Serendipity down on the farm JOAN ROBINSON MD STOLLERY CHILDREN’S HOSPTIAL EDMONTON, ALBERTA JUNE 2007

7-month old boy from a communal farm admitted to hospital Sept 2006 with 3-day history of fever, rhinitis, and cough No ill contacts Communal farm has horses, cows, swine, sheep, dogs, cats, turkeys, geese, ducks, and chickens Term infant – admitted for 21 days at 5 weeks of age with respiratory syncytial virus (RSV) and ventilated 6 days

Afebrile, HR 120/min, RR 56/min, 02 saturation 85% on room air Diffuse wheeze CXR normal Admitted with diagnosis of bronchiolitis (common problem in this age group but a bit unexpected in September – most commonly from RSV) Discharged well 2 days later Brother developed URI symptoms the day the index case was admitted to hospital but was never seen by a health care worker

DFA positive for influenza A Culture later confirmed this Isolate sent to NML in Winnipeg as no influenza identified in northern Alberta for months H3N2 very closely related to A/Swine/Ontario/33853/2005 (swine strain isolated from a farm worker in the only previously recognized case of human infection with swine influenza in Canada) Our virus has now been designated A/Canada/1158/06

Can we prove the isolate came from the child Can we prove the isolate came from the child? Can we prove the child had infection and not just colonization? HI titre to our swine isolate: 1:32 in both parents, 1:256 in index case and 19-month-old sibling who developed respiratory symptoms during his admission (serology negative in Ontario case) All had undetectable titres to A/NewCaledonia/20/99(H1N1) and A/Wisconsin/67/05 (H3N2)

So could this be the beginning of the next influenza pandemic?

Avian influenza hits Disneyland

Hemagglutinin – binds to sialic acid on target cells to let virus into cells (with different receptors in humans vs. birds) – must be cleaved by a protease to be activated, and more virulent strains have hemagglutinins that are susceptible to more proteases Virus multiples in the cell and then binds to sialic acid again on the way out Neuraminidase cleaves the bond and lets the virus go free to infect other cells

Avian influenza has one of 15 hemagglutinin (H1-H15) and 9 neuramindase types (N1-N9) while human disease up until recently was always H1-3, N1-2 (possibly N8 in 1800’s) Shifting is when a whole new H or N type appears on the scene (resulting in a pandemic if it is an H type) while drifting is the minor changes in H or N types that occur every year or two

Does swine influenza have the potential to cause human pandemics? All influenza A pandemics of the 20th century resulted from adaptation of avian strains to allow for human-to-human transmission (1918) or reassortment of avian and human strains (1957, 1968) Avian and human strains preferentially bind to different sialic acid-galactose receptors (2,3 versus 2,6 linkage) but swine contain both types of receptors (and have been shown to be infected with human strains) so would be the perfect mixing vessel

So other than in the case I just presented, what is the evidence humans have been infected with swine influenza? Great excitement occurred in January 1976 when 5 army recruits at Fort Dix,NJ developed influenza-like illness (ILI) and had swine H1N1 isolated – one died In retrospect, another 8 recruits who had been seem with ILI had HI titre of >/= 1:20 to same strain An estimated 250 people at Fort Dix were seropositive with no history of an ILI None had swine contact!

Resulted in a massive campaign to immunize as many American and Canadian adults as possible against swine flu After 45 MILLION doses, campaign halted Dec 1976 when increase of cases of Guillain Barre noted in immunized adults

Another 4 cases of human infection with H1N1 swine strains documented prior to the Fort Dix incident and another 29 cases since (Myers KP et al. Clin Infect Dis 2007;44:1084-8) Human infection with swine H3N2 documented in Netherlands in 1993 (n=2), Switzerland in 1999, Ontario in 2005 and then in our case No swine contact in 28 of the 50 previous cases Mainly previously well patients (12 children, 38 adults) Full spectrum of ILI with 6 deaths

Therefore, it is clear that swine influenza causes human disease, with cases like ours likely being “the tip of the iceberg”, with most never being recognized as most influenza isolates are not even sub-typed, let alone identified as a specific strain. Seems possible swine influenza could cause a pandemic if a mutation occurred that resulted in more efficient person-to-person spread ( a higher basic reproductive rate or Ro)

Why are we starting to see H3N2 cases in humans? swine in North America had almost exclusively H1N1 strains until 1998, but now often have H3N2 strains, with these strains not being recognized in Canada until 2005 – also found in turkeys in Canada Our strain and other recent H3N2s are triple reassortant strains with genetic material from human (hemagglutinin, neuraminidase, and RNA polymerase PB1), swine (nucleoprotein, matrix, and nonstructural genes), and avian (RNA polymerase PA and PB2) strains

Back to our case, what was the evidence for swine influenza in the pigs currently on the farm?

Last documented influenza one year prior, but breeding animals come from a herd in Manitoba with recent H3N2 swine influenza Nasal swabs on 10 grower pigs negative for influenza Serology drawn on 10 grower-finisher pigs – all negative for H1N1 but 4 had antibodies to H3N2 and one of these had antibodies to A/Canada/1158/06 Autopsies on 5 well pigs showed subacute bronchointerstitial pneumonia but no definite findings of recent influenza

So where did our baby’s virus come from?

Based on the literature, it is not surprising that a baby with no swine contact developed swine influenza with the source presumably being another person, either via direct spread or via fomites No one else on the farm was reported to have a recent influenza-like illness, but the question was “How many other people on the farm had been infected with swine influenza?”

Ethics approval obtained Written informed consent obtained Serology for our strain of swine influenza and the human H3N2 and H1N1 strains from 2005-6 were performed on as many residents of the farm as possible on a sunny December morning Age, time spent in swine barn, and history of influenza-like illness recorded

Results of study 54 of the 90 farm residents were tested (includes the testing of the family that was already mentioned) 4 of the 7 household contacts of index case were seropositive for swine influenza 16 other households had one or more members in the study 3 children seropositive in one household (father worked in swine barn and was not tested and mother was seronegative) and one child in another (father and one sibling negative) 20 other adults and 19 other children from 14 other households all seronegative, including 3 teens who worked in the swine barns

Results of study Only 2 of the 54 subjects were seropositive for human influenza (H3N2 in one of the subjects who was seropositive for swine influenza and H1N1 in a subject seronegative for swine influenza) Only 2 of the subjects described an influenza-like illness in the preceding year, including a 3-yr-old who was seropositive for swine influenza (not admitted to hospital and not tested for influenza when ill)

CONCLUSIONS Swine influenza strains can infect humans and can cause severe disease Unrecognized cases of human infection with swine influenza occur in Canada Person-to-person spread does occur, but to date the basic reproductive rate (Ro) has been too low to initiate a major epidemic Surveillance for ILI in swine workers may allow for early detection of a strain with an increased Ro