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Elevated Inflammatory Mediators in Adults with Oculorespiratory Syndrome following Influenza Immunization:… Al-Dabbagh, Mona; Lapphra, Keswadee; Scheifele, David W.; Halperin, Scott A.; Langley, Joanne M.; Cho, Patricia; Kollmann, Tobias R.; Li, Yan; De Serres, Gaston; Fortuno III, Edgardo S.; Bettinger, Julie A. Aug 31, 2013

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Elevated Inflammatory Mediators in Adults with OculorespiratorySyndrome following Influenza Immunization: a Public Health Agencyof Canada/Canadian Institutes of Health Research Influenza ResearchNetwork StudyMona Al-Dabbagh,a Keswadee Lapphra,a David W. Scheifele,a Scott A. Halperin,b Joanne M. Langley,b Patricia Cho,aTobias R. Kollmann,a Yan Li,c Gaston De Serres,d Edgardo S. Fortuno III,a Julie A. BettingeraVaccine Evaluation Center, BC Children’s Hospital, University of British Columbia, Vancouver, British Columbia, Canadaa; Canadian Center for Vaccinology, IWK HealthCentre, Dalhousie University, Halifax, Nova Scotia, Canadab; National Microbiology Laboratory, Public Health Agency of Canada, Winnipeg, Manitoba, Canadac; Unité deRecherche en Santé Publique (CHUQ), Quebec, Quebec, CanadadOculorespiratory syndrome (ORS) is an infrequent adverse event following influenza vaccination. Its clinical presentationsuggests that ORS is an immune-mediated phenomenon, but studies of symptomatic individuals have been few. This studymeasured cytokine levels in peripheral blood samples following influenza vaccination in those with and without currentORS symptoms. Canadian adults receiving the 2010-2011 seasonal influenza vaccine were recruited and asked to promptlyreport any adverse effects. ORS symptoms occurring 4 to 48 h after vaccination were identified using previously publishedcriteria. Two blood samples were collected from each subject to measure blood plasma cytokine and hemagglutination in-hibition antibody (HAI) titers; visit 1 occurred during the acute disease phase or 4 to 72 h after vaccination for controls,and visit 2 occurred another 21 days postimmunization. Nine ORS cases and 35 controls were enrolled. The median age ofORS cases was 49 years, and 89% were female. Most cases had multiple symptoms, but none required medical care. HAItiters before and after vaccination were similar for the cases and controls. Blood plasma cytokine concentrations did notdiffer between the ORS cases and controls for most cytokines measured (interleukin 4 [IL-4], IL-5, IL-10, IL-13, IL-1,IL-8, tumor necrosis factor alpha [TNF-], gamma interferon [IFN-], and IL-17A). However, ORS cases had higher levelsof IL-10 and IL-3 than the controls at visits 1 and 2, even after all symptoms had subsided. Persistent higher levels of IL-10and IL-3 in ORS cases suggest that host factors may have predisposed these individuals to develop ORS following influenzavaccination. Further investigations are warranted, as they might identify subjects who are at risk for ORS prior tovaccination.Influenza infection is a major cause of morbidity and mortal-ity worldwide, and vaccination is the cornerstone of infectionprevention. Administration of the seasonal influenza vaccine isassociated with a varied range of adverse events following im-munization (AEFI) that include local (injection-site reaction)and systemic manifestations. Oculorespiratory syndrome(ORS) is an influenza vaccine-associated adverse event that wasfirst described in Canada during the 2000-2001 influenza im-munization campaign (1). Patients usually presented within 24h after vaccination with bilateral red eyes, facial edema, and/orrespiratory symptoms (Table 1). Manifestations frequently re-solved within 48 to 72 h.The specific cause of ORS is not understood. Studies in Canadaduring the 2000-2001 season linkedmost ORS cases to a domesticmanufacturer’s vaccine that contained a higher-than-expectedcontent of unsplit and aggregated influenza virions (2). In subse-quent seasons, although at a lower frequency, cases of ORS werealso associated with influenza vaccines from other manufacturers(3). Although many ORS manifestations resemble allergic reac-tions, results fromaffected individuals whowere given skin testingsuggest that ORS is not a type-I hypersensitivity reaction (4).However, an immune-based pathogenesis of ORS appears likely,given the types and timing of symptoms (5).The role of cytokine production has been investigated in a fewinfluenza vaccine-associated adverse events. A recent Australianstudy demonstrated significantly higher levels of gamma inter-feron (IFN-)-induced protein 10 (IP-10) and macrophage in-flammatory protein 1 alpha (MIP-1) in children presenting withfebrile convulsions after trivalent influenza vaccine (TIV) immu-nization than in healthy controls (6). In vitro stimulation of pe-ripheral blood mononuclear cells (PBMCs) using the same influ-enza vaccine as had been administered to the subjects resulted insignificantly higher levels of IFN-, IL-1, IL-6, IL-10, IP-10, andMIP-1 than with use of other TIV vaccines, suggesting that thispyrogenic response was related to a component of the implicatedvaccine (6). Skowronski et al. (7) conducted a study to assess theassociation between in vitro cytokine balance (after stimulation ofPBMCs) and clinical ORS 6 months after influenza vaccination;significantly more IFN- was produced by individuals who re-ceived the influenza vaccine than by nonvaccinated individuals,Received 6 November 2012 Returned for modification 14 March 2013Accepted 13 May 2013Published ahead of print 22 May 2013Address correspondence to Julie A. Bettinger, jbettinger@cfri.ca.Copyright © 2013, American Society for Microbiology. All Rights Reserved.doi:10.1128/CVI.00659-121108 cvi.asm.org Clinical and Vaccine Immunology p. 1108–1114 August 2013 Volume 20 Number 8but the data failed to show any significant difference in IFN-levels between ORS-affected and -unaffected vaccinees.To our knowledge, no studies have been done to assess cyto-kine responses in vivo during the acute symptom phase of ORS orother allergy-like AEFI. A preseason evaluation in Canada of the2010/2011 TIV in adults identified a small number of cases thatmet theORS criteria.We aimed to evaluate a broad panel of in vivoinflammatory mediators in subjects with acute ORS symptomscompared to unaffected individuals following vaccination. Wealso aimed to evaluate hemagglutination inhibition (HAI) anti-body responses in subjects experiencing ORS compared to unaf-fected individuals following seasonal TIV vaccination, as titersmight differ between those with and without ORS.MATERIALS AND METHODSStudy design. This was a prospective observational study conducted dur-ing employee influenza immunization campaigns between October andDecember 2010 at two participating Canadian centers. The study wasapproved by the research ethics board of each center, and each participantprovided informed consent.Study population. Adults aged 20 to 65 years who experienced ORSshortly after receiving the seasonal influenza vaccine (Fluviral, Glaxo-SmithKline, Inc.) andwhowere still symptomatic were enrolled as cases atone study center (Vancouver). Similarly vaccinated adults without symp-toms were enrolled as controls at two study centers (Halifax and Vancou-ver). To identify cases, participants were given an information card con-taining a list of ORS symptoms at occupational health-based influenzaimmunization clinics and were asked to call a study nurse by telephone ifthey experienced any of the listed symptoms after immunization.Adults who reported postimmunization symptoms were eligible ascases if they experienced symptoms consistent with ORS starting 4 to 48 hafter vaccination that were still present at the time of the first blood draw.Control subjects (those who were asymptomatic) were recruited fromemployee immunization clinics.ORS cases were defined according to the 2001-2002 National AdvisoryCommitteeon ImmunizationORScriteria (8),with the exclusionof thepres-ence of coryza, to minimize the possibility of enrolling cases with symptomsrelated to infection. Adults were excluded if they had received blood or anyblood-derived productswithin the past 3months, had an active disease of theimmune system (such as transplantation, HIV infection, or congenital im-TABLE 1 Clinical manifestations of ORSaSymptom type Specific symptomsOcular Bilateral red eyes (conjunctival erythema)Respiratory Cough, sore throat, hoarseness, wheezing,chest tightness, difficulty breathing,difficulty swallowingFacial edema Lip, tongue, or eyelid swellinga ORS cases can present with symptoms from one or more categories, and ORSsymptoms can be associated with other systemic manifestations.TABLE 2 Demographic characteristics of study participantsCharacteristic Total ORS cases Controls Pn 44 9 35Female (no. [%]) 26 (59) 8 (89) 18 (51) 0.06Age (yr)Mean 42.8 45.2 42.2 0.43Median 43.5 49.0 41.0Range 24–65 29–54 24–65Ethnic background (no. [%])White 39 (89) 8 (89) 31 (89) 0.99Other 5 (11) 1 (11) 4 (11)Underlying medical conditiona (no. [%]) 24 (55) 7 (78) 17 (49) 0.15Hypertension 3 1 2 —Asthma 6 4 2 0.01Allergies 7 3 4 0.14Other 17 5 12 —Previous ORSb (no. [%]) 2 (5)c 2 (22)c 0 —Influenza vaccination status (no. [%])Previous vaccination 44 (100) 9 (100) 35 (100) —Pandemic 2009/2010 vaccine 39 (89) 8 (89) 31 (89) 0.99Seasonal vaccine last year 40 (91) 9 (100) 31 (89) 0.57Received medication within the past 24 ha (no. [%]) 20 (48)e 6 (86)e 14(40) 0.04NSAIDd 8 4 4 0.08Antihistamine 5 2 3 0.53Birth control or hormonal therapy 5 2 3 0.27Other 8 3 5 —a Some subjects had more than one condition.b Previous ORS was following a past influenza vaccine. One of the cases experienced ORS twice, and one had it once previously.c One missing response from an ORS case (43 total valid responses, 8 among ORS cases).d NSAID, nonsteroidal anti-inflammatory drugs.e Two missing responses in ORS cases (42 total valid responses, 7 among ORS cases).Oculorespiratory Syndrome and Influenza ImmunizationAugust 2013 Volume 20 Number 8 cvi.asm.org 1109mune defects), or received immunosuppressive medications (chemothera-peutic agents for the treatmentof canceror autoimmunediseases, or systemicsteroids for2weeks). Adults were also excluded if they had recovered fromORS symptoms, had any preexisting ocular or respiratory symptoms at thetime of vaccination, or developed symptoms in4 h after vaccination.Study procedures. A blood sample was drawn at visit 1 to measureinflammatory cytokines andHAI titers during the acute disease phase (forcases) or approximately 4 to 72 h postimmunization (for controls). Asecond blood sample was obtained 21 to 28 days postimmunization (visit2) to measure inflammatory mediators and HAI titers. Case subjects weregivenmemory aids during the first visit to record the perceived severity asmild (present, but does not interfere with daily activities), moderate (in-terferes with daily activities, but does not prevent them), or severe (pre-vents daily activities), date of maximum intensity, and duration of theirsymptoms for 7 days after vaccination. They were also asked to record anyassociated general symptoms (malaise, myalgia, arthralgia, fatigue, head-ache, rash, and itchiness) and to document the occurrence of any newsymptoms, including a runny nose, after the first visit. Cases werecontacted by telephone 7 days after vaccination for safety debriefingand to assess the resolution of symptoms. Those with ongoing symp-toms were asked to continue documenting their symptoms, and theirrecords were collected at the second visit. A third blood sample wasdrawn to measure select inflammatory cytokines 9 to 12 months afterTIV immunization.Subject characteristics, including demographic data, underlyingmed-ical conditions (including asthma or allergies), medication received priorto the first blood draw, previous influenza immunization history (includ-ing the pandemic influenza vaccine and/or seasonal influenza vaccine),and history of ORS were documented for all participants.Blood sample processing. Blood samples were processed promptly torecover plasma and serum fractions, which were stored at70°C pendingsubsequent assays. Samples were transferred between sites on dry ice.Laboratory personnel were blinded to the case and control statuses of theparticipants. Paired samples were analyzed concurrently.Cases: 25 screened fromVancouver 0 screened fromHalifaxControls: 27 recruited fromHalifax 10 recruited fromVancouver10 Cases enrolled 37 Controls enrolledTotal 9 cases included inthe final analysis1 withdrawal: 2nd bloodsample was not obtained2 withdrawals: 1st bloodsample was not obtainedTotal 35 controls includedin the final analysisTotal 44 subjects included in the final analysis FIG 1 Included cases and controls.TABLE 3 ORS symptoms among the ORS-affected group and their severityORS symptomNo. experiencingsymptom (%)(total n 9)Median duration(range [days])aNo. (%) experiencing maximum severity ofsymptomsbMild Moderate SevereRedness in both eyes 4 (44) 3 (2 to21)c 3 (33) 1 (11) 0RespiratoryCoughing 5 (56) 4 (3–6) 3 (33) 2 (22) 0Sore throat 6 (67) 3 (2 to21)c 3 (33) 3 (33) 0Hoarseness 5 (56) 4 (3–6) 4 (44) 1 (11) 0Wheezing 2 (22) 4.5 (3–6) 1 (11) 1 (11) 0Chest tightness 7 (78) 4 (2–7) 5 (56) 2 (22) 0Difficult breathing 1 (11) 4 0 1 (11) 0Difficulty swallowing 3 (33) 8 (2–17) 0 3 (33) 02 symptoms 8 (89) — — — —Facial swellingLip swelling 1 (11) 2 0 1 (11) 0Other swelling 0 — — — —a All cases had onset of symptoms 4 to 48 h after vaccination, as defined by the study protocol.b Mild, symptom(s) was present but did not interfere with daily activities; moderate, symptom(s) interfered with daily activities but did not prevent an individual from engaging inthem; severe, symptom(s) prevented engagement in daily activities.c One subject had ongoing symptoms at 21 days postvaccination; the end date of those symptoms is unknown.Al-Dabbagh et al.1110 cvi.asm.org Clinical and Vaccine ImmunologyPlasma cytokines. Cytokines were measured in pg/ml using a com-mercial kit (Milliplex MAP human cytokine/chemokine, premixed 39-plex; Millipore, Billerica, MA) on the Luminex platform (Luminex, Aus-tin, TX), as described in previous studies (9). Undetectable cytokines wereassigned a value of half the minimal level of detection. Samples wereanalyzed for 39 different plasma cytokines: epidermal growth factor(EGF), eotaxin, basic fibroblast growth factor (FGF-2), FMS-like tyrosinekinase-3 (Flt-3) ligand, fractalkine, granulocyte colony-stimulating factor(G-CSF), granulocyte macrophage colony-stimulating factor (GM-CSF),growth regulated oncogene (GRO), IFN-2, IFN-, IL-10, IL-12 (p40),IL-12 (p70), IL-13, IL-15, IL-17, IL-1R, IL-1, IL-1, IL-2, IL-3, IL-4,IL-5, IL-6, IL-7, IL-8, IL-9, IP-10, monocyte chemoattractant protein-1(MCP-1), MCP-3, macrophage-derived chemokine (MDC) (CCL22),MIP-1, MIP-1, transforming growth factor-alpha (TGF-), TNF-,TNF-, vascular endothelial growth factor (VEGF), soluble CD40 ligand(sCD40L), and soluble IL-2 receptor alpha (sIL-2R).Hemagglutination inhibition test (HAI). Serum samples were testedfor the presence ofHAI antibodies against the homologous antigens of the3 influenza strains in the 2010/2011 vaccine (A/California/07/09 [H1N1],A/Perth/16/09 [H3N2], and B/Brisbane/60/08) with chicken red bloodcells, following standard procedures (10). Seroprotection was defined asan HAI titer of40.Statistical analysis.Descriptive statistics were used to report the base-line characteristics of the participants. Continuous variables were com-pared using a two-sample Student’s t test, and categorical variables werecompared using the chi-square or Fisher’s exact test.The primary outcome of the study was the difference inmean individ-ual blood plasma cytokine concentrations between ORS cases and con-trols at visit 1. To assess the normalization of cytokine concentrations,mean differences between acute and convalescent values (visit 1 visit 2)were calculated. Logarithmic transformations were used prior to analysisto ensure the assumptions of normality, and comparison was done usinga two-sample t test. Calculations included the 95% confidence interval.For the primary outcome, significancewas determined using a Bonferronicorrection for the adjustment ofmultiple comparisons; an alpha of 0.0013was selected as the corrected level of statistical significance.The secondary outcomewas themean difference inHAI titers betweenvisit 1 and visit 2 for cases and controls. Logarithmic transformation togeometric mean titers (GMT) was done to meet a normality assumption,and the two-sample t test was used. Seroconversion rates, final HAI titers,andGMTs in cases and controlswere compared amongH1N1,H3N2, andB strains, including the calculation of the 95% confidence intervals. Dataanalysis was done using SAS 9.2 software (Cary, NC).RESULTSDescription of study sample.NineORS cases and 35 controls wereenrolled (Fig. 1), and all attended the follow-up visit between days 21and28postvaccination.All cases came fromone center (Vancouver),where the study informationwas provided to 3,172 immunized indi-viduals. Themean time from vaccination to the first blood drawwassimilar in cases and controls (49.4 h versus 48.3 h, respectively; P0.89).Baselinecharacteristicswere similarbetweencases andcontrolsin all clinical categories (Table 2). Two of the ORS cases reported ahistory of ORS following previous influenza immunizations.Description of AEFI symptoms. Among the nine ORS cases,the most commonly reported symptom was chest tightness, fol-lowed by sore throat, hoarseness, and cough (Table 3). ORS symp-toms ranged frommild tomoderate in severity and were generallywell tolerated. One case who rated her symptoms as moderatereported staying at home for 4 days due to symptoms. This casewas the only one with ORS symptoms persisting for21 days andshe had experienced ORS twice previously after TIV vaccination.None of the ORS cases sought medical advice or required hospi-talization.Seven of the ORS cases (78%) had systemic symptoms follow-ing vaccination, with fatigue (67%), headache (56%), and myal-gia/malaise (44%) reported most commonly. Most of these casesrated their symptoms as mild or moderate, with only four report-ing severe symptoms (two with headache, one with malaise, andone with itchiness).Description of study outcomes. (i) Cytokine levels.At visit 1,we found that themean production level of IL-10 in ORS-affected0.40.21.02.04.0Cytokine Level (pg/ml)Visit 1IL-3Control ORS Control ORSVisit 210.040.0100.0Cytokine Level (pg/ml)Visit 1IL-10 Control ORS Control ORSVisit 20.40.21.02.04.010.040.0100.0ABFIG 2 IL-10 and IL-3 levels at visits 1 and 2 for ORS cases and controls. (A andB) Mean and median plasma levels (pg/ml) (means and 95% confidence in-tervals are shown with closed circles and vertical lines, respectively, and medi-ans and quartiles are shown with horizontal lines and boxes, respectively).Open circles represent outliers, which are values more than 1.5 times higherthan 75% of the values.Oculorespiratory Syndrome and Influenza ImmunizationAugust 2013 Volume 20 Number 8 cvi.asm.org 1111caseswas higher than that in controls, 33.6 pg/ml (95%confidenceinterval [CI], 22.4 to 50.5) versus 4.9 pg/ml (2.5 to 9.5), respec-tively (P  0.0001), as was the mean IL-3 concentration: 26.8pg/ml (95% CI, 16.3 to 44.1) versus 6.0 pg/ml (3.41 to 10.7) (P0.0002) (Fig. 2). We found a slightly higher concentration ofMCP-1 (P  0.0049) in cases than in controls during acute dis-ease, although the difference fell short of statistical significance.None of the other 36 cytokine concentration levels evaluated werefound to be elevated in cases compared with controls. Of note, theconcentrations of IL-10, IL-3, and MCP-1 remained elevated incases (P 0.0001, P 0.0002, and P 0.001, respectively) 21 to28 days after vaccination. Seven ORS cases had an additionalblood draw 9 to 12months after vaccination tomeasure IL-10 andIL-3 concentrations; no change in the mean cytokine levels wasevident (data not shown).To determine if certain cytokine concentrations were acutelyelevated following vaccination in both cases and controls, themean difference in measured values between the first and secondsamples was computed for all 39 measured cytokines. No signifi-cant change (including decline) in values was evident with anycytokine (data not shown).(ii) Hemagglutination inhibition (HAI) antibody response.Seroprotection rates were similar in cases and controls for all threestrains contained in the influenza vaccine. In general, the baselineseroprotection rate was higher for the B strain than the A strain inboth cases and controls. The postimmunization seroprotectionrates were highest for the B strains (100% and 100%), followed byH1N1 (100% and 88%) and H3N2 (67% and 57%) in cases andcontrols, respectively, but the differences between the groupswerenot significant. The fold increase in GMTs was not significantlydifferent betweenORS cases and controls for theH1N1, H3N2, orB influenza strains (Fig. 3).DISCUSSIONThe mechanism for developing ORS post-influenza immuniza-tion is not well understood. Our results indicate that ORS caseshad greater concentrations of particular cytokines (IL-10 andIL-3) than did controls. No elevations were evident between casesor controls for the IL-4, IL-5, IL-13, IL-1, IL-8, TNF-, IFN-, orIL-17A cytokines. However, the cytokines that were elevated insymptomatic ORS cases were still high 21 to 28 days and 9 to 12months later. This suggests that the symptoms of ORS in affectedsubjects were not due to a sudden increased production of inflam-matory cytokines in response to influenza vaccination. Instead,elevated concentrations of these cytokines may represent a bio-marker for susceptibility to ORS without necessarily playing adirect role in its pathogenesis.We also found that there was no difference in the mean anti-body response from baseline to 21 to 28 days after immunizationin ORS cases compared to controls for any of the three influenza5102550100Visit 1Geometric Mean and Median Titers (Log Scale)A/California/07/09 (H1N1) Control ORS Control ORSVisit 22505002500Visit 1A/Perth/16/09 (H3N2) Control ORS Control ORSVisit 25102550100Geometric Mean and Median Titers (Log Scale)2505002500Visit 1B/Brisbane/60/08Control ORS Control ORSVisit 25102550100Geometric Mean and Median Titers (Log Scale)2505002500ABCFIG 3 Hemagglutination inhibition (HAI) antibody response in ORS casesand controls. Means and 95% confidence intervals are shown with closedcircles and vertical lines, respectively, and medians and quartiles are shownwith horizontal lines and boxes, respectively. Open circles represent outliers,which are values more than 1.5 times higher than 75% of the values. (A)MeanandmedianHAI titers for the A/CaliforniaH1N1 strain; (B)mean andmedianHAI titers for the A/Perth H3N2 strain; (C) mean and median HAI titers forthe B/Brisbane strain.Al-Dabbagh et al.1112 cvi.asm.org Clinical and Vaccine Immunologystrains contained in the vaccine; this indicates that ORS does notresult in higher antibody responses. The increase in cytokinesmaybe related to genetically determined differences in the baselineproduction of these two cytokines.The mechanism by which IL-10 and IL-3 might be associatedwith the development of ORS is not clear. IL-3 has been describedto play an important role in inducing chronic inflammation bysupporting cell-mediated immune responses, and it is also in-volved in eosinophil activation, B-cell differentiation, and controlof IgE synthesis (11). In contrast, IL-10 is a potent anti-inflamma-tory cytokine with several important immunoregulatory func-tions (12). It has the capability of inhibiting proinflammatorycytokines, such as TNF-, IL-1, and IL-6. IL-10 also has an anti-inflammatory effect on eosinophils, basophils, andmast cells, andthus, it plays a major role in the control and regulation of allergyand asthma (12, 13). It is thus difficult to implicate these cytokinesin specific cause-and-effect relationships with ORS.An association between host genetic factors and the develop-ment of AEFI has been hypothesized (14–16). Stanley et al. (19)demonstrated that certain haplotypes in the IL-1 gene complexand in the IL-18 gene were associated with the development offever after smallpox vaccination, whereas a haplotype in the IL-4genewas associatedwith a significant reduction in susceptibility tosuch an event. In addition, Vestergaard et al. (15) found that at 15to 17 months of age, the risk difference of febrile seizures within 2weeks followingmeasles,mumps, and rubella (MMR) vaccinationwas 3.97 per 1,000 (95% CI, 2.90 to 5.40) for siblings of childrenwith a history of febrile seizures compared to siblings of childrenwith no history of febrile seizure, strongly suggesting an underly-ing genetic predisposition. Finally, the Finnish data, which foundthe occurrence of narcolepsy following immunization with a pan-demic influenza vaccine to be increased among individuals with aparticular genetic factor (human leukocyte antigen DQB1*0602allele), support a potential genetic basis for this rare adverse event(17).Our study was exploratory, and its major limitation is itssmall sample size. Our numbers in this pilot study were insuf-ficient to detect all but the greatest differences between casesand controls for most cytokines. The reliance on self-reportingof ORS symptoms is another limitation of our study. This lim-ited our ability to identify all ORS cases that occurred duringthe campaign season. It is unclear to us why no ORS cases weredocumented in Halifax, as the same vaccine was used in bothprovinces; this may be due to an actual difference in the inci-dence of ORS between Nova Scotia and British Columbia anddeserves further investigation. Finally, although our propor-tion of females to males was not significantly unbalancedamong cases and controls, female predominance in ORS caseshas been documented in all previous reports (1–3, 8, 16, 18),and the effect of gender should be examined in future studies.This study demonstrates that in adults with ORS, a persis-tent elevation in blood plasma levels of specific cytokines(IL-10 and IL-3) compared to vaccine recipients without ORScan be detected. The persistent nature of the elevation suggeststhat underlying host factors may predispose certain individualsto develop ORS following influenza vaccination. Given the ex-ploratory nature of our data, further investigation of these phe-nomena in a study with a larger sample size may be warranted.ACKNOWLEDGMENTSThe Public Health Agency of Canada and the Canadian Institutes ofHealth Research provided the funding for this study. The funders had norole in study design, data collection and analysis, decision to publish, orpreparation of themanuscript. T.R.K. is supported in part by a BurroughsWellcome Career Award in the biomedical sciences. T.R.K and J.A.B. aresupported by Michael Smith Foundation for Health Research Career In-vestigator Awards.The Canadian Association for Immunization Research and Evaluations(CAIRE) provided networking assistance for this study. We gratefully ac-knowledge the expert assistance provided by the Vaccine Evaluation Center(Carol LaJeunesse,ArleneKallos,KimMarty, andShuYuFan), theCanadianCenter for Vaccinology, and the NationalMicrobiology Laboratory.We alsoacknowledge the laboratory personnel and technicians at BCChildren’sHos-pital, the Wadsworth Center, and the National Microbiology Laboratory, aswell as all participants in the study. Mona Al-Dabbagh, Keswadee Lapphra,and Patricia Cho were PCIRN trainees.M.A.-D., J.A.B., T.R.K., P.C., K.L., E.S.F., andY.L. disclose no conflictsof interest. D.W.S., S.A.H., and J.M.L. disclose that they have receivedfunding from GlaxoSmithKline, Sanofi Pasteur, and Novartis Vaccinesfor performance of other influenza-related clinical trials and have servedon ad hoc advisory boards for these companies. G.D.S. has received fund-ing fromGSK and Sanofi Pasteur for clinical trials not related to influenzaand reimbursement for travel expenses to attend a GSK advisory boardmeeting.REFERENCES1. Skowronski DM, Strauss B, De Serres G, MacDonald D, Marion SA,Naus M, Patrick DM, Kendall P. 2003. Oculo-respiratory syndrome: anew influenza vaccine-associated adverse event? Clin. Infect. Dis. 36:705–713.2. Public Health Agency of Canada. 2001. An Advisory Committee State-ment (ACS). National Advisory Committee on Immunization (NACI).Statement on influenza vaccination for the 2001-2002 season. Can. 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