global death data show that approximately 10% of female patients who died were pregnant or had delivered at the time of their death. Of note, the available data suggest that up to half of the women also had underlying medical conditions, including asthma, obesity, and heart disease. 45 The case fatality rates for 2009 H1N1 influenza have varied from country to country (Table 3). The worldwide alert to the disease in Mexico likely provided public health practitioners in other countries time to implement preparedness plans. PREVENTION To promote widespread immunity to the virus, four 2009 H1N1 influenza vaccines have been developed and approved for use by the Food and Drug Administration. There is 1 live attenuated virus formulation that is administered intranasally and 3 inactivated virus formulations that are administered intramuscularly. 47 The CDC s Advisory Committee on Immunization Practices recommends that vaccination efforts focus initially on 5 groups of people: pregnant women, those who live with and care for children younger than 6 months, health care and emergency service personnel, people between the ages of 6 months and 24 years of age, and those between 25 and 64 years old with health conditions associated with a higher risk of complications from 2009 H1N1 influenza. Because of the decreased risk of The CDC recommends that vaccination efforts focus initially on 5 groups of people: pregnant women, those who live with and care for children younger than 6 months, health care and emergency service personnel, people between the ages of 6monthsand24yearsofage,and those between 25 and 64 years old with health conditions associated with a higher risk of complications from 2009 H1N1 influenza. infection for those 65 years old and older, the CDC recommends their vaccination only after the vaccination of younger people has been completed. 48 The effectiveness of the vaccine against 2009 H1N1 influenza had been a main concern during production. A vaccine immunogenicity trial was conducted in China with 2200 subjects ranging in age from 3 to 77 years. A hemagglutination inhibition titer of 1:40 or more within 3 weeks of vaccination was considered protective. A single 15-μg dose of the inactivated vaccine produced a protective serologic immune response in subjects ranging in age from 12 to 60 years. Children that were 3 to 11 years old and adults that were 61 years or older required a second dose to produce a similar response. 49 Preliminary results from a vaccine immunogenicity trial in American children showed that a single 15-μg dose of the inactivated vaccine produced a protective serologic immune response in children that were 10 to 17 years old, whereas children that were 6 months to 9 years old had a less robust response. 50 The CDC therefore recommends that children who are 6 months

10 112 K. A. SWEDISH ET AL.: SPECIAL FEATURE FIRST SEASON OF 2009 H1N1 INFLUENZA to 9 years old receive 2 doses of vaccine approximately 4 weeks apart, whereas people over the age of 10 years require only 1 dose. 47 CONCLUSION The activity of the 2009 H1N1 influenza virus during the influenza season will hopefully answer the numerous questions that remain. The 1918 Spanish influenza pandemic was characterized by multiple waves in quick succession that occurred too quickly to have been caused by antigenic drift. The first wave had a low case fatality rate and was followed by a second wave (and, in some countries, a third wave) with a much higher case fatality rate. There is great concern that 2009 H1N1 influenza will follow a similar pattern. Currently, the H1N1 viruses from around the world remain genetically close. 28 Of great concern is whether 2009 H1N1 influenza will mutate to become more virulent by either antigenic drift or acquisition of the proapoptotic PB2-F1 accessory protein. Sporadic cases of oseltamivir-resistant 2009 H1N1 influenza viruses have raised concern about widespread resistance. Mass immunization campaigns have been shown to provide herd immunity against seasonal influenza. When 70% of 3- to 17-year-old children in one Moscow neighborhood were vaccinated in 2001, the incidence rate of influenza-like illness in unvaccinated adults over 60 years was one-third of the incidence rate of influenza-like illness in unvaccinated adults over 60 years in an unvaccinated neighborhood. 51 We do not yet know the vaccination coverage rate required for herd immunity against 2009 H1N1 influenza. Hopefully, herd immunity will be achieved early in the influenza season. It is unclear how the 2009 H1N1 influenza pandemic will continue and when it will end. Global surveillance of epidemiological, clinical, and virological data over the influenza season will likely answer these remaining questions and enable the medical and public health communities to remain prepared. DISCLOSURES Potential conflict of interest: Nothing to report. REFERENCES 1. Centers for Disease Control and Prevention. Outbreak of swine-origin influenza A (H1N1) virus infection Mexico, March-April MMWR Morb Mortal Wkly Rep 2009; 58: Centers for Disease Control and Prevention. Swine influenza A (H1N1) infection in two children Southern California, March-April MMWR Morb Mortal Wkly Rep 2009; 58: US Department of Health and Human Services. HHS declares public health emergency for swine flu. Available at: a.html. Accessed November World Health Organization. Influenza A (H1N1) update 23. Available at: /en/index.html. Accessed November World Health Organization. Pandemic (H1N1) 2009 update 66. Available at: /en/index.html. Accessed November Bouvier NM, Palese P. The biology of influenza viruses. Vaccine 2008; 26(suppl 4): D49 D Palese P. Influenza: old and new threats. Nat Med 2004; 10(suppl 12): S82 S Dias A, Bouvier D, Crépin T, et al. The cap-snatching endonuclease of influenza virus polymerase resides in the PA subunit. Nature 2009; 458: National Institute of Allergy and Infectious Disease. Flu (influenza): what s the difference between seasonal flu, pandemic flu, and avian (bird) flu? Available at: Flu/DefinitionsOverview.htm. Accessed November This Week in Virology. Interview with Dr. Peter Palese. Available at: pdf. Accessed November Ma W, Lager KM, Vincent AL, et al. The role of swine in the generation of novel influenza viruses. Zoonoses Public Health 2009; 56: Webster RG. Influenza: an emerging disease. Emerg Infect Dis 1998; 4: Barry JM, Viboud C, Simonsen L. Cross-protection between successive waves of the influenza pandemic: epidemiological evidence from US Army camps and from Britain. JInfect Dis 2008; 198: Taubenberger JK, Morens DM influenza: the mother of all pandemics. Emerg Infect Dis 2006; 12: Zimmer SM, Burke DS. Historical perspective emergence of influenza A (H1N1) viruses. NEngl JMed2009; 361: Stein RA. Lessons from outbreaks of H1N1 influenza. Ann Intern Med 2009; 151: World Health Organization. Fact sheet no. 211: influenza (seasonal). Available at: mediacentre/factsheets/fs211/en/index.html. Accessed November Centers for Disease Control and Prevention. Seasonal influenza: the disease. Available at: Accessed November Wang TT, Palese P. Unraveling the mystery of swine influenza virus. Cell 2009; 137: Shinde V, Bridges CB, Uyeki TM, et al. Triplereassortant swine influenza A (H1) in humans in the United States, NEngl JMed 2009; 360: Centers for Disease Control and Prevention. Update: swine influenza A (H1N1) infections California and Texas, April MMWR Morb Mortal Wkly Rep 2009; 58:

11 MOUNT SINAI JOURNAL OF MEDICINE Garten RJ, Davis CT, Russell CA, et al. Antigenic and genetic characteristics of swine-origin 2009 A (H1N1) influenza viruses circulating in humans. Science 2009; 325: McAuley JL, Hornung F, Boyd KL, et al. Expression of the 1918 influenza A virus PB1-F2 enhances the pathogenesis of viral and secondary bacterial pneumonia. Cell Host Microbe 2007; 2: Centers for Disease Control and Prevention. Serum cross-reactive antibody response to a novel influenza A (H1N1) virus after vaccination with seasonal influenza vaccine. MMWR Morb Mortal Wkly Rep 2009; 58: Novel Swine-Origin Influenza A (H1N1) Virus Investigation Team. Emergence of a novel swine-origin influenza A (H1N1) virus in humans. NEngl JMed 2009; 360: Jain S, Kamimoto L, Bramley AM, et al. Hospitalized patients with 2009 H1N1 influenza in the United States. NEnglJMed2009; 361: Centers for Disease Control and Prevention. Questions & answers: 2009 H1N1 flu (swine flu) and you. Available at: Accessed November World Health Organization. Preparing for the second wave: lessons from current outbreaks. Available at: h1n1 second wave /en/index.html. Accessed November Centers for Disease Control and Prevention. Interim recommendations for clinical use of influenza diagnostic tests during the influenza season. Available at: tests. htm. Accessed November Centers for Disease Control and Prevention. Updated interim recommendations for the use of antiviral medications in the treatment and prevention of influenza for the season. Available at: Accessed November Centers for Disease Control and Prevention. Oseltamivir-resistant novel influenza A (H1N1) virus infection in two immunosuppressed patients Seattle, Washington, MMWR Morb Mortal Wkly Rep 2009; 58: Centers for Disease Control and Prevention. Oseltamivir-resistant 2009 pandemic influenza A (H1N1) virus infection in two summer campers receiving prophylaxis North Carolina, MMWR Morb Mortal Wkly Rep 2009; 58: Chen H, Cheung CL, Tai H, et al. Oseltamivir-resistant influenza A pandemic (H1N1) 2009 virus, Hong Kong, China. Emerg Infect Dis. doi:// /eid Available at: World Health Organization. Pandemic (H1N1) 2009 update 70. Available at: don/ /en/index.html. Accessed November Ciblak MA, Albayrak N, Odabas Y, et al. Cases of influenza A (H1N1) reported in Turkey, May-July Euro Surveill 2009; 14: Centers for Disease Control and Prevention. Hospitalized patients with novel influenza A (H1N1) virus infection California, April-May MMWR Morb Mortal Wkly Rep 2009; 58: Centers for Disease Control and Prevention. Update: novel influenza A (H1N1) virus infection Mexico, March-May, MMWR Morb Mortal Wkly Rep 2009; 58: Centers for Disease Control and Prevention. Intensivecare patients with severe novel influenza A (H1N1) virus infection Michigan, June MMWR Morb Mortal Wkly Rep 2009; 58: Centers for Disease Control and Prevention pandemic influenza A (H1N1) virus infection Chicago, Illinois, April-July MMWR Morb Mortal Wkly Rep 2009; 58: Gilsdorf A, Poggensee G. Influenza A(H1N1)v in Germany: the first 10,000 cases. Euro Surveill 2009; 14: Health Protection Agency, Health Protection Scotland, National Public Health Service for Wales, and HPA Northern Ireland Swine Influenza Investigation Teams. Epidemiology of new influenza A (H1N1) virus infection, United Kingdom, April-June Euro Surveill 2009; 14: New York City Department of Health and Mental Hygiene New York City Department of Health and Mental Hygiene Health alert #27: pandemic (H1N1) 2009 influenza update, revised reporting requirements and testing procedures. Available at: /09md27.pdf. Accessed November Munayco CV, Gómez J, Laguna-Torres VA, et al. Epidemiological and transmissibility analysis of influenza A (H1N1)v in a Southern Hemisphere setting: Peru. Euro Surveill 2009; 14: Perez-Padilla R, de la Rosa-Zamboni D, Ponce de Leon S, et al. Pneumonia and respiratory failure from swineorigin influenza A (H1N1) in Mexico. NEngl JMed 2009; 361: Vaillant L, Ruche G, Tarantola A, Barboza P. Epidemiology of fatal cases associated with pandemic H1N1 influenza Euro Surveill 2009; 14: World Health Organization. Pandemic (H1N1) 2009 update 58. Available at: don/ /en/index.html. Accessed November Centers for Disease Control and Prevention. Update on influenza A (H1N1) 2009 monovalent vaccines. MMWR Morb Mortal Wkly Rep 2009; 58: Centers for Disease Control and Prevention. Use of influenza A (H1N1) 2009 monovalent vaccine: recommendations of the Advisory Committee on Immunization Practices (ACIP), MMWR Morb Mortal Wkly Rep 2009; 58: Zhu FC, Wang H, Fang HH, et al. A novel influenza A (H1N1) vaccine in various age groups. NEngl JMed. doi:// /nejmoa Available at: National Institutes of Health. Early results: in children, 2009 H1N1 influenza vaccine works like seasonal flu vaccine. Available at: nih.gov/news/health/sep2009/niaid-21.htm. Accessed November Ghendon YZ, Kaira AN, Elshina GA. The effect of mass influenza immunization in children on the morbidity of the unvaccinated elderly. Epidemiol Infect 2006; 134: