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Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza

Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza country to comprehensively assess its first 100 cases. By Background: We describe the disease characteristics and mid-May, many Canadian jurisdictions moved away from outcomes, including risk factors for admission to intensive this approach because it became increasingly taxing on both care unit (ICU) and death, of all patients in Canada admit- public health human resources and laboratory capacity. It ted to hospital with pandemic (H1N1) influenza during the was decided that reporting of individual cases would con- first five months of the pandemic. tinue nationally only for patients who were admitted to hos- pital or who died. We provide a detailed review of the dis- Methods: We obtained data for all patients admitted to hospital with laboratory-confirmed pandemic (H1N1) ease characteristics and outcomes, including risk factors for influenza reported to the Public Health Agency of Canada admission to intensive care unit (ICU) and death, of patients from Apr. 26 to Sept. 26, 2009. We compared inpatients admitted to hospital in Canada during the first five months of who had nonsevere disease with those who had severe dis- the pandemic. ease, as indicated by admission to ICU or death. Methods Results: A total of 1479 patients were admitted to hospital with confirmed pandemic (H1N1) influenza during the study period. Of these, 1171 (79.2%) did not have a severe Ascertainment of cases outcome, 236 (16.0%) were admitted to ICU and survived, All 13 provinces and territories in Canada participated in an and 72 (4.9%) died. The median age was 23 years for all of active national surveillance system that captured all cases of the patients, 18 years for those with a nonsevere outcome, laboratory-confirmed pandemic (H1N1) influenza in patients 34 years for those admitted to ICU who survived and 51 admitted to hospital or who died and then reported them to years for those who died. The risk of a severe outcome was the Public Health Agency of Canada. A laboratory-confirmed elevated among those who had an underlying medical case was defined as one involving a person with pandemic condition and those 20 years of age and older. A delay of (H1N1) influenza, with or without clinical symptoms, that one day in the median time between the onset of symp- toms and admission to hospital increased the risk of death was confirmed by one or more of the following tests: reverse by 5.5%. The risk of a severe outcome remained relatively transcription polymerase chain reaction, viral culture, or test constant over the five-month period. for antibodies against pandemic (H1N1) influenza virus showing four-fold rise in antibody levels. Probable or suspect Interpretation: The population-based incidence of admis- cases were not nationally reportable. This case definition was sion to hospital with laboratory-confirmed pandemic consistent over the study period. (H1N1) influenza was low in the first five months of the pandemic in Canada. The risk of a severe outcome was Patients admitted to hospital were prioritized for labora- associated with the presence of one or more underlying tory testing, so case ascertainment was also relatively consis- medical conditions, age of 20 years or more and a delay in tent over the study period. In the first six weeks of the pan- hospital admission. demic, the Public Health Agency of Canada recommended testing for the pandemic (H1N1) influenza virus in patients with influenza-like illness (in the community and in hospital) he first cases of pandemic (H1N1) influenza in Cana - da were reported on Apr. 26, 2009. Retrospective From the Centre for Immunization and Respiratory Infectious Diseases, Infectious Disease and Emergency Preparedness Branch (Campbell, Rodin, T case-finding determined that the onset of symptoms in Vachon, Spika, Pelletier); Chronic Disease Risk Assessment, Health Promo- the first Canadian case, involving a traveller returning from tion and Chronic Disease Prevention Branch (Mao); and the Centre for Com- Mexico, occurred on Apr. 12, 2009. The first patient admitted municable Diseases and Infection Control, Infectious Disease and Emergency Preparedness Branch (Kropp, Hong), Public Health Agency of Canada, to hospital began to experience symptoms on Apr. 18. Ottawa, Ont. During the first few weeks of the outbreak, in-depth fol- CMAJ 2010. DOI:10.1503/cmaj.091823 low-up and reporting of cases was conducted in keeping with CMAJ � MARCH 9, 2010 � 182(4) © 2010 Canadian Medical Association or its licensors DOI:10.1503/cmaj.091823 Research to facilitate characterization of the epidemiologic features, Statistical analysis clinical pres entation and outcomes associated with this novel We conducted a descriptive analysis of cases by age, sex, virus. A general shift to laboratory testing of only patients Aboriginal status, pregnancy status and presence or absence with severe illness and those admitted to hospital occurred by of underlying medical conditions. Because Ontario and mid-June. Testing of samples from patients in the community Nova Scotia did not report Aboriginal status, we excluded continued to varying degrees depending on provincial policies data from those provinces for Aboriginal-specific calcula- and laboratory capacity. tions. We removed missing and unknown information from In this article, we report on confirmed cases involving all calculations except for those on underlying medical con- patients admitted to hospital that were reported to the Public ditions; where data on underlying conditions were missing Health Agency of Canada from Apr. 26 to Sept. 26, 2009. (Ontario and Manitoba), we assumed that it reflected no underlying condition. We compared inpatients who had a Collection of data nonsevere outcome with inpatients who were admitted to Each week, the provincial and territorial surveillance partners ICU and survived, those who died and those who had either submitted lists of hospital cases and deaths. These lists con- severe outcome using univariable analysis and multivari- tained the following core data: a unique case identifier, the able logistic regression analysis. The factors included in the reporting province or territory, the province or territory of res- multivariable models were sex, age (categorical) and the idence, age, sex, Aboriginal status (defined as First Nations, presence or absence of underlying medical conditions. Métis or Inuit), pregnancy status, presence or absence of Owing to a high degree of missing data on Aboriginal sta- underlying medical conditions known to predispose individu- tus, we did not include this characteristic in the multivari- 3,4 als to complications of influenza, mechanical ventilation, able analysis. We calculated the incidence of outcomes by admission to ICU and death. For our study, we defined age, sex, Aboriginal status, pregnancy status, and province patients admitted to hospital who subsequently were admitted or territory. We did not include patient-level information on antiviral treatment or influenza vaccination in our analyses to ICU or who died as having a severe outcome. We consid- ered all of the other patients admitted to hospital to have a because it was not available. nonsevere outcome. We examined differences in time to hospital admission by Table 1: Characteristics of 1479 patients admitted to hospital with laboratory-confirmed pandemic (H1N1) influenza reported from Apr. 26 to Sept. 26, 2009, and risk of severe outcome Admission to ICU, nonfatal Death Any severe outcome† Nonsevere outcome, no. (%) No. (%) No. (%) No. (%) of patients of patients of patients of patients Characteristic n = 1171 n = 236 RR (95% CI)* n = 72 RR (95% CI)* n = 308 RR (95% CI)* Sex, female 581/1169 (49.7) 135/236 (57.2) 1.3 (1.0–1.6) 43/72 (59.7) 1.5 (0.9–2.3) 178/308 (57.8) 1.3 (1.1–1.6) Age, yr < 1 111/1166 (9.5) 11/235 (4.7) 0.7 (0.3–1.4) 1/72 (1.4) 0.3 (0.1–2.5) 12/307 (3.9) 0.6 (0.3–1.2) 1–4 168/1166 (14.4) 17/235 (7.2) 0.7 (0.4–1.3) 0/72 NA 17/307 (5.5) 0.6 (0.3–1.1) 5–9 159/1166 (13.6) 14/235 (6.0) 0.6 (0.3–1.2) 3/72 (4.2) 0.6 (0.1–2.5) 17/307 (5.5) 0.6 (0.3–1.1) 10–19 157/1166 (13.5) 23/235 (9.8) Reference 5/72 (6.9) Reference 28/307 (9.1) Reference 20–44 277/1166 (23.8) 86/235 (36.6) 2.1 (1.3–3.5) 18/72 (25.0) 2.0 (0.7–5.6) 104/307 (33.9) 2.1 (1.3–3.3) 45–64 210/1166 (18.0) 69/235 (29.4) 2.2 (1.3–3.8) 27/72 (37.5) 4.0 (1.5–10.7) 96/307 (31.3) 2.6 (1.6–4.1) 84/1166 (7.2) 15/235 (6.4) 1.2 (0.6–2.5) 18/72 (25.0) 6.7 (2.4–18.8) 33/307 (10.7) 2.2 (1.3–3.9) ≥ 65 Aboriginal 215/859 (25.0) 37/179 (20.7) 0.8 (0.6–1.1) 9/50 (18.0) 0.7 (0.3–1.4) 46/229 (20.1) 0.8 (0.6–1.1) Pregnant‡ 61/126 (48.4) 13/36 (36.1) 0.7 (0.4–1.2) 4/8 (50.0) 1.1 (0.3–4.1) 17/44 (38.6) 0.7 (0.4–1.3) 479/1071 (44.7) 126/217 (58.1) 1.6 (1.2–2.0) 49/70 (70.0) 2.7 (1.7–4.5) 175/287 (61.0) 1.7 (1.4–2.1) ≥ 1 underlying medical conditions§ Pre-existing heart 80/1049 (7.6) 35/209 (16.7) 2.0 (1.5–2.7) 16/65 (24.6) 3.5 (2.1–5.9) 51/274 (18.6) 2.1 (1.6–2.7) disease Diabetes mellitus 82/1047 (7.8) 42/211 (19.9) 2.3 (1.7–3.0) 13/65 (20.0) 2.7 (1.5–4.7) 55/276 (19.9) 2.2 (1.7–2.7) Renal disease 51/1044 (4.9) 14/204 (6.9) 1.3 (0.8–2.2) 7/64 (10.9) 2.2 (1.1–4.7) 21/268 (7.8) 1.5 (1.0–2.1) Immunosuppression 93/1041 (8.9) 21/200 (10.5) 1.2 (0.8–1.7) 17/64 (26.6) 3.3 (2.0–5.5) 38/264 (14.4) 1.5 (1.1–2.0) Lung disease 309/738 (41.9) 73/154 (47.4) 1.2 (0.9–1.6) 30/52 (57.7) 1.8 (1.1–3.1) 103/206 (50.0) 1.3 (1.0–1.6) (including asthma) Note: CI = confidence interval, ICU = intensive care unit, NA = not applicable, RR = relative risk. *For comparison with admission to hospital with nonsevere illness. †Admission to ICU or death. ‡Pregnancy among women of childbearing age (15–44 years of age). §Includes lung disease, asthma, diabetes and other metabolic disorders, pre-existing heart disease, renal disease, immunosuppression, anemia, liver disease, 3,4 neurologic disorder, or other chronic medical condition predisposing to complications of influenza. CMAJ � MARCH 9, 2010 � 182(4) Research severity of outcome. In addition, we looked at the risk of a Age severe outcome by age among patients without an underlying On average, patients with a nonsevere outcome were medical condition. For these analyses, we combined both younger than those admitted to ICU, who in turn were types of severe outcome (admission to ICU and death) younger than those who died (Figure 1). The median age because of the small number of cases. We calculated popula- was 23 years for all of the patients, 18 years for those with tion denominators using Statistics Canada census, pregnancy a nonsevere outcome, 34 years for those admitted to ICU 5–8 outcome and live-birth estimates. who survived and 51 years for those who died. Compared with patients aged 10–19 years, those aged 20–64 years Results were significantly more likely to be admitted to ICU, and those aged 45 years or more were significantly more likely Between Apr. 26 and Sept. 26, 2009, 1479 cases of patients to die, even after adjustment for sex and underlying med- admitted to hospital with laboratory-confirmed pandemic ical conditions (Tables 1 and 3). Despite higher population- based rates among children, inpatients at greatest risk for a (H1N1) influenza were reported to the Public Health Agency of Canada. Of these, 1171 (79.2%) did not have a severe outcome were those 20 years of age and older severe outcome, 236 (16.0%) were admitted to ICU and sur- (Tables 1 and 3). Patients less than five years old had the vived, and 72 (4.9%) died (Table 1). The incidence of highest population-based incidence of hospital admission admission to hospital without a severe outcome (3.47 per without a severe outcome and of admission to ICU; they 100 000 population), nonfatal admission to ICU (0.70 per were followed closely by children five to nine years old 100 000) and death (0.21 per 100 000) remained low during (Table 2). Patients aged 65 or more had the lowest inci- 9,10 the study period (Table 2). Five additional deaths dence of hospital admission without a severe outcome (1.79 involved people who were not reported as having been per 100 000 population) and the highest rate of death (0.38 admitted to hospital; we did not include these cases in the per 100 000); patients aged 45–64 years had the next high- est rate of death (0.29 per 100 000). current analyses. Sex Aboriginal status Females accounted for 51.4% (759/1477) of the patients. Aboriginal status was reported for 24.0% (261/1088) of the The risk of admission to ICU was greater among females patients. The proportion of Aboriginal patients did not differ significantly between those with a nonsevere outcome and than among males in the univariable analysis (Table 1); this difference disappeared in the multivariable analysis (Table 3). Table 3: Factors associated with severe outcome in relation to nonsevere outcome among patients admitted to hospital with Table 2: Incidence of nonsevere and severe outcomes among pandemic (H1N1) influenza 1479 patients admitted to hospital with pandemic (H1N1) influenza, by sex, age, Aboriginal status and pregnancy status Severe outcome; adjusted OR (95% CI)* Outcome; incidence Admission to per 100 000 population Factor ICU, nonfatal Death Any Nonsevere Admission to Sex outcome ICU, nonfatal Death Female 1.3 (0.9–1.7) 1.3 (0.8–2.1) 1.3 (0.9–1.3) Characteristic Population n = 1171 n = 236 n = 72 Male Reference Reference Reference Canada 33 739 859 3.47 0.70 0.21 Age, yr Sex < 1 0.9 (0.4–2.1) 0.5 (0.1–4.4) 0.8 (0.4–1.8) Male 16 732 476 3.50 0.60 0.17 1–4 0.7 (0.4–1.5) NA 0.6 (0.3–1.2) Female 17 007 383 3.42 0.79 0.25 5–9 0.6 (0.3–1.3) 0.8 (0.2–3.5) 0.6 (0.3–1.3) Age, yr 10–19 Reference Reference Reference < 1 376 842 29.46 2.92 0.27 20–44 2.2 (1.3–3.8) 2.6 (0.9–7.8) 2.3 (1.4–3.7) 1–4 1 460 882 11.50 1.16 0.00 45–64 2.3 (1.3–4.0) 4.2 (1.4–12.6) 2.6 (1.5–4.3) 5–9 1 799 302 8.84 0.78 0.17 ≥ 65 1.1 (0.5–2.3) 7.0 (2.3–21.7) 2.1 (1.2–3.9) 10–19 4 226 705 3.71 0.54 0.12 ≥ 1 underlying 1.5 (1.1–2.1) 1.6 (0.9–2.9) 1.5 (1.1–2.1) 20–44 11 718 791 2.36 0.73 0.15 medical conditions† 45–64 9 469 891 2.22 0.73 0.29 Note: CI = confidence interval, ICU = intensive care unit, NA = not applicable, 4 687 446 1.79 0.32 0.38 ≥ 65 OR = odds ratio. *Adjusted for sex, age and presence or absence of underlying medical Aboriginal 906 125 23.73 4.08 0.99 conditions. †Includes lung disease, asthma, diabetes and other metabolic disorders, Pregnant 501 504* 12.16 2.59 0.80 pre-existing heart disease, renal disease, immunosuppression, anemia, liver disease, neurologic disorder, or other chronic medical condition predisposing 3,4 *Estimated number of pregnant women in the five-month study period. to complications of influenza. CMAJ � MARCH 9, 2010 � 182(4) Research those with a severe outcome (Table 1). The Aboriginal popu- Time to hospital admission lation did experience a much higher incidence of nonsevere The median time from symptom onset to hospital admission and severe outcomes than the general population (Table 2). was two to three days. Overall, a one-day difference in the median time to hospital admission increased the risk of death Underlying medical conditions by 5.5%. The median time from symptom onset to death, In this cohort, 48.2% of the patients had one or more underly- available for 41 patients, was 12 days (range 1–75). ing medical conditions. This characteristic was associated with an increased risk of a severe outcome even after adjust- Geography and time ment for age and sex (Tables 1 and 3). The risk of a severe June was the month in which the majority of patients were outcome was greatest among patients with diabetes (relative admitted to hospital (63.5% [667/1050]) or reported symp- risk [RR] 2.2, 95% confidence interval [CI] 1.7–2.7) and tom onset (64.7% [941/1454]). The proportion of inpatients those with pre-existing heart disease (RR 2.1, 95% CI 1.6– who experienced a severe outcome was relatively constant 2.7), followed by those with immunosuppression (RR 1.5, throughout the study period (mean 20.8%, range 18%–23%, 95% CI 1.1–2.0). Lung disease, including asthma, was the Figure 2). The median age of patients with a severe outcome most common underlying condition and was associated with did not change significantly between April and September an elevated risk of death (RR 1.8, 95% CI 1.1–3.1). 2009. The epidemic curve (Figure 2) predominantly reflects For patients who had no underlying condition and were the evolution of the pandemic in Quebec, Ontario, Manitoba not pregnant, the risk of a severe outcome was greatest among and Alberta, where the greatest number of hospital admis- those 30–49 years old and those 60 years and older (Table 4). sions were reported. Mechanical ventilation was required in 15.7% (153/977) of The incidence rates of nonsevere outcome and admission the patients. The rate of mechanical ventilation was lower to ICU were highest in Nunavut, the Northwest Territories, among those with a nonsevere outcome (1.3%) than among Manitoba and Quebec; the incidence of death was highest in those with a severe outcome (65.0%). Nunavut, Saskatchewan and Manitoba (Table 5). Because of the small number of cases in Nunavut and the Northwest Ter- Pregnancy status ritories, the rates in those jurisdictions should be interpreted Of the 170 women in the study cohort who were of childbear- with caution. ing age (15–44 years), 78 (45.9%) were pregnant. The preg- nant women were not at increased risk of admission to ICU or Interpretation death compared with the 92 nonpregnant women of reproduc- tive age, but they did have a higher incidence of hospital The population-based incidence of admission to hospital with admission without a severe outcome (12.16 v. 0.94 per laboratory-confirmed pandemic (H1N1) influenza was low in 100 000 population), admission to ICU (2.59 v. 0.33 per the first five months of the pandemic in Canada. This experi- 9–12 100 000) and death (0.80 v. 0.05 per 100 000) compared with ence is consistent with that of other countries. As in the nonpregnant women of childbearing age. Canada, the highest rates of hospital admission in the United States, Australia and the United Kingdom were among chil- 13–15 dren less than five years old. Cumulative rates of death 40 during the study period were also low: in Canada 0.21 per Nonsevere outcome 100 000 population died, as compared with 0.19 confirmed 35 (n = 1166) deaths per 100 000 in the United States. Rates of death in Admission to ICU, nonfatal New Zealand, Australia, Chile, Paraguay, Argentina and (n = 235) South Africa, which experienced the first wave of the pan- Death (n = 72) demic during their usual influenza season, ranged from 0.19 to 1.4 per 100 000 over the same period. In Canada, the first wave of the pandemic had a geograph- ically and chronologically heterogeneous distribution. How- 15 ever, the risk of a severe outcome among patients admitted to hospital remained relatively constant during the study period and is consistent with other reports that the period and point prevalence of admission to ICU among inpatients ranged 16,17 from 12% to 20%. Requirements for mechanical ventila- tion may have been underreported through public health sur- < 1 1–4 5–9 10–19 20–44 45–64 ≥ 65 veillance, since a Canadian study reported that 81% of Age, yr patients admitted to ICU required mechanical ventilation. The demand for ventilators and ICU beds during the second Figure 1: Severity of outcome by age among 1473 cases of pan- wave may be mitigated by the availability of a vaccine and by demic (H1N1) influenza in patients admitted to hospital that earlier and broader use of antiviral agents. were reported from Apr. 26 to Sept. 26, 2009. (Information on The risk of a severe outcome was greatest among the inpa- age missing for six patients.) ICU = intensive care unit. tients who had one or more underlying medical conditions CMAJ � MARCH 9, 2010 � 182(4) % of patients Research and those who were 20 years of age or older. Those aged 65 Our analysis confirmed that the presence of one or more years and older were at greatest risk of death. Children less underlying medical conditions known to predispose to compli- than 10 years old, pregnant women and Aboriginal people cations of influenza contributed to an elevated risk of a severe were not at increased risk of a severe outcome, despite the rel- outcome among patients with pandemic (H1N1) influenza. atively high population-based incidence of these outcomes. Further research is needed to stratify risk based on the severity This paradoxical finding may be related to pediatric, pregnant of the underlying conditions to further focus recommendations and Aboriginal patients being admitted with milder disease for prevention and treatment. In our study, underlying lung dis- and thus a lower chance of a severe outcome, or to the fact ease was common in all three patient groups (those with a non- that population-based rates are crude measures that combine severe outcome, those admitted to ICU and those who died), a both probability of exposure and proba- bility of virulent infection. Children are Table 4: Risk of severe outcome among inpatients with pandemic (H1N1) influenza considered key transmitters of influenza who had no underlying medical condition,* by age and responsible for seeding households No. (%) with No. (%) with Risk of severe outcome, with the infection, so their likelihood of Age, yr nonsevere outcome severe outcome† OR (95% CI) exposure may have been higher in the first wave. < 1 81/92 (88.0) 7/11 (63.6) 0.6 (0.2–1.6) The risk of death from seasonal 1–4 104/149 (69.8) 8/14 (57.1) 0.5 (0.2–1.4) influenza is highest among people 70 5–9 84/148 (56.8) 7/15 (46.7) 0.6 (0.2–1.6) years of age or older, and hospital admis- 10–19 85/151 (56.3) 12/25 (48.0) Reference sions because of seasonal influenza are 20–29 68/126 (54.0) 14/41 (34.1) 1.5 (0.6–3.4) highest among children less than two 3,20 years old and adults over 65 years. In 30–39 41/91 (45.1) 20/38 (52.6) 3.5 (1.5–7.7) the case of pandemic (H1N1) influenza, 40–49 36/109 (33.0) 13/51 (25.5) 2.6 (1.1–6.1) hospital admissions and severe outcomes 50–59 32/106 (30.2) 10/48 (20.8) 2.2 (0.9–5.6) occurred in all age groups and in a much 22/102 (21.6) 10/48 (20.8) 3.2 (1.2–8.4) ≥ 60 younger Canadian population than sea- All 553/1074 (51.5) 101/291 (34.7) sonal influenza typically does. The age distribution of patients admitted to hospi- *Underlying condition includes lung disease, asthma, diabetes and other metabolic disorders, pre-existing heart disease, renal disease, immunosuppression, anemia, liver disease, neurological tal in Canada was similar to that in the 3,4 disorder, or other chronic medical condition predisposing to complications of influenza. Pregnant United States, where the median age of women were also removed from this analysis. †Admission to ICU or death. patients admitted to hospital was 20 years and the median age of death was 37 years. In our study, children had the Table 5: Incidence of nonsevere and severe outcomes among 1479 patients admitted highest absolute risk of severe and nonse- to hospital with pandemic (H1N1) influenza, by province and territory* vere outcomes, perhaps because of the tendency for influenza attack rates to be Outcome; incidence per 100 000 population highest among preschool and school-age 19 Nonsevere Admission to children. In terms of the timing of the outcome ICU, nonfatal All patients Death pandemic, the peak of the first wave Province/territory n = 1479 n = 1171 n = 236 n = 72 coincided with a period when Canadian British Columbia 1.2 0.7 0.4 0.1 students were in school. Resolution of the first wave coincided with the begin- Alberta 3.5 2.7 0.7 0.2 ning of the summer break in July. Saskatchewan 2.3 1.2 0.8 0.4 Although children congregate in other Manitoba 18.1 14.6 2.9 0.6 places in the summer, school breaks have Ontario 2.9 2.3 0.4 0.2 been reported to slow or delay the impact Quebec 7.4 6.0 1.1 0.3 of seasonal influenza and may have New Brunswick 0.3 0.1 0.1 0.0 played a role in interrupting transmis- Nova Scotia 1.8 1.0 0.7 0.1 sion. Patients 65 years of age and older experienced the lowest incidence of hos- Prince Edward Island 0.7 0.7 0.0 0.0 pital admission without a severe outcome Newfoundland and Labrador 0.6 0.4 0.2 0.0 but the highest population-based rate and Yukon Territory 0.0 0.0 0.0 0.0 relative risk of death among those admit- Northwest Territories 23.0 20.7 2.3 0.0 ted to hospital. This finding suggests the Nunavut 205.1 186.4 15.5 3.1 possibility of varying levels of immunity All 4.4 3.5 0.7 0.2 in this age group or a reduced penetration of the virus into the elderly community in *Because of the small number of cases in Nunavut and Northwest Territories, the incidence rates in those jurisdictions should be interpreted with caution. the first wave. CMAJ � MARCH 9, 2010 � 182(4) Research Nonsevere outcome Admission to ICU, nonfatal Death Date of symptom onset or collection of specimen Figure 2: Epidemic curve of laboratory-confirmed cases of pandemic (H1N1) influenza in patients admitted to hospital that were reported from Apr. 26 to Sept. 26, 2009, by date of symptom onset or collection of specimen. factor that may have contributed to the lack of elevated risk of because of pandemic (H1N1) influenza to be higher among admission to ICU among patients with lung disease. Given its pregnant women than in the general population. prevalence in our study cohort, lung disease should continue to A delay of one day in the median time between the onset be viewed as an important risk factor for hospital admission of symptoms and admission to hospital was associated with among patients with pandemic (H1N1) influenza. Among an increased risk of death. However, we did not have the patients without underlying medical conditions, the risk of information to determine whether this finding was related to severe outcomes appeared to be focused on those 30–49 years a delay in treatment. A report from the United States showed of age and patients 65 years and older. A similar demographic that, in a multivariable model including age, vaccination sta- 22,23 shift has been noted in other pandemics. We cannot rule out tus, time to hospital admission and time to antiviral treat- some age-related correlation with other conditions we did not ment, the only factor associated with positive outcomes was routinely survey (e.g., obesity). the receipt of antiviral treatment within 48 hours after onset We found that the risk of a severe outcome was not greater of symptoms. among Aboriginal patients than among non- Aboriginal patients. However, high population-based rates of hospital Limitations admission because of pandemic (H1N1) influenza have been We did not include probable or suspect cases of pandemic reported among Canadian Aboriginal people, a pattern similar (H1N1) influenza in our analysis. In addition, our inclusion of to that seen in New Zealand, where Maori and Pacific peoples cases from two provinces that were missing information on had higher rates of hospital admission (43.0 and 94.2 per underlying medical conditions may have underestimated the 100 000 respectively) than those of European descent (14.1 role of such conditions in causing severe outcomes. Finally, per 100 000). Similarly, indigenous Australians were 10 data on Aboriginal status was not reported by two provinces. times as likely to be admitted to hospital as nonindigenous Australians. Demographic and clinical factors such as Conclusion younger age distribution and higher prevalence of underlying The population-based incidence of admission to hospital with conditions in Aboriginal communities may be at play; how- laboratory-confirmed pandemic (H1N1) influenza was low in ever, additional contributing factors, including the role of the first five months of the pandemic in Canada. The risk of a socio-economic and geographic factors, and possibly genetic severe outcome was associated with the presence of one or susceptibility, need to be explored. more underlying medical conditions, age of 20 years or more Over the study period, 78 pregnant women were admitted and a delay in hospital admission. The ability to gather to hospital with pandemic (H1N1) influenza. Typically, 300 detailed, case-based information rapidly and in a relatively pregnant women in Canada are admitted to hospital because uniform manner across Canada reflects an important partner- of influenza each year, which corresponds to the rate ob - ship between provincial, territorial and federal public health served among men and women 65–69 years of age. Clini- authorities. As the pandemic evolves, continued investigation cians may therefore expect the rate of hospital admission of risk factors for severe outcomes is needed to provide CMAJ � MARCH 9, 2010 � 182(4) No. of patients 18-Apr-09 25-Apr-09 02-May-09 09-May-09 16-May-09 23-May-09 30-May-09 06-Jun-09 13-Jun-09 20-Jun-09 27-Jun-09 04-Jul-09 11-Jul-09 18-Jul-09 25-Jul-09 01-Aug-09 08-Aug-09 15-Aug-09 22-Aug-09 29-Aug-09 05-Sep-09 12-Sep-09 19-Sep-09 26-Sep-09 Research 10. Public Health Agency of Canada. Leading causes of death, Canada, 2004, males and timely evidence to inform the development and updating of females combined: counts (crude death rate per 100,000) [Table 1]. Ottawa (ON): clinical and public health guidelines. The Agency; 2008. Available: www.phac-aspc.gc.ca /publicat /lcd -pcd97 /table1 -eng .php (accessed 2010 Jan. 13). 11. Update: influenza activity — United States, April–August 2009. MMWR Morb This article has been peer reviewed. Mortal Wkly Rep 2009;58:1009-12. Available: www.cdc.gov/mmwr/preview /mmwrhtml /mm5836a6.htm (accessed 2009 Nov. 25). Competing interests: None declared. 12. Baker MG, Kelly H, Wilson N. Pandemic H1N1 influenza lessons from the south- ern hemisphere. Euro Surveill 2009;14. pii: 19370. Contributors: All of the authors contributed to the conception and design of 13. Bishop JF, Murnane MP, Owen R. Australia’s winter with the 2009 pandemic the study and to the interpretation of the data. Alexia Campbell, Rachel influenza A (H1N1) virus. N Engl J Med 2009;361:2591-4. Rodin, Rhonda Kropp, Julie Vachon, Zhiyong Hong and Louise Pelletier 14. US Centers for Disease Control and Prevention. Fluview: 2008–2009 influenza sea- drafted the manuscript. All of the authors reviewed the article for important son week 39 ending October 3, 2009. Atlanta (GA): The Center; 2009. Available: intellectual content and approved the final version submitted for publication. www.cdc.gov/flu/weekly/weeklyarchives2008-2009/weekly39.htm (ac cessed 2009 Nov. 26). Acknowledgements: The authors thank local, provincial and territorial sur- 15. Health Protection Agency. HPA weekly national influenza report, 24 September veillance partners whose exemplary work allowed for the timely collection, 2009 (week 39). London (UK): The Agency; 2009. Available: www.hpa.nhs.uk /web /HPAwebFile/HPAweb_C/1253205412438 (accessed Sept. 2009). analysis and public health application of this important information. They also 16. Baker MG, Wilson N, Huang AQ, et al. Pandemic influenza A(H1N1)v in New thank the management and support staff of the Centre for Immunization and Zealand: the experience from April to August 2009. 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Available: www.phac-aspc.gc.ca/publicat/lcd-pcd97 /table2-eng.php (accessed 2010 Jan. 13). rachel_rodin@phac-aspc.gc.ca CMAJ � MARCH 9, 2010 � 182(4) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Canadian Medical Association Journal Unpaywall

Risk of severe outcomes among patients admitted to hospital with pandemic (H1N1) influenza

Canadian Medical Association JournalFeb 16, 2010

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10.1503/cmaj.091823
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Abstract

country to comprehensively assess its first 100 cases. By Background: We describe the disease characteristics and mid-May, many Canadian jurisdictions moved away from outcomes, including risk factors for admission to intensive this approach because it became increasingly taxing on both care unit (ICU) and death, of all patients in Canada admit- public health human resources and laboratory capacity. It ted to hospital with pandemic (H1N1) influenza during the was decided that reporting of individual cases would con- first five months of the pandemic. tinue nationally only for patients who were admitted to hos- pital or who died. We provide a detailed review of the dis- Methods: We obtained data for all patients admitted to hospital with laboratory-confirmed pandemic (H1N1) ease characteristics and outcomes, including risk factors for influenza reported to the Public Health Agency of Canada admission to intensive care unit (ICU) and death, of patients from Apr. 26 to Sept. 26, 2009. We compared inpatients admitted to hospital in Canada during the first five months of who had nonsevere disease with those who had severe dis- the pandemic. ease, as indicated by admission to ICU or death. Methods Results: A total of 1479 patients were admitted to hospital with confirmed pandemic (H1N1) influenza during the study period. Of these, 1171 (79.2%) did not have a severe Ascertainment of cases outcome, 236 (16.0%) were admitted to ICU and survived, All 13 provinces and territories in Canada participated in an and 72 (4.9%) died. The median age was 23 years for all of active national surveillance system that captured all cases of the patients, 18 years for those with a nonsevere outcome, laboratory-confirmed pandemic (H1N1) influenza in patients 34 years for those admitted to ICU who survived and 51 admitted to hospital or who died and then reported them to years for those who died. The risk of a severe outcome was the Public Health Agency of Canada. A laboratory-confirmed elevated among those who had an underlying medical case was defined as one involving a person with pandemic condition and those 20 years of age and older. A delay of (H1N1) influenza, with or without clinical symptoms, that one day in the median time between the onset of symp- toms and admission to hospital increased the risk of death was confirmed by one or more of the following tests: reverse by 5.5%. The risk of a severe outcome remained relatively transcription polymerase chain reaction, viral culture, or test constant over the five-month period. for antibodies against pandemic (H1N1) influenza virus showing four-fold rise in antibody levels. Probable or suspect Interpretation: The population-based incidence of admis- cases were not nationally reportable. This case definition was sion to hospital with laboratory-confirmed pandemic consistent over the study period. (H1N1) influenza was low in the first five months of the pandemic in Canada. The risk of a severe outcome was Patients admitted to hospital were prioritized for labora- associated with the presence of one or more underlying tory testing, so case ascertainment was also relatively consis- medical conditions, age of 20 years or more and a delay in tent over the study period. In the first six weeks of the pan- hospital admission. demic, the Public Health Agency of Canada recommended testing for the pandemic (H1N1) influenza virus in patients with influenza-like illness (in the community and in hospital) he first cases of pandemic (H1N1) influenza in Cana - da were reported on Apr. 26, 2009. Retrospective From the Centre for Immunization and Respiratory Infectious Diseases, Infectious Disease and Emergency Preparedness Branch (Campbell, Rodin, T case-finding determined that the onset of symptoms in Vachon, Spika, Pelletier); Chronic Disease Risk Assessment, Health Promo- the first Canadian case, involving a traveller returning from tion and Chronic Disease Prevention Branch (Mao); and the Centre for Com- Mexico, occurred on Apr. 12, 2009. The first patient admitted municable Diseases and Infection Control, Infectious Disease and Emergency Preparedness Branch (Kropp, Hong), Public Health Agency of Canada, to hospital began to experience symptoms on Apr. 18. Ottawa, Ont. During the first few weeks of the outbreak, in-depth fol- CMAJ 2010. DOI:10.1503/cmaj.091823 low-up and reporting of cases was conducted in keeping with CMAJ � MARCH 9, 2010 � 182(4) © 2010 Canadian Medical Association or its licensors DOI:10.1503/cmaj.091823 Research to facilitate characterization of the epidemiologic features, Statistical analysis clinical pres entation and outcomes associated with this novel We conducted a descriptive analysis of cases by age, sex, virus. A general shift to laboratory testing of only patients Aboriginal status, pregnancy status and presence or absence with severe illness and those admitted to hospital occurred by of underlying medical conditions. Because Ontario and mid-June. Testing of samples from patients in the community Nova Scotia did not report Aboriginal status, we excluded continued to varying degrees depending on provincial policies data from those provinces for Aboriginal-specific calcula- and laboratory capacity. tions. We removed missing and unknown information from In this article, we report on confirmed cases involving all calculations except for those on underlying medical con- patients admitted to hospital that were reported to the Public ditions; where data on underlying conditions were missing Health Agency of Canada from Apr. 26 to Sept. 26, 2009. (Ontario and Manitoba), we assumed that it reflected no underlying condition. We compared inpatients who had a Collection of data nonsevere outcome with inpatients who were admitted to Each week, the provincial and territorial surveillance partners ICU and survived, those who died and those who had either submitted lists of hospital cases and deaths. These lists con- severe outcome using univariable analysis and multivari- tained the following core data: a unique case identifier, the able logistic regression analysis. The factors included in the reporting province or territory, the province or territory of res- multivariable models were sex, age (categorical) and the idence, age, sex, Aboriginal status (defined as First Nations, presence or absence of underlying medical conditions. Métis or Inuit), pregnancy status, presence or absence of Owing to a high degree of missing data on Aboriginal sta- underlying medical conditions known to predispose individu- tus, we did not include this characteristic in the multivari- 3,4 als to complications of influenza, mechanical ventilation, able analysis. We calculated the incidence of outcomes by admission to ICU and death. For our study, we defined age, sex, Aboriginal status, pregnancy status, and province patients admitted to hospital who subsequently were admitted or territory. We did not include patient-level information on antiviral treatment or influenza vaccination in our analyses to ICU or who died as having a severe outcome. We consid- ered all of the other patients admitted to hospital to have a because it was not available. nonsevere outcome. We examined differences in time to hospital admission by Table 1: Characteristics of 1479 patients admitted to hospital with laboratory-confirmed pandemic (H1N1) influenza reported from Apr. 26 to Sept. 26, 2009, and risk of severe outcome Admission to ICU, nonfatal Death Any severe outcome† Nonsevere outcome, no. (%) No. (%) No. (%) No. (%) of patients of patients of patients of patients Characteristic n = 1171 n = 236 RR (95% CI)* n = 72 RR (95% CI)* n = 308 RR (95% CI)* Sex, female 581/1169 (49.7) 135/236 (57.2) 1.3 (1.0–1.6) 43/72 (59.7) 1.5 (0.9–2.3) 178/308 (57.8) 1.3 (1.1–1.6) Age, yr < 1 111/1166 (9.5) 11/235 (4.7) 0.7 (0.3–1.4) 1/72 (1.4) 0.3 (0.1–2.5) 12/307 (3.9) 0.6 (0.3–1.2) 1–4 168/1166 (14.4) 17/235 (7.2) 0.7 (0.4–1.3) 0/72 NA 17/307 (5.5) 0.6 (0.3–1.1) 5–9 159/1166 (13.6) 14/235 (6.0) 0.6 (0.3–1.2) 3/72 (4.2) 0.6 (0.1–2.5) 17/307 (5.5) 0.6 (0.3–1.1) 10–19 157/1166 (13.5) 23/235 (9.8) Reference 5/72 (6.9) Reference 28/307 (9.1) Reference 20–44 277/1166 (23.8) 86/235 (36.6) 2.1 (1.3–3.5) 18/72 (25.0) 2.0 (0.7–5.6) 104/307 (33.9) 2.1 (1.3–3.3) 45–64 210/1166 (18.0) 69/235 (29.4) 2.2 (1.3–3.8) 27/72 (37.5) 4.0 (1.5–10.7) 96/307 (31.3) 2.6 (1.6–4.1) 84/1166 (7.2) 15/235 (6.4) 1.2 (0.6–2.5) 18/72 (25.0) 6.7 (2.4–18.8) 33/307 (10.7) 2.2 (1.3–3.9) ≥ 65 Aboriginal 215/859 (25.0) 37/179 (20.7) 0.8 (0.6–1.1) 9/50 (18.0) 0.7 (0.3–1.4) 46/229 (20.1) 0.8 (0.6–1.1) Pregnant‡ 61/126 (48.4) 13/36 (36.1) 0.7 (0.4–1.2) 4/8 (50.0) 1.1 (0.3–4.1) 17/44 (38.6) 0.7 (0.4–1.3) 479/1071 (44.7) 126/217 (58.1) 1.6 (1.2–2.0) 49/70 (70.0) 2.7 (1.7–4.5) 175/287 (61.0) 1.7 (1.4–2.1) ≥ 1 underlying medical conditions§ Pre-existing heart 80/1049 (7.6) 35/209 (16.7) 2.0 (1.5–2.7) 16/65 (24.6) 3.5 (2.1–5.9) 51/274 (18.6) 2.1 (1.6–2.7) disease Diabetes mellitus 82/1047 (7.8) 42/211 (19.9) 2.3 (1.7–3.0) 13/65 (20.0) 2.7 (1.5–4.7) 55/276 (19.9) 2.2 (1.7–2.7) Renal disease 51/1044 (4.9) 14/204 (6.9) 1.3 (0.8–2.2) 7/64 (10.9) 2.2 (1.1–4.7) 21/268 (7.8) 1.5 (1.0–2.1) Immunosuppression 93/1041 (8.9) 21/200 (10.5) 1.2 (0.8–1.7) 17/64 (26.6) 3.3 (2.0–5.5) 38/264 (14.4) 1.5 (1.1–2.0) Lung disease 309/738 (41.9) 73/154 (47.4) 1.2 (0.9–1.6) 30/52 (57.7) 1.8 (1.1–3.1) 103/206 (50.0) 1.3 (1.0–1.6) (including asthma) Note: CI = confidence interval, ICU = intensive care unit, NA = not applicable, RR = relative risk. *For comparison with admission to hospital with nonsevere illness. †Admission to ICU or death. ‡Pregnancy among women of childbearing age (15–44 years of age). §Includes lung disease, asthma, diabetes and other metabolic disorders, pre-existing heart disease, renal disease, immunosuppression, anemia, liver disease, 3,4 neurologic disorder, or other chronic medical condition predisposing to complications of influenza. CMAJ � MARCH 9, 2010 � 182(4) Research severity of outcome. In addition, we looked at the risk of a Age severe outcome by age among patients without an underlying On average, patients with a nonsevere outcome were medical condition. For these analyses, we combined both younger than those admitted to ICU, who in turn were types of severe outcome (admission to ICU and death) younger than those who died (Figure 1). The median age because of the small number of cases. We calculated popula- was 23 years for all of the patients, 18 years for those with tion denominators using Statistics Canada census, pregnancy a nonsevere outcome, 34 years for those admitted to ICU 5–8 outcome and live-birth estimates. who survived and 51 years for those who died. Compared with patients aged 10–19 years, those aged 20–64 years Results were significantly more likely to be admitted to ICU, and those aged 45 years or more were significantly more likely Between Apr. 26 and Sept. 26, 2009, 1479 cases of patients to die, even after adjustment for sex and underlying med- admitted to hospital with laboratory-confirmed pandemic ical conditions (Tables 1 and 3). Despite higher population- based rates among children, inpatients at greatest risk for a (H1N1) influenza were reported to the Public Health Agency of Canada. Of these, 1171 (79.2%) did not have a severe outcome were those 20 years of age and older severe outcome, 236 (16.0%) were admitted to ICU and sur- (Tables 1 and 3). Patients less than five years old had the vived, and 72 (4.9%) died (Table 1). The incidence of highest population-based incidence of hospital admission admission to hospital without a severe outcome (3.47 per without a severe outcome and of admission to ICU; they 100 000 population), nonfatal admission to ICU (0.70 per were followed closely by children five to nine years old 100 000) and death (0.21 per 100 000) remained low during (Table 2). Patients aged 65 or more had the lowest inci- 9,10 the study period (Table 2). Five additional deaths dence of hospital admission without a severe outcome (1.79 involved people who were not reported as having been per 100 000 population) and the highest rate of death (0.38 admitted to hospital; we did not include these cases in the per 100 000); patients aged 45–64 years had the next high- est rate of death (0.29 per 100 000). current analyses. Sex Aboriginal status Females accounted for 51.4% (759/1477) of the patients. Aboriginal status was reported for 24.0% (261/1088) of the The risk of admission to ICU was greater among females patients. The proportion of Aboriginal patients did not differ significantly between those with a nonsevere outcome and than among males in the univariable analysis (Table 1); this difference disappeared in the multivariable analysis (Table 3). Table 3: Factors associated with severe outcome in relation to nonsevere outcome among patients admitted to hospital with Table 2: Incidence of nonsevere and severe outcomes among pandemic (H1N1) influenza 1479 patients admitted to hospital with pandemic (H1N1) influenza, by sex, age, Aboriginal status and pregnancy status Severe outcome; adjusted OR (95% CI)* Outcome; incidence Admission to per 100 000 population Factor ICU, nonfatal Death Any Nonsevere Admission to Sex outcome ICU, nonfatal Death Female 1.3 (0.9–1.7) 1.3 (0.8–2.1) 1.3 (0.9–1.3) Characteristic Population n = 1171 n = 236 n = 72 Male Reference Reference Reference Canada 33 739 859 3.47 0.70 0.21 Age, yr Sex < 1 0.9 (0.4–2.1) 0.5 (0.1–4.4) 0.8 (0.4–1.8) Male 16 732 476 3.50 0.60 0.17 1–4 0.7 (0.4–1.5) NA 0.6 (0.3–1.2) Female 17 007 383 3.42 0.79 0.25 5–9 0.6 (0.3–1.3) 0.8 (0.2–3.5) 0.6 (0.3–1.3) Age, yr 10–19 Reference Reference Reference < 1 376 842 29.46 2.92 0.27 20–44 2.2 (1.3–3.8) 2.6 (0.9–7.8) 2.3 (1.4–3.7) 1–4 1 460 882 11.50 1.16 0.00 45–64 2.3 (1.3–4.0) 4.2 (1.4–12.6) 2.6 (1.5–4.3) 5–9 1 799 302 8.84 0.78 0.17 ≥ 65 1.1 (0.5–2.3) 7.0 (2.3–21.7) 2.1 (1.2–3.9) 10–19 4 226 705 3.71 0.54 0.12 ≥ 1 underlying 1.5 (1.1–2.1) 1.6 (0.9–2.9) 1.5 (1.1–2.1) 20–44 11 718 791 2.36 0.73 0.15 medical conditions† 45–64 9 469 891 2.22 0.73 0.29 Note: CI = confidence interval, ICU = intensive care unit, NA = not applicable, 4 687 446 1.79 0.32 0.38 ≥ 65 OR = odds ratio. *Adjusted for sex, age and presence or absence of underlying medical Aboriginal 906 125 23.73 4.08 0.99 conditions. †Includes lung disease, asthma, diabetes and other metabolic disorders, Pregnant 501 504* 12.16 2.59 0.80 pre-existing heart disease, renal disease, immunosuppression, anemia, liver disease, neurologic disorder, or other chronic medical condition predisposing 3,4 *Estimated number of pregnant women in the five-month study period. to complications of influenza. CMAJ � MARCH 9, 2010 � 182(4) Research those with a severe outcome (Table 1). The Aboriginal popu- Time to hospital admission lation did experience a much higher incidence of nonsevere The median time from symptom onset to hospital admission and severe outcomes than the general population (Table 2). was two to three days. Overall, a one-day difference in the median time to hospital admission increased the risk of death Underlying medical conditions by 5.5%. The median time from symptom onset to death, In this cohort, 48.2% of the patients had one or more underly- available for 41 patients, was 12 days (range 1–75). ing medical conditions. This characteristic was associated with an increased risk of a severe outcome even after adjust- Geography and time ment for age and sex (Tables 1 and 3). The risk of a severe June was the month in which the majority of patients were outcome was greatest among patients with diabetes (relative admitted to hospital (63.5% [667/1050]) or reported symp- risk [RR] 2.2, 95% confidence interval [CI] 1.7–2.7) and tom onset (64.7% [941/1454]). The proportion of inpatients those with pre-existing heart disease (RR 2.1, 95% CI 1.6– who experienced a severe outcome was relatively constant 2.7), followed by those with immunosuppression (RR 1.5, throughout the study period (mean 20.8%, range 18%–23%, 95% CI 1.1–2.0). Lung disease, including asthma, was the Figure 2). The median age of patients with a severe outcome most common underlying condition and was associated with did not change significantly between April and September an elevated risk of death (RR 1.8, 95% CI 1.1–3.1). 2009. The epidemic curve (Figure 2) predominantly reflects For patients who had no underlying condition and were the evolution of the pandemic in Quebec, Ontario, Manitoba not pregnant, the risk of a severe outcome was greatest among and Alberta, where the greatest number of hospital admis- those 30–49 years old and those 60 years and older (Table 4). sions were reported. Mechanical ventilation was required in 15.7% (153/977) of The incidence rates of nonsevere outcome and admission the patients. The rate of mechanical ventilation was lower to ICU were highest in Nunavut, the Northwest Territories, among those with a nonsevere outcome (1.3%) than among Manitoba and Quebec; the incidence of death was highest in those with a severe outcome (65.0%). Nunavut, Saskatchewan and Manitoba (Table 5). Because of the small number of cases in Nunavut and the Northwest Ter- Pregnancy status ritories, the rates in those jurisdictions should be interpreted Of the 170 women in the study cohort who were of childbear- with caution. ing age (15–44 years), 78 (45.9%) were pregnant. The preg- nant women were not at increased risk of admission to ICU or Interpretation death compared with the 92 nonpregnant women of reproduc- tive age, but they did have a higher incidence of hospital The population-based incidence of admission to hospital with admission without a severe outcome (12.16 v. 0.94 per laboratory-confirmed pandemic (H1N1) influenza was low in 100 000 population), admission to ICU (2.59 v. 0.33 per the first five months of the pandemic in Canada. This experi- 9–12 100 000) and death (0.80 v. 0.05 per 100 000) compared with ence is consistent with that of other countries. As in the nonpregnant women of childbearing age. Canada, the highest rates of hospital admission in the United States, Australia and the United Kingdom were among chil- 13–15 dren less than five years old. Cumulative rates of death 40 during the study period were also low: in Canada 0.21 per Nonsevere outcome 100 000 population died, as compared with 0.19 confirmed 35 (n = 1166) deaths per 100 000 in the United States. Rates of death in Admission to ICU, nonfatal New Zealand, Australia, Chile, Paraguay, Argentina and (n = 235) South Africa, which experienced the first wave of the pan- Death (n = 72) demic during their usual influenza season, ranged from 0.19 to 1.4 per 100 000 over the same period. In Canada, the first wave of the pandemic had a geograph- ically and chronologically heterogeneous distribution. How- 15 ever, the risk of a severe outcome among patients admitted to hospital remained relatively constant during the study period and is consistent with other reports that the period and point prevalence of admission to ICU among inpatients ranged 16,17 from 12% to 20%. Requirements for mechanical ventila- tion may have been underreported through public health sur- < 1 1–4 5–9 10–19 20–44 45–64 ≥ 65 veillance, since a Canadian study reported that 81% of Age, yr patients admitted to ICU required mechanical ventilation. The demand for ventilators and ICU beds during the second Figure 1: Severity of outcome by age among 1473 cases of pan- wave may be mitigated by the availability of a vaccine and by demic (H1N1) influenza in patients admitted to hospital that earlier and broader use of antiviral agents. were reported from Apr. 26 to Sept. 26, 2009. (Information on The risk of a severe outcome was greatest among the inpa- age missing for six patients.) ICU = intensive care unit. tients who had one or more underlying medical conditions CMAJ � MARCH 9, 2010 � 182(4) % of patients Research and those who were 20 years of age or older. Those aged 65 Our analysis confirmed that the presence of one or more years and older were at greatest risk of death. Children less underlying medical conditions known to predispose to compli- than 10 years old, pregnant women and Aboriginal people cations of influenza contributed to an elevated risk of a severe were not at increased risk of a severe outcome, despite the rel- outcome among patients with pandemic (H1N1) influenza. atively high population-based incidence of these outcomes. Further research is needed to stratify risk based on the severity This paradoxical finding may be related to pediatric, pregnant of the underlying conditions to further focus recommendations and Aboriginal patients being admitted with milder disease for prevention and treatment. In our study, underlying lung dis- and thus a lower chance of a severe outcome, or to the fact ease was common in all three patient groups (those with a non- that population-based rates are crude measures that combine severe outcome, those admitted to ICU and those who died), a both probability of exposure and proba- bility of virulent infection. Children are Table 4: Risk of severe outcome among inpatients with pandemic (H1N1) influenza considered key transmitters of influenza who had no underlying medical condition,* by age and responsible for seeding households No. (%) with No. (%) with Risk of severe outcome, with the infection, so their likelihood of Age, yr nonsevere outcome severe outcome† OR (95% CI) exposure may have been higher in the first wave. < 1 81/92 (88.0) 7/11 (63.6) 0.6 (0.2–1.6) The risk of death from seasonal 1–4 104/149 (69.8) 8/14 (57.1) 0.5 (0.2–1.4) influenza is highest among people 70 5–9 84/148 (56.8) 7/15 (46.7) 0.6 (0.2–1.6) years of age or older, and hospital admis- 10–19 85/151 (56.3) 12/25 (48.0) Reference sions because of seasonal influenza are 20–29 68/126 (54.0) 14/41 (34.1) 1.5 (0.6–3.4) highest among children less than two 3,20 years old and adults over 65 years. In 30–39 41/91 (45.1) 20/38 (52.6) 3.5 (1.5–7.7) the case of pandemic (H1N1) influenza, 40–49 36/109 (33.0) 13/51 (25.5) 2.6 (1.1–6.1) hospital admissions and severe outcomes 50–59 32/106 (30.2) 10/48 (20.8) 2.2 (0.9–5.6) occurred in all age groups and in a much 22/102 (21.6) 10/48 (20.8) 3.2 (1.2–8.4) ≥ 60 younger Canadian population than sea- All 553/1074 (51.5) 101/291 (34.7) sonal influenza typically does. The age distribution of patients admitted to hospi- *Underlying condition includes lung disease, asthma, diabetes and other metabolic disorders, pre-existing heart disease, renal disease, immunosuppression, anemia, liver disease, neurological tal in Canada was similar to that in the 3,4 disorder, or other chronic medical condition predisposing to complications of influenza. Pregnant United States, where the median age of women were also removed from this analysis. †Admission to ICU or death. patients admitted to hospital was 20 years and the median age of death was 37 years. In our study, children had the Table 5: Incidence of nonsevere and severe outcomes among 1479 patients admitted highest absolute risk of severe and nonse- to hospital with pandemic (H1N1) influenza, by province and territory* vere outcomes, perhaps because of the tendency for influenza attack rates to be Outcome; incidence per 100 000 population highest among preschool and school-age 19 Nonsevere Admission to children. In terms of the timing of the outcome ICU, nonfatal All patients Death pandemic, the peak of the first wave Province/territory n = 1479 n = 1171 n = 236 n = 72 coincided with a period when Canadian British Columbia 1.2 0.7 0.4 0.1 students were in school. Resolution of the first wave coincided with the begin- Alberta 3.5 2.7 0.7 0.2 ning of the summer break in July. Saskatchewan 2.3 1.2 0.8 0.4 Although children congregate in other Manitoba 18.1 14.6 2.9 0.6 places in the summer, school breaks have Ontario 2.9 2.3 0.4 0.2 been reported to slow or delay the impact Quebec 7.4 6.0 1.1 0.3 of seasonal influenza and may have New Brunswick 0.3 0.1 0.1 0.0 played a role in interrupting transmis- Nova Scotia 1.8 1.0 0.7 0.1 sion. Patients 65 years of age and older experienced the lowest incidence of hos- Prince Edward Island 0.7 0.7 0.0 0.0 pital admission without a severe outcome Newfoundland and Labrador 0.6 0.4 0.2 0.0 but the highest population-based rate and Yukon Territory 0.0 0.0 0.0 0.0 relative risk of death among those admit- Northwest Territories 23.0 20.7 2.3 0.0 ted to hospital. This finding suggests the Nunavut 205.1 186.4 15.5 3.1 possibility of varying levels of immunity All 4.4 3.5 0.7 0.2 in this age group or a reduced penetration of the virus into the elderly community in *Because of the small number of cases in Nunavut and Northwest Territories, the incidence rates in those jurisdictions should be interpreted with caution. the first wave. CMAJ � MARCH 9, 2010 � 182(4) Research Nonsevere outcome Admission to ICU, nonfatal Death Date of symptom onset or collection of specimen Figure 2: Epidemic curve of laboratory-confirmed cases of pandemic (H1N1) influenza in patients admitted to hospital that were reported from Apr. 26 to Sept. 26, 2009, by date of symptom onset or collection of specimen. factor that may have contributed to the lack of elevated risk of because of pandemic (H1N1) influenza to be higher among admission to ICU among patients with lung disease. Given its pregnant women than in the general population. prevalence in our study cohort, lung disease should continue to A delay of one day in the median time between the onset be viewed as an important risk factor for hospital admission of symptoms and admission to hospital was associated with among patients with pandemic (H1N1) influenza. Among an increased risk of death. However, we did not have the patients without underlying medical conditions, the risk of information to determine whether this finding was related to severe outcomes appeared to be focused on those 30–49 years a delay in treatment. A report from the United States showed of age and patients 65 years and older. A similar demographic that, in a multivariable model including age, vaccination sta- 22,23 shift has been noted in other pandemics. We cannot rule out tus, time to hospital admission and time to antiviral treat- some age-related correlation with other conditions we did not ment, the only factor associated with positive outcomes was routinely survey (e.g., obesity). the receipt of antiviral treatment within 48 hours after onset We found that the risk of a severe outcome was not greater of symptoms. among Aboriginal patients than among non- Aboriginal patients. However, high population-based rates of hospital Limitations admission because of pandemic (H1N1) influenza have been We did not include probable or suspect cases of pandemic reported among Canadian Aboriginal people, a pattern similar (H1N1) influenza in our analysis. In addition, our inclusion of to that seen in New Zealand, where Maori and Pacific peoples cases from two provinces that were missing information on had higher rates of hospital admission (43.0 and 94.2 per underlying medical conditions may have underestimated the 100 000 respectively) than those of European descent (14.1 role of such conditions in causing severe outcomes. Finally, per 100 000). Similarly, indigenous Australians were 10 data on Aboriginal status was not reported by two provinces. times as likely to be admitted to hospital as nonindigenous Australians. Demographic and clinical factors such as Conclusion younger age distribution and higher prevalence of underlying The population-based incidence of admission to hospital with conditions in Aboriginal communities may be at play; how- laboratory-confirmed pandemic (H1N1) influenza was low in ever, additional contributing factors, including the role of the first five months of the pandemic in Canada. The risk of a socio-economic and geographic factors, and possibly genetic severe outcome was associated with the presence of one or susceptibility, need to be explored. more underlying medical conditions, age of 20 years or more Over the study period, 78 pregnant women were admitted and a delay in hospital admission. The ability to gather to hospital with pandemic (H1N1) influenza. Typically, 300 detailed, case-based information rapidly and in a relatively pregnant women in Canada are admitted to hospital because uniform manner across Canada reflects an important partner- of influenza each year, which corresponds to the rate ob - ship between provincial, territorial and federal public health served among men and women 65–69 years of age. Clini- authorities. As the pandemic evolves, continued investigation cians may therefore expect the rate of hospital admission of risk factors for severe outcomes is needed to provide CMAJ � MARCH 9, 2010 � 182(4) No. of patients 18-Apr-09 25-Apr-09 02-May-09 09-May-09 16-May-09 23-May-09 30-May-09 06-Jun-09 13-Jun-09 20-Jun-09 27-Jun-09 04-Jul-09 11-Jul-09 18-Jul-09 25-Jul-09 01-Aug-09 08-Aug-09 15-Aug-09 22-Aug-09 29-Aug-09 05-Sep-09 12-Sep-09 19-Sep-09 26-Sep-09 Research 10. Public Health Agency of Canada. Leading causes of death, Canada, 2004, males and timely evidence to inform the development and updating of females combined: counts (crude death rate per 100,000) [Table 1]. Ottawa (ON): clinical and public health guidelines. The Agency; 2008. Available: www.phac-aspc.gc.ca /publicat /lcd -pcd97 /table1 -eng .php (accessed 2010 Jan. 13). 11. Update: influenza activity — United States, April–August 2009. MMWR Morb This article has been peer reviewed. Mortal Wkly Rep 2009;58:1009-12. Available: www.cdc.gov/mmwr/preview /mmwrhtml /mm5836a6.htm (accessed 2009 Nov. 25). Competing interests: None declared. 12. Baker MG, Kelly H, Wilson N. Pandemic H1N1 influenza lessons from the south- ern hemisphere. Euro Surveill 2009;14. pii: 19370. Contributors: All of the authors contributed to the conception and design of 13. Bishop JF, Murnane MP, Owen R. Australia’s winter with the 2009 pandemic the study and to the interpretation of the data. Alexia Campbell, Rachel influenza A (H1N1) virus. N Engl J Med 2009;361:2591-4. Rodin, Rhonda Kropp, Julie Vachon, Zhiyong Hong and Louise Pelletier 14. US Centers for Disease Control and Prevention. Fluview: 2008–2009 influenza sea- drafted the manuscript. All of the authors reviewed the article for important son week 39 ending October 3, 2009. Atlanta (GA): The Center; 2009. Available: intellectual content and approved the final version submitted for publication. www.cdc.gov/flu/weekly/weeklyarchives2008-2009/weekly39.htm (ac cessed 2009 Nov. 26). Acknowledgements: The authors thank local, provincial and territorial sur- 15. Health Protection Agency. HPA weekly national influenza report, 24 September veillance partners whose exemplary work allowed for the timely collection, 2009 (week 39). London (UK): The Agency; 2009. Available: www.hpa.nhs.uk /web /HPAwebFile/HPAweb_C/1253205412438 (accessed Sept. 2009). analysis and public health application of this important information. They also 16. Baker MG, Wilson N, Huang AQ, et al. Pandemic influenza A(H1N1)v in New thank the management and support staff of the Centre for Immunization and Zealand: the experience from April to August 2009. 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Published: Feb 16, 2010

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