Risk factors for severe illness with 2009 pandemic influenza A (H1N1) virus infection in China.

Abstract

Data on risk factors for severe outcomes from 2009 pandemic influenza A (H1N1) virus infection are limited outside of developed countries.
We reviewed medical charts to collect data from patients hospitalized with laboratory-confirmed 2009 H1N1 infection who were identified across China during the period from September 2009 through February 2010, and we analyzed potential risk factors associated with severe illness (defined as illness requiring intensive care unit admission or resulting in death).
Among 9966 case patients, the prevalence of chronic medical conditions (33% vs 14%), pregnancy (15% vs 7%), or obesity (19% vs 14%) was significantly higher in those patients with severe illness than it was in those with less severe disease. In multivariable analyses, among nonpregnant case patients aged ≥ 2 years, having a chronic medical condition significantly increased the risk of severe outcome among all age groups, and obesity was a risk factor among those <60 years of age. The risk of severe illness among pregnant case patients was significantly higher for those in the second and third trimesters. The risk of severe illness was increased when oseltamivir treatment was initiated ≥ 5 days after illness onset (odds ratio, 1.42; 95% confidence interval, 1.20-1.67). For persons <60 years of age, the prevalence of obesity among case patients with severe illness was significantly greater than it was among those without severe illness or among the general population.
Risk factors for severe 2009 H1N1 illness in China were similar to those observed in developed countries, but there was a lower prevalence of chronic medical conditions and a lower prevalence of obesity. Obesity was a risk factor among case patients < 60 years of age. Early initiation of oseltamivir treatment was most beneficial, and there was an increased risk of severe disease when treatment was started ≥ 5 days after illness onset.

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M A J O R A R T I C L E
Risk Factors for Severe Illness with 2009 Pandemic
Influenza A (H1N1) Virus Infection in China
Hongjie Yu,1Zijian Feng,1Timothy M. Uyeki,5Qiaohong Liao,1Lei Zhou,1Luzhao Feng,1Min Ye,1Nijuan Xiang,1
Yang Huai,1Yuan Yuan,3Hui Jiang,1Yingdong Zheng,4Paul Gargiullo,5Zhibin Peng,1Yunxia Feng,1Jiandong Zheng,1
Cuiling Xu,2Yanping Zhang,2Yuelong Shu,2Zhancheng Gao,3Weizhong Yang,1and Yu Wang1
1Office for Disease Control and Emergency Response and2State Key Laboratory for Infectious Disease Prevention and Control, National Institute for
Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention,3Peking University People's Hospital, Peking University Health
Science Center and4School of Public Health, Peking University Health Science Center, Beijing, China; and5Influenza Division, National Center for
Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia
Background.
are limited outside of developed countries.
Methods.We reviewed medical charts to collect data from patients hospitalized with laboratory-confirmed
2009 H1N1 infection who were identified across China during the period from September 2009 through February
2010, and we analyzed potential risk factors associated with severe illness (defined as illness requiring intensive care
unit admission or resulting in death).
Results.Among 9966 case patients, the prevalence of chronic medical conditions (33% vs 14%), pregnancy
(15% vs 7%), or obesity (19% vs 14%) was significantly higher in those patients with severe illness than it was
in those with less severe disease. In multivariable analyses, among nonpregnant case patients aged >2 years,
having a chronic medical condition significantly increased the risk of severe outcome among all age groups,
and obesity was a risk factor among those ,60 years of age. The risk of severe illness among pregnant case
patients was significantly higher for those in the second and third trimesters. The risk of severe illness was
increased when oseltamivir treatment was initiated >5 days after illness onset (odds ratio, 1.42; 95%
confidence interval, 1.20–1.67). For persons ,60 years of age, the prevalence of obesity among case patients with
severe illness was significantly greater than it was among those without severe illness or among the general
population.
Conclusions.Risk factors for severe 2009 H1N1 illness in China were similar to those observed in developed
countries, but there was a lower prevalence of chronic medical conditions and a lower prevalence of obesity. Obesity
was a risk factor among case patients ,60 years of age. Early initiation of oseltamivir treatment was most beneficial,
and there was an increased risk of severe disease when treatment was started >5 days after illness onset.
Dataon risk factors for severe outcomes from 2009 pandemic influenza A (H1N1) virus infection
The global epidemiology of human infection with
2009 pandemic influenza A (H1N1) virus indicates
that the age distribution of rates of hospitalization and
mortality [1–5] is different than that for seasonal in-
fluenza, which occurs predominantly among elderly
persons [6]. Risk factors for severe 2009 H1N1 disease
[4, 5, 7–15] have been reported to be similar to those
identified for complications from seasonal influenza
[6]. A higher risk of severe complications from 2009
H1N1 virus infection has also been reported in obese
individuals [5, 7, 16–18] and among indigenous
populations [9, 18, 19]; whether they are independent
risk factors is unknown [20].
Nationwide 2009 H1N1 surveillance was established
in China on 30 April 2009. Most Chinese cases identified
during the early containment phase of the pandemic
were clinically mild [21, 22]. In this report, we describe
the epidemiological and clinical characteristics of iden-
tifiedcasepatientswhowere hospitalized with
Received 23 August 2010; accepted 17 November 2010.
Correspondence: Yu Wang, MD, MPH, Chinese Center for Disease Control and
Prevention, 155 Changbai Rd, Changping District, Beijing, 102206, People's
Republic of China (wangyu@chinacdc.cn).
Clinical Infectious Diseases
? The Author 2011. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please
e-mail:journals.permissions@oup.com.
1058-4838/2011/00-0001$37.00
DOI: 10.1093/cid/ciq144
2011;1–9
Risk Factors for Severe 2009 H1N1
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laboratory-confirmed 2009 H1N1 infection across China from
September2009throughFebruary2010,and we analyze potential
risk factors associated with severe illness.
METHODS
Case Patients
Beginning on 30 April 2009, all laboratory-confirmed cases of
2009 H1N1 infection were required to be reported to the Chi-
nese Center for Disease Control and Prevention (China CDC).
During the first 4 months of the pandemic, all confirmed case
patients, regardless of the clinical severity of their illness, were
admitted to the hospital and placed in isolation at designated
hospitals for containment purposes [22]. By approximately
mid-August 2009, as 2009 H1N1 activity expanded, contain-
ment strategies were stopped and the clinical management
policy was changed by the Chinese Ministry of Health (MoH),
such that only confirmed case patients who required medical
treatment for complications, based on clinical judgment, were
admitted to hospitals.
A confirmed case patient was defined as a patient who was
hospitalized for at least 24 h with an acute influenza-like ill-
ness (temperature >38 ?C with either cough or sore throat)
and 2009 H1N1 virus infection detected by real-time reverse-
transcription polymerase chain reaction testing of respiratory
specimens. Details on laboratory testing and confirmation of
case patients are published elsewhere [22]. Confirmed case
patients were classified as having severe illness if they were
admitted to an intensive care unit (ICU) or died, and they
were classified as having nonsevere illness if they were alive
and had not been admitted to an ICU by the end of the study
period.
Data Collection
Each confirmed case patient with individual data on sex, age,
and location, was required to be reported from all admitting
hospitalsnationwidetotheChinaCDC.Under the coordination
of the MoH, alladmitting hospitalswere asked toretrospectively
collect detailed epidemiological and clinical data from a sample
of confirmed case patients on a voluntary basis as part of public
health response. Case patients were selected by physicians for
medical chart review and data abstraction to reflect the monthly
distribution of case patients per hospital. Data extraction was
performed by physicians using a standardized form to collect
data about demographic characteristics, underlying chronic
medical conditions, height and weight, pregnancy status, treat-
ment, and outcomes, and all data were reported electronically to
the China CDC. We included confirmed case patients reported
to the China CDC during the period from 1 September 2009
through 28 February 2010 for final analysis, and we censored
data collection by 7 March 2010.
Medical conditions associated with a high risk for influenza
complications were defined on the basis of those listed by the
United States Advisory Committee on Immunization Practices
[6]. Body mass index (BMI; defined as the weight in kilograms
divided bythe square ofheightinmeters)was calculatedfor case
patients with available height and weight data to assess obesity
using both Chinese and US criteria (Supplementary In-
formation). BMI was not calculated in young children aged ,2
years or for pregnant women. We defined pregnancy to include
pregnant women of any gestational age up to 2 weeks post-
partum (including after pregnancy loss), per previous reports
[12, 13]. We estimated 11,607,818 pregnant women in China
using census data [23] (Supplementary Information).
Statistical Analysis
Three subsets of the study population were analyzed separately
to assess risk factors associated with severe illness using multi-
variable logistic regression (Supplementary Information): (1)
nonpregnant patients >2 years of age, to assess chronic medical
conditions and obesity; (2) female patients of reproductive age,
to assess pregnancy; and (3) pregnant patients, to assess gesta-
tional age at illness onset. Odds ratios (ORs) and 95% confi-
dence intervals (CIs) were calculated. Hospitalization and
mortality rates and death-hospitalization ratios were calculated
(Supplementary Information). We compared the prevalence of
obesity and pregnancy among case patients with nonsevere ill-
ness and those with severe illness and among the general pop-
ulation. We also compared outcomes for case patients who
received early antiviral treatment (<2 days after illness onset)
with outcomes for those treated later.
Statistical analysis was performed using SAS, version 9.2 (SAS
Institute). For all analyses, probabilities were 2-tailed, and a P
value of ,.05 was considered to be statistically significant.
RESULTS
From September 2009 through February 2010, a total of 31,562
confirmed case patients were hospitalized throughout China and
were reported to the China CDC, including 793 (2.5%) who died
and 24,268 (77%) who were discharged from the hospital. Of
these patients, 9966 (32%), including 783 (8%) who died and
8491 (85%) who were discharged from the hospital, had com-
plete chart abstractions and were included in analyses of risk
factors. These represented35%ofall discharged patients (8491of
24,268 patients) and 99% of deaths (783 of 793 deaths) reported
from 30 of 31 provinces (Supplementary Figure 1). Illness onsets
of included case patients peaked in late November and decreased
after early December 2009 (Figure 1). The characteristics of in-
cluded case patients and reported case patients without chart
abstractions are shown in Supplementary Table 1; details of case
patients’ enrollments are provided in Supplementary Figure 2.
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A total of 31,562reportedhospitalized case patients, including
793 patients who died, were used to calculate hospitalization and
mortality rates, as well as death-hospitalization ratios. The
overall hospitalization and mortality rates during the 6-month
study period were 2.4 hospitalizations per 100,000 population
and 0.6 deaths per 1,000,000 population. Hospitalization rates
ranged from 6.1 hospitalizations per 100,000 population among
children 5–14 years of age to 0.6 hospitalizations per 100,000
population among persons >65 years of age. Mortality rates
ranged from 1.2 deaths per 1,000,000 population in children ,5
yearsofageto 0.3 deathsper 1,000,000 populationin children5–
14 years of age (Figure 2A). Death-hospitalization ratios were
highest among those >65 years of age (0.115) and lowest among
children 5–14 years of age (0.007) (Figure 2B).
Demographic Characteristics and Underlying Risk Conditions
The median age of the 9966 case patients was 22 years (range, 1
day–93 years), 58% were ,25 years of age, and 56% were male
(Table 1). The median age of case patients increased with in-
creasing disease severity, from 18 years for those without ICU
admission, to 27 years for those with ICU admission, to 30 years
for those with fatal outcomes. Of 9503 case patients with known
information, 21% had at least 1 high-risk chronic medical
condition; high-risk conditions were uncommon among those
,25 years of age (found in ,10% of such patients). The
prevalence of chronic medical conditions among hospitalized
case patients increased with increasing disease severity, from
14% among those without ICU admission, to 31% among those
with ICU admission, to 38% among those with fatal outcome.
A total of 1014 case patients (10%) were considered to be
pregnant, including 19 postpartum women who had delivered
within 2 weeks after illness onset. Of these, most (95%) were
,35 years of age, and only 63 (7%) had chronic high-risk
medical conditions. Of 563 pregnant women (56%) who re-
quired ICU admission, 156 (15%) died. Of 968 pregnant case
patients with known gestational age, 63% were in the 3rdand
29% were in the 2ndtrimester.
Of the 8456 nonpregnant case patients >2 years of age with
known BMI, 1002 (12%) or 1336 (16%) were obese, based on
US criteria and Chinese criteria, respectively; only 33 (0.7%) of
the adults were morbidly obese (BMI >40). Of the 1336 case
patients who were obese according to Chinese criteria, 559
(42%) required ICU admission, and 91 (7%) died. Twenty-four
percent of obese case patients (311 of 1287) also had chronic
high-risk medical conditions. Among obese case patients, 62%
of patients with nonsevere illness were ,15 yearsof age, whereas
68% of deaths were in those >25 years of age.
Treatment and Outcomes
Case patients were admitted to the hospital a median of 3 days
(interquartile range [IQR], 1–5 days) after illness onset (Ta-
ble 2). During hospitalization, 7266 case patients (76%),
Figure 1.
China, September 2009–February 2010. ICU, intensive care unit.
Case patients hospitalized with 2009 pandemic influenza A (H1N1) virus infection (n 5 9966) with chart review data, by date of illness onset,
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including 2683 (90%) of the case patients with ICU admission
and 622 (83%) of those with fatal outcomes, were treated with
neuraminidase inhibitors; all received oseltamivir, except 2 pa-
tients who only received inhaled zanamivir. Oseltamivir treat-
ment was started within 2 days after symptom onset for 1155
case patients (17%), on days 3–4 after symptom onset in 1703
(26%), and >5 days after symptom onset in 3807 (57%).
Themediantimefromillnessonsettoinitiationofoseltamivir
treatment was significantly shorter for case patients with non-
severe illness, compared with those who had severe illness,
among nonpregnant case patients >2 years of age (P ,.001;
Supplementary Table 2); this was also observed for female case
patients of reproductive age and for those who were pregnant
(Supplementary Tables 3–4). In multivariable analyses of the
effectiveness of early oseltamivir treatment (initiated within 2
days after illness onset) among nonpregnant case patients >2
years of age (Table 3), later initiation (3–4 days after onset) was
associated with a trend toward an increased risk of severe illness,
and initiating oseltamivir treatment >5 days after illness onset
was associated with a statistically significant risk of severe illness
(OR, 1.42; 95% CI, 1.20–1.67); this observation was consistent
for female case patients of reproductive age and for those who
were pregnant (data not shown).
Of the 9966 case patients, 3797 (38%), including 783 patients
with fatal outcome, were admitted to an ICU for a median of 5
days(IQR,2–10days),and1961(52%)ofcasepatientsadmitted
to the ICU required mechanical ventilation. Of the 9966 hos-
pitalized patients, 8491 (85%) were discharged from the hos-
pital; 783 (8%) died after a median of 11 days (IQR, 6–19 days)
after illness onset.
Risk Factors Associated with Severe Illness
The proportion of case patients with at least 1 high-risk chronic
medical condition (33% vs 14%; P , .001), pregnancy (15% vs
7%; P , .001), or obesity by Chinese criteria (19% vs 14%; P ,
.001) were all significantly higher among case patients with se-
vere illness than they were among case patients with nonsevere
illness (Table 1). The proportion of case patients with severe
illnesswhohad anyofthese 3 risk factors was significantly higher
than the proportion of case patients with nonsevere illness who
had any of these 3 risk factors (54% vs 31%; P , .001).
In multivariable analyses (Table 3), male sex (OR, 1.19; 95%
CI, 1.07–1.31) and delayed time to hospital admission (OR,
1.27; 95% CI, 1.13–1.42) were significantly associated with se-
vere illness among nonpregnant patients >2 years of age. In
a multivariable ‘‘main effects’’ model that did not account for
any interactions, obesity (OR, 1.54; 95% CI, 1.35–1.76) and
having a chronic disease (OR, 2.72; 95% CI, 2.41–3.08) were
independent risk factors for severe illness among all ages of
nonpregnant case patients (data not shown). Although age was
a modifier of the effect of both chronic medical conditions and
obesity on severe illness, results of the multivariable model that
accounted for interactions between age, chronic medical con-
ditions, and obesity indicated that having a chronic medical
condition significantly increased the risk of severe outcomes
with increasing age .18 years; the highest risk was observed
among patients
>60 years of age and those with chronic
medical conditions (OR, 6.88; 95% CI, 5.54–8.55), compared
with patients without chronic medical conditions. When obese
patients were compared with nonobese patients, multivariable
analyses indicated that obesity significantly increased the risk of
severe outcomes among those 2–17 years of age (OR, 1.34; 95%
CI, 1.10–1.63) and 18–59 years of age (OR, 1.91; 95% CI, 1.57–
2.31) but not in persons >60 years of age.
Age >35 years (OR, 1.40; 95% CI, 1.10–1.77) and delayed
time to hospital admission (OR, 1.80; 95% CI, 1.47–2.19) were
independent risk factors for severe illness among female case
patients of reproductive age (15–49 years of age) in
Figure 2.
(n 5 793) per 100,000 population. B, Death-hospitalization ratios. Error bars indicates 95% confidence intervals. Yrs, years.
Hospitalization and mortality rates and death-hospitalization ratios by age group. A, Hospitalization rates (n 5 31,562) and mortality rates
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multivariableanalyses.Chronic medicalconditionsmodified the
effect of pregnancy on severe illness. Compared with previously
healthy nonpregnantfemalecase patients,pregnantwomenwith
chronic medical conditions had the highest risk for severe illness
(OR, 3.69; 95% CI, 2.15–6.31) in multivariable analyses (Table
3). The risk of severe illness was markedly higher in the second
(OR, 6.10; 95% CI, 3.12–11.94) or third trimester (OR, 7.62;
95% CI, 3.99–14.55) among pregnant case patients; the risk of
severe illness appeared higher in the third trimester than in the
second trimester (OR, 1.25; 95% CI, 0.92–1.70) but was not
significantly different (P 5 .152). Pregnant multigravida case
patients had a higher risk of severe illness than did primgravida
case patients (OR, 1.56; 95% CI, 1.16–2.08).
The proportion of pregnant women among case patients
with nonsevere illness was higher than that among the general
Chinese population of reproductive-age women (31% vs 3%;
OR, 13.20; 95% CI, 11.82–14.75); a higher proportion of preg-
nant women experienced severe illness than experienced
nonsevere illness (51% vs 31%; OR, 2.39; 95% CI, 2.03–2.81)
(Table 4).
Except for those case patients >60 years of age, the proportion
of individuals with obesity was higher among patients with
nonsevere illness than it was among the general population, in-
cluding those 2–17 years of age (18% vs 2%; OR, 10.45; 95% CI,
9.49–11.52) and those 18–59 years of age (11% vs 8%; OR, 1.35;
95% CI, 1.18–1.54); the proportion of individuals with obesity
was also significantly higher among case patients with severe ill-
ness than among case patients with nonsevere illness (Table 4).
DISCUSSION
In this large series of case patients hospitalized with 2009 H1N1
virus infection, children and young adults ,25 years of age had
the highest rates of hospitalization. Although case patients >65
years of age had the highest death-hospitalization ratios, children
,5 years of age had the highest mortality rate. Risk factors for
Table 1.Demographic Characteristics and Underlying Conditions of Case Patients Hospitalized with 2009 Pandemic Influenza A (H1N1)
Characteristic
All case
patients
(n 5 9966)
Patients with
nonsevere
cases(n5 6169)
Patients with severe illness
Subtotal(n5 3797) Admitted to an ICU(n 5 3014)Death(n 5 783)
Male sex5558 (56)3470 (56)2088 (55)1688 (56)400 (51)
Age, median years (IQR)22 (11–39) 18 (10–31)28 (14–47)27 (12–46)30 (20–49)
At least 1 chronic medical
conditiona
1999 (21) 833 (14) 1166 (33) 896 (31)270 (38)
Chronic respiratory disease609 (6) 246 (4) 363 (10)291 (10) 72 (10)
Asthma204 (2)113 (2) 91 (3)80 (3) 11 (2)
Chronic cardiovascular disease422 (4) 127 (2) 295 (8)226 (8) 69 (10)
Type 1 or 2 diabetes 380 (4)129 (2) 251 (7)184 (6) 67 (9)
Chronic liver disease340 (4) 154 (3)186 (5) 151 (5)35 (5)
Chronic renal disease286 (3) 104 (2) 182 (5)134 (5) 48 (7)
Immunosuppression191 (2) 67 (1) 124 (3)80 (3)44 (6)
Neurological disease194 (2)71 (1) 123 (3)85 (3)38 (5)
Pregnancy1014 (10) 451 (7)563 (15)407 (14)156 (20)
Gestational weeks
0–1377 (8) 64 (15) 13 (2)11 (3)2 (1)
14–28
>29
278 (29) 124 (29)154 (28)100 (26)54 (36)
613 (63) 238 (56)375 (69)281 (72)94 (63)
Gravidity
1
>2
576 (63)280 (69)296 (58) 206 (57) 90 (63)
334 (37) 124 (31) 210 (42) 158 (43)52 (37)
Obesity
US criteria
BMI >40
1002 (12) 610 (11) 392 (13) 330 (14)62 (11)
33 (.7) 16 (.6)17 (1) 15 (1)2 (.4)
China criteria1336 (16) 777 (14) 559 (19)468 (19) 91 (16)
Influenza vaccination
during 2008–2009 season
178 (2)115 (2)63 (2)54 (2) 9 (2)
H1N1 vaccination22 (.2) 15 (.3) 7 (.2) 5 (.2)2 (.3)
NOTE.
an ICU. BMI, body mass index, defined as the weight in kilograms divided by the square of height in meters; ICU, intensive care unit; IQR, interquartile range.
Data are no. (%) of patients, unless otherwise indicated. Percentages may not total 100 because of rounding. All patients who died had been admitted to
aChronic medical conditions listed are not mutually exclusive.
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severe 2009 H1N1 disease were similar to those observed in de-
veloped countries [4, 5, 7–15] but with a lower prevalence of
underlying chronic medical conditions and a lower prevalence of
obesity among hospitalized patients and those with severe illness.
Notably, obesity was identified as a risk factor for severe illness
amongcasepatients,60yearsofage,andmultigravidapregnancy
was a risk factor among pregnant case patients. The risk of severe
disease increased when oseltamivir treatment was started .2 days
after illness onset, and initiation of treatment .4 days after onset
was associated with a significant risk of severe disease.
Obesity has not been identified as a risk factor for severe
complications from seasonal influenza. A high prevalence of
obesity has been reported among case patients hospitalized
with 2009 H1N1 virus infection [5, 7, 16–18], although
co-existing chronic medical conditions are often present.
A small observational study from the United States sug-
gested that morbid obesity was significantly associated with
hospitalization among adults [20]. However, the prevalence of
obesity among children and adolescents (2.1%), and among
adults (7.1%) is much lower in China [24] than in the United
States (16.9% and 33.8%, respectively) [25, 26]. Nearly half of
obese Chinese case patients required ICU admission or died,
but only 24% also had chronic medical conditions, although
the overall prevalence of obesity was lower than in previous
reports [5, 6, 16–18]. The age-specific prevalence of obesity
among those with severe illness was much higher than the
prevalence among patients with nonsevere illness and among
the general Chinese population for persons ,60 years of age.
The absence of increased risk of severe outcomes associated
with obesity in patients aged >60 years may be attributable to
the small numbers of obese patients in that age group or at-
tributable to a ‘‘survivor’’ effect, whereby obesity-related
mortality among the elderly population may have already
occurredbefore thepandemic,leaving more-resilient
Table 2.Treatment, Complications, and Clinical Course of Case Patients Hospitalized with 2009 Pandemic Influenza A (H1N1)
Characteristic
All case
patients
(n 5 9966)
Patients with
nonsevere
cases(n5 6169)
Patients with severe illness
Subtotal(n5 3797) Admitted to an ICU(n 5 3014) Death(n 5 783)
Antiviral treatment7266 (76) 3961 (67)3305 (89) 2683 (90)622 (83)
Antiviral initiation time
Median days (IQR) 4 (2–6)4 (2–6) 5 (2–7)4 (2–7) 5 (3–7)
Started on symptom day 1–2 1155 (17)671 (19) 484 (16) 401 (16)83 (14)
Started on symptom day 3–4
Started on symptom day >5
1703 (26)1006 (28) 697 (22) 574 (23)123 (21)
3807 (57)1883 (53)1924 (62)1532 (61)392 (66)
Duration of oseltamivir treatment
Median days (IQR) 5 (3–6) 5 (3–5) 5 (2–7) 5 (3–7)3 (2–7)
1–4 days 2296 (36)1158 (34)1138 (39)818 (35)320 (56)
5 days
>6 days
2038 (32)1413 (41) 625 (21) 567 (24)58 (10)
2018 (32) 842 (25)1176 (40) 985 (42)191 (34)
Mechanical ventilation 1961 (20)0 (0) 1961 (52)1326 (44) 635 (82)
Complications
Pneumonia 6682 (70)3198 (54) 3484 (94) 2761 (93) 723 (97)
Respiratory failure 2429 (25)0 (0)2429 (65) 1724 (58)705 (93)
Acute respiratory distress
syndrome
1574 (17)0 (0) 1574 (43)994 (34)580 (79)
Hepatic dysfunction1002 (11)184 (3) 818 (23)511 (18)307 (43)
Cardiac failure892 (9)0 (0)892 (24)503 (17)389 (53)
Renal dysfunction590 (6)60 (1) 530 (15) 243 (8) 287 (39)
Toxic shock syndrome430 (4) 0 (0)430 (12)177 (6)253 (35)
Neurologic disorders393 (4)88 (1)305 (8)174 (6) 131 (19)
Disseminated intravascular
coagulation
105 (1) 3 (.1) 102 (3) 33 (1) 69 (10)
Clinical course, median days (IQR)
From illness onset to hospital
admission
3 (1–5)3 (1–5)4 (1–6)4 (1–6)4 (2–6)
Length of stay in ICU5 (2–10) – 5 (2–10)6 (2–10)4 (2–11)
Length of stay in hospital 8 (6–13)7 (5–10)13 (8–19)13 (9–20)8 (2–15)
From illness onset to discharge or death12 (8–18)10 (7–15)16 (10–24) 17 (12–25)11 (6–19)
NOTE.
admitted to an ICU. ICU, intensive care unit; IQR, interquartile range.
Data are no. (%) of patients, unless otherwise indicated. Percentages may not total 100 because of rounding. All case patients who died had been
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individuals. Overall, our study provides robust evidence to
suggest that obesity is an independent risk factor associated
with severe illness from 2009 H1N1 virus infection for persons
,60 years of age in China.
\Compared with the age distribution in the United States,
younger age categories account for a much larger proportion
of the general Chinese population [23], which may account
for the observed lower median age of hospitalized case pa-
tients in China (22 years), compared with that in the United
States (27 years) [5]. In addition, the lower prevalence of
chronic high-risk conditions among hospitalized Chinese case
patients, compared with that reported in the United States
Table 3. Multivariable Analyses of Risk Factors associated with Severe Illness due to 2009 Pandemic Influenza A (H1N1) Virus Infection
Characteristic OR (95% CI)Pa
Risk factors associated with severe 2009 H1N1 illness
Among nonpregnant patients > 2 years of age
Male sex (vs female sex)
Delayed hospital admission (on symptom day >3 vs day ,3)
Age and chronic medical conditionsb
1.19 (1.07–1.31).001
,.0011.27 (1.13–1.42)
2–17 years of age and without chronic medical conditionsRef Ref
,.001
,.001
,.001
,.001
,.001
18–59 years of age and without chronic medical conditions
> 60 years of age and without chronic medical conditions
2.12 (1.86–2.41)
3.49 (2.51–4.85)
2–17 years of age and with chronic medical conditions 3.93 (3.03–5.08)
18–59 years of age and with chronic medical conditions
> 60 years of age and with chronic medical conditions
Age and obesityb
5.37 (4.55–6.34)
6.88 (5.54–8.55)
2–17 years of age
Not obeseRefRef
Obese1.34 (1.10–1.63).004
18–59 years of age
Not obeseRef Ref
,.001 Obese
> 60 years of age
1.91 (1.57–2.31)
Not obeseRef Ref
Obese 0.68 (.37–1.25).211
Among female patients of reproductive
age (15–49 years of age)
Age >35 years (vs 15–34 years)
Delayed hospital admission (on symptom day >3 vs day ,3)
Chronic medical conditions and pregnancyb
1.40 (1.10–1.77).006
,.0011.80 (1.47–2.19)
Without chronic medical conditions and nonpregnantRef Ref
,.001
,.001
,.001
With chronic medical conditions and nonpregnant3.62 (2.65–4.94)
Without chronic medical conditions but pregnant 3.30 (2.72–4.00)
With chronic medical conditions and pregnant
Effectiveness of early antiviral treatment on severe 2009 H1N1 illness among nonpregnant patients > 2 years of agec
3.69 (2.15–6.31)
Started on symptom day 1–2Ref Ref
Started on symptom day 3–4
Started on symptom day >5
1.01 (.84–1.22).885
,.001 1.42 (1.20–1.67)
NOTE.
CI, confidence interval; OR, odds ratio; Ref, reference.
aMultivariable logistic regression analyses were performed. Age, obesity, pregnancy, and chronic medical conditions were not highly correlated with each other
(Spearman’s rank correlation coefficients were calculated; r,.38 for all), which indicated little evidence for taking account of collinearity in multivariate analyses.
bChunkwise likelihood ratio tests suggested that there are statistical 2-way interactions between age and chronic medical conditions (P 5 .003), between age
and obesity (P 5 .001), and between chronic medical conditions and pregnancy (P , .001) but no 2-way statistical interaction between chronic medical conditions
and obesity (P 5 .073). Three-way interaction among age, chronic medical conditions, and obesity was evaluated as part of a model containing all possible 2-way
interactions but was not statistically significant (P 5 .489). The final model was used to estimate OR within strata defined by interactions between age and chronic
diseases and between age and obesity. Stratum-specific ORs equal eb, where e denotes the base of natural logarithms and b denotes regression efficient. ORs
were calculated as follows: eg, compared with reference group (those 2–17 years of age without chronic medical conditions), for those with chronic medical
conditions and > 60 years of age, b5b (> 60 years of age) 1 b (chronic medical conditions) 1 b (interaction term); here, the latter 3 b values were obtained from the
multivariable logistic regression model.
cOnly patients who received antivirus treatment and have had clinical outcome defined as discharged from the hospital or died during study period were included
in the analysis.
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[5, 7] and Canada [9], may be partially explained by un-
recognized underlying chronic medical conditions among
Chinese case patients and a lower prevalence of chronic dis-
eases among the general Chinese population [27]. Multivar-
iable analyses also suggested that chronic medical conditions
significantly increased the risk of severe outcomes from 2009
H1N1 virus infection, although age modified the effect of
chronic medical conditions.
Similar to previous studies [12–15], our study found that
2009 H1N1 has had a major impact upon pregnant women in
China. Twenty percent of 2009 H1N1–related deaths in China
were in pregnant women, but only 7% of pregnant case patients
had chronic medical conditions. Similar to other studies [12–
15], and consistent with past pandemics [28–30], we found that
pregnancy significantly increased the risk of severe outcomes
from 2009 H1N1 virus infection, and later gestational age at
illness onset was associated with a trend toward severe illness,
with the highest risk in the third trimester. Additionally, we
found that multigravida pregnancy was associated with an in-
creased risk of severe 2009 H1N1 illness.
Our findings support those from other observational studies
that suggest early initiation of oseltamivir treatment of hospi-
talizedpatientsmay reducesubsequentradiographicpneumonia
[22], disease severity, and mortality for both 2009 H1N1 virus
infection [7, 15, 17] and seasonal influenza [31–33]. Our mul-
tivariable analyses suggested that delayed initiation of oselta-
mivir treatment was associated with severe 2009 H1N1 illness,
with a trend toward an increased risk from initiation of <2 days
after illness onset to initiation 3–4 days after illness onset and
a significant risk of severe illness when treatment was started >5
days after illness onset. Consistent with observational treatment
studies involving hospitalized patients with seasonal influenza
[33, 34], these data suggest that some benefit might be achieved
even if initiation of oseltamivir treatment occurs up to 4 days
after symptom onset.
A limitation of this retrospective study is that the included
case patients with completed chart abstractions accounted for
32%ofall hospitalizedpatientswithconfirmedcases reportedto
the China CDC. Case patients with data available for risk factor
analyses were older and were hospitalized more often in late
2009, compared with those patients without chart review. Chart
abstractions were performed voluntarily, rather than systemat-
ically, and possibly reflect the willingness and capacity of
physicians to perform chart abstraction at admitting hospitals
during the pandemic response. This highlights the challenges of
collecting nationally representative data for assessment and
monitoring of severity and risk factors during an evolving
pandemic in the setting of a very large middle-income, but re-
source-limited, country. We censored data collection by 1 week
after the end of the study period, which may have introduced
incomplete data collection on clinical outcomes and antiviral
treatment, although 93% of included case patients had been
discharged from hospitals or died. To avoid selection bias, we
compared risk factors for patients admitted to an ICU and pa-
tients with fatal cases with risk factors among patients with
nonsevere illness, instead of comparing patients with fatal cases
to patients with nonfatal cases. Although the large number of
case patients allowed statistical power to assess potential in-
dependent risk factors associated with severe 2009 H1N1 illness,
our findings should be interpreted with caution because of the
retrospective study design and selection bias.
Our findings reinforce current recommendations for pre-
viously recognized high-risk populations [15], which include
2009 H1N1 vaccination [35] and empirical oseltamivir treat-
ment of all hospitalized patients with suspected influenza as
soon as possible [36]. In addition, obese persons ,60 years of
age in China should also be considered a high-risk group and
targeted for influenza prevention and control interventions,
including influenza vaccination [37].
Supplementary Material
Supplementary materials are available at Clinical Infectious Dis-
eases online (http://www.oxfordjournals.org/our_journals/cid/).
Supplementary materials consist of data provided by the
author that are published to benefit the reader. The posted
Table 4.
Influenza A (H1N1) Illness and the General Chinese Population
Comparison of Prevalence of Pregnancy and Obesity between Case Patients with Nonsevere and Severe 2009 Pandemic
Variable
No. (%) of patients (or persons) with obesity or pregnancy Odds ratios (95% confidence interval), P
Severe
illness
Nonsevere
illness
General
population
Severe illness vs
Nonsevere illness
Nonsevere illness vs
general population
Pregnancya
Obesityb
562 (51) 450 (31)11,607,818 (3) 2.39 (2.03–2.81), ,.001 13.20 (11.82–14.75), ,.001
1.36 (1.21–1.53), ,.001
1.40 (1.17–1.69), ,.001 10.45 (9.49–11.52), ,.001
1.99 (1.66–2.37), ,.001
559 (19) 777 (14)88,303,356 (7) 2.26 (2.09–2.44), ,.001
2–17 years of age198 (24) 498 (18)5,714,358 (2)
18–59 years of age
>60 years of age
335 (19)251 (11) 66,542,622 (8) 1.35 (1.18–1.54), ,.001
26 (6) 28 (9) 16,046,376 (9)0.66 (.38–1.15), .1421.02 (.69–1.51), .906
aPrevalence of pregnancy was expressed as the percentage of pregnant women among women of reproductive age (15–49 years of age).
bChildren ,2 years of age and pregnant women were excluded.
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materials are not copyedited. The contents of all supple-
mentary data are the sole responsibility of the authors.
Questions or messages regarding errors should be addressed
to the author.
Acknowledgments
We thank the participating hospitals, local health departments and
Centers for Disease Control and Prevention in China for assistance in
coordinating data collection, and the Ministry of Health, China for sup-
porting this study. The views expressed are those of the authors and do not
necessarily represent the policy of the China CDC or the U.S. Centers for
Disease Control and Prevention.
Financial support. US National Institutes of Health (Comprehensive
International Program for Research on AIDS grant U19 AI51915) and the
China-U.S. Collaborative Program on Emerging and Re-emerging In-
fectious Diseases.
Potential conflicts of interest.All authors: no conflicts.
References
1. Transmission dynamics and impact of pandemic influenza A (H1N1)
virus. Wkly Epidemiol Rec 2009; 84:481–484.
2. Centers for Disease Control Prevention. 2009–2010. Influenza Season
Week 19 ending May 15, 2010. http://www.cdc.gov/flu/weekly/
weeklyarchives2009-2010/weekly19.htm. Accessed 28 September 2010.
3. Echevarrı ´a-Zuno S, Mejı ´a-Arangure ´ JM, Mar-Obeso AJ, et al. Infection
and death from influenza A H1N1 virus in Mexico: a retrospective
analysis. Lancet 2009; 374:2072–2079.
4. Writing Committee of the World Health Organization Consultation on
Clinical Aspects of Pandemic (H1N1) 2009 Influenza. Bautista E,
Chotpitayasunondh T, Gao ZC, et al. Clinical aspects of pandemic 2009
influenza A (H1N1) virus infection. N Engl J Med 2010; 362:1708–1719.
5. Louie J, Acosta M, Winter K, et al. Factors associated with death or
hospitalization due to pandemic 2009 influenza A (H1N1) infection in
California. JAMA 2009; 302:1896–1902.
6. Fiore AE, Shay DK, Broder K, et al. Prevention and control of seasonal
influenza with vaccines: recommendations of the Advisory Committee
on Immunization Practices (ACIP), 2009. MMWR Recomm Rep 2009;
58:1–52.
7. JainS, KamimotoL,BramleyAM,et al.Hospitalized patientswith2009
H1N1 influenza in the United States, April–June 2009. N Engl J Med
2009; 361:1935–1944.
8. Libster R, Bugna J, Coviello S, et al. Pediatric hospitalization associated
with 2009 pandemic influenza A (H1N1) in Argentina. N Engl J Med
2010; 362:45–55.
9. Campbell A, Rodin R, Kropp R, et al. Risk of severe outcomes among
patients admitted to hospital with pandemic (H1N1) influenza. CMAJ
2010; 182:349–355.
10. Zarychanski R, Stuart TL, Kumar A, et al. Correlates of severe disease in
patients with 2009 pandemic influenza (H1N1) virus infection. CMAJ
2010; 182:257–264.
11. Pebody RG, McLean E, Zhao H, et al. Pandemic influenza A (H1N1)
2009 mortality in the United Kingdom: risk factors for death, April
2009 to March 2010. Euro Surveill 2010; 15:pii. 19571.
12. Jamieson DJ, Honein MA, Rasmussen SA, et al. H1N1 2009
influenza virus infection during pregnancy in the USA. Lancet 2009;
374:451–4518.
13. Louie JK, Acosta M, Jamieson DJ, Honein MA; California Pandemic
(H1N1) Working Group. Severe 2009 H1N1 influenza in pregnant and
postpartum women in California. N Engl J Med 2010; 362:27–35.
14. The ANZIC Influenza Investigators and Australasian Maternity Out-
comes Surveillance System. Critical illness due to 2009 A/H1N1 in-
fluenza in pregnant and postpartum women: population based cohort
study. BMJ 2010; 340:c1279.
15. Siston AM, Rasmussen SA, Honein MA, et al. Pandemic 2009 influenza
A(H1N1) virus illness among pregnant women in the United States.
JAMA 2010; 303:1517–1525.
16. Centers for Disease Control Prevention. Intensive-care patients with
severe novel influenza A (H1N1) Virus infection—Michigan, June
2009. MMWR Morb Mortal Wkly Rep 2009; 58:749–752.
17. Dominguez-CheritG,LapinskySE,MaciasAE,etal.Criticallyillpatients
with 2009 influenza A(H1N1) in Mexico. JAMA 2009; 302:1880–1887.
18. ANZIC Influenza Investigators; Webb SA, Pettila ¨ V, Seppelt I, et al.
Critical care services and 2009 H1N1 influenza in Australia and
New Zealand. N Engl J Med 2009; 361:1925–1934.
19. Kumar A, Zarychanski R, Pinto R, et al. Critically ill patients with 2009
influenza A(H1N1) infection in Canada. JAMA 2009; 302:1872–1879.
20. Morgan OW, Bramley A, Fowlkes A, et al. Morbid obesity as a risk
factor for hospitalization and death due to 2009 pandemic influenza
A(H1N1) disease. PLoS One 2010; 5:e9694.
21. Cao B, Li XW, Mao Y, et al. Clinical features of the initial cases of 2009
pandemic influenza A (H1N1) virus infection in China. N Engl J Med
2009; 361:2507–2517.
22. Yu HJ, Liao QH, Yuan Y, et al. Effectiveness of oseltamivir on disease
progression andviral RNA shedding in patients with mild pandemic
2009 influenza A H1N1: opportunistic retrospective study of medical
charts in China. BMJ 2010; 341:c4779.
23. National Bureau of Statistics of China. China statistical yearbook 2008.
http://www.stats.gov.cn/tjsj/ndsj/2008/indexeh.htm. Accessed 28 Sep-
tember 2010.
24. Wang LD. In: Comprehensive report, Chinese nutrition and health
survey in 2002. Beijing, China: People’s Medical Publishing House,
2005: 50–52.
25. FlegalKM, CarrollMD, OgdenCL, CurtinLR.Prevalenceandtrendsin
obesity among US adults, 1999–2008. JAMA 2010; 303:235–241.
26. Ogden CL, Carroll MD, Curtin LR, Lamb MM, Flegal KM. Prevalence
of high body mass index in US children and adolescents, 2007–2008.
JAMA 2010; 303:242–249.
27. WorldHealth Organization. Theglobal burden ofdisease: 2004update.
http://www.who.int/healthinfo/global_burden_disease/GBD_re-
port_2004update_full.pdf. Accessed 28 September 2010.
28. Dodds L, McNeil SA, Fell DB, et al. Impact of influenza exposure on
rates of hospital admissions and physician visits because of respiratory
illness among pregnant women. CMAJ 2007; 176:463–468.
29. Freeman DW, Barno A. Deaths from Asian influenza associated with
pregnancy. Am J Obstet Gynecol 1959; 78:1172–1175.
30. Harris JW. Influenza occurring in pregnant women. JAMA 1919;
72:978–980.
31. Lee N, Chan P, Choi K, et al. Factors associated with early hospital
discharge of adult influenza patients. Antivir Ther 2007; 12:501–508.
32. Hanshaoworakul W, Simmerman JM, Narueponjirakul U, et al. Severe
human influenza infections in Thailand: oseltamivir treatment and risk
factors for fatal outcome. PLoS One 2009; 4:e6051.
33. McGeer A, Green KA, Plevneshi A, et al. Antiviral therapy and out-
comes of influenza requiring hospitalization in Ontario, Canada. Clin
Infect Dis 2007; 45:1568–1575.
34. Lee N, Cockram CS, Chan PK, Hui DS, Choi KW, Sung JJ. Antiviral
treatment for patients hospitalized with severe influenza infection may
affect clinical outcomes. Clin Infect Dis 2008; 46:1323–1324.
35. Centers for Disease Control and Prevention. 2009 H1N1 vaccination
recommendations. http://www.cdc.gov/h1n1flu/vaccination/acip.htm.
Accessed 28 September 2010.
36. World Health Organization. Clinical management of human infection
with pandemic (H1N1) 2009: revised guidance. http://www.who.int/
csr/resources/publications/swineflu/clinical_management_h1n1.pdf.
Accessed 28 September 2010.
37. World Health Organization. Recommended viruses for influenza vac-
cines for use in the 2010–2011 northern hemisphere influenza season.
http://www.who.int/csr/disease/influenza/201002_Recommendation.
pdf. Accessed 28 September 2010.
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