Natural History of Pandemic H1N1 2009 Influenza Infection in Healthy Pediatric Outpatients

Natural History of Pandemic H1N1 2009 Influenza Infection in Healthy Pediatric Outpatients Michael Hawkes, MD; Suzanne Schuh, MD; Moshe Ipp, MD; Ari Bitnun, MD, MSc; Susan E. Richardson, MD; Patricia C. Parkin, MD; Derek Stephens, BSc, MSc; Dat Tran, MD, MSc From the Divisions of Infectious Diseases (Drs Hawkes, Bitnun, and Tran), Paediatric Emergency Medicine (Dr Schuh), and Paediatric Medicine (Drs Ipp and Parkin), Department of Paediatrics, The Hospital for Sick Children, Toronto, Canada; Division of Microbiology, Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada (Dr Richardson); Divison of Biostatistics, Clinical Research Support Unit, The Hospital for Sick Children, Toronto, Canada (Mr Stephens); Child Health Evaluative Sciences, Research Institute, The Hospital for Sick Children, Toronto, Canada (Drs Schuh, Bitnun, Parkin, and Tran, and Mr Stephens); Physiology and Experimental Medicine, Research Institute, The Hospital for Sick Children, Toronto, Canada (Dr Richardson); Department of Health Policy, Management and Evaluation, University of Toronto, Canada (Dr Parkin); Department of Pediatric Laboratory Medicine and Pathobiology, University of Toronto, Canada (Dr Richardson); Division of Biostatistics, Department of Public Health Sciences, Dalla Lana School of Public Health, University of Toronto, Canada (Mr Stephens); Genetics and Genome Biology, Research Institute, The Hospital for Sick Children, Toronto, Canada (Dr Tran); and University of Toronto, Canada (Drs Hawkes, Schuh, Ipp, Bitnun, and Tran) The authors have no conflicts of interest to disclose. Address correspondence to Dat Tran, MD, MSc, Division of Infectious Diseases, Department of Paediatrics, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8 (e-mail: [email protected]). Received for publication September 10, 2010; accepted December 9, 2010.

ABSTRACT OBJECTIVE: The pandemic influenza H1N1 2009 (pH1N1)

included. Presenting symptoms and duration of symptoms associated with pH1N1 were similar to those with seasonal influenza. Median fever duration in pH1N1 was 3 days and had resolved within 8 days in 95% of patients. Among patients with pH1N1, abnormalities on chest auscultation (10 of 101), the hospitalization rate (2 of 101), the proportion of children receiving intravenous fluid therapy (1 of 101) or supplemental oxygen (1 of 101) were not significantly different from patients with seasonal influenza. CONCLUSIONS: In most children without underlying risk factors for severe influenza, pH1N1 virus causes an uncomplicated respiratory tract illness, no more severe than seasonal influenza.

virus is expected to remain a prominent circulating strain in the current and subsequent influenza seasons. The objective of this study was to compare the clinical course of infection with laboratory-confirmed pH1N1 and seasonal influenza A and B in a cohort of previously healthy children managed in the outpatient setting without antiviral therapy. METHODS: Previously healthy children 17 years of age or younger were prospectively enrolled during the first wave of the 2009 pandemic (May–July 2009) and the 2 preceding influenza seasons from a single primary care physician office and a tertiary children’s hospital emergency department. Inclusion criteria were: age #17 years; laboratory-confirmed influenza; and not receiving antiviral agents. Follow-up telephone interviews were conducted approximately 2 days and 14 days after presentation to assess symptom duration. RESULTS: A total of 251 patients (101 with pH1N1, 90 with seasonal influenza A, 60 with seasonal influenza B) were

KEYWORDS: child; outpatient; pandemic 2009 H1N1 influenza; seasonal influenza A; seasonal influenza B ACADEMIC PEDIATRICS 2011;11:66–74

WHAT’S NEW

locations around June and October, whereas the Southern Hemisphere experienced a single typical influenza season dominated by pH1N1.3 By August 1, 2010, more than 214 countries had reported laboratory-confirmed cases to the World Health Organization, including over 18 449 deaths.4 The pH1N1 virus is expected to remain a prominent circulating strain in the current and subsequent influenza seasons in North America and is incorporated into the 2010–2011 trivalent inactivated influenza vaccine.5 Published reports of pH1N1 have largely focused on hospitalized populations,6–8 patients requiring intensive care unit admission,9,10 or fatal cases.11–13 However, the majority of pH1N1 infections are mild and self-limited.14 As many as one third of pH1N1 infections in boarding schools were asymptomatic,14 and among symptomatic patients, only 1.44% were hospitalized,15 underscoring

We provide a detailed description of the natural history of medically attended pH1N1 in previously healthy pediatric outpatients, with comparison to seasonal influenza A and B. Illness associated with pH1N1 is no more severe than seasonal influenza.

THE NOVEL SWINE-ORIGIN pandemic influenza A H1N1 (pH1N1) virus was first detected in 2 children in California in April 2009.1 Shortly thereafter, pH1N1 was linked to a large outbreak of respiratory tract infection in Mexico and subsequently spread worldwide, prompting the World Health Organization to declare a level 6 pandemic.2 North America experienced 2 waves of pH1N1 activity in 2009, with peaks in incidence in most ACADEMIC PEDIATRICS Copyright ª 2011 by Academic Pediatric Association

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the large outpatient burden of illness. School-age children were disproportionately affected, as demonstrated by seroprevalence rates of 45% in 10–19-year-olds (compared to 21% of the population overall) after the second North American pH1N1 wave.3 Data from the 2009 pandemic are critical for public health planning both for future pandemics and for interpandemic influenza seasons during which the novel 2009 H1N1 strain is expected to continue to circulate.16,17 Crucial to a balanced approach to influenza management and public health policy is information derived from healthy patients in the community who bear the majority of the burden of influenza illness, but are underrepresented in existing reports in the medical literature. The primary objective of this study was to compare the duration of symptoms of laboratory-confirmed pH1N1 and seasonal influenza A and B in a cohort of previously healthy children managed in the outpatient setting without antiviral therapy. Our secondary objectives were to compare demographic features, symptoms and signs at presentation, treatment, and outcome between influenza types.

PATIENTS AND METHODS PARTICIPANTS Patients 17 years old and younger with typical influenza symptoms who presented for medical care were prospectively enrolled from December 2007 through April 2008, from December 2008 through May 2009, and from May through July 2009 (first wave of the 2009 pandemic).8 Patients were recruited at the emergency department (ED) at The Hospital for Sick Children (SickKids) and a community general pediatric outpatient clinic. SickKids provides acute care for a culturally diverse urban population in the greater Toronto area, offers tertiary and quaternary care for patients from the province of Ontario, and receives referrals for complex medical and surgical cases from around the world. Our general pediatric clinic provides primary and secondary services to a nearby urban population in central Toronto. The outpatient clinic recruited patients during the 2008–2009 season only. Children were eligible for inclusion if they had 2 or more of the following symptoms: fever lasting #1 week, cough, headache, myalgia, lethargy/fatigue, or loose stools. Patients meeting these criteria were tested for influenza viruses, and laboratory-confirmed cases were included in this analysis. Exclusion criteria included underlying conditions at higher risk of complications of influenza16: chronic pulmonary, cardiovascular, gastrointestinal, neurologic, neuromuscular, metabolic, endocrine or renal disease, immunosuppressive condition, underlying hemoglobinopathy, malignancy, upper airway abnormality, or pregnancy. Patients with mixed influenza infections (multiple influenza types), and patients who received oseltamivir were also excluded. The latter exclusion criterion was justified by the limited use of oseltamivir at our institution during the first wave of the pH1N1 pandemic (only one outpatient without underlying risk factors received antiviral medication), attributable to the close involvement of the infectious

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disease consultation service with ED cases and a hospital guideline recommending that antiviral use be reserved for inpatients and those with underlying risk factors for severe influenza. This circumstance provided a unique opportunity to study the natural history of pH1N1 influenza. Ethics approval was obtained from the Research Ethics Board at SickKids. Written informed consent was obtained before enrollment from parents or caregivers of children, or from older teenagers who could provide consent for themselves. Children $7 years of age also provided assent for study participation. VIROLOGIC CONFIRMATION Upon presentation to the ED or outpatient pediatric clinic, consenting eligible patients underwent testing for influenza viruses. Dedicated trained study personnel collected specimens from participants with minitip flocked nasopharyngeal swabs (Copan Diagnostics, Brescia, Italy) during the 2007–2008 season or midturbinate pediatric flocked swabs (Copan Diagnostics) during the 2008– 2009 season. Specimens were examined by direct fluorescent antigen (DFA) assay, virus culture, and/or reverse transcription–polymerase chain reaction (RT-PCR) for specific identification of the novel pandemic H1N1 influenza virus. DFA used fluorophore-conjugated monoclonal antibodies directed against influenza A/B (Chemicon, Temecula, Calif). Virus culture used R-Mix Too cells (A549 and MDCK cells, Diagnostic Hybrids, Athens, Ohio) for up to 4 days. RT-PCR primers were developed by the National Microbiology Laboratory, Winnipeg, and target a 517 bp segment specific for the pandemic H1N1 2009 influenza A virus.18 During the 2007–2008 season, DFA and virus isolation were performed on all specimens. During the 2008–2009 season, DFA was performed on all specimens, but virus isolation was only performed on DFA-negative specimens. Testing for pH1N1 by RT-PCR began in May 2009 and continued through July 2009. During this time, all specimens were also tested by DFA; however, samples that tested positive by DFA for influenza A or B or RT-PCR for pH1N1 were not tested by virus culture, given the unknown biohazard to laboratory personnel of culture amplification of the novel virus. CLINICAL INFORMATION History and physical examination findings and treatments administered were abstracted from the health record at the time of enrollment onto the study. Widely used agespecific clinical thresholds from the Pediatric Advanced Life Support guidelines19 were used to define abnormal vital signs (tachycardia, tachypnea, and hypotension). Additional information, including demographic details (ethnic background and socioeconomic status) and detailed clinical symptoms, was collected by interviewing the patient’s caregiver. In the ED, study personnel also performed a standardized physical examination on all patients to supplement the recorded findings of the clinical care team. They cross-referenced their findings with those of

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ETHNICITY Caregivers were asked about ethnic origin of the patient’s biological grandparents. Ethnic origin was broadly categorized as European, African/Caribbean, Southeast Asian (Chinese, Japanese, and Korean), South Asian (Indian and Pakistani), Latin American, or aboriginal. Where all 4 grandparents belonged to a common ethnic category, the patient was classified in that category; in cases where the ethnic categories differed between grandparents, the patient was classified as mixed ethnicity. SOCIOECONOMIC STATUS The method of Hollingshead was used to estimate household socioeconomic status (SES).20 The Hollingshead index is one of several accepted estimates of SES,21 correlates strongly with other indices of SES,21 and has been used in other studies of SES.22 In brief, the education (graded on a 7-point scale) and occupation (graded on a 9point scale that was based on an exhaustive list of occupational titles) of parents were used to determine an index of household SES. The status score of an individual was calculated by multiplying the scale value for education by a weight of 5, and the scale value for occupation by a weight of 3. In families where only one parent was gainfully employed, that individual determined the household SES index. In families where both parents were employed, the average index was used for the household SES index. STATISTICAL CONSIDERATIONS Standard descriptive and comparative statistics were used as appropriate on data categorized by virus type (pH1N1, seasonal influenza A and B). Where potential confounding variables were present (eg, patient age), we performed a stratified analysis (eg, age strata <5 years and $5 years). With respect to demographic data, where multiple variables (age, ethnic group, and SES) were associated with pH1N1 infection relative to other influenza types, we constructed a binary logistic regression model to explore the independent effect of each variable. The logistic regression model was tested for reliability by the Hosmer-Lemeshow test for goodness of fit and for discriminatory ability using the c index. To examine differences in symptom duration between different influenza virus types, we used Cox proportional hazard modeling. With respect to our primary objective

(symptom duration), we controlled for the inflation of familywise type 1 error rate associated with multiple hypothesis testing (22 pairwise comparisons of 11 symptoms) by adjusting P values by the Bonferroni correction.

RESULTS A total of 1120 patients with typical influenza symptoms who sought care at the hospital ED or the outpatient pediatric clinic were screened for inclusion in the study. Of these, 124 (11%) were excluded because they had an underlying illness predisposing them to severe influenza, and another 176 (18%) did not consent to participate in the study. Similar proportions of patients were excluded for underlying illness and lack of consent, respectively, in the 2007–2008 season (13% and 17%), the December 2008 to May 2009 influenza season (11% and 19%), and the first wave of the 2009 pandemic (10% and 15%). Of the remaining 818 patients, 255 (31%) tested positive for influenza. We excluded 4 patients with mixed influenza A and B infections and 1 patient with pH1N1 who had received oseltamivir, leaving a sample of 251 patients with influenza (101 pH1N1, 90 seasonal influenza A, and 60 seasonal influenza B) in whom the natural history of untreated influenza could be followed. This sample consisted of 37 patients recruited during the 2007–2008 season (all from the ED), 113 during the December 2008 to May 2009 influenza season (77 from the ED and 36 from the pediatric clinic), and 101 in the first wave of the 2009 pandemic (65 from the ED and 36 from the pediatric clinic), as shown in Figure 1. Regarding study participant retention, at least one follow-up telephone interview was available to determine symptom duration for 94% of pH1N1 patients (6 lost to follow up), 91% of seasonal influenza A (8 lost to follow-up), and 90% of influenza B (6 lost to follow-up). Patients with pH1N1 were significantly older than patients with seasonal influenza A (Table 1, P < .001) 80 70

pH1N1

60

seasonal influenza A

50

seasonal influenza B

40 30 20 10 0 Nov Dec Jan Feb Mar Apr May Jun Jul Aug Sep Oct Nov Dec Jan Feb Mar Apr May Jun Jul

the ED physician, and where there was a discrepancy, the physician’s findings were recorded. In the outpatient clinic, a physician performed the standardized physical examination. Because most patients were discharged from the ED or outpatient clinic, follow-up telephone interviews were conducted to document duration of symptoms. We aimed to perform at least 2 telephone follow-up interviews, the first approximately 2 days (actual range 1–5 days) and the second approximately 2 weeks (actual range 10–20 days) after presentation. Where possible, patients were followed until complete resolution of symptoms. All data were collected using standardized data collection forms.

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monthly cases

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2008

2009

Figure 1. Monthly distribution of influenza cases over the study period. The first wave of pandemic H1N1 influenza activity in 2009 occurred between May and July (heavy line, gray fill). Cases of seasonal influenza A (thin line) and B (dotted line) over the 2007– 2008 season and the December 2008–May 2009 season were used for comparison.

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Table 1. Demographic Characteristics of Children With Influenza According to Virus Type Characteristic Age Median (range)* Age distribution, n (%) 0–11 mo 12–59 mo 6–10 y 11–17 y Sex, n (%) Male Female Ethnicity, n (%)† European African/Caribbean Southeast Asian South Asian Latin American Aboriginal Mixed Socioeconomic quintile, n (%)‡ Upper Upper-middle Middle Lower-middle Lower Enrollment location, n (%) Emergency department Outpatient clinic Enrollment season, n (%) 2007–2008 2008–2009§ 2009 (first pandemic wave)k

pH1N1 (n ¼ 101)

Seasonal Influenza A (n ¼ 90)

Seasonal Influenza B (n ¼ 60)

9 y (2 mo–17 y)

3 y (6 wk–17 y)

4 y (6 mo–17 y)

4 (4) 17 (17) 35 (35) 45 (45)

18 (20) 41 (45) 22 (24) 9 (10)

2 (3) 31 (52) 17 (28) 10 (17)

63 (62) 38 (38)

59 (66) 31 (34)

38 (63) 22 (37)

46 (46) 10 (10) 9 (9) 7 (7) 4 (4) 1 (1) 21 (21)

36 (41) 13 (14) 15 (15) 13 (14) 5 (6) 0 8 (9)

8 (13) 12 (20) 19 (32) 13 (22) 1 (2) 0 6 (10)

41 (41) 28 (28) 12 (12) 9 (9) 10 (10)

18 (20) 29 (32) 10 (11) 13 (14) 13 (14)

13 (22) 18 (30) 9 (15) 9 (15) 6 (10)

65 (64) 36 (36)

74 (82) 16 (18)

40 (66) 20 (33)

0 0 101 (100)

23 (26) 67 (74) 0

14 (23) 46 (77) 0

*P < .0001 (pH1N1 vs seasonal influenza A), P < .0001 (pH1N1 vs influenza B); Mann-Whitney U test. †P < .001 for difference in ethnic distribution between virus types; c2 test. ‡P ¼ .003 (pH1N1 vs seasonal influenza A), P ¼ .024 (pH1N1 vs influenza B); Mann-Whitney U test using Hollingshead household socioeconomic index. §The 2008–2009 season includes cases of seasonal influenza from December 2008 to May 2009 (Figure 1). kThe first pandemic wave includes pH1N1 cases from May to July, 2009 (Figure 1).

and seasonal influenza B (Table 1, P < .001). The majority of patients with pH1N1 were male, with a similar sex distribution among patients with seasonal influenza. Ethnic distribution was significantly different between influenza types (Table 1, P < .001). Specifically, in 2008–2009, European ethnicity was overrepresented among patients with pH1N1 relative to influenza A (55% vs 26%, P < .001) and influenza B (55% vs 12%, P ¼ .003) in the ED during the pandemic season. Family socioeconomic index was significantly higher in children with pH1N1 than seasonal influenza A (Table 1, P ¼ .003) or seasonal influenza B (Table 1, P ¼ .02). This difference was most pronounced in the hospital ED during the pandemic season (P < .001, pH1N1 vs seasonal influenza A; P ¼ .011, pH1N1 vs influenza B). Because significant associations of the socioeconomic index with age and ethnic origin were detected, we adjusted for these possible confounders in a binary logistic regression model that included age (<5 vs $5 years), ethnicity (European vs other), and SES (highest quintile vs other), with influenza virus type serving as the dependent variable (pH1N1 vs seasonal influenza A or B). The model fit the observed data well (Hosmer-Lemeshow P ¼ .85) and discriminated well between pH1N1 and seasonal influenza

(c index 0.82; 95% confidence interval [95% CI] 0.76– 0.89). Older age, European ethnicity, and highest socioeconomic quintile remained significant independent predictors of pH1N1 in the multivariate model (Table 2). Among the component variables used to calculate the family SES index, paternal occupation (father’s score on the occupation scale in the Hollingshead index, an ordinal variable) was also independently and significantly associated with pH1N1 infection in a multivariable logistic regression model. Prior vaccination with trivalent seasonal influenza vaccine was less commonly reported in patients with seasonal influenza A than in those with pH1N1 (4.6% vs 19%, odds ratio [OR] 0.16, 95% CI 0.053–0.50, P ¼ .0031) and influenza B (4.6% vs 16%, OR 0.26, 95% CI 0.053–0.50, P ¼ .036). No differences in vaccination rates were observed across age groups, socioeconomic strata or ethnic groups (P > .05 for all comparisons). Differences in vaccination rates between seasonal influenza A and pH1N1 patients remained significant after adjustment for age and SES in a logistic regression model (adjusted OR 0.23 [95% CI 0.070–0.77], P ¼ .017). The prevalence of typical symptoms of influenza at presentation, together with the duration of symptoms

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Table 2. Demographic Predictors of pH1N1 Versus Seasonal Influenza Types (A or B) Among Patients Seeking Care at the Hospital Emergency Department During Pandemic Season (2008–2009) Univariate Analysis

Multivariate Logistic Regression Model*

Demographic

Odds Ratio (95% Confidence Interval)

P

Adjusted Odds Ratio (95% Confidence Interval)

P

Age $5 y European ethnicity vs other Highest socioeconomic quintile

4.7 (2.3–9.5) 4.5 (2.2–9.4) 4.6 (2.2–9.6)

<.001 <.001 <.001

7.4 (3.0–18) 7.0 (2.8–18) 5.2 (2.1–12)

<.001 <.001 <.001

*The logistic regression model includes a dichotomous dependent variable (pH1N1 vs seasonal influenza), and 3 binary independent variables: age (dichotomized as age <5 vs age $5 years); European vs other ethnicity; and highest socioeconomic quintile vs lowest 4 quintiles.

(median and 95th percentile), is provided in Table 3 and Figure 2. Although sore throat, myalgia, headache, and decreased activity level were more commonly reported in patients with pH1N1, none of these differences remained statistically significant after adjusting for age (P > .05 for all comparisons). The interval between symptom onset and clinical encounter was similar between influenza types with median (interquartile range) of 2 (1–3) days for pH1N1, 2 (1–4) for seasonal influenza A, and 3 (1–5) for

seasonal influenza B (P ¼ .33). The duration of symptoms was likewise similar across virus types, with a few statistically significant differences (Figure 2). Fever and rhinorrhea resolved more quickly in pH1N1 than in influenza B (uncorrected P ¼ .003 and P ¼ .008, respectively); however, after correction for multiple testing, these differences were no longer statistically significant (Bonferroni correction, P ¼ .06 and P ¼ .17, respectively). Of note, across all influenza virus types, cough was the most

Table 3. Proportion of Patients With Symptoms of Influenza at Presentation Median and Upper Limit (95th percentile) of Duration of Symptoms for: Symptom

pH1N1 (n ¼ 101)

Seasonal Influenza A (n ¼ 90)

Seasonal Influenza B (n ¼ 60)

Fever, n (%) Median duration (d) 95th percentile Cough, n (%) Median duration (d) 95th percentile Sore throat, n (%)* Median duration (d) 95th percentile Rhinorrhea, n (%) Median duration (d) 95th percentile Myalgia, n (%)† Median duration (d) 95th percentile Headache, n (%)‡ Median duration (d) 95th percentile Fatigue, n (%) Median duration (d) 95th percentile Malaise, n (%) Median duration (d) 95th percentile Decreased activity, n (%)§ Median duration (d) 95th percentile Vomiting, n (%) Median duration (d) 95th percentile Diarrhea, n (%) Median duration (d) 95th percentile

98 (97) 3 8 92 (91) 5 19 38 (38) 3 7 56 (55) 4 16 41 (41) 3 14 52 (51) 3 6 81 (80) 3 10 71 (70) 3 9 75 (74) 3 13 26 (26) 3 7 10 (10) 3 11

87 (97) 3 7 80 (89) 5 21 21 (23) 4 13 53 (59) 4 19 23 (25) 2 12 18 (20) 3 13 62 (69) 4 13 59 (66) 3 13 57 (63) 4 14 22 (24) 3 17 13 (14) 6 14

58 (97) 5 11 51 (85) 6 21 19 (32) 5 24 42 (70) 6 26 22 (37) 5 9 16 (27) 4 9 43 (72) 5 17 39 (65) 5 9 33 (55) 5 15 13 (22) 5 14 8 (13) 7 14

*P ¼ .028k (pH1N1 vs seasonal influenza A); c2 test. †P ¼ .003k (pH1N1 vs seasonal influenza A); c2 test. ‡P < .001k (pH1N1 vs seasonal influenza A), P ¼ .002k (pH1N1 vs influenza B); c2 test. §P ¼ .012 (pH1N1 vs influenza B); c2 test. kNone of these differences remained statistically significant after adjustment for age in a stratified analysis.

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fever

100

Percentage remaining symptomatic

PANDEMIC H1N1 INFLUENZA IN HEALTHY CHILDREN

cough

100

50

71

50

0

0 0

7

14

rhinorrhea

100

0

14 pH1N1 seasonal influenza A seasonal influenza B

decreased activity

100

50

7

50

0

0

0

7

14

0

7

14

Time since symptom onset (days) Figure 2. Prevalence and duration of selected symptoms among previously healthy children with pH1N1, seasonal influenza A and B who were not treated with antiviral agents. Fever and rhinorrhea resolved faster in patients with pH1N1 compared to influenza B, although differences were not significant after correction for multiple testing (P ¼ .06 and P ¼ .17, respectively).

protracted symptom, persisting for more than 14 days in approximately 20% of patients (Figure 2). Signs noted during the physical examination at presentation are listed in Table 4. No differences were seen between groups in any of the physical signs with the exception of tachycardia and irritability, which lost significance after stratification by patient age. Of note, irritability was observed only in children <5 years, and no statistically significant difference in the prevalence of irritability was detected in this subgroup (P ¼ .17). Few patients received intravenous fluids or oxygen therapy (Table 5). Antibiotics were administered to 12% of patients with pH1N1, mostly those with radiographically confirmed consolidation, with no differences observed between influenza types. Although chest radiographs were performed less frequently among patients with pH1N1 relative to influenza A (P ¼ .049) and influenza B (P ¼ .005), these differences were no longer significant after adjustment for age. Overall, the outcome in most patients was favorable, with no mortality and minimal hospitalization rates across study groups (Table 5). To ensure that differences in diagnostic testing modality (RT-PCR for pH1N1 vs DFA and virus culture for seasonal influenza strains) did not bias our findings, we also performed an analysis restricted to patients who tested positive for influenza A or B by DFA (n ¼ 223) and found equivalent results. Likewise, restricting the analysis to patients who presented to the ED in 2007–2008 and

2008–2009 (n ¼ 179) did not demonstrate any differences in markers of disease severity by virus type.

DISCUSSION Our examination of symptom duration, symptoms and signs at presentation, supportive treatment, and outcomes from a prospectively enrolled cohort of previously healthy pediatric outpatients with virologically confirmed influenza infection without antiviral treatment revealed no substantial differences between pH1N1 and seasonal influenza A and B infection. On the other hand, differences in the demographic features of patients presenting with pH1N1 may reflect differences in health-seeking behaviors in a pandemic situation among different ethnic, socioeconomic, and age groups. As expected, nonspecific complaints dominated the clinical picture, fever was virtually ubiquitous, and cough was the most persistent symptom. These features are consistent with and indistinguishable from seasonal influenza.23,24 Only nonsignificant differences in the duration of fever and rhinorrhea were noted, perhaps as a result of parental anxiety, which may have prompted the parents of children with milder disease to seek care for their children during the pandemic season dominated by pH1N1. Gastrointestinal symptoms were common in our study and occurred with similar frequency in patients with pH1N1 and seasonal influenza viruses, in

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Table 4. Physical Signs at Presentation in Patients With Influenza

Sign Vital sign abnormalities, n (%) Tachycardia* Tachypnea Hypotension General appearance, n (%) Unwell Irritable† Lethargic Signs of dehydration, n (%) Signs of respiratory distress, n (%) Nasal flaring Intercostal retractions Grunting Cyanosis Any sign Findings on chest auscultation, n (%) Decreased breath sounds Crackles Wheeze

Seasonal Seasonal pH1N1 Influenza A Influenza B (n ¼ 101) (n ¼ 90) (n ¼ 60) 16 (16) 8 (8) 1 (1)

16 (18) 7 (8) 0

3 (5) 6 (10) 0

28 (28) 1 (1) 9 (9) 5 (5)

36 (40) 11 (12) 12 (13) 7 (8)

18 (30) 2 (3) 7 (12) 5 (8)

3 (3) 2 (2) 1 (1) 1 (1) 4 (4)

2 (2) 2 (2) 3 (3) 1 (1) 4 (4)

0 0 0 0 0

8 (8) 7 (7) 4 (4)

3 (3) 7 (8) 3 (3)

2 (3) 3 (5) 2 (3)

*P ¼ .035 (pH1N1 vs influenza B); Fisher’s exact test. †P ¼ .002 (pH1N1 vs seasonal influenza A); Fisher’s exact test. Neither of these differences remained statistically significant after adjustment for age in a stratified analysis.

accordance with other studies of pH1N125 and seasonal influenza.26,27 No significant differences in symptoms and signs at presentation, treatment, and outcome were observed between virus types after adjustment for differences in age between groups. Our findings agree with a recent study comparing pH1N1 with seasonal influenza A viruses, which documented similar clinical manifestations between influenza A strains by means of active surveillance in a well-defined US population.28 Another recent community-based study demonstrated that the household attack rate and virus shedding were similar.29 In our cohort, only 2% of children with pH1N1 were hospitalized, comparable to previous reports indicating a hospitalization rate of 1.44% for pH1N1 infections15 and 2.5% for influenza-like illness.30 Further, the hospitalization rate for pH1N1 was similar to that for seasonal Table 5. Treatment and Outcome of Patients With Influenza

Treatment IV fluids, n (%) Oxygen, n (%) Antibiotic therapy, n (%) Radiographic features, n (%) Chest x-ray performed* Chest radiograph abnormality Hospital admission, n (%)

Seasonal Seasonal pH1N1 Influenza A Influenza B (n ¼ 101) (n ¼ 90) (n ¼ 60) 1 (1) 1 (1) 12 (12)

2 (2) 1 (1) 12 (13)

1 (2) 0 6 (10)

10 (10) 7/10 (70)

18 (20) 13/18 (72)

16 (27) 8/16 (50)

2 (2)

3 (3)

0

*P ¼ .049 (pH1N1 vs seasonal influenza A), P ¼ .0052 (pH1N1 vs influenza B); c2 test. Neither of these differences remained statistically significant after adjustment for age in a stratified analysis.

influenza A and B, consistent with another US study.28 No deaths occurred in our study, as expected in a cohort of previously healthy children of moderate size. Although some studies have suggested that pH1N1 may be associated with a higher mortality than seasonal influenza,6 others indicate that mortality associated with pH1N1 is no different from influenza A among hospitalized children.8 The case fatality rate for symptomatic pH1N1 in the United States and the UK was estimated to be 0.048% and 0.026%, respectively.13,15 Our results suggest that previously healthy children with these influenza types appear to experience comparable disease severity, although these conclusions may not be generalizable to children with underlying risk factors. Among patients with acute respiratory illness, supportive therapies (intravenous fluids and supplemental oxygen), radiographic investigations, and antibiotics are provided according to clinical judgment in patients who appear most unwell and thus represent proxy markers of disease severity. None of these markers differed between patients with pH1N1 compared to seasonal influenza after adjustment for age. Few patients received intravenous fluids (1%) or supplemental oxygen (1%) in our study. Only 10% of patients with pH1N1 had chest radiographs; of these, 70% demonstrated infiltrates, a finding similar to that of another pediatric study (66%).7 The rate of antibiotic use among patients with pH1N1 (12%) was not higher than other influenza types, but it highlights the large burden of antibiotic use associated with medically attended influenza during a pandemic. Notwithstanding similar patterns of morbidity to other influenza types, the 2009 influenza pandemic likely had greater socioeconomic impact than typical influenza seasons by virtue of the larger number of cases and different age distribution of infected children. For example, our study and that of another group28 indicated that children with pH1N1 were older than those with seasonal influenza strains, suggesting that the 2009 pandemic may have interrupted school attendance more than previous influenza seasons, and may have led to a greater number of lost work days for parents. In our cohort, trivalent inactivated influenza vaccination in the previous year was associated with a decreased odds of seasonal influenza A, relative to pH1N1 and influenza B. This is consistent with reports that the annual influenza vaccine over the past 2 years has been well matched to the observed influenza A strains, but not to the circulating influenza B or the novel pH1N1 strains.31,32 SES affects numerous health outcomes, including influenza prevalence,33 incidence,34 and mortality.35,36 Increased risk of influenza and its complications was associated with lower SES during the Spanish influenza pandemic of 1918,37 as well as the recent 2009 H1N1 pandemic, where higher intensive care unit admission rates were observed among medically uninsured patients.38 Differences in influenza incidence, severity, and mortality have also been noted across racial/ethnic groups during the pH1N1 pandemic.12 Furthermore, influenza-related health-seeking behaviors (eg, influenza vaccination rates)

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differ between racial/ethnic groups in the United States.39 Health-seeking behavior is likely to increase during an influenza pandemic,40 but it can be expected to differ between ethnic and socioeconomic groups.41 In our cohort, European ethnicity and higher SES were independently associated with pH1N1 in a logistic regression model in patients seen in the hospital ED. Thus, differences in health-seeking behavior across ethnic and socioeconomic groups in response to the highly publicized pandemic may have influenced the distribution of influenza types in our ED. Alternatively, genetic or environmental factors such as travel patterns and social networks could account for these findings. Limitations of our study include its observational design, which limits our ability to exclude the effect of measured or unmeasured covariates in our analysis. Of note, age was a confounding factor in our statistical analysis because of differences in the age distribution of pH1N1 vs seasonal influenza A and B, and because some features (sore throat, myalgia, headache, and decreased activity level) are more likely to be reported by older children, whereas others (irritability) are more common in younger patients. It is also possible that milder cases of influenza were captured during the season dominated by pH1N1 because of parental anxiety associated with the widely publicized pandemic. To mitigate this limitation, we confined our analysis to patients recruited only during the first pH1N1 wave of 2009 (May 2008 through July 2009) because of the overwhelming volume of patients presenting to the ED during the second wave. This affected our recruitment process, resulting in a cohort that was not comparable to previous seasons. The rate of oseltamivir therapy among patients in our study during the first wave of the pandemic was very low (one patient with pH1N1, none with seasonal influenza), consistent with the pattern of antiviral prescription in previous influenza seasons. The infrequent use of antiviral agents allowed us to study the natural history of pH1N1 by excluding a single patient who received treatment. Community-based cases were recruited from a single office, which may limit the generalizability of our findings to all practices. Although different diagnostic modalities were used for identification of pH1N1 and seasonal influenza, we demonstrated that our results also held true in the subset of patients who tested positive by DFA, representing a uniform diagnostic standard with presumed similar virus burden. Although the inclusion criteria used for our study did not correspond exactly to the case definition of influenza-like illness of the Centers for Disease Control and Prevention (fever plus cough or sore throat), only 10 patients (4%) in our cohort did not meet this definition. Thus, the findings of our study are generalizable to children meeting the definition of the Centers for Disease Control and Prevention. In conclusion, previously healthy children with pH1N1 appear to exhibit clinical manifestations, rates of antibiotic use, and complications comparable to those of seasonal influenza A and B. These data may be helpful in outpatient settings to reassure caregivers and health care professionals: although severe cases of pH1N1 do occur, the

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typical spectrum of illness is no different from seasonal influenza types that circulate every year; the expected duration of symptoms is on the order of 1 week from the time of presentation, although cough may linger for much longer; and antiviral treatment may not be required for many healthy outpatients.

ACKNOWLEDGMENT This study was funded in part by CIHR/SickKids Foundation New Investigator grant XG08-049R, CIHR Catalyst grant CAT86860, and the University of Toronto Dean’s Fund Pilot Study grant. The funding agencies had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. We thank Jungmin Hong, Suganya Lee, Calvin Liu, Rinu Mathew, Peregrina Peralta, Hilary Reddin, Dr Yvonne Yau, Karan Greenock, the Virology and Molecular Microbiology technologists, and the physicians, nurses and administrative staff at The Hospital for Sick Children ED.

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