From: Subject: NEJM -- Triple-Reassortant Swine Influenza A (H1) in Humans in the United States, 2005-2009 Date: Fri, 8 May 2009 09:06:27 -0700 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_004E_01C9CFBC.44FA85C0" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_004E_01C9CFBC.44FA85C0 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://content.nejm.org/cgi/content/full/NEJMoa0903812?query=TOC NEJM -- Triple-Reassortant Swine Influenza A (H1) in = Humans in the United States, 2005-2009
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Published at www.nejm.org May 7, 2009=20 (10.1056/NEJMoa0903812) =

Triple-Reassortant Swine Influenza = A (H1) in=20 Humans in the United States, 2005=962009
Vivek Shinde, M.D., M.P.H., Carolyn B. = Bridges, M.D.,=20 Timothy M. Uyeki, M.D., M.P.H, M.P.P., Bo Shu, B.S., Amanda Balish, = B.S., Xiyan=20 Xu, M.D., Stephen Lindstrom, Ph.D., Larisa V. Gubareva, M.D., Ph.D., = Varough=20 Deyde, Ph.D., Rebecca J. Garten, Ph.D., Meghan Harris, M.P.H., Susan = Gerber,=20 M.D., Susan Vagoski, D.V.M., Forrest Smith, M.D., Neal Pascoe, R.N., = Karen=20 Martin, M.P.H., Deborah Dufficy, D.V.M., M.P.H., Kathy Ritger, M.D., = M.P.H.,=20 Craig Conover, M.D., Patricia Quinlisk, M.D., M.P.H., Alexander Klimov, = Ph.D.,=20 Joseph S. Bresee, M.D., and Lyn Finelli, Dr.P.H. =

 
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ABSTRACT

Background Triple-reassortant = swine=20 influenza A (H1) viruses =97 containing genes from avian, = human, and=20 swine influenza viruses =97 emerged and became enzootic among = pig=20 herds in North America during the late 1990s.

Methods We report the clinical features of the first 11 = sporadic=20 cases of infection of humans with triple-reassortant swine = influenza=20 A (H1) viruses, occurring from December 2005 through February = 2009, until just before the current epidemic of swine-origin=20 influenza A (H1N1) among humans. These data were obtained = from=20 routine national influenza surveillance reports and from = joint=20 case investigations by public and animal health agencies. =

Results The median age of the 11 patients was 10 years = (range,=20 16 months to 48 years), and 4 had underlying health = conditions.=20 Nine of the patients had had exposure to pigs, five through=20 direct contact and four through visits to a location where = pigs=20 were present but without contact. In another patient, = human-to-human=20 transmission was suspected. The range of the incubation = period,=20 from the last known exposure to the onset of symptoms, was 3 = to=20 9 days. Among the 10 patients with known clinical symptoms, = symptoms=20 included fever (in 90%), cough (in 100%), headache (in 60%), = and=20 diarrhea (in 30%). Complete blood counts were available for = four=20 patients, revealing leukopenia in two, lymphopenia in one, = and=20 thrombocytopenia in another. Four patients were hospitalized, = two of=20 whom underwent invasive mechanical ventilation. Four patients = received oseltamivir, and all 11 recovered from their = illness.=20

Conclusions From December 2005 until just before the = current=20 human epidemic of swine-origin influenza viruses, there was=20 sporadic infection with triple-reassortant swine influenza A=20 (H1) viruses in persons with exposure to pigs in the United=20 States. Although all the patients recovered, severe illness = of=20 the lower respiratory tract and unusual influenza signs such = as=20 diarrhea were observed in some patients, including those who = had been=20 previously healthy.

Pigs have been hypothesized to act as a mixing vessel for the=20 reassortment of avian, swine, and human influenza viruses and = might play an important role in the emergence of novel = influenza=20 viruses capable of causing a human pandemic.1,2,3=20 Recent reports of widespread transmission of swine-origin = influenza A=20 (H1N1) viruses in humans in Mexico, the United States, and=20 elsewhere highlight this ever-present threat to global public = health.4,5=20 Between the 1930s and the 1990s, the most commonly = circulating=20 swine influenza virus among pigs =97 classic swine influenza = A=20 (H1N1) =97 underwent little change. However, by the late = 1990s,=20 multiple strains and subtypes (H1N1, H3N2, and H1N2) of=20 triple-reassortant swine influenza A (H1) viruses =97 whose = genomes=20 included combinations of avian, human, and swine influenza = virus gene=20 segments =97 had emerged and became predominant among North = American=20 pig herds.6,7=20

Influenza virus infection was identified as a cause of febrile=20 respiratory illness in pigs as early as 1931, 3 years before=20 influenza viruses were identified as a cause of illness in = people.8=20 Classic swine influenza viruses are enzootic among pigs in = North=20 America.9,10=20 Cases and clusters of human infections with swine influenza = viruses=20 have been reported sporadically in the United States since = the=20 1970s.4,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28=20 Worldwide, more than 50 cases of swine influenza virus = infection=20 in humans, most due to classic swine influenza virus, have = been=20 documented in the past 35 years,4,23,25,28,29,30=20 and serologic studies suggest that people with occupational = swine=20 exposure are at highest risk for infection.22,24,31,32=20

Before the current epidemic of swine-origin influenza A (H1N1)=20 viruses, illness from classic swine influenza viruses, = including=20 seven deaths, had been reported in both previously healthy = persons=20 and those with preexisting medical conditions (including = pregnancy).13,16,17,20,21,27,29=20 Signs and symptoms of infection with classic swine influenza=20 virus in humans are often indistinguishable from those of = infection=20 with human influenza viruses.29=20 Until April 2009, only limited, nonsustained human-to-human=20 transmission of swine influenza virus had been reported.19,33,34=20

Outside the United States, there have been two published case=20 reports of human infection with triple-reassortant swine = influenza=20 A (H1) viruses (both subtype H3N2).25,35=20 Before 2005, the Centers for Disease Control and Prevention = (CDC) had=20 been receiving approximately one or two case reports of human = infection with classic swine influenza viruses per year. The = CDC=20 identified the first human infection with triple-reassortant = swine=20 influenza A (H1) viruses in the United States in December = 2005.23=20 In June 2007, human infection with a novel influenza A virus=20 (including influenza viruses of animal origin) was classified = as a=20 nationally notifiable infectious disease in the United = States.36=20 From December 2005 through February 2009, the CDC received 11 = notifications of human infection with triple-reassortant = swine=20 influenza A (H1) viruses, 8 of which occurred after June = 2007. In=20 this article, we characterize the epidemiologic and clinical = features=20 of the first 11 cases in humans reported in the United States = between December 2005 and February 2009. An additional human = case=20 of infection with triple-reassortant swine influenza A (H1)=20 viruses was detected in South Dakota in January 2009 but is = not=20 described here, because serologic studies for the patient and = the=20 patient's contacts are pending finalization of the serologic = assay=20 for infection with triple-reassortant swine influenza A (H1)=20 viruses.

Methods

Surveillance, Reporting, and Data Collection

A confirmed case of human infection with triple-reassortant = swine=20 influenza A (H1) viruses was defined as any case with = laboratory=20 confirmation at the CDC (see the Laboratory Confirmation = section=20 below). Clinical and demographic information about the first = three=20 patients identified (Patients 1, 2, and 3) were obtained = before 2007,=20 the year when human infection with a novel influenza A virus = became a=20 nationally notifiable disease and systematic data collection = was=20 initiated. The infection in Patient 1 was jointly = investigated by the=20 Wisconsin State Division of Public Health and the CDC and has = been=20 reported previously.23=20 Epidemiologic data for Patient 2 were limited, since the = family=20 declined to participate in a case investigation. The Iowa = State=20 Department of Public Health and the CDC collaborated to = conduct=20 an investigation of the illness in Patient 3.

Cases of human infection with a novel influenza A virus are=20 reported to the CDC by state public health laboratories in=20 conjunction with state public health departments through the=20 Nationally Notifiable Diseases Surveillance System (see the = Suppl= ementary=20 Appendix, available with the full text of this article at = NEJM.org). All cases are reported in the CDC's weekly = surveillance=20 reports (www.cdc.gov/flu). As=20 part of the reporting process, a standardized surveillance = reporting=20 form is submitted, including the following information: = demographic=20 characteristics, chronic medical conditions, status with = respect to=20 seasonal influenza vaccination, clinical signs and symptoms, = results=20 of diagnostic testing for influenza, antiviral treatment, = laboratory=20 abnormalities, clinical complications, outcome, and exposures = to=20 swine and other animals. All cases of laboratory-confirmed = human=20 infection with triple-reassortant swine influenza A (H1) = viruses=20 identified in the United States since 2007 (i.e., the cases = in=20 Patients 4 though 11) (Table=20 1) were formally reported to the CDC in this way. Besides = reports of human infection with triple-reassortant swine = influenza=20 A (H1) viruses, no human infections with other novel animal=20 influenza viruses (e.g., avian influenza viruses) have been = reported=20 since national reporting of novel influenza A virus = infections=20 was instituted in 2007.

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 =20 		Table 1.=20 Demographic and Exposure Characteristics of 11 = Patients=20 Infected with Triple-Reassortant Swine Influenza A (H1) = Viruses. =

 
Desc= riptive=20 data were analyzed with the use of Stata statistical software = (version 8). The analysis of data presented in this report = was not=20 subject to review by the institutional review board, and the = Privacy=20 Rule of the Health Insurance Portability and Accountability = Act=20 (HIPAA) did not apply because the collection, analysis, and=20 dissemination of data for human cases of novel influenza = virus=20 infection is considered a public health surveillance = activity.=20

Laboratory Confirmation

All patients in this series had respiratory samples collected=20 during their illness, which were submitted to their state = public=20 health laboratories for microbiologic testing. All but one = patient=20 (Patient 7) initially received a diagnosis of infection with = an=20 influenza A virus that could not be subtyped, on the basis of = reverse-transcriptase=96polymerase-chain-reaction (RT-PCR) = testing.=20 (Influenza A viruses that cannot be subtyped are defined as = those for=20 which the subtype cannot be determined with the use of = standard=20 laboratory methods and reagents for circulating human = influenza A=20 virus strains =97 subtype H1N1 or H3N2.) The clinical = specimen obtained=20 from Patient 7 was found to be positive for influenza A = (H1N2) on=20 viral culture performed at the Michigan State Public Health=20 Laboratory and was then sent to the CDC for further = testing.=20

Samples of influenza A viruses that cannot be subtyped are = routinely=20 forwarded to the Influenza Division laboratories at the CDC = for=20 further characterization and sequencing. At the CDC, all 11 = cases of=20 swine influenza virus infection were confirmed and viruses = subtyped=20 with the use of real-time RT-PCR and the = hemagglutination-inhibition=20 assay.37,38=20 For swine influenza virus detected in respiratory-fluid = samples from=20 patients, complete genome-sequence analysis was performed on=20 amplified RNA to determine the constellation of genes and = whether the=20 identified swine influenza virus was a triple-reassortant = virus=20 containing gene segments from swine, avian, and human = influenza=20 viruses. The GenBank accession numbers of five = triple-reassortant=20 swine influenza A (H1) viral isolates are listed in the Suppl= ementary=20 Appendix. The internal gene components of a = triple-reassortant=20 swine influenza A (H1) virus isolated from ill pigs = associated with=20 both patients in Ohio (Patients 4 and 5) have recently been=20 reported.28=20

Susceptibility to antiviral drugs, the adamantanes (amantadine = and=20 rimantadine), was assessed by means of the pyrosequencing = assay39=20 with the use of viral RNA extracted from the original = clinical=20 specimens, viral isolates, or both. Susceptibility of the = viral=20 isolates to the neuraminidase inhibitors oseltamivir and = zanamivir=20 was assessed by means of the chemiluminescent=20 neuraminidase-inhibition assay, with the use of the NAStar = Kit,=20 as previously described.40=20

Results

The demographic and epidemiologic characteristics of the = patients=20 and their illnesses, including the incubation period and = source=20 of swine exposure, are listed in Table=20 1. The median age of the patients was 10 years (range, 16 = months=20 to 48 years); eight patients were younger than 18 years of = age. Seven=20 of the 11 patients (64%) were male. Patients 4 and 5 were a=20 father=96daughter pair. Patient 3 was part of a family with = three other=20 members who had suspected, but not laboratory-confirmed, = cases of=20 infection with swine influenza virus. All patients resided in = either=20 the midwestern or southern United States.41=20 Four of the 11 cases (36%) were reported in August, 1 (9%) in = October, 2 (18%) in November, 1 (9%) in December, 2 (18%) in = January,=20 and 1 (9%) in February.

Exposures to pigs occurred on pig farms (for three patients), = at=20 agricultural fairs (for four patients), at a live-animal = market (for=20 one patient), and in a custom slaughterhouse (for one = patient). In 8=20 of the 11 cases (73%), pigs were reported to have shown signs = of=20 respiratory illness. Five of the 11 patients (45%) touched = pigs, 3=20 patients (27%) came within 1.83 m (6 ft) of pigs but had no = known=20 direct contact, and 1 patient (9%) attended a fair but did = not visit=20 areas where pigs were exhibited. The exposure was unknown for = one=20 patient (9%), and another patient (9%) was epidemiologically = linked=20 to a person with a suspected case of infection who had had = direct=20 contact with ill pigs =97 suggesting limited human-to-human=20 transmission of a triple-reassortant swine influenza A (H1) = virus.=20 Among the seven patients with exposure to pigs or venues with = pigs at=20 a discrete time (known within 1 day), the median incubation = period=20 (the interval between the most recent exposure and the onset = of=20 illness) was 3.5 days (range, 3 to 9).

The clinical characteristics of the patients are shown in Table=20 2. Four of the 11 patients (36%) had a preexisting = medical=20 condition: asthma (Patients 6 and 10), an uncharacterized=20 immunodeficiency (Patient 2), or eczema (Patient 11). At = least three=20 patients had received current-season influenza vaccine in the = season when the triple-reassortant swine influenza A (H1) = virus=20 infection was diagnosed; two of the three did not require=20 hospitalization. Among the 10 patients for whom clinical = information=20 was available, symptoms included fever (9 patients), cough = (10=20 patients), headache (6 patients), sore throat (6 patients), = and=20 diarrhea (3 patients). Myalgia, vomiting, and shortness of = breath=20 were reported in two patients each; one patient had = conjunctivitis.=20 Among the six patients whose temperature had been reported, = the=20 median was 39.7=B0C (103.5=B0F) (range, 38.5 to 40.4 [101.3 = to=20 104.8]).

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 =20 		Table 2. = Clinical=20 Characteristics of 11 Patients Infected with = Triple-Reassortant=20 Swine Influenza A (H1) Viruses. =

 
Four= =20 patients (Patients 3, 6, 7, and 9) were hospitalized because = of the=20 severity of their illness. In Patients 3 and 7, the disease = was=20 self-limited. Patient 3, a 4-year-old, previously healthy = girl, was=20 hospitalized because of dehydration and a need for medical = monitoring=20 after a 3-day history of fever (temperature, 39.2 to 39.9=B0C = [102.5 to=20 103.9=B0F]), vomiting, cough, headache, and congestion; a = rapid=20 influenza test was positive for influenza A virus (see the Suppl= ementary=20 Appendix) on day 2 of hospitalization, but she was not = treated=20 with oseltamivir. She was discharged from the hospital, fully = recovered, after 3 days. Patient 7, a 16-month-old, = previously=20 healthy boy, was hospitalized for 1 day for dehydration; he = presented=20 with fever (38.5=B0C [101.3=B0F]), cough, sore throat, = rhinorrhea,=20 and anorexia. A rapid influenza test was positive for = influenza=20 A virus, but he was not treated with oseltamivir.

In Patients 6 and 9, the disease was severe and prolonged. = Patient=20 6, a 48-year-old woman with a history of smoking, = gastroesophageal=20 reflux disease, and asthma controlled with inhaled = corticosteroids,=20 was hospitalized after a 2-day history of fever, chills, = cough,=20 and subsequent cyanosis. She underwent intubation and = mechanical=20 ventilation for pneumonia and respiratory failure on = admission.=20 Specimens from bronchoscopy and bronchoalveolar lavage, = initially=20 performed 7 days after admission, yielded influenza A virus = on=20 viral culture and Pseudomonas aeruginosa on bacterial = culture.=20 The patient was treated with multiple broad-spectrum = antibiotics=20 and oseltamivir (starting on day 11 of hospitalization) and = was=20 discharged, in improved condition, on day 19.

Patient 9, a 26-year-old, previously healthy woman, was = hospitalized=20 with pneumonia and sepsis after presenting with a 3-day = history=20 of fever (a temperature as high as 40.4=B0C [104.8=B0F]), = cough,=20 vomiting, diarrhea, shortness of breath, and evidence of = hypoxia=20 (oxygen saturation, 86%). Initial laboratory testing showed=20 leukopenia (white-cell count, 2100 per cubic millimeter) and=20 thrombocytopenia (platelet count, 135,000 per cubic millimeter). = Both=20 viral culture and RT-PCR testing performed on a nasopharyngeal-wash = specimen collected on day 2 of hospitalization were positive=20 for influenza A virus. The hospital course was complicated by = respiratory failure requiring invasive mechanical = ventilation,=20 hypotension requiring a brief course of inotropic medication, = and progression to multilobar pneumonia. The patient was = treated=20 with multiple broad-spectrum antibiotics and oseltamivir = (beginning=20 on day 19 of hospitalization). She was discharged in improved = condition approximately 30 days after admission and = eventually=20 had a full recovery.

Of the four patients who underwent chest radiography, the two = who=20 were critically ill (Patients 6 and 9) had abnormal findings = that=20 were consistent with pneumonia. In addition to these two = critically=20 ill patients, two outpatients were treated with oseltamivir = (Patient=20 5, who was treated within 1 day after the onset of symptoms, = and=20 Patient 4, who was treated within 3 days). All patients, = including=20 the four with severe disease requiring hospitalization, = recovered=20 from their illness. Three of four patients with complete = blood counts=20 performed during the course of their disease had abnormal = findings;=20 two had leukopenia (a white-cell count of <5000 per cubic=20 millimeter), one had lymphopenia (a total lymphocyte count of = <800=20 per cubic millimeter or a total white-cell count with <15% = lymphocytes), and one had thrombocytopenia (a total platelet = count of=20 <150,000 per cubic millimeter).

Results of laboratory and virologic testing performed by = hospital=20 laboratories and state public health laboratories are listed = in=20 Table=20 3. The results of rapid influenza point-of-care tests = were=20 positive in seven of the eight patients who underwent testing = by this=20 method. The presence of influenza A virus was initially = detected by=20 means of rapid influenza point-of-care testing in 64% of = patients,=20 viral culture in 18%, and RT-PCR testing in 9%; one patient = (9% of=20 the total) was negative for the virus on rapid testing but = was=20 positive on viral culture. Of the five patients who underwent = both=20 rapid influenza point-of-care testing and viral culture, = three had=20 positive results for both tests.

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 =20 		Table 3. = Results=20 of Laboratory and Virologic Testing of 11 Patients Infected = with=20 Triple-Reassortant Swine Influenza A (H1) Viruses. =

 
The = CDC=20 confirmed that all 11 patients had infection with = triple-reassortant=20 swine influenza A (H1) viruses. The eight individual gene = segments=20 found in all 11 viral isolates are shown in Figure=20 1. With regard to the triple-reassortant swine influenza = A=20 subtype, 10 of the 11 patients (91%) were infected with viral = subtype=20 H1N1, and 1 patient (9%) was infected with H1N2.


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 =20 		Figure 1. = Genetic=20 Components of Triple-Reassortant Swine Influenza A (H1) = Viruses=20 Isolated from 11 Patients between December 2005 and February = 2009 in=20 the United States.

HA denotes the hemagglutinin gene, M the = matrix=20 protein gene, NA the neuraminidase gene, NP = the=20 nucleocapsid protein gene, NS the nonstructural = protein gene,=20 PA the polymerase PA gene, PB1 the polymerase = PB1=20 gene, and PB2 the polymerase PB2 gene. =

 
The = hemagglutinin (HA) genes of the triple-reassortant swine = influenza A=20 (H1) viruses isolated from five patients in this series were = found to=20 come from two different phylogenetic lineages currently = circulating=20 in North American swine: swH1-beta and swH1-gamma28=20 (see Fig. 1 in the Suppl= ementary=20 Appendix). Although each lineage has 98 to 100% identical = amino=20 acids within itself, the two lineages have diverged from one = another=20 by approximately 50 amino acids in the HA gene since their=20 establishment and differ from circulating human seasonal = influenza=20 (H1) viruses by more than 100 amino acids. Preliminary data = suggest=20 that there is no cross-reactivity between ferret antiserum=20 raised against triple-reassortant swine influenza A (H1) = viral=20 isolates and contemporary seasonal human influenza A (H1) = viruses.=20 All viral isolates from the 11 patients in this series were=20 susceptible to both adamantanes (amantadine and rimantadine) = and=20 neuraminidase inhibitors (oseltamivir and zanamivir). =

Discussion

In this report, we describe the clinical and epidemiologic=20 characteristics of 11 cases of laboratory-confirmed infection = with=20 triple-reassortant swine influenza A (H1) viruses, which were = identified and reported in the United States before the = current=20 epidemic of swine-origin influenza A (H1N1) viruses in = humans. The=20 patients' exposures to pigs or their environments varied = widely in=20 setting and degree, and almost half the patients had not = directly=20 touched pigs. The median incubation period was 3.5 days = (range, 3 to=20 9) from the most recent exposure to pigs or their = environment, but=20 in general it appeared to be longer than the incubation = period=20 for seasonal influenza.42=20 However, exposure to a human with a triple-reassortant swine=20 influenza A (H1) virus as the source of infection could not = be ruled=20 out as a possible explanation for the apparently longer = incubation=20 period. The most frequent signs and symptoms in the patients = were=20 nonspecific and indistinguishable from those of human = influenza.=20 However, some of the patients with triple-reassortant swine = influenza=20 A (H1) viruses had evidence of severe lower respiratory tract = illness=20 and signs that are unusual for influenza, such as diarrhea. = Although=20 all patients recovered, a wide spectrum of clinical severity = was=20 seen, including two cases of critical illness, one of which = occurred=20 in a previously healthy woman.

Although the causes of the increased case reports since December = 2005 are unclear, improved virologic surveillance and testing = capacity in state public health laboratories and heightened=20 awareness of novel reporting requirements for cases of = influenza=20 A may be contributing factors. Alternatively, recent = increases=20 in case reporting might reflect a true increase in human = infections=20 due to changes in zoonotic transmission arising from recent=20 genetic evolution in circulating triple-reassortant swine = influenza=20 A (H1) viruses. The phylogenetic data indicate that more than = one currently circulating lineage of North American=20 triple-reassortant swine influenza A (H1) viruses has been=20 responsible for recent human infections, with no evidence of = adaptive=20 changes shared among them to explain the increase in detected = cases.

Few, if any, patients in this series were initially suspected = of=20 having swine influenza virus infection. Most cases were discovered=20 through virologic testing of respiratory specimens as part of = routine seasonal influenza surveillance, highlighting the = importance=20 of routine influenza surveillance in the detection of human=20 infections with either seasonal influenza virus or novel = influenza=20 virus of animal origin. Although the incidence of infections=20 with triple-reassortant swine influenza A (H1) viruses in the = general population is unknown, the number of cases in our = series=20 is most likely an underestimate of the true incidence of = swine=20 influenza virus infections in the United States. Several=20 seroepidemiologic studies have consistently shown a higher = risk of=20 infection with classic swine influenza virus in = occupationally=20 exposed populations than in the general population.22,24,32=20

Given the zoonotic potential of influenza viruses, clinicians=20 should consider animal influenza virus infections in the = differential=20 diagnosis for patients presenting with febrile respiratory = illness=20 and a recent history of exposure (direct, close, distant, or=20 epidemiologically linked) to swine, poultry, or wild birds = (e.g.,=20 at agricultural fairs or on farms),43=20 especially when human influenza viruses are not circulating = in the=20 community. However, during periods when there is evidence of=20 efficient human-to-human transmission of a novel influenza A = virus in=20 the community, clinicians should have a low threshold for = suspecting,=20 diagnosing, and treating infection appropriately on the basis = of the=20 most current recommendations (www.cdc.gov/flu). Clinicians who = suspect=20 swine or other zoonotic influenza virus infections in = patients=20 with acute respiratory illness should contact their state or=20 local health department to facilitate appropriate specimen = collection=20 and timely diagnostic testing at a state public health = laboratory.4=20

Our findings underscore the need for close communication and=20 collaboration between human and animal health agencies for = ongoing=20 surveillance, investigation, research, prevention, and = control=20 efforts. In the context of current reports of epidemic = swine-origin=20 influenza A (H1N1) viruses in the United States and Mexico4,5=20 and global concern regarding the emergence of a human = influenza=20 pandemic of animal-influenza origin, epidemiologic and = laboratory=20 surveillance of interspecies transmission of influenza = viruses=20 should be increased, especially in environments in which = humans=20 and swine are routinely exposed to each other. Cases of = infection=20 in persons who have been exposed to pigs may be sentinels for = early zoonotic transmission of novel triple-reassortant swine = influenza A (H1) viruses to humans. Consequently, = surveillance=20 in settings involving pigs might facilitate early = identification=20 and joint responses of public health and animal health = agencies=20 to contain potential outbreaks before widespread community=20 transmission occurs. The mechanism and relative efficiency of = indirect and remote exposures to swine influenza (through = close=20 proximity, fomites, aerosols, or person-to-person = transmission) in=20 the acquisition of human infection with triple-reassortant = swine=20 influenza A (H1) viruses require further study. Although = uncommon,=20 such cases are likely to continue to occur sporadically, = since=20 the triple-reassortant swine influenza A (H1) viruses are = endemic=20 in North American swine herds. Clinical and epidemiologic = features=20 of human illness, including the usefulness of rapid influenza = point-of-care testing and any determinants of antiviral = resistance,=20 should continue to be assessed.

Our data are subject to several limitations. Cases of infection=20 with triple-reassortant swine influenza A (H1) viruses were=20 reported through passive influenza surveillance systems; = therefore=20 additional cases might have occurred that were not = identified.=20 Overall, few patients with influenza-like symptoms are tested = for influenza, and even fewer would undergo specific testing=20 that would lead to a diagnosis of infection with = triple-reassortant=20 swine influenza A (H1) virus (with severe infections perhaps=20 more likely to be diagnosed). Complete clinical and = epidemiologic=20 data were not available for some cases, especially those = identified=20 before the start of systematic data collection.

As recent events suggest, the generation of novel influenza=20 viruses through the reassortment of swine influenza viruses=20 with other human and animal influenza viruses may be inevitable.7=20 In this context, the possibility of novel influenza viruses=20 causing epidemic and pandemic disease in large populations of = immunologically susceptible humans remains a major ongoing = public=20 health threat. Consequently, during interpandemic periods, = all=20 human infections with influenza viruses of animal origin, = even=20 those that appear to be clinically mild, warrant a thorough=20 public health investigation to assess the epidemiologic and=20 clinical risk to humans.

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

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

We thank the public health laboratory personnel and = epidemiologic=20 public health staff in the states of Wisconsin, Missouri, = Iowa,=20 Ohio, Illinois, Michigan, Minnesota, South Dakota, and Texas; = Sally Bidol, M.P.H (of the Michigan Department of Community=20 Health); our colleagues at the Animal and Plant Health = Inspection=20 Service, Veterinary Services, Agricultural Research Service,=20 and National Animal Disease Center of the U.S. Department of=20 Agriculture; and state animal health authorities for their=20 cooperation and assistance with these investigations. =


Source Information

From the Influenza Division (V.S., C.B.B., T.M.U., = B.S., A.B.,=20 X.X., S.L., L.V.G., V.D., R.J.G., A.K., J.S.B., L.F.), the Epidemic = Intelligence=20 Service Program (V.S., D.D.), and the Preventive Medicine Residency = Program=20 (V.S.), Centers for Disease Control and Prevention, Atlanta; the Iowa = Department=20 of Public Health, Des Moines (M.H., P.Q.); the Chicago Department of = Public=20 Health, Chicago (S.G., K.R.); the Michigan Department of Community = Health,=20 Lansing (S.V.); the Ohio Department of Health, Columbus (F.S.); the = Texas=20 Department of State Health Services, Austin (N.P.); the Minnesota = Department of=20 Health, St. Paul (K.M.); and the Illinois Department of Public Health,=20 Springfield (C.C.).

This article=20 (10.1056/NEJMoa0903812) was published at NEJM.org on May 7, 2009. It = will appear=20 in the July 2 issue of the Journal.

Address reprint requests to Dr. Finelli at the = Centers for=20 Disease Control and Prevention, 1600 Clifton Rd., NE Mailstop A-32, = Atlanta, GA=20 30333, or at lfinelli{at}cdc.gov .

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------=_NextPart_000_004E_01C9CFBC.44FA85C0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://survey.nejm.org/scripts/survey.js function invite(inviteurl,frmWidth,frmHeight,svyName,expire) { //******************************************************************** // Display invitation if specific cookie not found and set cookie // Parameters // inviteurl: URL of invite form // frmWidth & frmHeight: dimensions of invitation window // svyName: Name of the specific survey // expire: Number of days before cookie expires //=20 // Created by Chris Miceli 2/25/2004 //******************************************************************** // define variables var theCookie =3D document.cookie; var today =3D new Date(); var expDate =3D new Date(); // Check if user has visited page before if (theCookie.indexOf(svyName) =3D=3D -1) { =20 expDate =3D whenIs(today, expire); expDate =3D expDate.toGMTString(); document.cookie =3D svyName + "; path=3D/; expires=3D" + expDate + = ";"; window.open(inviteurl, "", "toolbar=3Dno,status=3Dno,width=3D" + = frmWidth + ",height=3D" + frmHeight + ",top=3D150,left=3D50"); //window.open(surveyurl, "", = "toolbar=3Dno,status=3Dno,width=3D270,height=3D220,top=3D150,left=3D50");= } } function invite(inviteurl,frmWidth,frmHeight,svyName,expire,path) { //******************************************************************** // Display invitation if specific cookie not found and set cookie // Parameters // inviteurl: URL of invite form // frmWidth & frmHeight: dimensions of invitation window // svyName: Name of the specific survey // expire: Number of days before cookie expires // path: cookie path //=20 // Created by Chris Miceli 2/25/2004 //******************************************************************** // define variables var theCookie =3D document.cookie; var today =3D new Date(); var expDate =3D new Date(); // Check if user has visited page before if (readCookie(svyName) =3D=3D null) { =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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"; domain=3D" + domain : "" ) + "; expires=3DThu, 01-Jan-70 00:00:01 GMT"; } } function createCookie(name, value, days) { if (days) { var date =3D new Date; date.setTime(date.getTime() + days * 24 * 60 * 60 * 1000); var expires =3D "; expires=3D" + date.toGMTString(); } else { var expires =3D ""; } document.cookie =3D name + "=3D" + value + expires + "; path=3D/" } function readCookie(name) { var nameEQ =3D name + "=3D"; var ca =3D document.cookie.split(";"); for (var i =3D 0; i < ca.length; i++) { var c =3D ca[i]; while (c.charAt(0) =3D=3D " ") { c =3D c.substring(1, c.length); } if (c.indexOf(nameEQ) =3D=3D 0) { return c.substring(nameEQ.length, c.length); } } return null; } ------=_NextPart_000_004E_01C9CFBC.44FA85C0 Content-Type: application/octet-stream Content-Transfer-Encoding: quoted-printable Content-Location: http://ipinvite.iperceptions.com/Invitations/Javascripts/ip_Layer_Invitation_624.js var browser =3D new BrowserDetect();=20 var localSwitch=3D true; //var localSwitch=3D false; var _http =3D document.location.protocol; //var gJSFile =3D "javascript/Layer_624.js"; var gJSFile =3D _http + = "//ipinvite.iperceptions.com/Invitations/Javascripts/Layer_624.js"; function BrowserDetect() { ua =3D navigator.userAgent.toLowerCase(); this._string =3D = navigator.userAgent.toLowerCase(); this.isOpera=3D (ua.indexOf('opera') !=3D -1); this.isGecko=3D = (ua.indexOf('gecko') !=3D -1 && ua.indexOf('safari') =3D=3D -1); this.isIE=3D (ua.indexOf('msie') !=3D -1 && !this.isOpera && = (ua.indexOf('webtv') =3D=3D -1) );=20 this.isMozilla=3D (this.isGecko && ua.indexOf('gecko/') + 14 =3D=3D = ua.length); this.isFirefox=3D (ua.indexOf('firefox') !=3D -1); } function lScript(file) { var script =3D document.createElement('script'); script.type =3D 'text/javascript'; script.src =3D file;=09 if (typeof(script.onreadystatechange) =3D=3D 'undefined')=20 script.onload =3D function() { this.onload =3D null; };=20 else =20 script.onreadystatechange =3D function() { if (this.readyState !=3D = 'loaded' && this.readyState !=3D 'complete') return; = this.onreadystatechange =3D null; };=20 =09 document.getElementsByTagName('head')[0].appendChild(script); } function CC(name,value,days) { if (days) { var expDate =3D new Date(); = expDate.setTime(expDate.getTime()+(days*24*60*60*1000)); var expires =3D = "; expires=3D"+expDate.toUTCString(); }=09 else var expires =3D ""; document.cookie =3D = name+"=3D"+value+expires+"; path=3D/"; } function RC(NameOfCookie) { if (document.cookie.length > 0) { begin =3D document.cookie.indexOf(NameOfCookie+"=3D"); if (begin !=3D -1) { begin +=3D NameOfCookie.length+1; end =3D = document.cookie.indexOf(";", begin); =20 if (end =3D=3D -1) end =3D document.cookie.length; return unescape(document.cookie.substring(begin, end));=20 } } return null; } =09 function EC(name) { CC(name,"",-1); } function Exec() { var sCName =3D "IPERCEPTIONS_624"; var sCVal =3D = "IPERCEPTIONS_624_COOKIE"; var sCValRet; var tCVName=3D"IPERCEPTIONS_TEST"; var = tCVVal=3D"IPERCEPTIONS_TEST_COOKIE"; var tCVValRet; CC(tCVName,tCVVal,1); tCVValRet =3D RC(tCVName); =09 sCValRet =3D RC(sCName); EC(tCVName); var rndNum=3D Math.floor ((Math.random()*1050)); =09 if (rndNum < 2 && tCVValRet !=3D null && sCValRet =3D=3D null) { =20 CC(sCName, sCVal, SetVariantCookie()); lScript(gJSFile); } } if (localSwitch) { var GJS =3D _http + = "//ipinvite.iperceptions.com/Invitations/Javascripts/Layer_Global.js"; = lScript(GJS); }=09 =09 var SubscriberType =3D "1" // IsInstitution=3D1 ; IsSubscriber =3D 2 function SetVariantCookie() { var IsInstitution =3D document.getElementById('IsInstitution'); var IsSubscriber=3D document.getElementById('IsSubscriber'); if (IsInstitution !=3D null )=20 { if (IsInstitution.value.toLowerCase() =3D=3D"true") { = SubscriberType =3D 1; return 3; } } if ( IsSubscriber !=3D null) { if (IsSubscriber.value.toLowerCase() =3D=3D"true") { = SubscriberType =3D 2; return 90; } } SubscriberType =3D 1; =20 return 90; } ------=_NextPart_000_004E_01C9CFBC.44FA85C0--

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