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Published at www.nejm.org May 7, 2009=20 (10.1056/NEJMoa0903810) =

Emergence=20 of a Novel Swine-Origin Influenza A (H1N1) Virus in = Humans
Novel Swine-Origin Influenza A (H1N1) Virus=20 Investigation Team

 
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ABSTRACT

Background On April 15 and = April 17,=20 2009, novel swine-origin influenza A (H1N1) virus (S-OIV) was = identified in specimens obtained from two epidemiologically = unlinked=20 patients in the United States. The same strain of the virus = was=20 identified in Mexico, Canada, and elsewhere. We describe 642=20 confirmed cases of human S-OIV infection identified from the = rapidly=20 evolving U.S. outbreak.

Methods Enhanced surveillance was implemented in the = United=20 States for human infection with influenza A viruses that = could=20 not be subtyped. Specimens were sent to the Centers for = Disease=20 Control and Prevention for real-time=20 reverse-transcriptase=96polymerase-chain-reaction = confirmatory testing=20 for S-OIV.

Results From April 15 through May 5, a total of 642 = confirmed=20 cases of S-OIV infection were identified in 41 states. The = ages=20 of patients ranged from 3 months to 81 years; 60% of patients = were 18 years of age or younger. Of patients with available=20 data, 18% had recently traveled to Mexico, and 16% were = identified=20 from school outbreaks of S-OIV infection. The most common = presenting=20 symptoms were fever (94% of patients), cough (92%), and sore=20 throat (66%); 25% of patients had diarrhea, and 25% had = vomiting.=20 Of the 399 patients for whom hospitalization status was = known,=20 36 (9%) required hospitalization. Of 22 hospitalized patients = with available data, 12 had characteristics that conferred an = increased risk of severe seasonal influenza, 11 had = pneumonia,=20 8 required admission to an intensive care unit, 4 had = respiratory=20 failure, and 2 died. The S-OIV was determined to have a = unique=20 genome composition that had not been identified previously. =

Conclusions A novel swine-origin influenza A virus was = identified=20 as the cause of outbreaks of febrile respiratory infection = ranging=20 from self-limited to severe illness. It is likely that the = number=20 of confirmed cases underestimates the number of cases that = have=20 occurred.

Triple-reassortant swine influenza viruses, which contain genes = from=20 human, swine, and avian influenza A viruses, have been = identified in=20 swine in the United States since 1998,1,2=20 and 12 cases of human infection with such viruses were=20 identified in the United States from 2005 through 2009.3=20 On April 15 and April 17, 2009, the Centers for Disease = Control and=20 Prevention (CDC) identified two cases of human infection with = a=20 swine-origin influenza A (H1N1) virus (S-OIV) characterized = by a=20 unique combination of gene segments that had not been = identified=20 among human or swine influenza A viruses. As of May 5, 2009, = cases of=20 human infection with the same novel virus have also been=20 identified in Mexico, Canada, and elsewhere. We report the = first 643=20 confirmed cases of human infection with this virus in the = United=20 States.

Methods

Patients in Outbreak

On March 30, 2009, in San Diego County, California, a = 10-year-old=20 boy with asthma (Patient 1) had an onset of fever, cough, and = vomiting. On April 1, he was evaluated in an urgent care = clinic,=20 where he received treatment for his symptoms. He recovered = from=20 the illness within approximately 1 week. An influenza A virus = that could not be sub-typed was identified from a = nasopharyngeal=20 specimen that was collected from Patient 1 as part of a = clinical=20 trial to evaluate an experimental diagnostic test. As = specified=20 by the study protocol, the specimen was then sent to a = reference=20 laboratory for further testing and was found to be positive = for=20 influenza A virus but negative for both human H1 and H3 = subtypes,=20 with the use of real-time = reverse-transcriptase=96polymerase-chain-reaction=20 (RT-PCR) testing. On April 15, the CDC received the clinical=20 specimen and identified a novel influenza A (H1N1) virus of=20 swine origin. On the same day, the CDC notified the = California=20 Department of Public Health, and an epidemiologic = investigation=20 was initiated by state and local health department officials=20 and animal health officials. A viral isolate was found to = contain=20 genes from triple-reassortant swine influenza viruses that = were=20 known to circulate among swine herds in North America and two = genes encoding the neuraminidase and matrix proteins that = were=20 most closely related to genes of viruses obtained from ill = pigs=20 in Eurasia, according to results available in GenBank.

On March 28, 2009, in Imperial County, California, a 9-year-old=20 girl (Patient 2) without an epidemiologic link to Patient 1 = had=20 an onset of cough and fever. Two days later, she was taken to = an=20 outpatient clinic that was participating in an influenza = surveillance=20 project. A nasopharyngeal swab was collected at the clinic. = Patient 2=20 was treated with amoxicillin=96clavulanate, and she had an = uneventful=20 recovery. The nasopharyngeal specimen was sent to the Naval = Health=20 Research Center in San Diego, where an influenza A virus that = could=20 not be subtyped was identified. The specimen was shipped to = the CDC,=20 where it was received on April 17, and a novel influenza A = (H1N1)=20 virus of swine origin was identified. The genotype of the = virus was=20 similar to that of the virus isolated from the sample = obtained from=20 Patient 1. On April 17, both cases were reported to the World = Health Organization (WHO), according to the provisions of the = International Health Regulations.

Epidemiologic investigation of Patients 1 and 2 revealed that=20 neither patient had a recent history of exposure to swine. = According=20 to protocol, the identification of these two = epidemiologically=20 unlinked patients with novel S-OIV infection prompted the CDC = to notify state and local health departments, which initiated = case investigations and implemented enhanced surveillance for = influenza A viruses that could not be subtyped. The CDC = issued=20 recommendations to clinicians, asking that they consider the=20 diagnosis of S-OIV infection in patients with an acute = febrile=20 respiratory illness who met the following criteria: residence = in an area where confirmed cases of human infection with = S-OIV=20 had been identified, a history of travel to such areas, or = contact=20 with ill persons from these areas in the 7 days before the = onset=20 of illness. If S-OIV infection was suspected in a patient, = clinicians=20 were asked to obtain a nasopharyngeal swab from the patient = and=20 to contact their state and local health departments in order = to=20 facilitate initial testing of the specimen by RT-PCR assay at = the=20 state public health laboratory. State public health laboratories = were=20 asked to send all specimens identified as influenza A viruses = that=20 could not be subtyped to the CDC for further investigation.=20 Additional cases were identified with the use of a nationally = standardized case definition of confirmed swine influenza A=20 (H1N1) virus infection, which was defined as an acute febrile = respiratory illness with the presence of S-OIV confirmed by=20 real-time RT-PCR, viral culture, or both.

This report was exempt from the requirement for institutional=20 review, and the privacy rule of the Health Insurance = Portability=20 and Accountability Act did not apply since it was a public = health=20 investigation.

Real-Time RT-PCR

The CDC has developed a real-time RT-PCR assay to detect = seasonal=20 influenza A, B, H1, H3, and avian H5 serotypes. This assay = has=20 been approved by the Food and Drug Administration (FDA) and = was=20 distributed in December 2008 through U.S. Public Health = laboratories=20 and the WHO's Global Influenza Surveillance Network. Primers = and=20 probes specific for swine influenza A (H1 and H3 subtypes) = were=20 recently developed and tested for use in a modified version = of this=20 assay for the detection of human infection with swine = influenza=20 viruses. These previously developed reagents allowed the CDC = to=20 quickly modify the existing assay for specific detection of = S-OIV.=20 Technical details on this assay have been published on the = WHO Global=20 Influenza Programme Web site at www.who.int/csr/resources/publications/swine= flu/CDCrealtimeRTPCRprotocol_20090428.pdf.=20

Nucleotide Sequencing and Phylogenetic Analysis

A total of 49 viral isolates from specimens obtained from = patients=20 with confirmed S-OIV infection in 13 states in the United = States=20 were grown in MDCK cell cultures. Amplicons for sequencing = were=20 generated by reverse transcription, followed by PCR = amplification=20 to generate overlapping double-stranded DNA amplicons = covering=20 each of eight segments of the influenza virus genome. Primers = were designed to bind approximately every 200 to 250 = nucleotides=20 along the genome with degenerate bases to allow for sequence=20 variation (for details, see the Suppl= ementary=20 Appendix, available with the full text of this article at = NEJM.org).

Sequencing reactions were performed on a standard = high-throughput=20 sequencing system with the use of BigDye Terminator, version=20 3.1 (Applied Biosystems) with 1 mm3 of template=20 double-stranded DNA. Sequence data were assembled and = contiguous=20 sequences were generated with the Sequencher software = package,=20 version 4.7 (Gene Codes). All sequence data that were used in = this=20 study are available from GenBank (see the Suppl= ementary=20 Appendix for details).

Phylogenetic Analysis

Phylogenetic trees were inferred with the use of the = maximum-likelihood=20 method in the GARLI 0.96b7 package. All phylogenetic analyses = were visualized in TreeView, version 1.6.6.

Results

Patients

From April 15 through May 5, 2009, a total of 642 confirmed = cases=20 of human infection with the outbreak strain of S-OIV were = identified=20 in 41 states (Figure=20 1 and Figure=20 2). Cases of human infection with the outbreak strain of = S-OIV=20 were also reported in Mexico, Canada, and other countries.4=20 Among 381 U.S. patients for whom data were available, 18% = reported=20 having traveled to Mexico within 7 days before the onset of = illness;=20 of these patients, 7 were subsequently hospitalized. =


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 =20 		Figure 1.=20 Epidemiologic Curve of Confirmed Cases of Human = Infection=20 with Swine-Origin Influenza A (H1N1) Virus with Known Date = of=20 Illness Onset in the United States (March 28=96May 5, 2009).

Data regarding the date of onset of illness were = available for=20 394 patients. This epidemiologic curve does not reflect all = cases of=20 infection with S-OIV from March 28 through May 5, 2009, = because of=20 the lag in case reporting and laboratory confirmation. =

 

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 =20 		Figure 2.=20 Distribution of 642 Confirmed Cases of Human = Infection with=20 Swine-Origin Influenza A (H1N1) Virus in the United States = (May 5,=20 2009).

There were no cases in the District of Columbia. =

 
Four= =20 clusters of confirmed S-OIV infection were identified early = in the=20 investigation in schools and universities in South Carolina = (7=20 students), Delaware (22 students), Texas (5 students), and = New York=20 (70 students, school staff, and contacts of students). Some = students=20 attending the school in New York where the cluster of = confirmed cases=20 occurred and who did not have confirmed infection were = reported to=20 have traveled to Mexico during the week preceding the cluster = of=20 illnesses. In addition to the confirmed cases that were = identified in=20 the four school outbreaks, respiratory illnesses for which = samples=20 were not obtained occurred among household and school = contacts of=20 patients with confirmed S-OIV infection.

Demographic and Clinical Features

The age of patients with confirmed S-OIV infection ranged from = 3=20 months to 81 years (Table=20 1). A total of 40% of patients were between the ages of = 10 and 18=20 years, and only 5% of patients were 51 years of age or older. = Among=20 the patients for whom clinical information was available, the = most=20 common symptoms were fever (94%), cough (92%), and sore = throat (66%).=20 In addition, 25% of patients had diarrhea, and 25% had = vomiting.=20

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 =20 		Table 1.=20 Characteristics and Symptoms of the 642 Patients = with=20 Confirmed Swine-Origin Influenza A (H1N1). =

 
Of = the 399=20 patients with confirmed S-OIV infection for whom = hospitalization=20 status was known, 36 (9%) required hospitalization. The age = of=20 hospitalized patients ranged from 19 months to 51 years. Of = the 22=20 hospitalized patients for whom data were available, 4 (18%) = were=20 children under the age of 5 years, and 1 patient (4%) was = pregnant.=20 Nine patients (41%) had chronic medical conditions: a = 41-year-old=20 woman with autoimmune disease treated with multiple = immunosuppressive=20 agents; a 35-year-old man with Down's syndrome and a history = of=20 congenital heart disease; a 33-year-old woman with asthma, = rheumatoid=20 arthritis, and psoriasis who was 35 weeks pregnant; a = 22-month-old=20 child with a history of neonatal myasthenia gravis, a=20 ventriculoseptal defect, swallowing dysfunction, and chronic = hypoxia;=20 and five patients with asthma alone. Seven patients (32%) = reported=20 having traveled to Mexico within 7 days before the onset of = illness.=20 Eleven patients (50%) had radiologically confirmed pneumonia, = including one patient who had pneumomediastinum, one patient = who had=20 necrotizing pneumonia, and one patient who had an empyema = that was=20 surgically drained, with no growth from culture of empyema = fluid.=20 Eight patients (36%) required admission to an intensive care = unit,=20 and four patients (18%) had respiratory failure requiring = mechanical=20 ventilation. Fourteen patients (74%) were treated with = oseltamivir=20 after admission to the hospital. As of May 5, 18 of the 22 = patients=20 (82%) had recovered from the acute illness; 2 patients =97 a = previously=20 healthy 23-month-old child and a previously healthy = 30-year-old woman=20 =97 remained critically ill with respiratory failure, and the = 22-month-old child with neonatal myasthenia gravis and the=20 33-year-old woman who was pregnant when she became ill = died.=20

Laboratory Analyses

Original clinical samples that were obtained from all 642 = patients=20 with confirmed infection and that were received by the CDC = were=20 tested with the use of real-time RT-PCR assays for swine = influenza,=20 and all the samples were confirmed to be positive for S-OIV.=20 Among the 49 S-OIV isolates from 13 states in the United = States=20 that were sequenced at the CDC as of May 5, 2009, all were 99 = to 100% identical in all genes. Phylogenetic analysis of = sequences=20 of all genes of A/California/04/2009, the virus isolated from = Patient 1, showed that its genome contained six gene segments = (PB2, PB1, PA, HA, NP, and NS) that were similar to ones = previously=20 found in triple-reassortant swine influenza viruses = circulating=20 in pigs in North America (Table=20 2). The genes encoding neuraminidase (NA) and M = protein=20 (M) were most closely related to those in influenza A = viruses=20 circulating in swine populations in Eurasia (Figure=20 3). This particular genetic combination of influenza = virus=20 segments had not been seen before in the United States or = elsewhere.=20 Previous North American triple-reassortant swine influenza A = (H1)=20 viruses were known to be composed of the hemagglutinin = (HA),=20 nucleoprotein (NP), NA, M, and nonstructural protein=20 (NS) genes, originating from classic swine influenza A = viruses; the polymerase PB2 (PB2) and polymerase = (PA)=20 genes from avian influenza viruses from the North American = lineage;=20 and the polymerase PB1 (PB1) gene from human influenza = A=20 viruses.

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 =20 		Table 2.=20 Phylogenetic Analysis of Sequences of all Genes = Identified=20 in A/California/04/2009. =

 

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 =20 		Figure 3.=20 Comparison of H1N1 Swine Genotypes in Recent Cases = in the=20 United States.

The triple-reassortant strain was identified in specimens = from=20 patients with infection with triple-reassortant swine = influenza=20 viruses before the current epidemic of human infection with = S-OIV.=20 HA denotes the hemagglutinin gene, M the M = protein=20 gene, NA the neuraminidase gene, NP the = nucleoprotein=20 gene, NS the nonstructural protein gene, PA = the=20 polymerase PA gene, PB1 the polymerase PB1 gene, and=20 PB2 the polymerase PB2 gene. =

 
Alth= ough=20 the HA of S-OIV belongs to the same lineage as the = gene found=20 in recent human cases of triple-reassortant influenza A (H1) = virus=20 infection, the two genes differ by approximately 20 to 30 = amino acids=20 in the HA1 regions alone (Fig. 1 in the Suppl= ementary=20 Appendix). Among viral isolates from the current = epidemic, there=20 were up to five nucleotide changes resulting in four amino = acid=20 changes in HA.

The NA of S-OIV has the closest homology to the Eurasian = lineage=20 of swine influenza viruses, such as A/swine/Belgium/1/83 H1N1 = (Fig. 2 in the Suppl= ementary=20 Appendix). In contrast, the H1N1 triple-reassortant swine = influenza virus in the recent human infections contains = NA=20 from the North American swine lineage.3=20 The NA genes from the Eurasian and North American swine=20 influenza virus lineages are highly divergent, with more than = 77=20 differences in amino acids between these lineages. There are = two=20 differences in nucleotides and one difference in amino acids = between=20 the viruses isolated from specimens taken from Patients 1 and = 2.=20 Data from both genetic sequencing and functional=20 neuraminidase-inhibition assays indicate that all S-OIVs that = have=20 been examined are susceptible to both oseltamivir and = zanamivir, two=20 antiviral medications approved for the prevention and = treatment of=20 influenza in the United States (Table=20 3).

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 =20 		Table 3.=20 Susceptibility of 37 Isolates of Swine-Origin = Influenza A=20 (H1N1) Virus to Neuraminidase Inhibitors. =

 
Like= =20 NA, the M gene of A/California/04/2009 has the = closest=20 homology to the M gene in the Eurasian lineage of swine=20 influenza viruses (Fig. 3 in the Suppl= ementary=20 Appendix). Analyses of the M gene from all samples = from=20 the current epidemic showed a serine 31-to-asparagine = mutation that=20 confers resistance to M2 blockers (adamantanes), including = amantadine=20 and rimantadine. This phenotype is typical for recent = Eurasian=20 lineage swine influenza viruses but has not previously been = seen in=20 American swine viruses.

Sequences of the PB1, PB2, PA, NP (replication complex), = and=20 NS genes obtained from samples from the current epidemic = have=20 the closest homology to the genes in the swine influenza = viruses=20 that have been recently isolated in the United States from = the=20 North American swine lineage. These sequences were 99 to 100% = identical at the amino acid level (data not shown; sequences=20 are available from GenBank).

Discussion

As of May 5, 2009, a total of 642 cases of human infection with = a=20 novel swine-origin influenza A (H1N1) virus have been identified = in=20 the United States, and additional cases have been identified = in=20 Mexico, Canada, and elsewhere.4=20 On April 25, the WHO declared a public health emergency of=20 international concern, and on April 26, the United States = declared a=20 public health emergency. On April 29, the WHO raised the = pandemic=20 influenza phase from 4 to 5, indicating that human-to-human=20 transmission of the virus was occurring in at least two = countries in=20 one WHO region. The emergence of S-OIV infection among humans = presents the greatest pandemic threat since the emergence of=20 influenza A (H3N2) virus in 1968.

In the United States to date, most confirmed cases of S-OIV=20 infection have been characterized by self-limited, = uncomplicated=20 febrile respiratory illness and symptoms similar to those of=20 seasonal influenza (cough, sore throat, rhinorrhea, headache, = and myalgia), but approximately 38% of cases have also = involved=20 vomiting or diarrhea, neither of which is typical of seasonal = influenza. However, some patients have been hospitalized with = more severe disease, and two patients have died. The = observation=20 that 60% of patients were 18 years of age or younger suggests = that children and young adults may be more susceptible to = S-OIV=20 infection than are older persons or that because of = differences=20 in social networks, transmission to older persons has been = delayed.=20 It is also possible that elderly persons may have some level = of=20 cross-protection from preexisting antibodies against S-OIV = infection,=20 as suggested by serologic studies of the 1976 swine influenza = vaccine.5,6=20 A potential case-ascertainment bias may also exist, with more = young=20 people being tested as part of outbreaks of S-OIV infection = in=20 schools7=20 and fewer older persons being tested for influenza. However, = the=20 epidemic is evolving rapidly, and the number of confirmed = cases is an=20 underestimate of the number of cases that have occurred. =

Continued identification of new cases in the United States and=20 elsewhere indicates sustained human-to-human transmission of=20 this novel influenza A virus. The modes of transmission of = influenza=20 viruses in humans, including S-OIV, are not known but are = thought=20 to occur mainly through the dissemination of large droplets = and=20 possibly small-particle droplet nuclei8=20 expelled when an infected person coughs. There is also = potential for=20 transmission through contact with fomites that are = contaminated with=20 respiratory or gastrointestinal material.9,10=20 Since many patients with S-OIV infection have had diarrhea, = the=20 potential for fecal viral shedding and subsequent = fecal=96oral=20 transmission should be considered and investigated. Until = further=20 data are available, all potential routes of transmission and = sources=20 of viral shedding should be considered.

The incubation period for S-OIV infection appears to range from = 2=20 to 7 days; however, additional information is needed. On the = basis of=20 data regarding viral shedding from studies of seasonal = influenza,=20 most patients with S-OIV infection might shed virus from 1 = day before=20 the onset of symptoms through 5 to 7 days after the onset of = symptoms=20 or until symptoms resolve; in young children and in = immunocompromised=20 or severely ill patients, the infectious period might be = longer.11=20 Studies of viral shedding to define the infectious period are = under=20 way. The potential for persons with asymptomatic infection to = be the=20 source of infection to others is unknown but should be=20 investigated.

The clinical spectrum of novel S-OIV infection is still being=20 defined, but both self-limited illness and severe outcomes,=20 including respiratory failure and death, have been observed=20 among identified patients =97 a wide clinical spectrum = similar to=20 that seen among persons infected with earlier strains of = swine-origin=20 influenza viruses3=20 and seasonal influenza viruses.12=20 The severe illness and deaths associated with seasonal = influenza=20 epidemics are in large part the result of secondary = complications,=20 including primary viral pneumonia, secondary bacterial = pneumonia=20 (particularly with group A streptococcus, Staphylococcus=20 aureus, and Streptococcus pneumoniae),13,14,15=20 and exacerbations of underlying chronic conditions.16=20 These same complications may occur with S-OIV infection. = Patients who=20 are at highest risk for severe complications of S-OIV = infection are=20 likely to include but may not be limited to groups at highest = risk=20 for severe seasonal influenza: children under the age of 5 = years,=20 adults 65 years of age or older, children and adults of any = age=20 with underlying chronic medical conditions, and pregnant = women.17,18=20 Of the 22 hospitalized patients with confirmed S-OIV = infection=20 who have been identified thus far and for whom data are = available,=20 12 had characteristics (pregnancy, chronic medical = conditions,=20 or an age of less than 5 years) that conferred an increased=20 risk of severe seasonal influenza, although none of the = patients=20 were 65 years of age or older.

Human infection with novel S-OIV emerged in the United States = at a=20 time when seasonal influenza A and B virus activity was = decreasing.=20 The cocirculation of human influenza A (H1N1) virus, = influenza A=20 (H3N2) virus, or influenza B virus in areas where human cases = of=20 S-OIV infection are being identified presents diagnostic and=20 treatment challenges for clinicians. Clinicians should = consider the=20 diagnosis of S-OIV infection in patients with febrile = respiratory=20 illness seeking care in affected areas or in those who have = traveled=20 to affected areas. The CDC has developed a Swine Influenza = Virus=20 Real-Time RT-PCR Detection Panel. Under the Project Bioshield = Act of=20 2004, the FDA has issued an emergency-use authorization, = allowing for=20 the use of this assay by state public health laboratories to=20 respond to the current outbreak.19=20 If S-OIV infection is suspected and diagnostic testing is = indicated,=20 clinicians should obtain a nasopharyngeal specimen, notify = their=20 local public health department, and arrange for specimens to = be=20 tested for S-OIV by Swine Influenza Virus Real-Time RT-PCR = Detection=20 Panel, according to local and state public health guidance = and after=20 consideration of local laboratory capacity for diagnostic=20 testing.

Two classes of antiviral medication are available for the = treatment=20 of seasonal human influenza: neuraminidase inhibitors = (oseltamivir=20 and zanamivir) and adamantanes (rimantadine and amantadine).=20 During the 2008=962009 influenza season, almost all = circulating=20 human influenza A (H1N1) viruses in the United States were = resistant=20 to oseltamivir.20=20 However, genetic and phenotypic analyses indicate that S-OIV = is=20 susceptible to oseltamivir and zanamivir but resistant to the = adamantanes.21=20 At this time, the clinical effectiveness of antiviral = treatment of=20 S-OIV is unknown. As of May 5, 2009, the CDC has recommended = that=20 given the severity of illness observed among some patients = with S-OIV=20 infection, therapy with neuraminidase inhibitors should be=20 prioritized for hospitalized patients with suspected or = confirmed=20 S-OIV infection and for patients who are at high risk for=20 complications from seasonal influenza. As recommendations are = updated, they will be posted on the CDC's Web site at www.cdc.gov/h1n1f= lu/recommendations.htm.=20 The FDA has issued an emergency-use authorization that = approves=20 the use of oseltamivir to treat influenza in infants under = the=20 age of 1 year (treatment that is normally approved for those = 1=20 year of age or older) and for chemoprophylaxis in infants = older=20 than 3 months of age (chemoprophylaxis that is normally = approved=20 for children 1 year of age or older).19=20

Prevention and control measures for S-OIV are based on our = understanding=20 of seasonal human influenza22=20 and consideration of potential modes of transmission. As of = May 5,=20 2009, the CDC has recommended that health care workers who = provide=20 direct care for patients with known or suspected S-OIV = infection=20 should observe contact and droplet precautions, including the = use of=20 gowns, gloves, eye protection, face masks, and fit-tested, = disposable=20 N95 respirators. In addition, patients with confirmed or = suspected=20 S-OIV infection should be placed in a single-patient room = with the=20 door kept closed, and airborne-infection isolation rooms with = negative-pressure handling should be used whenever an=20 aerosol-generating procedure is being performed. Frequent = hand=20 washing with soap and water may reduce the risk of infection = and=20 transmission.23=20 As recommendations are updated, they will be posted at www.= cdc.gov/h1n1flu/guidelines_infection_control.htm.=20 Because the novel S-OIV strain is antigenically distinct from = the influenza A (H1N1) strain represented in the 2008=962009=20 influenza vaccine, seasonal influenza vaccination during the=20 2008=962009 influenza season is not anticipated to provide=20 protection against novel S-OIV infection. A strain of S-OIV = has=20 been identified as a potential egg-derived candidate strain = for S-OIV=20 vaccine development and has been sent to partner laboratories = for=20 evaluation and further development.

Given the rapidly evolving nature of this outbreak, the CDC's=20 recommendations are likely to change as more information = becomes=20 available. Clinicians are advised to monitor the H1N1 Influenza Center=20 (NEJM.org) and the CDC Web site (www.cdc.gov/h1n1flu/) for = changes=20 in guidance for testing, treatment, and infection control. =

In conclusion, we report an outbreak of human infection with = a=20 novel influenza A (H1N1) virus of swine origin in the United = States,=20 which is spreading through sustained human-to-human = transmission in=20 multiple countries. The identification of human S-OIV = infection in=20 geographically dispersed countries and across continents = demonstrates=20 the ease with which infection can be spread and facilitated = by air=20 and land travel and community networks and gatherings. As = enhanced=20 surveillance for S-OIV infection is implemented globally, = additional=20 cases are expected to be identified. The cases of infection = with=20 S-OIV described in this report may provide guidance for = clinicians=20 with respect to presenting symptoms and outcomes of infection = with=20 this novel virus.

No potential conflict of interest relevant to this = article=20 was reported.

The findings and conclusions in this article are those of the=20 authors and do not necessarily represent the views of the = CDC.

* = The members of=20 the Novel Swine-Origin Influenza A (H1N1) Virus Investigation = Team=20 are listed in the Appendix.


Source=20 Information

The members of the writing group (Fatimah S. Dawood, = M.D.,=20 Epidemic Intelligence Service, Office of Workforce and Career = Development; and=20 Seema Jain, M.D., Lyn Finelli, Dr.P.H., Michael W. Shaw, Ph.D., Stephen=20 Lindstrom, Ph.D., Rebecca J. Garten, Ph.D., Larisa V. Gubareva, M.D., = Ph.D.,=20 Xiyan Xu, M.D., Carolyn B. Bridges, M.D., and Timothy M. Uyeki, M.D., = M.P.H,=20 M.P.P., Influenza Division, National Center for Immunization and = Respiratory=20 Diseases =97 all at the Centers for Disease Control and Prevention, = Atlanta)=20 assume responsibility for the overall content and integrity of the = article.=20

This article (10.1056/NEJMoa0903810) was = published=20 at NEJM.org on May 7, 2009. It will appear in the July 2 issue of the=20 Journal.

Address reprint requests to Dr. Dawood at the = Influenza=20 Division, Centers for Disease Control and Prevention, 1600 Clifton Rd. = NE, MS=20 A-32, Atlanta, GA 30333, or at fdawood{at}cdc.gov ; or to Dr. Shaw at the Influenza Division, Centers for Disease Control = and=20 Prevention, 1600 Clifton Rd. NE, MS G-16, Atlanta, GA 30333, or at mshaw1{at}cdc.gov .

References

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  14. McCullers JA. Insights into the interaction between = influenza=20 virus and pneumococcus. Clin Microbiol Rev 2006;19:571-582. [Free Full Text]=
  15. O'Brien KL, Walters MI, Sellman J, et al. Severe = pneumococcal=20 pneumonia in previously healthy children: the role of preceding = influenza=20 infection. Clin Infect Dis 2000;30:784-789. [CrossRef][ISI][Medline]
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Appendix

The members of the Novel Swine-Origin Influenza A (H1N1) = Investigation=20 Team are as follows (asterisks indicate members of the = Epidemic=20 Intelligence Service, Office of Workforce and Career = Development,=20 Centers for Disease Control and Prevention): Alabama = Department=20 of Public Health: S. Massingale, T. Pippin, S. Davidson;=20 Alaska Department of Health and Social Services: J. = Butler, J.=20 McLaughlin, E. Funk; California Department of Public = Health:=20 M. Acosta, G. Chavez, C. Glaser, H. Guevara, K. Harriman, D. = Hatch,=20 A. Kimura, J. Louie, B. Matyas, H. Rosen, D. Schnurr, D. = Vugia,=20 K. Winter; Colorado Department of Public Health and=20 Environment: J. Kenfield, K. Gershman, N. Calonge; = Connecticut=20 Department of Public Health: M. Cartter, J. Fontana, P. = Mshar;=20 Dickinson County Health Department: L. Davies, B.L. = Holmes;=20 District of Columbia Department of Health: C. Glymph, = G. Lum,=20 R. Diggs; Florida Department of Health: L. Ball, J. = Hamilton,=20 R. Hopkins; Georgia Department of Public Health: C.L. = Drenzek;=20 Houston Department of Health and Human Services: D.=20 Awosika-Olumo; Imperial County Public Health = Department: P.=20 Kriner, K. Lopez, M. Rios; Kansas Department of Health and = Environment: M.C. Ba=F1ez Ocfemia, D.C. Hunt, D. Neises, = I.C.=20 Trevino-Garrison; Naval Health Research Center: D. = Faix, P.=20 Blair; Navy Medical Center, San Diego, CA: S. Sherman, = J.=20 Tueller; New York City Department of Health and Mental=20 Hygiene: Swine Flu Investigation Team; Ohio Department = of=20 Health: J. O'Quin, F. Smith, K. Smith, K. Winpisinger; = Randolph=20 Air Force Base 12th Medical Group: S.Y. Green; San Antonio=20 Metropolitan Health District: B.J. Alsip, F.A. Blevins, = F.A.=20 Guerra, R. Sanchez; San Diego County Health and Human=20 Services: M. Ginsberg, J. Johnson, A. Maroufi, D. Sunega; = Texas Department of State Health Services: C. Alaniz, = C.=20 Davis, R. Espinoza, V.P. Fonseca, S. Guerra, B. Hannemann, G. = Heseltine, R. Jones, C. Morgan, N. Pascoe, S. Penfield, C.=20 Rohr-Allegrini, T. Shim, J. Taylor, R. Taylor, N. Walea, D. = Zane;=20 U.S. Air Force School of Aerospace Medicine: L.E. = Sinclair,=20 M.J. Shim, P.M. Lucas, T.F. Gibbons; Centers for Disease = Control=20 and Prevention: A. Balish, J. Barnes, L. Berman, D.M. = Blau,* L.=20 Brammer, J. Bresee, N. Cox, C. Davis, V. Deyde, N. Dharan,* = R. Donis,=20 S. Doshi,* S. Emery, S. Epperson, D.H. Esposito,* A. Foust, = A.=20 Fowlkes, R. Garten, R.M. Gladden,* D. Gross, L. Gubareva, H. = Hall,=20 G.S. Han,* M. Hillman, B.H. Harcourt, I. Hwang, M.L. = Jackson,* S.=20 Jain, J.L. Jaeger,* D. Jernigan, A.A. Klimov, J. Katz, K. = Kniss, L.=20 Kamimoto, F. Loustalot,*, O.W. Morgan,* C.L. Mattson,* M. = Nowell, M.=20 Okomo-Adhiambo, S. Olsen, M.K. Patel,* S. Parks,* P. Peebles, = T.=20 Pilishvili, S. Redd, C. Reed,* S.L. Schrag, W. Sessions, C. = Smith, D.=20 Sugerman,* A. Suryaprasad,* D. Swerdlow, B. Shu, B.J. Silk,* = J.E.=20 Tate, X. Xu, J.R. Verani, J. Villenueva, K.-H. Wu. =


 
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{ =09 createCookie(svyName, svyName, expire); window.open(inviteurl, "", "toolbar=3Dno,status=3Dno,width=3D" + = frmWidth + ",height=3D" + frmHeight + ",top=3D150,left=3D50"); } } function whenIs(anyDate, n){ //-- Returns the date that is n days from any date. var newDate =3D new Date(); newDate.setTime(anyDate.getTime()+(n*1000*60*60*24)); return newDate; } //******************************************************************** // Display invitation if specific cookie not found and set cookie // Parameters // Display invitation every nthe hit on page, every 5th customer or = every 163rd customer. =20 // Created by SFungafat , Modified RKumar June 2004 //******************************************************************** function intercept(surveyurl) { // define variables var cookie_ls =3D document.cookie; var date_ls =3D new Date(); var S =3D new Date(); // if not yet sampled if (cookie_ls.indexOf("NEJM062004WEB") =3D=3D -1) { rnd.today=3Dnew Date(); rnd.seed=3Drnd.today.getTime(); =20 function whenIs(anyDate, n){ //-- Returns the date that is n days from any date. var newDate =3D new Date(); = newDate.setTime(anyDate.getTime()+(n*1000*60*60*24)); return newDate; } function rnd() { rnd.seed =3D (rnd.seed*9301+49297) % 233280; return rnd.seed/(233280.0); }; function rand(number) { return Math.ceil(rnd()*number); }; =20 sample=3Drand(5); // for the sample grab 1 in 5 if (sample=3D=3D5) { S =3D whenIs(date_ls, 3); S =3D S.toGMTString(); document.cookie =3D "NEJM062004WEB; path=3D/; expires=3D" + = S + ";"; window.open(surveyurl, "", = "toolbar=3Dno,status=3Dno,width=3D600,height=3D300,top=3D150,left=3D50") } } } //************************************************ // Set pop-up cookie based on country and IP type // Parameters // country: two character country code // instFlag: NEJM Institution, 1=3DTrue, 0=3DFalse // ** Use ISO 3166 standard 2-letter country codes ** //************************************************ function intlSurvey(country, instFlag) { /* var validCtys =3D "GB"; if (cookiesAreEnabled()) { country =3D country.toUpperCase() =09 // Invite only displayed for valid countries if (country.indexOf(validCtys) > -1) { if (instFlag =3D=3D 1) { //Set cookie one day for NEJM Institutions = invite('http://survey.nejm.org/NEJMUK0608/popup.aspx',510,260,'NEJMGBINST= ',1, 'nejm.org'); } else { //45 days for all others = invite('http://survey.nejm.org/NEJMUK0608/popup.aspx',510,260,'NEJMGBNONI= NST',45, 'nejm.org'); } =09 } } */ } //************************************************ // Set pop-up cookie based on country.=20 // Parameters // userCty: Country user from // validCty: Country or countries to test against // inviteurl: URL of invite form // svyName: Name of the specific survey // expire: Number of days before cookie expires // frmWidth & frmHeight: dimensions of invitation window //************************************************ function surveyByCty(userCty, validCty, inviteurl, svyName, expire, = frmWidth, frmHeight) { if (cookiesAreEnabled()) { userCty =3D userCty.toUpperCase() validCty =3D validCty.toUpperCase() =09 // Invite only displayed for valid countries if (userCty.indexOf(validCty) > -1) { //Display invite invite(inviteurl, frmWidth, frmHeight, svyName, expire); } } } // Checks if cookies are enabled in browser. function cookiesAreEnabled() { setCookie( "foo", "bar" ); if ( getCookie( "foo" ) ) { deleteCookie( "foo" ); return true; } else { return false; } } function setCookie( name, value, expires, path, domain, secure ) { document.cookie =3D name + "=3D" + escape (value) + ( ( expires ) ? 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