Abstract
Background
Severe respiratory syncytial virus (RSV)–associated pneumonia in adults has rarely been addressed. We investigated the burden and clinical characteristics of severe RSV-associated pneumonia in critically ill adult patients.
Methods
We analyzed a prospective cohort of 2865 adults with severe pneumonia who were admitted to the intensive care unit in a 2700-bed tertiary care hospital from 2010 to 2019. The epidemiology, characteristics, and outcomes of 92 cases of severe RSV-associated pneumonia and 163 cases of severe influenza virus (IFV)–associated pneumonia were compared.
Results
Of 1589 cases of severe community-acquired pneumonia, the incidence of RSV-associated pneumonia was less than half that of IFV-associated pneumonia (3.4% vs 8.1%). However, among 1276 cases of severe hospital-acquired pneumonia (HAP), there were slightly more cases of RSV-associated than IFV-associated pneumonia (3.8% vs 3.5%). During the 9 epidemic seasons, RSV-A (5 seasons) and RSV-B (4 seasons) predominated alternately. Structural lung disease, diabetes mellitus, and malignancy were common underlying diseases in both groups. Immunocompromise (57.6% vs 34.4%; P < .001) and hospital acquisition (47.8% vs 23.9%; P < .001) were significantly more common in the RSV group. Coinfection with Streptococcus pneumoniae (3.3% vs 9.8%; P = .08) and methicillin-susceptible Staphylococcus aureus (1.1% vs 6.8%; P = .06) tended to be less frequent in the RSV group. The 90-day mortality was high in both groups (39.1% vs 40.5%; P = .89).
Conclusions
RSV infection was associated with substantial morbidity and mortality in critically ill adult patients, similar to IFV. The relatively higher incidence of RSV in severe HAP suggests that the transmissibility of RSV can exceed that of IFV in a hospital setting.
Keywords: respiratory syncytial virus, hospital-acquired pneumonia, influenza, intensive care unit, severe adult pneumonia
Respiratory syncytial virus (RSV) is an enveloped, negative-sense single-stranded RNA virus in the Pneumoviridae family, previously a subfamily within the Paramyxoviridae family [1]. It consists of 2 subtypes, RSV-A and RSV-B, based on their antigenic and sequence differences. RSV is the most frequent viral cause of acute lower respiratory tract infection in infants and children, with a worldwide distribution and seasonal occurrence [2]. RSV-associated acute lower respiratory tract infections resulted in an estimated 3.6 million hospitalizations and up to 50 000 in-hospital deaths in children under the age of 5 years globally per year in 2019 [3]. RSV infection also constitutes a substantial disease burden in older adults aged ≥65 years [4]. A 4-year prospective cohort study indicated that RSV infection developed in 3%–7% of healthy community-dwelling older adults [5]. It is estimated that 177 000 hospitalizations and 14 000 deaths associated with RSV infections occur annually in US adults alone [6].
Prior studies on RSV infection are limited by the number of seasons studied, simultaneous enrollment of both pneumonic and nonpneumonic patients, and dedication to high-risk groups such as the elderly or patients with hematologic malignancy [7, 8]. With the advent of multiplex polymerase chain reaction (PCR) testing, it has been reported that RSV also causes severe respiratory disease in hospitalized adults [9]. However, even in recent studies regarding the burden and outcomes of RSV infection in adult hospitalized patients, no attention has been paid to the role of RSV in severe pneumonia, especially hospital-acquired pneumonia (HAP) [7, 10–13]. Therefore, we evaluated the epidemiology, clinical characteristics, and outcomes of severe RSV-associated pneumonia over 9 epidemic seasons in a large cohort of critically ill adults with severe pneumonia admitted to the intensive care unit (ICU). We compared the clinical features and outcomes of severe RSV-associated pneumonia with well-characterized severe influenza virus (IFV)–associated pneumonia.
METHODS
Study Design, Data Collection, and Patient Selection
This study, nested in a prospective cohort of patients with severe pneumonia, was conducted at a 28-bed medical ICU at the Asan Medical Center, a 2700-bed tertiary hospital in Seoul, Republic of Korea [14]. From March 2010 to February 2019, all patients aged ≥16 years admitted to the ICU with severe pneumonia were prospectively identified and monitored until the time of discharge or death. Data regarding demographics, underlying diseases or conditions, clinical characteristics, laboratory findings, radiologic findings, and mortality were collected using a standardized protocol. Mortality was described as 30-day, 60-day, and 90-day all-cause mortality after ICU admission. The current study included patients with severe RSV- or IFV-associated pneumonia. Cases of mixed RSV and IFV infection were excluded from the analysis. This study was approved by the Institutional Review Board of Asan Medical Center, which waived informed consent requirements due to the observational nature of the study.
Definition
Pneumonia was defined as the presence of a new or progressive infiltrate on chest radiographs plus 2 or more of the following symptoms: fever, cough, sputum production, dyspnea, or prescription of antibiotics for pneumonia by the attending physician. Severe pneumonia was diagnosed if there was a requirement for invasive mechanical ventilation or septic shock with the need for a vasopressor [15]. Septic shock was defined according to the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) [16]. According to acquisition sites, HAP was defined as pneumonia that occurred 48 hours or more after admission and did not appear to be incubating at the time of admission. Otherwise, the pneumonia episode was categorized as community-acquired pneumonia (CAP) [14, 17]. RSV seasons were defined as ranging from September to August of the subsequent calendar year [18–20]. The primary outcome was defined as 90-day all-cause mortality.
Clinical Samples and Microbiologic Evaluation
Microbiological evaluations were performed as described previously [14]. Respiratory specimens, including nasopharyngeal swabs, sputum, or bronchoalveolar lavage fluid (BAL), were collected from adult patients with severe pneumonia. Respiratory virus detection was performed by a multiplex PCR assay (Seeplex RV Detection Kit, Seegene, Seoul, Korea), and the multiplex respiratory virus PCR was recommended as a standard part of the evaluation of patients who were admitted to the ICU for severe pneumonia. Testing for respiratory viruses was performed using a respiratory virus panel, which simultaneously detects influenza A virus, influenza B virus, RSV-A and -B, parainfluenza viruses 1, 2, 3, and 4, adenovirus, human metapneumovirus, coronaviruses 229E, NL63, OC43, and HKU1, enterovirus, rhinovirus, and human bocavirus.
Statistical Analysis
Numerical values were summarized as average values (mean, median), together with indicators of dispersion (standard deviation, interquartile range). Categorical variables were compared using the chi-square test or Fisher exact test, and continuous variables were compared using the Student t test or the Mann-Whitney U test. The survival analysis was performed using a Cox proportional hazards model. We used multivariate regression to determine independent risk factors for 90-day mortality. Confounders with a P value <.10 in the univariate analysis were included in the multivariate analysis. The results are summarized as adjusted hazard ratios (aHRs) with 95% CIs. P values <.05 were considered statistically significant. Statistical data were analyzed using SPSS, version 24.0 (SPSS, Chicago, IL, USA).
RESULTS
Epidemiology of Severe Viral Pneumonia Over Nine Years
During the study period, 2865 patients with severe pneumonia were admitted to the medical ICU, and among them, 94% (1494/1589) of patients with CAP and 67.2% (857/1276) of patients with HAP were tested by multiplex PCR. Bacterial pathogens were identified in 46.5% of patients (1331/2865), while viral pathogens were identified in 26.1% of patients (747/2865).
Overall, IFV was the most commonly identified virus (6.1%, n = 174), followed by rhinovirus (5.7%, n = 162), parainfluenza virus (4.4%, n = 126), RSV (3.6%, n = 102), endemic human coronavirus including HCoV-OC43/HKU1 and HCoV-229E/NL63 (3.0%, n = 85), and human metapneumovirus (2.1%, n = 59). Among 747 patients with severe viral pneumonia, 174 patients (23.3%) and 102 patients (13.6%) had IFV and RSV infections, respectively. RSV and IFV accounted for 3.4% and 8.1% of 1589 cases of severe CAP, respectively, whereas 3.8% and 3.5% of 1276 cases of severe HAP were caused by RSV and IFV, respectively.
Comparison of Patients With Severe RSV and IFV
After excluding 9 patients with RSV and IFV coinfection, we included 92 patients with severe RSV-associated pneumonia and 163 patients with severe IFV-associated pneumonia in this study. The RSV group was composed of 47 patients with RSV-A and 45 with RSV-B, whereas the IFV group consisted of 132 patients with influenza A and 31 patients with influenza B virus infection.
Demographics, Underlying Diseases or Conditions, and Categories of Pneumonia
The median ages of patients in the RSV and IFV groups were 65.0 years and 68.0 years, respectively (Table 1). Structural lung disease, diabetes mellitus, and malignancy were the most common underlying diseases in both groups. Of these, hematologic malignancy was significantly more common in the RSV group than in the IFV group (32.6% vs 14.1%; P = .01). Fifty-three patients (57.6%) in the RSV group and 56 (34.4%) in the IFV group were categorized as immunocompromised (P < .001). A low body mass index (BMI) tended to be more commonly observed in the IFV group (9.8% vs 18.5%; P = .06). CAP was more common in the IFV group (21.7% vs 41.7%; P = .001), and HAP was significantly more frequent in the RSV group (47.8% vs 23.9%; P < .001).
Table 1.
Demographics, Categories of Pneumonia, and Underlying Disease/Conditions of 255 Patients With Severe Virus-Associated Pneumonia
| Characteristic | Respiratory Syncytial Virus (n = 92) | Influenza Virus (n = 163) | P Value | RSV-A (n = 47) | RSV-B (n = 45) | P Value |
|---|---|---|---|---|---|---|
| Demographics | … | … | … | … | … | … |
| Male sex | 51 (55.4) | 99 (60.7) | .43 | 31 (66.0) | 20 (44.4) | .06 |
| Median age (IQR), y | 65.0 (57–73) | 68.0 (58–77) | .62 | 65.0 (57–72) | 65.0 (57–76) | .26 |
| Underlying disease or conditiona | … | … | … | … | … | … |
| Structural lung disease | 19 (20.7) | 68 (29.5) | .14 | 10 (21.3) | 9 (20.0) | >.99 |
| Chronic obstructive lung disease | 8 (8.7) | 22 (13.5) | .31 | 5 (10.6) | 3 (6.7) | .71 |
| Interstitial lung disease | 10 (10.9) | 15 (9.2) | .67 | 5 (10.6) | 5 (11.1) | >.99 |
| Bronchiectasis | 1 (1.1) | 7 (4.3) | .27 | 0 | 1 (2.2) | .49 |
| Destroyed lung due to tuberculosis | 1 (1.1) | 4 (2.5) | .66 | 1 (2.1) | 0 | >.99 |
| Bronchiolitis obliterans | 0 | 1 (0.6) | .45 | 0 | 0 | … |
| Diabetes mellitus | 32 (34.8) | 44 (27.0) | .20 | 17 (36.2) | 15 (33.3) | .83 |
| Hematologic malignancy | 30 (32.6) | 23 (14.1) | .01 | 17 (36.2) | 13 (28.9) | .51 |
| Solid cancer | 9 (9.8) | 18 (11.0) | .83 | 2 (4.3) | 7 (15.6) | .09 |
| End-stage renal disease | 4 (4.4) | 12 (7.4) | .43 | 1 (2.1) | 3 (6.7) | .36 |
| Congestive heart failure | 5 (5.4) | 10 (6.1) | >.99 | 3 (6.4) | 2 (4.4) | >.99 |
| Liver cirrhosis | 2 (2.2) | 5 (3.1) | >.99 | 2 (4.3) | 0 | .50 |
| Chronic renal failure | 4 (4.4) | 12 (7.4) | .43 | 1 (2.1) | 3 (6.7) | .36 |
| S/p cerebrovascular attack | 13 (14.1) | 10 (6.1) | .04 | 7 (14.9) | 6 (13.3) | >.99 |
| Immunocompromised stateb | 53 (57.6) | 56 (34.4) | <.001 | 26 (55.3) | 27 (60.0) | .68 |
| Receipt of immunosuppressantc | 30 (32.6) | 30 (18.4) | .01 | 19 (40.4) | 11 (24.4) | .12 |
| Receipt of chemotherapyd | 28 (30.4) | 26 (16.0) | .01 | 14 (29.8) | 14 (31.1) | >.99 |
| Solid organ transplant | 4 (4.4) | 4 (2.5) | .46 | 2 (4.3) | 2 (4.4) | >.99 |
| Hematopoietic stem cell transplant | 9 (9.8) | 11 (6.8) | .47 | 7 (14.9) | 2 (4.4) | .16 |
| Active smoker | 5 (5.4) | 14 (8.6) | .36 | 4 (8.5) | 1 (2.2) | .68 |
| Ex-smoker | 23 (25.0) | 53 (32.5) | .21 | 18 (38.3) | 15 (33.3) | … |
| Body mass index, mean ± SD, kg/m2 | 22.7 ± 3.4 | 22.0 ± 3.7 | .18 | 22.6 ± 3.9 | 22.4 ± 3.0 | .87 |
| Underweight (BMI < 18.5 kg/m2) | 9 (9.8) | 30 (18.5) | .06 | 3 (6.4) | 2 (4.4) | .09 |
| Overweight (25 ≤ BMI < 30 kg/m2) | 18 (19.6) | 31 (19.1) | .93 | 2 (4.3) | 8 (17.8) | … |
| Obesity (BMI > 30 kg/m2) | 3 (3.3) | 3 (1.9) | .48 | 2 (4.3) | 0 | … |
| Category of pneumonia | … | … | … | … | … | … |
| Community-acquired | 48 (52.2) | 124 (76.1) | <.001 | 23 (48.9) | 25 (55.6) | .54 |
| Hospital-acquired | 44 (47.8) | 39 (23.9) | <.001 | 24 (51.1) | 20 (44.4) | … |
| General ward | 43/44 (97.7) | 34/39 (87.2) | .09 | 23/24 (95.8) | 20/20 (100) | > .99 |
| Intensive care unit | 1/44 (2.3) | 5/39 (12.8) | … | 1/24 (4.2) | 0 | … |
| Seasonality | … | … | .07 | … | … | .13 |
| Spring (March–May) | 19 (20.7) | 43 (26.0) | … | 9 (19.1) | 10 (22.2) | … |
| Summer (June–August) | 3 (3.2) | 4 (2.5) | … | 3 (6.4) | 0 | … |
| Autumn (September–November) | 11 (12.0) | 6 (3.7) | … | 3 (6.4) | 8 (17.8) | … |
| Winter (December–February) | 59 (64.1) | 110 (67.5) | … | 32 (68.1) | 27 (60.0) | … |
Data are presented as No. (%) unless otherwise stated.
Abbreviations: BMI, body mass index; IQR, interquartile range; RSV, respiratory syncytial virus; s/p, status post.
Some patients had 1 or more underlying diseases or conditions.
Defined as 1 of the following conditions: (i) daily receipt of immunosuppressants including corticosteroids; (ii) HIV infection; (iii) solid organ or hematopoietic stem cell transplant recipients; (iv) receipt of chemotherapy for underlying malignancy during the previous 6 months; and (v) presence of an underlying immune deficiency disorder.
Defined as daily receipt of immunosuppressants including corticosteroids.
Defined as receipt of chemotherapy for underlying malignancy during the previous 6 months.
In a subgroup of 109 immunocompromised patients, the RSV group had significantly more HAP than the IFV group (66.0% vs 33.9%; P = .001). Among patients who were not immunocompromised, there were no significant between-group differences with regard to the site of acquisition (23.1% vs 18.7%; P = .64).
Annual Changes in Predominant Subtypes, Prevalence, and Seasonality
In the RSV group, during the 9 epidemic seasons between the 2010/2011 season and the 2018/2019 season, the dominant RSV subtype changed from year to year (B-A-A-B-A-B-A-B-A) (Figure 1). Through all the included seasons, type A viruses were prevalent in the IFV group, accounting for 81.0%.
Figure 1.
Prevalence data for RSV serotypes over 9 epidemic seasons. Abbreviation: RSV, respiratory syncytial virus.
The yearly prevalence data of both groups in the total study population and the subgroups of nonimmunocompromised and immunocompromised patients are summarized in Figure 2. In the overall population, RSV peaks in the 2012/2013 season were associated with decreased influenza incidence (Figure 2A). In nonimmunocompromised hosts, the yearly prevalence of RSV was very low compared with that of IFV, except in the 2012/2013 season (Figure 2B). However, the prevalence of the 2 viruses fluctuated during the studied epidemic seasons, showing alternating dominance patterns in the immunocompromised subgroup, with 4 RSV- and 5 IFV-dominant seasons (Figures 2C).
Figure 2.
Yearly prevalence of RSV and IFV: (A) total patients, (B) nonimmunocompromised subgroup, and (C) immunocompromised subgroup. Abbreviations: IFV, influenza virus; RSV, respiratory syncytial virus.
The seasonality of RSV infection was overall similar to that of IFV infection, with the peak in January and February. RSV infection tended to more common in the autumn season than IFV (12.0% vs 3.7%; without a P value) (Figure 3).
Figure 3.
Combined monthly prevalence data for RSV and influenza virus IFV over the 9-year study period. Abbreviations: IFV, influenza virus; RSV, respiratory syncytial virus.
Clinical Manifestations, Laboratory Findings, and Coinfections
Table 2 shows the clinical manifestations and laboratory findings of the enrolled patients. The most common clinical presentations of RSV- and IFV-associated severe pneumonia were dyspnea and fever. Clinical symptoms were not associated with specific viral pathogens, except that cough was reported less frequently in the RSV group (60.9% vs 75.3%; P = .02). The mean APACHE II scores did not differ between the 2 groups (27.3 vs 26.9; P = .67) as laboratory observations did.
Table 2.
Clinical Manifestations and Laboratory Findings of Patients With Severe RSV-Associated Pneumonia Compared With Patients With Severe IFV-Associated Pneumonia
| Characteristic | Respiratory Syncytial Virus (n = 92) | Influenza Virus (n = 163) | P Value | RSV-A (n = 47) | RSV-B (n = 45) | P Value |
|---|---|---|---|---|---|---|
| Clinical manifestations | … | … | … | … | … | … |
| Dyspnea | 82 (89.1) | 143 (88.3) | >.99 | 43 (91.5) | 39 (86.7) | .52 |
| Fever (≥38℃) | 75 (81.5) | 135 (82.8) | .87 | 37 (78.7) | 38 (84.4) | .59 |
| Cough | 56 (60.9) | 122 (75.3) | .02 | 31 (66.0) | 25 (55.6) | .39 |
| Sputum | 59 (64.1) | 118 (72.8) | .16 | 32 (68.1) | 27 (60.0) | .52 |
| Altered mental status | 24 (26.1) | 41 (25.3) | .88 | 15 (31.9) | 9 (20.0) | .24 |
| Diarrhea | 7 (7.6) | 6 (3.7) | .24 | 3 (6.4) | 4 (8.9) | .71 |
| Septic shock at ICU admission | 51 (55.4) | 106 (65.0) | .14 | 25 (53.2) | 26 (57.8) | .68 |
| Mechanical ventilation | 89 (96.7) | 159 (97.6) | .71 | 45 (95.7) | 44 (97.8) | >.99 |
| APACHE II score, mean ± SD | 27.3 ± 6.9 | 26.9 ± 7.3 | .67 | 26.5 ± 6.4 | 28.2 ± 7.3 | .24 |
| Laboratory findings, median (IQR) | … | … | … | … | … | … |
| White blood cell, counts/mm3 | 7700 (2750–12 350) | 9600 (5400–15 800) | .09 | 7700 (2000–13 200) | 7400 (3600–11 350) | .68 |
| Platelet counts, 103/mm3 | 136 (52–233) | 149 (90–216) | .49 | 128 (37–246) | 158 (69–232) | .54 |
| C-reactive protein, mg/dL | 11.2 (4.8–19.2) | 13.1 (5.4–21.0) | .50 | 10.3 (4.3–19.6) | 11.6 (5.0–18.9) | .82 |
| Procalcitonin, ng/mL | 0.79 (0.2–5.6) | 1.1 (0.2–6.7) | .60 | 0.57 (0.3–4.7) | 0.91 (0.3–9.2) | .79 |
Data are presented as No. (%) unless otherwise stated.
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; ICU, intensive care unit; IQR, interquartile range; RSV, respiratory syncytial virus.
The respiratory organisms involved in coinfections are summarized in Table 3 and Supplementary Table 1. The rate of coinfection did not differ between the RSV and IFV groups (41.3% vs 49.1%; P = .24). Of these, more patients tended to be coinfected with Streptococcus pneumoniae (P = .08) and methicillin-susceptible Staphylococcus aureus (P = .06) in the IFV group.
Table 3.
Identity of Respiratory Co-pathogens in Patients With Severe RSV- and IFV-Associated Pneumonia
| Co-pathogensa | Respiratory Syncytial Virus (n = 92) | Influenza Virus (n = 163) | P Value | RSV-A (n = 47) | RSV-B (n = 45) | P Value |
|---|---|---|---|---|---|---|
| Any | 38 (41.3) | 80 (49.1) | .24 | 19 (40.4) | 19 (42.2) | >.99 |
| Bacteria | 26 (28.3) | 60 (36.8) | .17 | 13 (27.7) | 13 (28.9) | >.99 |
| Streptococcus pneumoniae | 3 (3.3) | 16 (9.8) | .08 | 3 (6.38) | 0 | .24 |
| Staphylococcus aureus | 7 (7.6) | 18 (11.0) | .51 | 4 (8.5) | 3 (6.7) | >.99 |
| Methicillin-susceptible S. aureus | 1 (1.1) | 11 (6.8) | .06 | 0 | 1 (2.2) | .49 |
| Methicillin-resistant S. aureus | 6 (6.5) | 7 (4.3) | .56 | 4 (8.5) | 2 (4.4) | .68 |
| Other virus | 12 (13.0) | 17 (10.4) | .54 | 6 (12.8) | 6 (13.3) | >.99 |
| Rhinovirus | 3 (3.3) | 7 (4.3) | >.99 | 2 (4.3) | 1 (2.2) | >.99 |
| Endemic human coronavirus | 3 (3.3) | 7 (4.3) | >.99 | 1 (2.1) | 2 (4.4) | .61 |
| Parainfluenza virus | 2 (2.2) | 1 (0.6) | .30 | 1 (2.1) | 1 (2.2) | >.99 |
| Human metapneumovirus | 1 (1.1) | 1 (0.6) | >.99 | 1 (2.1) | 0 | >.99 |
| Adenovirus | 1 (1.1) | 0 | .36 | 1 (2.1) | 0 | >.99 |
| Bocavirus | 0 | 1 (0.6) | >.99 | 0 | 0 | … |
| Nontuberculous mycobacteria, unspecified | 0 | 2 (1.2) | .54 | 0 | 0 | … |
| Fungus | 8 (8.7) | 13 (8.0) | .84 | 3 (6.4) | 5 (11.1) | .42 |
| Aspergillus species | 5 (5.4) | 12 (7.4) | .61 | 2 (4.3) | 3 (6.7) | .67 |
| Pneumocystis jirovecii | 3 (3.3) | 1 (0.6) | .14 | 1 (2.1) | 2 (4.4) | .31 |
Abbreviation: RSV, respiratory syncytial virus.
Within 24 hours before or after a diagnosis of viral infection.
Treatment
Among 92 patients with severe RSV-associated pneumonia, 50 patients (54.3%) received oral ribavirin therapy, 6 (6.5%) received intravenous immunoglobulin (IVIG) only, and 25 (27.2%) received oral ribavirin in combination with IVIG. In the RSV group, oral ribavirin with or without IVIG was more frequently prescribed for patients with a hematologic malignancy (ribavirin therapy with hematologic malignancy 80.0% [24/30] vs without hematologic malignancy 41.9% [26/62]; P = .001) and for immunocompromised patients (ribavirin therapy for immunocompromised patients 71.7% [38/53] vs nonimmunocompromised patients 30.8% [12/39]; P < .001). Almost all patients (96.9%) in the IFV group received antiviral therapy with either oseltamivir (73.6%) or peramivir (21.5%) (Table 4).
Table 4.
Treatment and Outcomes of Patients With Severe RSV- and IFV-Associated Pneumonia
| Outcome | Respiratory Syncytial Virus (n = 92) | Influenza Virus (n = 163) | P Value | RSV-A (n = 47) | RSV-B (n = 45) | P Value |
|---|---|---|---|---|---|---|
| Treatment | … | … | … | … | … | … |
| Total | … | … | … | … | … | … |
| No therapy | 36 (39.1) | 5 (3.1) | <.001 | 22 (46.8) | 14 (31.1) | .13 |
| Antiviral therapya | 56 (60.9) | 158 (96.9) | … | 25 (53.2) | 31 (68.9) | … |
| Nonimmunocompromised patients | 39 | 107 | … | 21 | 18 | … |
| No therapy | 23 (59.0) | 2 (1.9) | <.001 | 15 (71.4) | 7 (38.9) | .04 |
| Antiviral therapya | 16 (41.0) | 105 (98.1) | … | 6 (28.6) | 11 (61.1) | … |
| Immunocompromised patients | 53 | 56 | … | 26 | 27 | … |
| No therapy | 13 (24.5) | 3 (5.4) | .005 | 7 (26.9) | 6 (22.2) | .69 |
| Antiviral therapya | 40 (75.5) | 53 (94.6) | … | 19 (73.1) | 21 (77.8) | … |
| Mortality | … | … | … | … | … | … |
| Total | … | … | … | … | … | … |
| 30-d mortality | 24 (26.1) | 49 (30.1) | .57 | 13 (27.7) | 11 (24.4) | .81 |
| 60-d mortality | 36 (39.1) | 66 (40.5) | .89 | 19 (40.4) | 17 (37.8) | .83 |
| 90-d mortality | 40 (43.5) | 66 (40.5) | .69 | 21 (44.7) | 19 (42.2) | .84 |
| In-hospital mortality | 40 (43.5) | 66 (40.5) | .69 | 21 (44.7) | 19 (42.2) | .84 |
| Nonimmunocompromised patients | 39 | 107 | … | 21 | 18 | … |
| 30-d mortality | 7 (18.0) | 20 (18.7) | >.99 | 3 (14.3) | 4 (22.2) | .68 |
| 60-d mortality | 11 (28.2) | 30 (28.0) | >.99 | 6 (28.6) | 5 (27.8) | >.99 |
| 90-d mortality | 11 (28.2) | 30 (28.0) | >.99 | 6 (28.6) | 6 (33.3) | >.99 |
| In-hospital mortality | 11 (28.2) | 31 (29.0) | >.99 | 6 (28.6) | 6 (33.3) | >.99 |
| Immunocompromised patients | 53 | 59 | … | 26 | 27 | … |
| 30-d mortality | 17 (32.1) | 29 (49.2) | .05 | 10 (38.5) | 7 (25.9) | .39 |
| 60-d mortality | 25 (47.2) | 36 (61.0) | .09 | 13 (50.0) | 12 (44.4) | .79 |
| 90-d mortality | 28 (52.8) | 36 (61.0) | .25 | 13 (50.0) | 15 (55.6) | .59 |
| In-hospital mortality | 29 (54.7) | 36 (61.0) | .50 | 15 (57.7) | 15 (55.6) | .89 |
| Complicated by ventilator-associated pneumonia | 10 (10.9) | 21 (12.9) | .69 | 5 (10.6) | 5 (11.1) | >.99 |
| ICU stay, median (IQR), d | 11.0 (6–24) | 12.0 (7–26) | .76 | 10.0 (7–20) | 16.0 (6–25) | .51 |
| Hospital stay, median (IQR), d | 36.5 (19–71) | 37.0 (17–70) | .65 | 35.0 (18–69) | 43.0 (20–72) | .59 |
Data are presented as No. (%) unless otherwise stated.
Abbreviations: ICU, intensive care unit; IFV, influenza virus; IQR, interquartile range; IVIG, intravenous immunoglobulin; RSV, respiratory syncytial virus.
Antiviral therapy included oral ribavirin (1 patient received aerosolized ribavirin followed by oral ribavirin), IVIG, or ribavirin with IVIG for RSV infection and oseltamivir or peramivir with or without the combination of oral amantadine or ribavirin for IFV infection.
Outcomes and Risk Factors for Mortality
The outcomes of enrolled patients are summarized in Table 4. The mortality rate was similar between the RSV and IFV groups (90-day mortality: 43.5% vs 40.5%; P = .69). Among the overall study patients, immunocompromise (aHR, 2.08; 95% CI, 1.43–3.01; P < .001), an APACHE II score ≥25 at ICU admission (aHR, 2.43; 95% CI, 1.60–3.67; P < .001), and failure of radiographic improvement within 72 hours (aHR, 2.00; 95% CI, 1.22–3.29; P = .01) were significant risk factors for 90-day mortality (Table 5). Bacterial and fungal coinfections were included in multivariate analysis as covariates; however, they failed to show a statistically significant association with 90-day mortality. The outcomes of cases without coinfection and outcomes of cases according to fungal coinfection are shown in Supplementary Tables 2 and 3. In addition, the median lengths of ICU stay (11.0 days vs 12.0 days; P = .76) and hospital stay (36.5 days vs 37.0 days; P = .76) were not significantly different between the 2 groups.
Table 5.
Univariate and Multivariate Analyses of 90-Day Mortality in Patients With Severe RSV- and IFV-Associated Pneumonia
| … | Univariate Analysis | Multivariate Analysis | ||
|---|---|---|---|---|
| Hazard Ratio (95% CI) | P Value | Adjusted Hazard Ratio (95% CI) | P Value | |
| Immunocompromised state | 2.43 (1.65–3.57) | <.001 | 2.08 (1.43–3.01) | <.001 |
| Leukopenia | 1.84 (1.08–3.13) | .025 | … | … |
| Site of acquisition | … | … | … | … |
| Community-acquired | Reference | … | … | … |
| Hospital-acquired | 1.64 (1.12–2.40) | .01 | … | … |
| APACHE2 ≥25 | 2.51 (1.60–3.92) | <.001 | 2.43 (1.60–3.67) | <.001 |
| Low platelet count (<100 000/mm3) | 1.87 (1.28–2.73) | .001 | … | … |
| Failure of radiographic improvement in <72 h | 2.08 (1.24–3.49) | .01 | 2.00 (1.22–3.29) | .01 |
| Failure of C-reactive protein to decrease in <72 h | 1.53 (1.05–2.24) | .03 | … | … |
| Bacterial coinfection | 0.69 (0.46–1.03) | .07 | … | … |
| Fungal coinfection | 1.85 (1.03–3.30) | .04 | … | … |
Abbreviations: APACHE, Acute Physiology and Chronic Health Evaluation; IFV, influenza virus; RSV, respiratory syncytial virus.
Among 92 patients with severe RSV-associated pneumonia, an APACHE II score ≥25 at ICU admission (aHR, 2.56; 95% CI, 1.17–5.59; P = .02) and a low platelet count (≤100 000/mm3; aHR, 2.04; 95% CI, 1.08–3.83; P = .03) were associated with 90-day mortality. The subtype of the RSV strain was not a relevant factor associated with mortality (P = .79, data are not shown).
DISCUSSION
This prospective cohort study, which spanned 9 consecutive epidemic seasons, demonstrated that RSV is a significant cause of severe pneumonia in the community and the hospital, accounting for approximately half of IFV cases. RSV infection was more commonly associated with hospital acquisition and an immunocompromised status. The mortality in patients with severe RSV-associated pneumonia was as high as that in patients with IFV-associated pneumonia. To our knowledge, this study is the only cohort study of adult ICU patients with severe RSV-associated pneumonia to address the substantial burden and serious outcomes of severe RSV-associated pneumonia.
Although the incidence of severe RSV-associated CAP was less than half that of IFV-associated CAP (3.4% vs 8.1% of cases of severe CAP), the incidence of severe RSV-associated HAP was slightly higher than that of IFV-associated HAP (3.8% vs 3.5% of cases of severe HAP). This finding of a relatively higher incidence of severe RSV-associated pneumonia in health care settings than in the community suggests that there might be increased transmissibility of RSV in hospital settings [21]. In this study, transmissibility refers not only to viral biology but also to human behaviors, which can lead to higher rates of subclinical infections among hospital personnel without wearing masks or taking sick leave than occur with IFV. We speculate the following reasons for this finding: First, in contrast to IFV, the absence of licensed vaccines or effective antiviral agents for RSV may lead to higher contagiousness and susceptibility in hospital settings. Both hospitalized patients and healthy medical staff are potentially susceptible to RSV infection. Acquisition of RSV infections by medical personnel is of particular concern as staff may become effective occult vectors for transmission on the ward [22]. Second, the prompt diagnosis and initiation of RSV-directed infection control measures are often delayed. Diagnostic tests targeting RSV such as multiplex respiratory virus PCR are not as frequently performed as rapid IFV-targeted diagnostic tests such as PCR or rapid antigen tests in adults. Third, indirect contact (ie, via fomites) can be a more efficient transmission route for RSV infection [23] than for IFV. Hall et al. showed that [24] RSV might survive in the environment long enough to be transferred to hands touching contaminated surfaces. Infectious RSV could be recovered from hands for significantly longer than IFV [24, 25]. Indirect virus transfer via fomites may not be as efficient a route for IFV transmission as for RSV [26, 27]. Finally, RSV clearance may be more delayed than that of IFV. The Singapore group suggested that IFV induces strong type 1 inflammation [28], resulting in strong induction of antiviral clearance [28, 29]. In contrast, in RSV infection, weak type 1 inflammation leads to imperfect clearance of the virus and thus persistent RSV shedding, which may contribute to an increased risk of nosocomial RSV transmission [30, 31]. These characteristics may provide advantages to RSV in hospital settings. Therefore, constant awareness of the possibility of RSV infection and timely infection control measures for RSV are essential, especially in immunocompromised patients.
In our results, the annual incidence of RSV-A and -B alternately prevailed, especially since the 2013/2014 season. When we analyzed the genotypes of RSV strains isolated from 2015 to 2019, ON1 and BA9 were the only circulating genotypes of RSV-A and RSV-B, respectively (abstract, IDWeek 2022, http://idweek.org). The subtype predominancies reported here fell within the range of recent Korean data [32, 33]. These ON1 and BA9 genotypes have become globally dominant RSV-A and RSV-B genotypes and have completely replaced all the RSV-A and RSV-B genotypes since 2013/2014 and 2015/2016, respectively [34, 35]. To properly understand the effect of genetic changes and to prepare the development of vaccines and therapeutic agents, active monitoring of the molecular RSV epidemic dynamics and clinical data are required. Bacterial coinfection is a well-known complication of severe IFV infection [36]. The 2 most common bacterial co-pathogens, S. aureus and S. pneumoniae, are common colonizers of the nasopharynx [36]. In the present study, coinfection with S. pneumoniae (3.3% vs 9.8%; P = .08) and methicillin-susceptible S. aureus (1.1% vs 6.8%; P = .06) tended to be less frequent in the RSV group than in the IFV group. Methicillin-susceptible S. aureus was almost exclusively identified in the IFV group except in 1 case. Bacterial coinfection in severe influenza infection is likely caused by IFV-induced respiratory epithelial cell dysfunction and damage [36]. As previously mentioned, IFV induces strong type 1 inflammation and cell death, resulting in more respiratory epithelial destruction. In contrast, RSV often leads to a type 2–skewed inflammatory response that prevents inflammatory damage to the virus-infected respiratory epithelium [28, 29].
The mortality data in our cohort should be interpreted with caution. Almost all patients with severe IFV-associated pneumonia received antiviral therapy with either oseltamivir or peramivir, whereas 54.3% (50/92) of patients with RSV received oral ribavirin with or without IVIG therapy. Furthermore, oral ribavirin with or without IVIG showed no difference in treating patients with severe RSV-associated pneumonia in our study. Despite a lack of effective antiviral therapy in patients with RSV, the similar 90-day mortality rates between the 2 groups indicate that the virulence potential of RSV might be lower than that of IFV. In addition, the more common immunocompromise among patients with RSV could enhance the severity of the infection. To date, aerosolized ribavirin is the only Food and Drug Administration–approved drug for the treatment of severe RSV infection in infants and young children [37]. Unfortunately, it is cumbersome to administer and expensive. Previous studies on oral and intravenous ribavirin have highlighted the lack of consensus on treatment strategies concerning for toxicities such as hemolytic anemia [38, 39]. Earlier studies showed that a combination treatment of ribavirin with RSV IVIG yielded encouraging results [40, 41]. Still, RSV IVIG was voluntarily withdrawn from the market in 2004 after the approval of palivizumab [42]. Several antiviral agents including AK0529 have shown promising results in preclinical studies [43–45]. There is an urgent need for effective antiviral agents for RSV infection in adults.
There are some limitations to this study. First, the study was conducted at a single center. Thus, our findings may not be generalizable. Second, we could not evaluate the impact of the genotypes on clinical characteristics and outcomes. Third, as this study was confined to patients with severe pneumonia who were admitted to the ICU, the characteristics of non-ICU patients have not been evaluated. Moreover, due to the observational nature of the study, we were unable to obtain test results for blood parameters other than white blood cell counts to demonstrate an immunocompromised state. Finally, less than half of the patients underwent BAL. BAL is not always available for patients with severe pneumonia in critical settings. We may have included coincidental upper respiratory viral infections or colonization in cases in which viruses were isolated only from upper respiratory tract specimens.
In conclusion, our study indicated that severe RSV-associated pneumonia is a significant cause of morbidity and mortality in the critically ill adult population, comparable to IFV-associated pneumonia. In addition, the severe RSV-associated pneumonia group was more likely to be immunocompromised and to have hospital-acquired infections. Given the higher incidence of RSV in severe HAP observed in the current study, the transmissibility of RSV could exceed that of IFV in a hospital setting. Current data highlight the need for thorough infection control measures and novel therapeutic approaches to RSV infection, especially in hospitalized immunocompromised adults.
Supplementary Material
Acknowledgements
Financial support. None.
Patient consent. This study was approved by the Institutional Review Board of Asan Medical Center, which waived informed consent requirements due to the observational nature of the study.
Contributor Information
Taeeun Kim, Division of Infectious Diseases, Department of Medicine, Nowon Eulji University Hospital, Seoul 01830, Republic of Korea.
Jin Won Huh, Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Sang-Bum Hong, Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Jiwon Jung, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Min Jae Kim, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Yong Pil Chong, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Heungsup Sung, Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Kyung Hyun Doh, Department of Radiology and the Research Institute of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Sung-Han Kim, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Sang-Oh Lee, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Yang Soo Kim, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Chae-Man Lim, Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Younsuck Koh, Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Sang-Ho Choi, Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea.
Supplementary Data
Supplementary materials are available at Open Forum Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
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