H3N2v Virus

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Interim Information for Clinicians about Human Infections with H3N2v Virus

Posted August 10, 2012

Background

Influenza A viruses circulating in pigs that have infected humans are referred to as “variant” viruses. Human infections with an influenza A (H3N2) variant (H3N2v) virus that contains the M gene from the influenza A(H1N1)pdm09 virus (2009 H1N1 pandemic virus) were first detected in 2011. Notably, a large increase in cases of H3N2v virus infection has been identified since July 2012. (This virus has been circulating among pigs in the U.S. since 2011, has been detected in pigs in many states, and appears to be circulating widely in swine in the U.S.) The majority of H3N2v cases have been in children, although some adults have been infected, and linked to recent direct or indirect exposure to pigs. To date, almost all of the H3N2v cases in 2012 have been epidemiologically linked to agricultural fairs, either through exhibiting pigs or walking through a swine barn. Occupational exposure to pigs was reported in one H3N2v case. Limited, non-sustained human-to-human transmission of H3N2v virus was noted in 2011, including in households and a child care setting. Since 2011, a small number of H3N2v case-patients have been hospitalized, including previously healthy people and people with chronic underlying conditions. To date, no deaths have occurred and all cases have recovered fully. CDC is monitoring the situation closely with state health departments and will issue updates accordingly as additional information is available.


Clinical Presentation and Risk Groups

Clinical characteristics of human cases of influenza A (H3N2) variant virus infection generally have been similar to signs and symptoms of uncomplicated seasonal influenza, including fever, cough, pharyngitis, rhinorrhea, myalgia, and headache. Vomiting and diarrhea have also been reported in some pediatric cases. Milder clinical illness is possible, including lack of fever. The duration of illness in most cases appears to be similar to uncomplicated seasonal influenza, approximately 3-5 days. While assumed to be similar to seasonal influenza virus infection, the duration of viral replication and possible infectiousness in H3N2v cases has not been studied.

Exacerbation of underlying conditions (e.g. asthma) has occurred. The same people at increased risk for complications of seasonal influenza are likely at high risk for serious complications from H3N2v virus infection, including children aged <5 years, pregnant women, people 65 years and older, those who are immunosuppressed, and persons with chronic pulmonary, cardiac, metabolic, hematologic, neurological and neurodevelopmental conditions, renal, hepatic, as well as those with other co-morbidities, including morbid obesity.

Limited serologic data suggest that children younger than 10 years lack immunity to H3N2v virus and therefore are likely to be most susceptible to H3N2v virus infection. Adolescents and younger adults may have cross-protective antibodies, but some would be expected to be susceptible. Middle-aged adults and elderly may have lower levels of cross-protective antibodies and may also be susceptible to H3N2v virus infection. Seasonal influenza vaccination does not provide protection against H3N2v virus infection.


CONTINUED:
www.cdc.gov/flu/swineflu/h3n2v-clinician.htm

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Minnesota reports first variant H3N2 cases, CDC urges school vigilance
Lisa Schnirring Staff Writer


Aug 20, 2012 (CIDRAP News) – Minnesota health officials today reported the state's first cases of the novel H3N2 flu mainly linked to contact with pigs at agricultural fairs. And with cases of H3N2v climbing across the nation, the US Centers for Disease Control and Prevention (CDC) recently urged schools to be on the lookout for infections.

The Minnesota Department of Health (MDH) said in a statement today that it has confirmed one H3N2v case in a preschool-aged child and a probable infection in an older sibling. The children, who live in the Twin Cities metropolitan area, got sick 2 days after their family visited a live animal market at the Dakota County fair on Aug 10. The MDH said both children were most likely exposed to the virus at the animal market.

Though both children were tested, the result was positive only for the younger child, but the MDH said it considers the older sibling a probable case, based on the history of flulike illness and the family connection to the younger child. Neither child has been hospitalized, and both are recovering. The MDH said no further spread of the virus from the children to other people has been detected.

Minnesota officials aren't discouraging people from going to live markets or attending fairs, such as the Minnesota State Fair, which begins on Aug 23. However, it is stepping up surveillance for the disease and is urging fairgoers and exhibitors to take precautions, such as washing hands with soap and running water after exposure to animals. They also urged people with flu symptoms to avoid contact with pigs, since the virus can also be transmitted from humans to pigs. The MDH urged sick exhibitors and others who can't avoid contact with pigs to wear protective clothing such as gloves and masks.

The MDH said the Minnesota Board of Animal Health is encouraging pork producers to observe good biosecurity practices, and it emphasized that the new virus doesn't pose a food safety risk.

Elsewhere, Ohio officials are reporting 79 infections with the new strain, an increase of seven from the previous week, the Associated Press (AP) reported on Aug 18. The addition of Ohio's seven latest cases and the two cases from Minnesota would push the nation's number of H3N2v cases to 239 cases in 10 states.

In other developments, the CDC on Aug 17 said no school outbreaks have been reported of the H3N2v viral infection. The H3N2v contains the matrix gene from the 2009 H1N1 virus, which the CDC said might allow it to spread more easily among humans.

Though the risk seems to be mainly limited to pig exposure, some person-to-person transmission has been identified with the virus before and may crop up again, the CDC said in its guidance for schools.

Schools can play a key role in identifying suspected H3N2v infections and helping to slow the spread of the virus, the CDC said. It urged schools to ask students who have flulike symptoms if they recently had direct contact with pigs or close contact with a person who has been near pigs, especially in states where H3N2v cases have already been detected. Local health departments should be notified about sick students with a history of direct or indirect contact with pigs so that children can be tested for H3N2v infection.

To curb the spread of H3N2v and any flu virus, the CDC urged schools to refer students who have flulike symptoms and are at high risk for complications, such as those with asthma and other chronic conditions, to healthcare providers regardless of whether they have recently been exposed to pigs. It also recommended encouraging sick students and staff to stay home until their symptoms subside and to practice routine precautions, such as covering coughs and sneezes and practicing good hand hygiene.

In a separate update on the new virus, the CDC shared some information on surveillance on swine testing for flu viruses. It said when H3N2 viruses that contain the 2009 H1N1 pandemic matrix gene turn up in swine, they are called H3N2pM. It said further that testing from the US Department of Agriculture (USDA) and its partners first found the H2N2pM virus in isolates collected in late 2010 and that the virus has turned up in sampling ever since.

Of 138 H3N2 samples identified from Oct 1, 2011, through Jul 31, 2012, 57 contained the pandemic M gene and were classified as H3N2pM, the CDC said in an Aug 17 statement. It added that several more H3N2 isolates are undergoing more advanced testing to characterize the virus.

Last week, a group from the CDC and several universities reported that pigs testing positive for the H3N2pM virus often show no symptoms, which makes it more difficult for fair organizers and other authorities to visually flag sick animals as part of their efforts to control the spread of the virus to people and other pigs.

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Swine H3N2v Matches With LaPorte and Butler Cases
Recombinomics Commentary 16:15
September 19, 2012

The USDA has released a series of July / August, 2012 swine sequences including July 13 collections from Indiana (A/swine/Indiana/A00968370/2012, A/swine/Indiana/A00968373/2012, A/swine/Indiana/A00968376/2012, A/swine/Indiana/A00968379/2012) and July 28 collections (A/swine/Ohio/12TOSU268/2012 and A/swine/Ohio/12TOSU293/2012). These collections dates are 3 days and 1 day prior to collections from cases at the La Porte County Fair in Indiana and the Butler County Fair in Ohio, respectively, strongly suggesting that the collections were from swine at the fairs. These origins are also supported by the sequence data which show a high degree of similarity between the swine in human cases including exact matches between A/swine/Indiana/A00968376/2012 and LaPorte cases or A/swine/Ohio/12TOSU293/2012 and Butler cases.

Thus, the sequence data strongly supports interspecies transmissions at both county fairs.

However, these sequences don’t address the direction of the transmission. Prior to the fairs, only 2 of 31 swine matches with human 2011 and 2012 cases are from the sub-clade found in all 2012 human H3N2v cases. Moreover, none of the 57 public sequences from July and August 2012 cases are from the sub-clade found in the first 10 human cases in 2011. This novel sub-clade was first detected at the West Virginia day care center in late 2011 (A/West Virginia/06/2011 and A/West Virginia/07/2011), as well as the first 2012 H3N2 case, A/Utah/10/2012.

These distribution raise concerns that this novel sub-clade is widespread in humans (July / August cases were identified across the United States, from Hawaii to Maryland) and agricultural fairs create interactions leading to frequent human to swine transmission.

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H3N2v Ohio Cases Increase to 107 in 25 Counties
Recombinomics Commentary 16:00
September 26, 2012

Ashland (1), Athens (8), Butler (17), Champaign (15), Clark (3), Fairfield (1), Franklin (4), Gallia (12), Greene (6), Hamilton (3), Henry (6), Huron (3), Jackson (1), Lake (1), Licking (2), Madison (1), Medina (1), Monroe (2), Montgomery (5), Morrow (1), Preble (3), Richland (2), Ross (7), Union (1), Warren (1).[/b]

The above list represents the September 26 tally of H3N2v cases confirmed in Ohio by the Ohio Department of Health (ODH). The number of cases increased from 106 to 107, while the number of counties remained at 25.

Montgomery County added the new case.

Although the increase in H3N2v cases has slowed dramatically, the detection of cases is still largely dependent on the monitoring of agricultural fairs.

The CDC has released 57 sets of H3N2v sequences from July/August collections and all matched the novel sub-clade first noted in 2011 at the West Virginia day care center. The detection of this novel sub-clade in all recent collections, as well as the first 2012 isolate (A/Utah/10/2012), signal human transmission, which is also supported by the absence of any reported human cases with the H3N2v sub-clade detected in the first 10 cases in 2011. This earlier sub-clade continues to be detected in recent (May, June, July, 2012) swine isolates.

Similarly, the recent paper on the 2011 Washington County fair cites 80 suspect cases based on ILI symptoms, highlighting the limitations of the CDC routine surveillance, which failed to detect any of these cases.

H3N2v continues to spread in humans in the US, which is largely missed by the current surveillance system.


CONTINUED: www.odh.ohio.gov/features/odhfeatures/H3N2v%20influenza/H3N2v%20Influenza.aspx

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Wisconsin Mink H3N2v Matches 2011 Human Cases
Recombinomics Commentary 23:45
September 26, 2012

The USDA has released a full set of H3N2v sequences from a Wisconsin mink isolate, A/mink/Wisconsin/31512-7/2012, which matches H3N2v cases from 2011. The sample was collected on August 14 and deposited at Genbank on August 30, signaling a high priority by the USDA.

Although details surrounding the detection of this infection are not know, this recent isolate extends to spread of this sub-clade, which has been frequently detected in swine, including a July 21 collection from Illinois, A/swine/Illinois/A01203672/2012, as well as June isolates from Ohio (A/swine/Ohio/1/2012, A/swine/Ohio/6/2012, A/swine/Ohio/7/2012, A/swine/Ohio/9/2012).

Although this sub-clade is common and widespread in swine, including Ohio and Indiana where most of the recent human H3N2v cases were isolated, none of these swine (or mink) infections have produced a reported human case in 2012.

The most recent human cases with this sub-clade were in the 2011 Iowa cluster (which had no swine exposure) in November. Since that outbreak the CDC has released 60 sets of H3N2v sequences and all 60 matched the sub-clade identified at the West Virginia day care center in November / December. 2011.

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CDC Describes 11 Hospitalized H3N2v Cases In Ohio
Recombinomics Commentary 19:15
September 27, 2012

Patients lived in eight counties and attended six fairs. Direct contact with swine prior to illness onset was reported by six patients (five children and one adult), and of these, one patient might have had direct contact with an ill pig.

The above comments are from a CDC MMWR report, “Influenza A (H3N2) Variant Virus-Related Hospitalizations — Ohio, 2012” which provides some detail on 11 H3N2v infected Ohio patients who visited agricultural fairs and were subsequently hospitalized. The adult mention above is the only reported fatal H3N2v case (61M) and the sample collection date of August 25, 2012 matches the isolate A/Ohio/74/2012 which is closely related to multiple human and swine cases including Ohio and Wisconsin cases with an identical H3 (A/Ohio/75/2012, A/Ohio/64/2012, A/Wisconsin/22/2012, A/Wisconsin/23/2012, A/Wisconsin/27/2012, A/swine/Ohio/12TOSU447/2012, A/swine/Ohio/12TOSU450/2012.

However, the report focused on swine exposure and ignored the large number of human H3N2v cases at these fairs. The report failed to name the six fairs or eight counties, although media reports indicated the fatal case (61F) attended the Ross County Fair and live in London, Ohio which is the county seat for Madison County. Similarly media reports cited a Lake County case without swine exposure, which matches case #10 who developed symptoms on August 25, which was in the same time frame as the media reports and the Ohio Department of Health’s addition of a Lake County case.

In addition to the case with no swine exposure, 4 additional cases had “indirect” exposure, and one of the direct exposure cases developed symptoms 6 days after exposure suggesting most of the cases were not infected by swine. Moreover, as cited above, only one of the cases with direct exposure “might” have had contact with a symptomatic swine.

Although only one of the 11 cases might have had contact with a symptomatic swine, it is likely that the vast majority had contact with symptomatic people who attended the fairs. Details of the number of symptomatic cases at these fairs are limited because of the CDC heavy bias toward swine transmission (and corresponding lack of information on the number of symptomatic cases at the fairs), but reports from Gallia County in southeastern Ohio indicated the local department of health ran rapid test on 200 symptomatic attendees and 69 were influenza A positive, suggesting virtually all 200 were symptomatic because of an influenza A infection (the sensitivity of raid tests for H3N2v is in the 30-40% range). Moreover, ODH reported 12 confirmed H3N2v cases from Gallia County, while the West Virginia reported 3 confirmed H3N2v from residents who attended the Gallia Junior County Fair. In addition, many additional symptomatic attendees were not tested, indicating hundreds of attendees were H3N2v infected. Similarly, other counties (Butler and Champaign) reported higher numbers of confirmed cases than Gallia.

The large number of human cases at these fairs was not limited to Ohio. In Indiana, Monroe County reported 61 H3N2v confirmed cases.

These large numbers of symptomatic / H3N2v confirmed cases were also seen last year. An early release of a December EID paper on the 2010 Washington County Fair outbreak described serological and phone surveys of a subset of 4-H Club attendees. Earlier reports had described the 3 H3N2v confirmed cases, but the serological studies identified 4 additional probable cases with H3N2v antibodies, as well as 82 symptomatic cases. Moreover, since only 1/3 of the 4-H Club attendee list was called (247/994 members), and 127 of those contacted agreed to be interviewed, the number of symptomatic cases linked to the 4-H Club was likely in the hundreds. No H3N2v infected swine were identified at the fair and only one swine was symptomatic (and removed after 1 day). Moreover, none of the thirteen 2011 or twenty 2012 swine matches for the 2011/2012 H3N2v cases were from Pennsylvania.

Thus, there is little evidence to support extensive swine to human transmission at the 2011 or 2012 agricultural fairs. Although the genetic matches with the 2011 H3N2v cases are widespread in swine, including Ohio and Indiana isolates, no 2012 matching human H3N2v case has been reported. All 2012 human cases match a novel H3N2v sub-clade which was first detected at a West Virginia day care center in late 2011.

However, in spite of these match failures, the CDC continues to focus on swine to human transmission, and ignores the human to swine and human to human transmission at agricultural fairs.

[dothedd]

Ohio H3N2v Swine With PB1 E618D and H1N1pdm09 M Gene
Recombinomics Commentary 19:45
October 1, 2012

The USDA has released addition recent H3N2v swine sequences. Included were sequences for the internal genes (PB2, PB1, PA, NP, NS) for 3 June, 2012 isolates from Ohio. Earlier sequences for the other three genes (HA, NA, MP) were released ((A/swine/Ohio/1/2012, A/swine/Ohio/6/2012 , A/swine/Ohio/7/2012) and the sequences matched the initial 10 human cases in 2011. The H3N2v was created though reassortment which had 5 genes from the 2010 human cases (PB2, PA, HA, NP, NS), as represented by A/Wisconsin/12/2010 and A/Pennsylvania/40/2010, and 3 genes (PB1, NA, MP) from swine H1N2 isolates which had an H1N1pdm09 M gene. The new PB1 did not have E618D, which is in all H1N1pdm09 isolates and was also in the first US H3N2v case, A/Kansas/13/2009, as well as all six 2010 human cases.

The release of the sequences from the three Ohio swine (A/swine/Ohio/1/2012, A/swine/Ohio/6/2012, A/swine/Ohio/7/2012), identified a PB1 sequence in all three isolates which was closely related to the sequences from the human 2010 case and had E618D. All human variant sequences since 2010 have had a PB1 with E618D or an H1N1pdm09 M gene, but none had both changes (which are present in all human and swine H1N1pdm09 isolates).

Therefore, the presence of both changes in the June Ohio swine raises concerns that this combination will increase the potential for human adaptation and transmission. However, these isolates, like the first 10 human cases in 2011, have an NA lineage found in H1N2v swine, but all 2012 human cases (58 public sets of sequences) have had an N2 lineage found in H3N2v swine and first seen in human cases in the sequences from the 2011 West Virginia day care outbreak in Mineral county (A/West Virginia/06/2011 and A/West Virginia/07/2011).


Michigan H3N2v Cases With PB1 E618D and H1N1pdm09 M Gene
Recombinomics Commentary 21:45
October 4, 2012

The CDC has released a large series of H3N2v sequences from August, 2012 cases, increasing the number of July/August sets to 90. Included were two sets of sequences from two cases in Michigan collected on August 16. Sequences from one case, A/Michigan/20/2012, cover seven of the eight gene segments (all except NS), while the second set, A/Michigan/19/2012, from an adult (54M), covered PB1 and PA. The shared sequences were virtually identical suggesting all 8 gene segments match. Both PB1 sequences had E618D and were closely related to sequences from 2010 human cases, as was seen in recent swine sequences from June collections in Ohio (A/swine/Ohio/1/2012, A/swine/Ohio/6/2012, A/swine/Ohio/7/2012).

As seen in the Ohio swine sequences, the N2 was closely related to sequences from the first 10 cases in 2011 and were from a lineage found in H1N2 swine. Moreover, these sequences also had an H1N1pdm09 M gene as well as an H3 gene that was related to human H3N2v sequences from US cases (2009-2012).

The presence of PB1 E618D and H1N1pdm09 M genes in the Ohio swine sequences raised concerns of increased human adaptation, although prior to the release of the Michigan sequences, this combination had not been reported in humans. All 2012 cases had an H1N1pdm09 M gene, but none had PB1 E618D or the N2 lineage seen in early 2011 cases. Instead, all had an N2 lineage that circulated in H3N2v swine and was first seen in human H3N2v in sequences from the West Virginia day care center ((A/West Virginia/06/2011 and A/West Virginia/07/2011).

The presence of PB1 E618D in two cases in Michigan raises concerns of increased transmission. Michigan reported 5 cases in August and sequences from the first case, A/Michigan/14/2012, was similar to other 2012 H3N2v cases. However, Michigan has announced a sixth case which has been “under investigation” for several weeks (as noted in the past 3 Michigan flu updates for weeks 36-38). More information on this case and other cases “under investigation” would be useful.

The two cases with PB1 E618D and an N2 gene found in 2011 cases once again highlights the discordance between human and swine cases. The N2 gene found in the two 2012 Michigan cases are widespread in swine (including the 4 June cases in Ohio), yet all other reported human H3N2v cases in 2012 have the N2 lineage found in the West Virginia outbreak. Prior to the explosion of cases in July and August, swine with this N2 as well as H3 and MP which matches the human cases was limited to two examples (in North Carolina and Indiana).

The limited number of human cases with the N2 that is widespread in swine suggests that jumps from swine to human are relatively rare, but the two newly released sequences from Michigan raises concerns that the spread of this novel constellation may be increasing.

[dothedd]

Influenza A(H3N2)

CDC warns of early, severe flu season

CDC officials announced Monday that the 2012-13 flu season has started nearly a month earlier than expected, with influenza A(H3N2) being this year's dominant strain, and they said this could be a bad year for flu. However, the influenza vaccine this year is a 90% match for the samples examined by the agency, officials said. "My advice is: Get the vaccine now," said infectious diseases specialist Dr. James Steinberg of Emory University.

[dothedd]

Potential for H3N2 Flu Pandemic

Information by Massachusetts Institute of Technology - Published: 2013-05-11


MIT study reveals there are many strains of H3N2 circulating in birds and pigs that have the potential to generate a pandemic if they leap to humans:

Potential flu pandemic lurks - MIT study identifies influenza viruses circulating in pigs and birds that could pose a risk to humans.


In the summer of 1968, a new strain of influenza appeared in Hong Kong. This strain, known as H3N2, spread around the globe and eventually killed an estimated 1 million people.

A new study from MIT reveals that there are many strains of H3N2 circulating in birds and pigs that are genetically similar to the 1968 strain and have the potential to generate a pandemic if they leap to humans. The researchers, led by Ram Sasisekharan, the Alfred H. Caspary Professor of Biological Engineering at MIT, also found that current flu vaccines might not offer protection against these strains.

“There are indeed examples of H3N2 that we need to be concerned about,” says Sasisekharan, who is also a member of MIT’s Koch Institute for Integrative Cancer Research. “From a pandemic-preparedness point of view, we should potentially start including some of these H3 strains as part of influenza vaccines.”

The study, which appears in the May 10 issue of the journal Scientific Reports, also offers the World Health Organization and public-health agencies’ insight into viral strains that should raise red flags if detected.

Influenza evolution

In the past 100 years, influenza viruses that emerged from pigs or birds have caused several notable flu pandemics. When one of these avian or swine viruses gains the ability to infect humans, it can often evade the immune system, which is primed to recognize only strains that commonly infect humans.

Strains of H3N2 have been circulating in humans since the 1968 pandemic, but they have evolved to a less dangerous form that produces a nasty seasonal flu. However, H3N2 strains are also circulating in pigs and birds.

Sasisekharan and his colleagues wanted to determine the risk of H3N2 strains re-emerging in humans, whose immune systems would no longer recognize the more dangerous forms of H3N2. This type of event has a recent precedent: In 2009, a strain of H1N1 emerged that was very similar to the virus that caused a 1918 pandemic that killed 50 million to 100 million people.

“We asked if that could happen with H3,” Sasisekharan says. “You would think it’s more readily possible with H3 because we observe that there seems to be a lot more mixing of H3 between humans and swine.”

Genetic similarities

In the new study, the researchers compared the 1968 H3N2 strain and about 1,100 H3 strains now circulating in pigs and birds, focusing on the gene that codes for the viral hemagglutinin (HA) protein.

After comparing HA genetic sequences in five key locations that control the viruses’ interactions with infected hosts, the researchers calculated an “antigenic index” for each strain. This value indicates the percentage of these genetic regions identical to those of the 1968 pandemic strain and helps determine how well an influenza virus can evade a host’s immune response.

The researchers also took into account the patterns of attachment of the HA protein to sugar molecules called glycans. The virus’ ability to attach to glycan receptors found on human respiratory-tract cells is key to infecting humans.

Seeking viruses with an antigenic index of at least 49 percent and glycan-attachment patterns identical to those of the 1968 virus, the research team identified 581 H3 viruses isolated since 2000 that could potentially cause a pandemic. Of these, 549 came from birds and 32 from pigs.

The researchers then exposed some of these strains to antibodies provoked by the current H3 seasonal-flu vaccines. As they predicted, these antibodies were unable to recognize or attack these H3 strains. Of the 581 HA sequences, six swine strains already contain the standard HA mutations necessary for human adaptation, and are thus capable of entering the human population either directly or via genetic reassortment, Sasisekharan says.

“One of the amazing things about the influenza virus is its ability to grab genes from different pools,” he says. “There could be viral genes that mix among pigs, or between birds and pigs.”

Sasisekharan and colleagues are now doing a similar genetic study of H5 influenza strains. The H3 study was funded by the National Institutes of Health and the National Science Foundation.

[dothedd]

H3N2 - (Influenza A virus subtype H3N2) - a subtype of viruses that causes influenza (flu). H3N2 Viruses can infect birds and mammals. In birds, humans, and pigs, the virus has mutated into many strains. H3N2 is increasingly abundant in seasonal influenza. Both the H2N2 and H3N2 pandemic flu strains contained genes from avian influenza viruses. The new subtypes arose in pigs coinfected with avian and human viruses and were soon transferred to humans. Swine were considered the original "intermediate host" for influenza, because they supported reassortment of divergent subtypes. However, other hosts appear capable of similar coinfection (e.g., many poultry species), and direct transmission of avian viruses to humans is possible. H1N1 may have been transmitted directly from birds to humans (Belshe 2005). H3N2v is a variant of H3N2 influenza virus. When this virus occurs in pigs, it is called “swine influenza.” The virus does not usually infect people or spread among people. It is very different from human seasonal H3N2 viruses.

[dothedd]

Indiana H3N2v Outbreak Raises Concerns
Recombinomics Commentary 21:30
June 27, 2013

Detection of four cases of variant influenza A (H3N2v).

All individuals visited the Grant County Agricultural Fair, June 16-22, prior to illness,

The above comments from the Indiana State Health Department represent the third year in a row where the first H3N2v cases for the summer swine flu season were from Indiana (see map). However, the above cases are the earliest reported cases for the season.

In 2011 the first case was noted in late August based on sequences deposited by the CDC at GISAID, which were generated from a July 27 collection. The case (2M) was not directly linked to swine, but his caretaker had prior contact with swine at a fair. The sequence of the isolate, A/Indiana/08/2011, was the first human H3N2v case with an H1N1pdm09 M gene, That Indiana case was followed by confirmation of 3 cases at the Washington County fair in Pennsylvania, which at the time were the most H3N2v confirmed cases reported from the same venue. However, a follow-up study involving calls to 4-H members for participated in the fair identified 4 additional cases based on H3N2v antibody levels, as well as 81 additional cases with flu-like symptoms, which are uncommon in Pennsylvania in August. The three Pennsylvania sequences, as well as sequences from all subsequent H3M2v cases had an H1N1pdm09 M gene. The subsequent isolates from Indiana, Maine, and Iowa were closely related to the Indiana sequences.

However, at the end of 2011 an outbreak at a day care center in West Virginia involved H3N2v (A/West Virginia/06/2011) with an N2 from a different lineage (from H3N2v instead of H1N2v) and that constellation became dominant in human cases. The first 2012 case was in March in Utah, but the first case linked to fairs was again in Indiana. The La Porte fair outbreak was reported on July 26 with sequences from collections on July 16. The 2012 had many more case (309 vs 12 in 2011) and outbreaks were larger. The Gallia Fair outbreak in Ohio involved 100’s of attendees. The first 200 with symptoms were tested with an influenza A raid test and the 69 positives indicated virtually all were infected since the sensitivity of the rapid test was below 40%. Only 12 confirmed cases were reported by Ohio as well as 3 from West Virginia who also attended the fair, but the 200 attendees tested represented a subset of cases with symptoms.

The USDA monitors swine and prior to the explosion of cases in 2012, the H3N2 in swine matched the human cases from early 2011 (and N2 from H1N2v). However, all of the human cases matched the West Virginia sub-clade (N2 from H3N2v), with the exception of three cases from Michigan with a novel constellation.

Swine isolates from swine infected after the explosion of cases in 2012 are dominated by the human constellation. This week the USDA released sequences from seven 2013 isolates from Indiana. One had a H1N1pdm09 M gene with H3 and N2 lineages not found in human cases. However, the other six ((A/swine/Indiana/A01260252/2013, A/swine/Indiana/A01260254/2013, A/swine/Indiana/A01260261/2013, A/swine/Indiana/A01260276/2013, A/swine/Indiana/A01260280/2013, A/swine/Indiana/A01260284/2013) matched the human cases, raising concerns that the number of 2013 H3N2v cases will be significantly higher than the levels reported in 2012.

[dothedd]

2013 Grant County Indiana H3N2v Matches 2012 Cases
Recombinomics Commentary 18:15
June 28, 2013

One virus sample has been fully characterized by CDC and is 99% similar to H3N2v viruses identified in the 309 human infections that occurred in the United States in 2012. None of the four persons were hospitalized. At this time no ongoing human-to-human transmission has been identified and all four cases have reported close contact with swine in the week prior to illness onset. Public health and agriculture officials are investigating the extent of disease among humans and swine, and additional cases may be identified as the investigation continues.

The above comments are from the CDC week 25 Fluview, which has additional information on the four H3N2v confirmed attendees of the Indiana Grant County Fair (see map). Although the sequence described above has not been released, the comment of 99% similarity with the 2012 cases suggests that the 2013 sequences have the same lineages for each of the 8 gene segments that were present in the vast majority of human H3N2v sequences.

These sequences were dominant in the recent Indian swine sequences released by the USDA and suggest the above sequence will be closely related to those sequences ((A/swine/Indiana/A01260252/2013, A/swine/Indiana/A01260254/2013, A/swine/Indiana/A01260261/2013, A/swine/Indiana/A01260276/2013, A/swine/Indiana/A01260280/2013, A/swine/Indiana/A01260284/2013). Similar sequences were found in 2013 isolates from Ohio swine, raising concerns that Indiana and Ohio will again have the most confirmed cases in 2013, which were 138 and 107, respectively, in 2012.

However, the dominance of this sub-clade in the 2013 H3N2v swine sequences released by the USDA, and the early occurrence of the Indiana, outbreak raises concerns that the 2013 human H3N2v cases will exceed 2012.

[dothedd]

2013 Grant Co Indiana H3N2v Matches 2012 Cases & Swine
Recombinomics Commentary 22:15
June 28, 2013

The CDC has release complete or nearly complete sequences for all 8 gene segments from one of the H3N2v infected attendees of the Indiana Grant County Fair, A/Indiana/04/2013 (see map). The CDC is to be commended for the rapid release of these sequences. As suggested by the 99% similarity sated in the week 25 FluView, all 8 gene segments matched the lineages dominant in the 2012 H3N2v cases, including an N2 matching the sequences from the 2011 cases linked to a West Virginia day care center.

Earlier this week the USDA released a series of 2013 H3N2 Indiana swine sequences which included collections on April 30 (A/swine/Indiana/A01260252/2013, A/swine/Indiana/A01260254/2013, A/swine/Indiana/A01260261/2013, A/swine/Indiana/A01260276/2013, A/swine/Indiana/A01260280/2013, A/swine/Indiana/A01260284/2013) that matched the lineages that dominated human H3N2 cases in 2012. In addition, the USDA has recently released a series of 2013 sequences from Ohio swine (A/swine/Ohio/A01349615/2013, A/swine/Ohio/A01349495/2013, A/swine/Ohio/A01349485/2013, A/swine/Ohio/A01349302/2013, A/swine/Ohio/A01349305/2013) which also matched the human 2012 lineages.

However, the segments from A/Indiana/04/2013 were most closely related to human and swine sequences from 2012. This discordance between the human sequences a year ago, and the H3N2v swine sequences released by the USDA from collections prior to the human infections. In 2012 the swine sequences from the first six months of 2012 were dominated by sequences with an N2 that matched the early 2011 human sequences (which had an N2 matching H1N2 swine). Swine sequences with an N2 matching the West Virginia day care center (A/West Virginia/06/2011), which was an N2 matching H3N2 swine, were rare, yet virtually all human cases in 2012 had this N2 (with the exception of 3 cases in Michigan, which had an unusual constellation).

This discordance suggests the H3N2v at fairs is largely due to humans infecting swine leading to significant inter-species transmission.

[dothedd]

2013 H3N2v Cases Spread To Hancock County Fair Indiana
Recombinomics Commentary 21:00
July 4, 2013

detection of 12 cases of variant influenza A (H3N2v), also known as swine influenza. At least 10 individuals had exposure to swine at the Grant and Hancock county fairs and one individual had contact with swine at their home farm.

29 pigs from the Grant and Hancock county fairs have tested positive for influenza.

The above comments from the Indiana State Department of Health describe 8 additional H3N2v cases as well as 17 additional swine infected with influenza. The initial four cases were from the Grant County fair (see map) and sequences from three of the cases have been released. As noted for the first sequence, A/Indiana/04/2013, the two additional sequences, A/Indiana/05/2013 and A/Indiana/07/2013 matched human 2012 H3N2v cases and all three sequences were closely related to each other, signaling clonal expansion. These cases from the Grant County fair represented the earliest report of H3N2v cases in the summer fair season. The cases from the Hancock County Fair (see map) also were prior to the earliest cases from prior years, increasing concerns that the number of cases in 2013 will be significantly higher than the record 309 confirmed cases reported for 2012.

Moreover, as noted above, at least one case was not linked to the two fairs and at least one additional case was not linked to attendance at either fair or a home farm, and is likely linked to human to human transmission.

The increase in cases is also suggested by additional May and June 2013 H3N2v swine sequences released through the USDA surveillance program which have the same constellation of genes seen in the 2012 and 2013 cases.

[dothedd]

H1N1pdm09 PA In Illinois and Indiana H3N2v Cases
Recombinomics Commentary 23:45
August 14, 2013

The CDC has released a full set of H3N2v sequences from the first 2013 confirmed cases in Illinois, A/Illinois/03/2013, as well as the most recent case in Indiana, A/Indiana/11/2013 (14th 2013 Indiana confirmed case). As was seen in the case in Virginia (Ohio resident who visited an agricultural fair in northwestern Virginia), A/Ohio/05/2013, both of the newly released sequences included an H1N1pdm09 PA gene segment (in addition to a H1N1pdm09 M gene segment). Moreover, the two most recent PA sequences were identical and differed from the Virginia sequences at two positions (the three human PA sequences were much more closely related to each other than any reported H1N1pdm09 PA sequence in swine).

Thus, the three most recent human H3N2v cases have H1N1pdm09 PA, increasing the total number of gene segments with a recent history of efficient transmission in humans to five. In the early 1990’s three human genes (H3, N2, PB1) were identified in swine. All human H3N2v sequences (first case was in 2009) have H3 and N2 that trace back to seasonal H3N2 circa 2003. The acquisition of H1N1pdm09 M gene in 2011 and PA in 2013 create a majority for human lineage genes in human H3N2v isolates.

These acquisitions signal further human adaptation that increase pandemic concerns.

[dothedd]

H3N2v In Michigan With H1N1pdm09 PA & MP?
Recombinomics Commentary 21:45
August 29, 2013

Today, August 29, 2013, the Michigan Departments of Community Health (MDCH), and Agriculture and Rural Development (MDARD), along with the Berrien County Health Department (BCHD) have identified one case of an H3N2 variant (H3N2v) in a child who was a swine exhibitor at the recent Berrien County Youth Fair, which took place August 12-17, 2013.

The child, who was not hospitalized, is reported to have contracted H3N2v after exposure to swine at the fair. In addition, a sick pig from the fair tested positive for Influenza A H3N2 at the National Veterinary Services Laboratories in Ames, Iowa. MDCH, MDARD, and BCHD are working with the Berrien County Youth Fair (BCYF) board to reach out to swine exhibitors who attended the fair to identify additional illnesses.

The above comments from a MDCH press release describe the first H3N2v case in Michigan this year and the seventeenth 2013 case reported in the United States. The three most recent cases prior to the above case were infected by H3N2 with H1N1pdm09 PA and MP genes. The first sequence with this combination, A/Ohio/05/2013, was from an Ohio resident who had visited an agricultural fair in north western Virginia prior tp disease onset. All prior human H3N2v had a signature change at position 145 (H3 numbering) which was N145K in the intial cases in Indiana and K145R in the subsequent case that were identified prior to the Ohio/ Virginia case. A/Ohio/05/2013 had K145R. However, the next two sequences, A/Illinois/03/2013 and A/Indiana/11/2013, had an H1N1pdm09 PA gene that exactly matched each other and differed from A/Ohio/05/2013 at two positions. The Illinois and Indiana sequences had N145K.

The proximity of the Michigan fair to Indiana and Illinois locations (see map) suggests that the Michigan case will have N145K as well as H1N1pdm09 PA and MP genes.

Although the characterization sheets for the three prior cases with H1N1pdm09 PA clearly note that the cases have H1N1pdm09 MP and PA genes, the CDC has not addressed this development or the fact that none of the published swine H3N2v sequences match the most recent human sequences (the only closely related sequences are from an Illinois swine, A/swine/Illinois/A01432795/2013, which had N145K and was closely related to the initial Indiana sequences, which also did not have H1N1pdm09 PA.

The CDC update on H3N2v spread at agricultural fairs notes that H3N2v can transmit from swine to humans as well as humans to swine, but the emphasis remains on transmission from swine to humans, even though swine sequences collected prior to the start of the agricultural fair season show discordance with subsequent human sequences.

[dothedd]

US : Michigan Reports First Case Of Human H3N2v Swine Flu, Brings National Total To 17

" The Michigan Departments of Community Health (MDCH) and their local and state health partners have identified a case of an H3N2 variant (H3N2v) in a child who was a swine exhibitor at the recent Berrien County Youth Fair, which took place August 12-17, 2013.

According to MDCH officials, the child, who was not hospitalized, is reported to have contracted H3N2v after exposure to swine at the fair. In addition, a sick pig from the fair tested positive for Influenza A H3N2 at the National Veterinary Services Laboratories in Ames, Iowa. MDCH, the MIchigan Department of Agriculture and Rural Development (MDARD), and the Berrien County Health Department (BCHD) are working with the Berrien County Youth Fair (BCYF) board to reach out to swine exhibitors who attended the fair to identify additional illnesses.

As a precaution, Michigan public health agencies have conducted an extensive multi-state outreach to meat processing plants that were identified as being in receipt of live swine from the fair. These facilities have been made aware of the potential exposure to their employees, symptoms of illness, and given instruction on seeking care and testing."

[dothedd]

Michigan H3N2v With H1N1pdm09 PA & MP
Recombinomics Commentary 23:45
September 3, 2013

The CDC has released a full set of H3N2v sequences from the Michigan case (6M) who exhibited swine at the Berrien County Fair in southwestern Michigan (see map). The case was diagnosed in Indiana and named A/Indiana/21/2013. As expected, the sequence was closely related to the three most recent sequences (A/Ohio/05/2013, A/Illinois/03/2013, A/Indiana/11/2013) and had H3 N145K as well as H1N1pm09 PA and MP gene segments.

Thus, all four of the most recent cases (with collection dates between July 21 and August 22) have an H1N1pdm09 PA gene segment which is virtually identical to each other. These four cases are linked to agricultural fairs in Virginia, Illinois, Indiana, and Michigan.

However, the CDC has not addressed in the presence of H1N1pdm09 PA gene in the four most recent cases, although its presence is noted in the characterization sheet for each of the four cases. The presence of H1N1pdm09 PA signals further human adaptation and raises concerns regarding limited surveillance and sub-typing of summer influenza A cases not linked to swine or agricultural fairs.

[dothedd]

More H3N2v Cases In Michigan With H1N1pdm09 PA & MP?
Recombinomics Commentary 17:15
September 6, 2013

One additional infection with influenza A (H3N2) variant (H3N2v) virus was reported to CDC during week 35 from Michigan. A total of 18 H3N2v cases have been reported this summer (Illinois [1], Indiana [14], Michigan [2], and Ohio [1]). So far during 2013, one person has been hospitalized as a result of H3N2v illness;

The above comments from the CDC week 35 FluView cite a second confirmed H3N2v case in Michigan. Recombinomics was referred to the Berrien County Department of Health for more information, since the second case was linked to Barrien County (see map). However, there is also appears to be an Ingham County case, so it is unclear if the second case resides in Ingham County or there are now three cases in Michigan.

The CDC has released full sequences from the first Michigan case (designated A/Indiana/21/2013 because Indiana collected the sample and made the diagnosis), which like the three prior cases had change at position 145 and had H1N1pdm09 PA and MP gene segments. The linkage to Barrien County suggests the second case in Michigan will also have H1N1pdm09 PA and MP genes, extending the number of human cases with that constellation to five (and extending the number of 2013 H3N2v cases with N145K or K145R to 18 - all cases confirmed in 2013).

The increasing number of human cases with H1N1pdm09 PA and MP genes and the absence of this constellation in H3N2v swine sequences, including collection in July, 2013, have not been addressed by the CDC.