Download High Morbidity and Mortality in Adults Hospitalized for Respiratory

Clinical Infectious Diseases Advance Access published August 13, 2013
MAJOR ARTICLE
High Morbidity and Mortality in Adults
Hospitalized for Respiratory Syncytial Virus
Infections
N. Lee,1,2 G. C. Y. Lui,1 K. T. Wong,3 T. C. M. Li,1 E. C. M. Tse,1 J. Y. C. Chan,4 J. Yu,3 S. S. M. Wong,3 K. W. Choi,1
R. Y. K. Wong,1 K. L. K. Ngai,5 D. S. C. Hui,1,2 and P. K. S. Chan2,5
1
Department of Medicine and Therapeutics, 2Stanley Ho Center for Emerging Infectious Diseases, 3Department of Radiology and Organ Imaging,
The Jockey Club School of Public Health and Primary Care, and 5Department of Microbiology, Chinese University of Hong Kong, Hong Kong Special
Administrative Region, China
4
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Background. Better understanding of complications and outcomes of adults hospitalized with respiratory syncytial virus (RSV) infection is necessary.
Methods. A retrospective cohort study was conducted on all adults (≥18 years) admitted to 3 acute care general
hospitals in Hong Kong with virologically confirmed RSV infection during 2009–2011 (N = 607). Adults hospitalized for seasonal influenza during the period were used for comparison (n = 547). Both infections were prospectively
diagnosed following a standard protocol. Independent reviews of chest radiographs were performed by radiologists.
Main outcome measures were all-cause death, respiratory failure requiring ventilatory support, and hospitalization
duration. Cox proportional hazards models were used for analyses.
Results. The mean age of RSV patients was 75 (SD, 16) years; 87% had underlying conditions. Lower respiratory
and cardiovascular complications were diagnosed in 71.9% (pneumonia, 42.3%; acute bronchitis, 21.9%; chronic obstructive pulmonary disease/asthma exacerbation, 27.3%) and 14.3% of patients, respectively; 12.5% had bacterial
superinfections. Supplemental oxygen and ventilatory support were required in 67.9% and 11.1%, respectively.
Crude all-cause mortality was 9.1% and 11.9% within 30 days and 60 days, respectively; mean length of stay of survivors was 12 (SD, 13) days. Advanced age, radiographic pneumonia, requirement for ventilation, bacterial superinfection, and elevated urea level and white blood cell count were independently associated with poorer survival.
Systemic corticosteroid use was associated with longer hospitalization and secondary infections. The overall outcomes of survival and length of stay were not significantly different from those in influenza.
Conclusions. RSV can cause severe lower respiratory complications in older adults, resulting in respiratory
failure, prolonged hospitalization, and high mortality similar to seasonal influenza. Corticosteroids did not seem to
improve outcomes. The unmet need for antiviral therapy and vaccination against RSV in adults should be promptly
addressed.
Keywords.
RSV; hospitalization; respiratory failure; lower respiratory tract infection; adults.
Respiratory syncytial virus (RSV) is known to be an
important cause of lower respiratory tract infection in
Received 23 March 2013; accepted 8 June 2013.
Correspondence: N. Lee, MD, Chinese University of Hong Kong, 9/F Clinical
Sciences Bldg, Prince of Wales Hospital, Shatin, Hong Kong, SAR (leelsn@cuhk.
edu.hk).
Clinical Infectious Diseases
© The Author 2013. Published by Oxford University Press on behalf of the Infectious
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
[email protected].
DOI: 10.1093/cid/cit471
infants and young children, leading to hospitalizations
and deaths [1]. Its impact in adults, however, has only
been appreciated in recent years. It has been estimated
that RSV infects 3%–10% of adults annually; although
most infections are mild, increasing evidence suggests
that severe lower respiratory tract infections can occur,
especially among older adults and those with underlying
conditions [2–4]. RSV may have accounted for 5%–15%
of community-acquired pneumonia, 9%–10% of hospital admissions for acute cardiorespiratory diseases, and
excessive deaths during seasonal peaks [3, 4]. The disease
Outcomes of Hospitalized Adults With RSV
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METHODS
Study Population and Case Finding Procedures
A retrospective cohort study on hospitalized adults with RSV
infections was conducted. All patients aged ≥18 years admitted
to 1 of the 3 participating medical units between 1 January
2009 and 31 December 2011 (ie, 36 months) with laboratoryconfirmed RSV infections were studied (N = 607). In Hong
Kong, peak RSV activities occur in spring or summer, or both,
with yearly variations [12, 13]. No case was excluded from the
analysis. All 3 participating hospitals (A, B, and C) are acute
care, general public hospitals operating under the Hospital Authority of Hong Kong. The 3 hospitals serve an urban population of >1.5 million accounting for >20% of the population in
Hong Kong [14, 15]. The Hospital Authority is the main provider of acute medical care in Hong Kong. Ethical approval for
the study was obtained from the institutional review boards of
the Hospital Authority of Hong Kong and the Chinese University of Hong Kong.
During the study period, respiratory viral infections including RSV and influenza in the hospitalized adults were prospectively diagnosed according to a standard protocol as part of
patients’ routine care, as previously described [14–16]. In brief,
patients presenting with symptoms of acute respiratory infections were admitted if they developed potentially serious
medical conditions and/or if their exacerbation of chronic illnesses or their severe symptoms were considered to be impossible to be managed at home [14, 16]. Nasopharyngeal aspirates
(NPAs) were collected at presentation from all such patients,
regardless of perceived etiology and disease severity, to test for
RSV and influenza antigens using an immunofluorescence
assay (see next section) [4, 12, 14–16]. In a minority of cases
where NPA cannot be performed, nasopharyngeal flocked
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swabs were collected for testing. Test results were generally
made available to physicians within a few hours to assist patient
management and infection control precautions. In addition,
chest radiography was performed at admission for all patients,
and sputum samples were routinely collected for bacterial
culture. Blood cultures were also performed when there were
signs of sepsis [14–16].
Data Collection and Definitions of Variables
All patients with laboratory-confirmed RSV infections admitted during the study period were identified from a computerized laboratory record system. Patients’ electronic (hospital
Clinical Management System [CMS]) and written records were
reviewed, and the clinical and laboratory information was systematically recorded using a standardized research tool [14–
16]. Clinical data collected included demographics, comorbidities, illness onset time, presenting symptoms, cardiorespiratory
complications, requirement for supplemental oxygen therapy
and/or ventilatory support, antibiotic use, use of systemic corticosteroids (eg, intravenous hydrocortisone, oral prednisolone),
hospitalization duration, and all-cause death. Laboratory data
included routine blood test results and bacterial pathogens cultured from respiratory and/or blood samples at presentation
and during hospitalization [14]. Pneumonia was defined as
physician-diagnosed pneumonia based on symptoms and signs
of acute lower respiratory tract infection together with new pulmonary infiltrates on a patient’s chest radiographs [5, 14–17].
Acute respiratory failure requiring ventilatory support was
defined as persistent respiratory failure despite supplemental
oxygen therapy (eg, SaO2 <92%) which necessitated the use of
noninvasive positive pressure ventilation (NIPPV) or invasive
mechanical ventilation for support [14, 15]. The main outcome
measure in this analysis was all-cause death; the secondary
outcome measures were (1) development of acute respiratory
failure requiring ventilatory support and (2) total duration of
hospitalization among survivors [14, 15]. In addition, we compared the RSV patients with a cohort of patients admitted to
these hospitals for seasonal influenza in 2009–2011 [14, 15].
The same research tools and definitions were used for both
study cohorts. Patients hospitalized with pandemic 2009 H1N1
infections were not included for comparison as they were significantly younger and shown to have a different clinical course
compared to seasonal influenza, as described elsewhere [15].
Virological Investigations
All NPAs collected were subjected to viral antigen detection for
a panel of respiratory viruses including RSV, influenza A and B,
and parainfluenza 1, 2, and 3 viruses using an immunofluorescence assay (IFA) as previously described [14–16]. NPA contained
more abundant epithelial cells for immunofluorescence staining;
false-positive results are rare (see Discussion) [3, 4, 12, 18–20].
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burden of RSV can approach that of influenza [3, 5–8]. However,
except, perhaps, in the profoundly immunosuppressed, little is
known about the clinical manifestations, complications, and outcomes of severe RSV infections in adults. Factors associated with
severe and fatal infections are largely unknown. Data from Asian
countries are particularly scarce [9–12].
This study examined a large cohort of adults hospitalized
with laboratory-confirmed RSV infections in Hong Kong, China.
Clinical, laboratory, and radiological findings were reported and
analyzed to identify factors associated with pneumonia development, respiratory failure, and death. Their severity of illness and
outcomes were compared with patients admitted for seasonal
influenza during the same period. Such information, when
available, not only improves our understanding on severe RSV
disease in adults and its impact on the healthcare system, but
also provides valuable data to support future planning of clinical trials on RSV therapeutics and prevention.
In brief, NPA samples were washed with phosphate-buffered
saline. The cells were fixed on the wells of a glass slide with
acetone and stained with respiratory virus–specific antibodies
(LIGHT DIAGNOSTICS Respiratory Syncytial Virus FITC
Reagent, Chemicon/Millipore). Specific fluorescent signals
were cross-checked by 2 experienced technicians and reviewed
by clinical virologists. A repeat sample would be requested if
necessary. Virus isolation was performed for all influenza cases
using methods previously described (but not routinely for RSV
because of its low sensitivity and logistic demands) [4, 16, 12].
performed for the whole cohort, and repeated in the subgroup
with additional radiographic reviews performed. We also compared the manifestations and outcomes of RSV patients to a
concurrent seasonal influenza cohort using similar analytic
methods [14, 15]. All probabilities were 2-tailed, and a P value
of <.05 was considered to indicate statistical significance. We
also calculated a conservative, Bonferroni-adjusted P value
threshold (P < .002) for the multiple comparisons in Table 1 for
reference. Statistical analysis was performed using PASW Statistics software, version 18.0.
Radiographic Assessment
RESULTS
Statistical Analysis
The Student t, Mann-Whitney U, and χ2 tests with continuity
correction were used for univariate comparisons whenever appropriate. Variables with P values < .1 in the univariate analyses
were entered into multivariate Cox proportional hazards
models (backward, stepwise regression) to determine independent factors associated with death that occurred within 30 days
and 60 days from time of hospitalization [6, 8, 14, 15]. Variables
including demographics, comorbidities, cardiorespiratory complications, ventilation requirement, bacterial superinfection,
and corticosteroid use were examined. Adjusted hazard ratios
(AHRs) and 95% confidence intervals (CIs) were calculated
for each explanatory variable. An AHR >1 indicated a higher
chance of death. A Kaplan-Meier curve was constructed to
show survival of patients with or without pneumonia development, and compared using the log-rank test. Cox regression
models were also used to determine independent factors associated with time to hospital discharge. Multivariate logistic regression was used to analyze factors associated with pneumonia
and acute respiratory failure requiring ventilatory support; adjusted odds ratios (AORs) and 95% CIs were reported for explanatory variables [14–16]. Analyses of clinical outcomes were
Patient Descriptions and Clinical Manifestations
During the 3-year study period, a total of 607 RSV cases were
diagnosed among the hospitalized adults: 2009, n = 123; 2010,
n = 237; 2011, n = 247. The median RSV-positive rate among
submitted respiratory samples during the seasonal peaks of the
years was: 5.8% (interquartile range [IQR], 4.8%–6.5%), 6.6%
(IQR, 5.8%–9.8%), and 9.1% (IQR, 5.7%–13.7%), respectively
(Figure 1). Patients’ baseline characteristics and clinical manifestations are described in Table 1. The mean and median ages
were 75 (SD, 16) years and 80 (IQR, 68–86) years, respectively;
87.3% had 1 or more coexisting medical conditions (eg, chronic
lung diseases, 35.6%, major systemic comorbidities, 74.0%; immunocompromised, 13.7%; see Table 1). The mean and
median time of admission from symptom onset was 2.6 (SD,
2.2) days and 2 (IQR, 1–3) days, respectively. Fever (75.0%),
cough (87.5%), sputum production (81.2%), and wheezy
breathing and dyspnea (68.9%) were the commonest presenting
symptoms. One or more complications were documented in
80.4%. Lower respiratory tract complications were diagnosed in
71.9%, including pneumonia (42.3%), acute bronchitis (21.9%),
and exacerbation of chronic obstructive pulmonary disease
(COPD)/asthma (with or without pneumonia, 27.3%). Bacterial
superinfection was evidenced in 12.5% at presentation; Streptococcus pneumoniae, Haemophilus influenzae, and Pseudomonas
aeruginosa were the commonest isolates (Table 1). Cardiovascular complications (eg, exacerbation of heart failure, acute coronary events) were diagnosed in 14.3% of patients.
Among the subset of patients with additional radiographic
review performed, 141 of 286 (49.3%) had shown active pneumonic changes; consolidations (23.8%) and ground-glass opacities (19.9%) were the commonest findings. Most (81.8%) changes
were unilateral. Examples of patients’ chest radiographs at presentation are shown in Figure 2. Symptoms associated with radiographic pneumonia included fever (82.0% pneumonia vs
72.5% without pneumonia, P = .058) and wheezy breathing
and dyspnea (79.9% vs 66.2%, P = .010). Runny nose (23.7% vs
35.2%, P = .035) and sore throat (9.4% vs 16.2%, P = .086) were
less common. Multivariate analysis showed that presence of
Outcomes of Hospitalized Adults With RSV
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To further characterize RSV-related lower respiratory tract
complications and their impacts in adults, additional, detailed
radiographic review was performed for all RSV cases admitted
to the largest study site (hospital A, n = 286; 47% of the entire
cohort). The chest radiographs at admission were reviewed by 2
independent, experienced radiologists using dedicated Picture
Archiving and Communication System workstations in retrospect; images were interpreted in consensus for the few discrepant cases [21–23]. The reviewers were blinded to all clinical
information of patients and their outcomes. Previous chest radiographs were used for comparison whenever available (86%).
The chest radiographs were assessed for the presence of any
active lung parenchymal changes (including consolidation,
ground glass opacity, and reticulonodular shadows) that were
compatible with the diagnosis of pneumonia, and their patterns
and extent [22, 23]. Radiologists’ reviews were considered final.
Table 1. Baseline Characteristics, Presenting Symptoms, Complications, and Outcomes of 607 Adults Hospitalized With Respiratory Syncytial Virus Infection, 2009–2011
Variable
RSV (N = 607)
Influenza (N = 547)
P Value
Age, y, mean (SD)
75.1 (16.4)
74.7 (16.6)
.650
Male sex
Resident of long-term care facility
48.6
32.9
49.5
30.5
.749
.378
Comorbidity, major systemic (except chronic lung diseases)a
74.0
65.8
Chronic lung diseasesa
Symptom onset to admission, d, mean (SD)
35.6
2.6 (2.2)
24.1
2.0 (1.7)
<.001
<.001
.003
Fever >37.5°C
75.0
94.2
<.001
Cough
Sputum production
87.5
81.2
85.7
72.5
.513
.010
68.9
53.2
<.001
Sore throat
Runny nose
11.8
25.6
14.3
30.2
.364
.214
Pneumonia
42.3
36.7
.006
Lower respiratory complicationsb
Cardiovascular complicationsb
71.9
14.3
55.6
13.3
<.001
.653
Complications, anyb
80.4
72.8
.002
Bacterial infection, overallc
Bacterial infection, at presentationc
14.8
12.5
14.3
9.1
.790
.066
Supplemental oxygen therapy
67.9
59.0
.002
Ventilation, noninvasive or invasive
30-day mortality
11.1
9.1
6.2
8.0
.003
.538
60-day mortality
11.9
8.8
.086
Time to death, d, median (IQR)
Extended care in subacute hospitals
13 (7–29)
25.2
7 (3–13)
19.7
.001
.027
7 (5–14)
6 (5–11)
.238
Duration of hospitalization for survivors, d, median (IQR)
Data are percentages unless otherwise indicated. Patients hospitalized with seasonal influenza during the same period are used for comparison.
RSV cohort: hospital A, 47.4%; B, 32.5%; C, 20.1%; never-smoker, 43.7%; (non-Chinese, 1; pregnant female, 1). Specimen for diagnosis: nasopharyngeal aspirate,
90.6%; nasopharyngeal flocked swabs, 9.1%; bronchial/tracheal aspirates, 0.3%. Seasonal influenza cohort: H3N2, 79.2%; H1N1, 0.7%; B, 20.1%; >95%
immunofluorescence assay positive (nearly all confirmed with culture; remainder diagnosed by culture/polymerase chain reaction); 91.2% received oseltamivir
treatment [14–16]. Two patients had RSV and influenza A coinfection. A Bonferroni-corrected P value significance threshold (P < .002) is calculated for reference.
Abbreviations: IQR, interquartile range; RSV, respiratory syncytial virus; SD, standard deviation.
a
Major systemic comorbidity: congestive heart failure; cerebrovascular, neoplastic, and chronic liver or renal diseases; other chronic cardiovascular and neurologic
conditions (except hypertension); diabetes mellitus; autoimmune disorders; immunocompromised (immunocompromising conditions and/or use of
immunosuppressants). Chronic lung diseases: chronic obstructive pulmonary disease, asthma, bronchiectasis, and pulmonary fibrosis [14–16].
b
Lower respiratory complications: pneumonia, acute bronchitis, acute exacerbation of chronic obstructive pulmonary disease/asthma. Cardiovascular complications:
exacerbation of heart failure, atrial fibrillation, acute coronary events, acute cerebrovascular events. Other complications: drowsiness, delirium, seizure (6.1%); syncope,
fall, renal impairment, dehydration, metabolic disturbances (15.9%). Patients may have >1 complication [14–16].
c
Bacterial superinfection: evidenced by positive culture of a bacterial pathogen from respiratory (sputum, bronchial/tracheal aspirates) and/or blood samples; infections
with onset >2 days after admission were considered hospital-acquired [14, 15]. At presentation: Streptococcus pneumoniae, 15; Haemophilus influenzae, 14;
Staphylococcus aureus, 5; Moraxella catarrhalis, 2; Pseudomonas aeruginosa, 20; Klebsiella spp, 10; other gram-negative bacteria, 9; other gram-positive cocci,
1. Hospital-acquired: P. aeruginosa, 5; other gram-negative bacteria, 9. Most (94.7%) patients received antibiotic treatment.
major systemic comorbidities (AOR, 1.85; 95% CI, 1.05–3.26)
and elevated white blood cell counts (AOR, 1.07; 95% CI, 1.01–
1.13, per unit increase) were independently associated with radiographic pneumonia, adjusted for demographic and bacteriological variables (Supplementary Data 1).
Patient Management and Outcomes
Systemic corticosteroids were given to 38.9% of patients to treat
acute airway diseases (eg, COPD/asthma exacerbations), and
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antibiotics were used in 94.7% of cases. Two-thirds (67.9%) of
patients were given supplemental oxygen therapy; 11.1% developed persistent respiratory failure and required ventilatory
support (NIPPV, 9.1%, invasive ventilation, 2.0%). Underlying chronic lung diseases, pneumonia ( particularly the presence of ground-glass opacities), and elevated serum urea and
alanine aminotransferase levels were shown to be independent
factors associated with requirement of ventilatory support
(Table 2).
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Wheezy breathing and dyspnea
The crude all-cause mortality within 30 days and 60 days of
this RSV cohort was 9.1% (n = 55) and 11.9% (n = 72), respectively. The median time to death was 13 (IQR, 7–29) days after
admission (90th percentile, 45 days). The reported direct
causes of death were pneumonia (n = 48), COPD exacerbation
(n = 5), acute cardiovascular events (n = 12), and underlying
medical conditions complicated by pneumonia/sepsis (n = 7)
Comparisons With Seasonal Influenza
When patients with RSV were compared with hospitalized patients with seasonal influenza (n = 547), we found that patients
with RSV infections were similar in age but more frequently
had underlying chronic lung diseases and major systemic comorbidities; time to presentation was longer; wheezy breathing
and dyspnea was more frequent; and high fever was less
common (Table 1). Substantial proportions of patients in both
cohorts had cardiorespiratory complications. Rates of use of supplemental oxygen and assisted ventilation tended to be higher
among RSV patients, but there was no significant difference in
Figure 2. Representative frontal chest radiographs of patients with respiratory syncytial virus (RSV) infections. A, Frontal chest radiograph of a male RSV
patient with underlying diabetes mellitus and ischemic stroke. There are ground glass opacities at the right middle, right lower, and left lower zones. He
had a normal white blood cell (WBC) count (8 × 109/L), and no bacterial pathogen was isolated. He required supplemental oxygen therapy. B, Frontal chest
radiograph of an elderly male RSV patient with history of old tuberculosis and diabetes mellitus. It shows consolidative changes at the left lower zone. He
had a normal WBC count (5 × 109/L), and no bacterial pathogen was isolated.
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Figure 1. Time of hospital admission of 607 adult patients with virologically confirmed respiratory syncytial virus (RSV) infection, Hong Kong,
2009–2011. RSV seasonal peaks occurred during weeks 35–41 in 2009,
weeks 8–14 in 2010, and weeks 33–39 in 2011; the median test positivity
rates during these periods were 5.8% (interquartile range [IQR], 4.8%–
6.5%), 6.6% (IQR, 5.8%–9.8%), and 9.1% (IQR, 5.7%–13.7%), respectively
[12, 13]. Abbreviation: RSV, respiratory syncytial virus.
(Table 3). For the survivors, the median and mean durations of
hospitalization were 7 (IQR, 5–14) days and 12 (SD, 13) days,
respectively.
Development of pneumonia in adult RSV patients was associated with lower survival; mortality within 30 days and 60 days
for pneumonia cases was 15.6% (vs 4.3%) and 20.3% (vs 5.7%),
respectively (Figure 3). Cox regression analyses showed that advanced age >75 years, pneumonia, requirement for ventilatory
support, bacterial superinfection, and elevated serum urea level
and white blood cell count were independent factors associated
with lower survival, adjusted for potential confounders
(Table 4; Supplementary Data 2). Use of systemic corticosteroids was not shown to be associated with survival. However,
advanced age, presence of comorbidities, requirement for ventilatory support, and use of systemic corticosteroids were shown
to be independently associated with longer hospitalization durations (Table 5; Supplementary Data 2). Rates of cultureproven, hospital-acquired bacterial infection were higher in patients who received corticosteroids than in those who did not
(4.3% vs 1.1%, P = .012).
Table 2. Explanatory Variables Associated With Acute Respiratory Failure Requiring Ventilatory Support in Hospitalized Respiratory Syncytial Virus Patients as Shown in the Final Logistic
Regression Models
Variables Associated
With Acute Respiratory
Failure
Adjusted Odds Ratio
(95% Confidence
Interval)
P Value
RSV cohort, all cases (N = 607)
No.
Pneumonia
35
Pneumonia, COPD
Pneumonia, multiorgan failure
5
2
Pneumonia, renal failure
2
Pneumonia, acute cardiovascular events
Pneumonia, carcinoma of lung
3
1
<.001
Pneumonia
1.84 (1.03–3.28)
.038
Acute cardiovascular events
8
1.05 (1.01–1.10)
.008
Acute cardiovascular events, pneumonia
Acute cardiovascular events, sepsis
3
1
1.01 (1.00–1.02)
.004
COPD exacerbation
3
COPD exacerbation, sepsis
COPD exacerbation, GI bleeding
1
1
Underlying malignancy (pneumonia)
5
1
1
Underlying chronic lung
diseases
Pneumoniab
3.65 (1.52–8.75)
.004
3.05 (1.22–7.61)
.017
GI bleeding (pneumonia)
CAPD peritonitis (pneumonia)
Serum alanine
aminotransferase
concentration, IU/L
1.01 (1.00–1.02)
.037
Total
Covariates in the model (all cases) included age, sex, major systemic
comorbidity, and culture-confirmed bacterial superinfection. Overall, 18.7%
and 15.0% of patients with chronic lung diseases and pneumonia,
respectively, developed respiratory failure requiring ventilatory support.
Covariates in the model (subgroup) included age, sex, major systemic
comorbidity, culture-confirmed bacterial superinfection, and serum urea
concentration at presentation.
Abbreviation: RSV, respiratory syncytial virus.
Additional radiographic review performed by independent radiologists.
b
Presence vs absence of ground-glass opacities on chest radiographs, as
confirmed by radiologists.
the overall outcomes of survival and duration of hospitalization
from influenza patients, as shown in the univariate and multivariate analyses (Table 1; Supplementary Data 3 and 4).
DISCUSSION
Our data show that RSV can cause severe lower respiratory
complications in older adults, resulting in respiratory failure,
prolonged hospitalization, and high mortality similar to influenza. Corticosteroids did not seem to improve clinical outcomes.
The unmet need for effective antiviral therapy and vaccination
against RSV in adults should be promptly addressed.
To our knowledge, this study describes the largest adult
cohort of hospitalized RSV patients reported to date, and represents one of the few studies performed in Asia [9–11]. Consistent with data from Western countries, such patients were
mostly of advanced age and had underlying chronic lung diseases or other major medical comorbidities [3–5, 17]; notably,
>70% suffered from severe lower respiratory complications,
including pneumonia, acute bronchitis, and exacerbations of
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Altogether, 72 patients died within 60 days postadmission; 52 (72.2%) had
pneumonia diagnosed at presentation. The 50th, 75th, and 90th percentiles of
time to death were 13, 29, and 45 days postadmission, respectively.
Abbreviations: CAPD, continuous ambulatory peritoneal dialysis; COPD,
chronic obstructive pulmonary disease; GI, gastrointestinal.
COPD/asthma, and 14% developed cardiovascular complications [7, 17]. Although fulminant RSV pneumonia is typically
described in patients who are profoundly immunosuppressed
(eg, recipients of hematopoietic stem cell transplant) [2, 3, 24],
we found clinicoradiological evidence of pneumonia (unilateral,
patchy, ground glass opacity or consolidation) in >40% of these
hospitalized adults, which was associated with high fever,
dyspnea, and respiratory failure (more than two-thirds of cases
required supplemental oxygen) [2–5, 17]. Upper respiratory
symptoms of runny nose and sore throat could be absent [2–4,
6, 17, 21]. Importantly, we documented the poor outcomes of
adults hospitalized for RSV infection: >10% of cases necessitated
ventilatory support and the overall death rate exceeded 10% [2, 4, 5].
Pneumonic cases were shown to have the worst prognosis, with a
ventilation rate of about 15% and mortality as high as 15%–20%.
For the survivors, prolonged hospitalization was often required
for the management of cardiorespiratory complications (eg,
COPD exacerbation, congestive heart failure) [5]. Late deaths occurred because of secondary infections, cardiovascular events, or
decompensation of comorbid conditions (Table 3) [6, 8].
Furthermore, we were able to show that among hospitalized
adults, clinical manifestations, complications, and outcomes of
RSV infection are comparable to those of seasonal influenza
(majority being A/H3N2 in this series) [3, 5, 6]. Although in RSV
patients, wheezy breathing and dyspnea might be more common,
and the magnitude of fever sometimes lower, such symptoms
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3.45 (1.93–6.20)
Serum alanine
aminotransferase
concentration, IU/L
Subgroupa (N = 286)
6
Cause of Death
Underlying chronic lung
diseases
Serum urea concentration,
mmol/L
a
Table 3. Reported Direct Causes of Death in 72 Patients Hospitalized With Respiratory Syncytial Virus Infection
Table 4. Explanatory Variables Associated With Death in Hospitalized Respiratory Syncytial Virus Patients as Shown in the Final
Cox Proportional Hazards Models (N = 607)
Variables Associated
With Death
Adjusted Hazard
Ratio (95% CI)
P Value
Events censored within 30 days postadmission
Advanced age (>75 y)
2.85 (1.43–5.68)
could not reliably differentiate it from influenza [3, 4, 17]. High
rates of respiratory (56%–72%) and cardiovascular (13%–14%)
complications occurred in both infections, with substantial proportions of patients requiring supplemental oxygen therapy
(59%–68%) and ventilatory support (6%–11%) [5, 6]. Respiratory
failure appeared to be more common among RSV patients, but
there was a higher prevalence of chronic lung diseases among
them. The overall outcomes of survival and hospitalization duration were not shown to be significantly different between RSV
and influenza patients after adjustment for confounders [4–9].
Unlike influenza, antiviral treatment or vaccine is currently not
available for RSV. Ribavirin and immunoglobulins have been
used to treat (or prevent) severe RSV pneumonia in immunocompromised patients; however, controlled data are lacking,
and whether these can be applied to the older adults are uncertain [3, 4, 24–26]. Our findings thus highlight the need for therapeutic and preventive interventions against RSV in adults.
Recent progress on their development and the obstacles encountered has been reviewed elsewhere [3, 4, 24].
In addition, we examined the roles of bacterial infections and
systemic corticosteroids in adult RSV infections. We found evidence of bacterial superinfection in about 15% of patients during
their course of illness, which was a significant contributory factor
to mortality (similar in influenza diseases) [4, 5, 9, 15, 17].
2.80 (1.53–5.14)
Requirement of ventilatory support
Bacterial superinfection
6.21 (3.39–11.35)
2.02 (1.11–3.66)
.001
Serum urea concentration, mmol/L
1.04 (1.00–1.08)
.035
1.05 (1.00–1.10)
Total WBC count, ×109/L
Events censored within 60 days postadmission
.059
<.001
.021
Advanced age (>75 y)
2.10 (1.18–3.73)
.011
Pneumonia
Requirement of ventilatory support
2.99 (1.75–5.11)
4.65 (2.71–7.98)
<.001
<.001
Cardiovascular complications
1.71 (.97–3.02)
.063
Bacterial superinfection
Serum urea concentration, mmol/L
2.04 (1.20–3.48)
1.05 (1.01–1.08)
.009
.004
Total WBC count, ×109/L
1.06 (1.01–1.10)
.009
Adjusted hazard ratio >1 indicated increased risk of death. Covariates in the
models included sex, major systemic comorbidities, chronic lung disease
exacerbations, hospital site, and use of systemic corticosteroids. Subgroup
analysis on cases with additional radiographic reviews showed similar results
(Supplementary Data 2).
Abbreviations: CI, confidence interval; WBC, white blood cell.
As such, any bacterial infection should be promptly detected
and treated according to local resistance profiles. Besides
S. pneumoniae and H. influenzae, P. aeruginosa and other
gram-negative bacilli may need to be considered in patients
with underlying chronic lung diseases [4, 9, 15]. Corticosteroids
Table 5. Explanatory Variables Associated With Duration of Hospitalization Among Survivors (n = 535) as Shown in the Final Cox
Proportional Hazards Model
Variables Associated With
Duration of Hospitalization
Adjusted Hazard Ratio
(95% Confidence Interval)
P Value
Advanced age (>75 y)
0.74 (.62–.89)
.001
Comorbidity, major systemic
0.77 (.64–.94)
.010
Requirement of ventilatory
support
0.39 (.28–.54)
<.001
Use of systemic
corticosteroids
0.76 (.63–.91)
.002
An adjusted hazard ratio <1 indicated a lower chance of discharge. Covariates
in the model included sex, chronic lung disease exacerbations, presence of
pneumonia, bacterial superinfection, and hospital site. Subgroup analysis
on cases with additional radiograph reviews showed similar results
(Supplementary Data 2). The median duration of hospitalization among
patients who received systemic corticosteroids was 8 (interquartile range
[IQR], 5–18) days, and 6 (IQR, 5–12) days in patients who had not received
corticosteroids; 73% of patients who received systemic corticosteroids also
received inhaled corticosteroids [14–16].
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Figure 3. Kaplan-Meier survival curves of 607 adults hospitalized for respiratory syncytial virus (RSV) infection. Patients who developed pneumonia were shown to have lower survival. Among RSV patients who had
pneumonia, the crude 30-day and 60-day mortality was 15.6% and 20.3%,
respectively (4.3% and 5.7%, respectively, in those without pneumonia).
Subgroup analysis on cases with additional radiograph reviews showed
similar results (data not shown).
.003
Pneumonia
8
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Lee et al
therapies and immunization of high-risk adults (eg, small
interfering RNA, fusion protein inhibitor, newer generation
immunoglobulins, subunit vaccines) [3, 4, 24, 38, 39] are
urgently needed.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online
(http://cid.oxfordjournals.org/). Supplementary materials consist of data
provided by the author that are published to benefit the reader. The posted
materials are not copyedited. The contents of all supplementary data are the
sole responsibility of the authors. Questions or messages regarding errors
should be addressed to the author.
Note
Potential conflicts of interest. All authors: No reported conflicts.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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