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Characteristics, complications, and mortality of respiratory syncytial virus compared with influenza infections in hospitalized adult patients in Thailand

Open AccessPublished:July 21, 2021DOI:https://doi.org/10.1016/j.ijid.2021.07.045

      Highlights

      • RSV is exclusively circulated during the rainy season in Thailand
      • RSV results in less myalgia, less fever, and more wheezing than influenza
      • Pneumonia is the most common pulmonary complication in both RSV and influenza
      • Cardiovascular complications are common in both RSV and influenza
      • Mortality rates are similar in adult hospitalized RSV and influenza

      Abstract

      Introduction

      RSV is increasingly recognized in adults. An improved understanding of clinical manifestations and complications may facilitate diagnosis and management.

      Methods

      This was a retrospective study of hospitalized patients aged ≥ 18 years with RSV or influenza infection at Siriraj hospital, Thailand between January 2014 and December 2017.

      Results

      RSV and/or influenza were detected by RT-PCR in 570 (20.1%) of 2836 patients. After excluding patients coinfected with influenza A and B (n = 5), and with influenza and RSV (n = 3), 141 (5.0%) RSV and 421 (14.8%) influenza patients were analyzed. Over the study period, RSV circulated during the rainy season and peaked in September or October. Patients with RSV were older than patients with influenza and presented significantly less myalgia and fever, but more wheezing. Pneumonia was the most common complication, occurring in 110 (78.0%) of RSV cases and in 295 (70.1%) of influenza cases (p = 0.069). Cardiovascular complications were found in 30 (21.3%) RSV and 96 (22.8%) influenza (p = 0.707), and were reasons for admission in 15 (10.6%) RSV and 50 (11.9%) influenza. The in-hospital mortality rates for RSV (17; 12.1%) and influenza (60; 14.3%) were similar (p = 0.512).

      Conclusions

      In Thailand, RSV is a less common cause of adult hospitalization than influenza, but pulmonary and cardiovascular complications, and mortality are similar. Clinical manifestations cannot reliably distinguish between RSV and influenza infection; laboratory-confirmed diagnosis is needed.

      Keywords

      Background

      Influenza virus is an important cause of adult hospitalization, while respiratory syncytial virus (RSV) infection is becoming increasingly recognized, especially in older adults with comorbidities (
      • Falsey AR
      • McElhaney JE
      • Beran J
      • et al.
      Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ;
      • Olsen SJ
      • Thamthitiwat S
      • Chantra S
      • et al.
      Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.
      ;
      • Walker E
      • Ison MG
      Respiratory viral infections among hospitalized adults: experience of a single tertiary healthcare hospital.
      ). In studies from America, Europe, and Asia, RSV infection represented 2.3% to 13.0% of adult hospitalizations (
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Falsey AR
      • McElhaney JE
      • Beran J
      • et al.
      Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ;
      • Loubet P
      • Lenzi N
      • Valette M
      • et al.
      Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.
      ;
      • Malosh RE
      • Martin ET
      • Callear AP
      • et al.
      Respiratory syncytial virus hospitalization in middle-aged and older adults.
      ;
      • Naorat S
      • Chittaganpitch M
      • Thamthitiwat S
      • et al.
      Hospitalizations for acute lower respiratory tract infection due to respiratory syncytial virus in Thailand, 2008–2011.
      ;
      • Olsen SJ
      • Thamthitiwat S
      • Chantra S
      • et al.
      Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.
      ). These studies confirm that influenza and RSV are important causes of disease, especially in patients with pulmonary and cardiovascular complications. Adults hospitalized with RSV have been shown to have mortality rates similar to (
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ;
      • Loubet P
      • Lenzi N
      • Valette M
      • et al.
      Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.
      ) or higher than (
      • Kwon YS
      • Park SH
      • Kim MA
      • et al.
      Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.
      ;
      • Pastula ST
      • Hackett J
      • Coalson J
      • et al.
      Hospitalizations for respiratory syncytial virus among adults in the United States, 1997–2012.
      ) those with influenza infection. In addition, influenza and RSV display similar seasonality (
      • Bloom-Feshbach K
      • Alonso WJ
      • Charu V
      • et al.
      Latitudinal variations in seasonal activity of influenza and respiratory syncytial virus (RSV): a global comparative review.
      ;
      • Kwon YS
      • Park SH
      • Kim MA
      • et al.
      Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.
      ;
      • Olsen SJ
      • Thamthitiwat S
      • Chantra S
      • et al.
      Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.
      ), making it difficult to distinguish between them without laboratory confirmation.
      Molecular diagnosis with reverse-transcription polymerase chain reaction (RT-PCR) assay can simultaneously identify influenza and RSV, and is a routine procedure in our hospital. There are few studies of adult hospitalized patients with RSV infection (
      • Fry AM
      • Chittaganpitch M
      • Baggett HC
      • et al.
      The burden of hospitalized lower respiratory tract infection due to respiratory syncytial virus in rural Thailand.
      ;
      • Naorat S
      • Chittaganpitch M
      • Thamthitiwat S
      • et al.
      Hospitalizations for acute lower respiratory tract infection due to respiratory syncytial virus in Thailand, 2008–2011.
      ;
      • Olsen SJ
      • Thamthitiwat S
      • Chantra S
      • et al.
      Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.
      ) and no published reports that compare RSV and influenza in adult hospitalized patients in Thailand. An improved understanding of the clinical manifestations and complications of RSV may facilitate awareness, diagnosis, and optimal clinical management. Therefore, our study aimed to evaluate the clinical characteristics, complications, and mortality of RSV compared with influenza among adult hospitalized patients.

      Study design

      Subjects

      Using an electronic medical records database, hospitalized patients aged ≥ 18 years with suspected viral respiratory tract infection, whose clinical specimens had been tested for influenza and/or RSV by RT-PCR at Siriraj Hospital in Bangkok, Thailand between January 2014 and December 2017, were identified. Siriraj Hospital is Thailand's largest tertiary referral center. Patients with laboratory-confirmed RSV or influenza were included in the study. Demographic data, clinical manifestations, laboratory data, and outcomes until discharge or death were collected. The study protocol was approved by the Institutional Review Board of the Faculty of Medicine (COA No. 185/2017).

      Virological methods

      Laboratory analysis for detection of influenza and RSV was performed using real-time RT-PCR. The NucliSENS®easyMag® nucleic acid extraction platform (bioMérieux, Marcy-l'Étoile, France) was used to extract influenza and RSV RNA from 200 µl of patient respiratory sample. Viral RNA was eluted with 80 µl elution buffer. Influenza A (including subtypes H1N1, H1N1pdm09, and H3N2), influenza B, and RSV RNA were identified using the Allplex™ Respiratory Panel 1A Assay (Seegene, Seoul, South Korea). Amplification was performed on a CFX96 Touch Real-Time PCR Detection System (Bio-Rad Laboratories, Hercules, CA, USA). The result was automatically interpreted by Seegene Viewer software (Seegene).

      Definitions

      Fever was defined as a body temperature of ≥ 37.5°C (
      • Falsey AR
      • McElhaney JE
      • Beran J
      • et al.
      Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness.
      ). Immunocompromised status was defined as patients who received current corticosteroids equivalent to > 20 mg/day prednisolone, immunosuppressive drugs, or chemotherapy, or with untreated human immunodeficiency virus (HIV) infection. Pneumonia was diagnosed if patients had new pulmonary infiltrates on chest X-ray, accompanied with fever, cough, and/or dyspnea. Chest X-rays taken within 24 hours of admission were retrieved and independently interpreted by two chest radiologists to confirm the diagnosis of pneumonia. In cases of discordant interpretation, a consensus was reached after discussion. COPD exacerbation was defined as a sustained worsening of the COPD patient's condition beyond normal day-to-day variations, acute onset, and necessitating a change in regular medication (
      • Rodriguez-Roisin R
      Toward a consensus definition for COPD exacerbations.
      ). Asthma exacerbation was defined by changes in symptoms and rescue use that were outside the patient's usual range of day-to-day variation (
      • Reddel HK
      • Taylor DR
      • Bateman ED
      • et al.
      An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice.
      ). Common cold was defined as nasal stuffiness and discharge, sneezing, sore throat, and cough (). Acute bronchitis was diagnosed if patients had acute cough and there was no pneumonia, common cold, or exacerbation of asthma or COPD (
      • Irwin RS
      • Baumann MH
      • Bolser DC
      • et al.
      Diagnosis and management of cough executive summary: ACCP evidence-based clinical practice guidelines.
      ). Hospital-acquired pneumonia (HAP) was pneumonia that had developed ≥ 48 hours after admission without endotracheal intubation. Ventilator-associated pneumonia (VAP) was pneumonia that had developed > 48 hours after endotracheal intubation (
      • Anand N
      • Kollef MH
      The alphabet soup of pneumonia: CAP, HAP, HCAP, NHAP, and VAP.
      ). Cardiovascular complications (acute myocardial infarction, myocarditis, congestive heart failure, and arrhythmia) were diagnosed by cardiologists based on clinical signs, laboratory data, chest X-ray, electrocardiography (ECG), echocardiography, and/or coronary angiography.

      Statistical analysis

      Continuous data with normal distributions were described using mean ± standard deviation (SD). Non-normal data were described using the median and interquartile range (IQR). Categorical data were described as number and percentage. Continuous data that compared two unmatched groups were analyzed using an Unpaired t-test or the Mann-Whitney U-test. One-way analysis of variance (ANOVA) or the Kruskal-Wallis test was used for three or more unmatched groups, as appropriate. The χ2 test or Fisher's exact was used to compared categorical variables. Covariates with a p-value < 0.2 in univariate analysis were first included in multivariate analysis using a backward stepwise logistic regression model to identify factors independently associated with mortality. The results were presented as odds ratio (OR) for univariate analyses and adjusted OR (aOR) for multivariate analyses, with 95% confidence intervals (CI). A p-value < 0.05 was considered statistically significant. PASW Statistics 18.0 (SPSS, Inc., Chicago, IL, USA) was used for statistical analyses.

      Results

      Influenza and/or RSV were detected by RT-PCR in 570 of 2836 adult hospitalized patients between January 2014 and December 2017 (Figure 1). Five patients with influenza A and influenza B coinfection, and three patients with influenza and RSV coinfection were excluded from the analyses. In total, 562 patients were analyzed (421 influenza and 141 RSV). The treating physicians ordered PCR testing for both influenza and RSV in 425 (75.6%) patients, influenza only in 135 (24.0%), and RSV only in 2 (0.4%) of patients (supplementary Table S1). Most positive specimens were obtained from nasopharyngeal washing (399; 71.0%), followed by tracheal suction (131; 23.3%), nasopharyngeal swab (26; 4.6%), sputum (3; 0.5%), throat swab (2; 0.4%), and bronchoalveolar lavage (1; 0.2%).
      Figure 1
      Figure 1Percentages of influenza, influenza subtype (H3N2, H1N1, and B), respiratory syncytial virus (RSV), and their coinfections among adult (age ≥ 18 years) hospitalized patients with suspected viral respiratory tract infection who had respiratory specimens sent to detect influenza and RSV by real-time reverse-transcription polymerase chain reaction (RT-PCR) between January 2014 and December 2017.
      Abbreviations: H3N2, influenza A(H3N2); H1N1, influenza A(H1N1pdm09); B, influenza B
      During 2014−2017, RSV was confirmed in 141 (5.0%) and influenza in 421 (14.8%) of 2836 specimens (p < 0.001). In 2014, there were 36 (7.6%) RSV positive vs 86 (18.1%) influenza positive from 476 specimens. In 2015, there were 21 (3.2%) RSV positive vs 94 (14.2%) influenza positive from 664 specimens. In 2016, there were 40 (5.2%) RSV positive vs 115 (14.9%) influenza positive from 772 specimens. In 2017, there were 44 (4.8%) RSV positive vs 126 (13.6%) influenza positive from 924 specimens. All influenza A(H1N1) cases identified during the study were influenza A(H1N1)pdm09. Influenza A(H3N2) was the most common influenza subtype (Figure 1 and Figure 2A), although influenza A(H1N1)pdm09 predominated in 2014 (Figure 2A). RSV was detected during July to November and overlapped with influenza, whereas influenza was found throughout the year, but with two peak periods (Figure 2B). The unimodal peak for RSV-positive cases in each year was 24.6% (14 of 57 specimens) in September 2014, 13.3% (6 of 45 specimens) in September 2015, 16.8% (17 of 101 specimens) in September 2016, and 11.7% (13 of 111 specimens) in October 2017 (Figure 2B).
      Figure 2
      Figure 2(A) Percentages of influenza A subtypes (H1N1pdm09 and H3N2), influenza B, and respiratory syncytial virus (RSV), and number of respiratory specimens per month. (B) Percentages of influenza (combination of influenza A and influenza B) and RSV, and number of respiratory specimens per month (total n = 2836) detected by RT-PCR, collected in adult hospitalized patients with suspected viral respiratory tract infection between January 2014 and December 2017.

      Clinical characteristics

      Patients with RSV were significantly older than patients with influenza (72 ± 15 years vs 66 ± 18 years, respectively; p < 0.001) (Table 1). Patients with RSV had significantly higher percentages of: pre-existing cardiovascular diseases, with 70 (49.6%) vs 149 (35.4%) (p = 0.003); asthma, with 19 (13.5%) vs 29 (6.9%) (p = 0.015); hematologic malignancy, with 15 (10.6%) vs 19 (4.5%) (p = 0.008); and bedridden status, with 13 (9.2%) vs 17 (4.0%) (p = 0.018) than patients with influenza.
      Table 1Demographic and clinical characteristics of adult hospitalized patients with influenza
      Combined influenza A and influenza B
      and RSV infections (n = 562)
      CharacteristicsInfluenza (n = 421)RSV (n = 141)p-value
      Age (years), mean ± SD66 ± 1872 ± 15<0.001
      Female sex251 (59.6%)92 (65.2%)0.236
      History of contact ARI109 (25.9%)45 (31.9%)0.165
      Annual influenza vaccination48 (11.4%)17 (12.1%)0.833
      Underlying diseases385 (91.4%)139 (98.6%)0.004
      Hypertension259 (61.5%)88 (62.4%)0.851
      Cardiovascular diseases
      Includes coronary artery disease, congestive heart failure, atrial fibrillation, and valvular heart diseases
      149 (35.4%)70 (49.6%)0.003
      Coronary artery disease78 (18.5%)31 (22.0%)0.369
      Congestive heart failure50 (11.9%)21 (14.9%)0.351
      Atrial fibrillation60 (14.3%)33 (23.4%)0.011
      Dyslipidemia170 (40.4%)59 (41.8%)0.759
      Chronic kidney disease135 (32.1%)49 (34.8%)0.556
      Pulmonary diseases
      Includes COPD, asthma, bronchiectasis, and old pulmonary tuberculosis
      115 (27.3%)48 (34.0%)0.128
      COPD39 (9.3%)14 (9.9%)0.815
      Asthma29 (6.9%)19 (13.5%)0.015
      Diabetes mellitus169 (40.1%)41 (29.1%)0.019
      Immunocompromised host
      Includes human immunodeficiency virus (HIV) infection, on immunosuppressive drugs, chemotherapy, or corticosteroid treatment equivalent to > 20 mg/day prednisolone
      60 (14.3%)27 (19.1%)0.164
      Hematologic malignancy
      Includes leukemia, lymphoma, and multiple myeloma Abbreviations: RSV, respiratory syncytial virus; SD, standard deviation; ARI, acute respiratory illness; COPD, chronic obstructive pulmonary disease
      19 (4.5%)15 (10.6%)0.008
      Solid malignancy37 (8.8%)16 (11.3%)0.368
      Bedridden17 (4.0%)13 (9.2%)0.018
      Data presented as number and percentage unless otherwise indicated.
      Combined influenza A and influenza B
      Includes coronary artery disease, congestive heart failure, atrial fibrillation, and valvular heart diseases
      Includes COPD, asthma, bronchiectasis, and old pulmonary tuberculosis
      low asterisk Includes human immunodeficiency virus (HIV) infection, on immunosuppressive drugs, chemotherapy, or corticosteroid treatment equivalent to > 20 mg/day prednisolone
      Includes leukemia, lymphoma, and multiple myelomaAbbreviations: RSV, respiratory syncytial virus; SD, standard deviation; ARI, acute respiratory illness; COPD, chronic obstructive pulmonary disease
      The most common presenting symptoms for patients with RSV were productive cough (93.3%), followed by dyspnea (89.7%), self-reported fever (75.9%), and rhinorrhea (62.8%) (Table 2). On physical examination, patients with RSV had statistically less fever (BT ≥ 37.5°C; 76 (53.9%) RSV vs 298 (70.8%) influenza; p < 0.001) and more wheezing (65.2% (92 of 141) for RSV vs 42.0% (177 of 421) for influenza; p<0.001). After excluding patients with asthma and COPD, 56.3% (63 of 112) of patients with RSV vs 34.1% (126 of 370) of patients with influenza (p < 0.001) had wheezing (Table 2).
      Table 2Clinical presentations and findings for adult hospitalized patients with influenza
      Combined influenza A and influenza B
      and RSV infections (n = 562)
      Presentations and findingsInfluenza (n = 421)RSV (n = 141)p-value
      Onset of symptoms (days), median (IQR)3 (2, 4)3 (2, 5)0.012
      Time to specimen collection (days)
      Duration from symptoms to specimen collection (days), median, IQR
      3 (2, 5)4 (3, 7)0.009
      Symptoms
      Includes pneumonia, acute bronchitis, exacerbation of COPD, and asthma
      Cough96.0 (93.7–97.6)95.5 (90.1–97.9)0.793
      Productive cough85.3 (81.4–88.5)93.3 (87.7–96.4)0.017
      Dyspnea83.4 (79.0–87.0)89.7 (83.1–93.9)0.090
      Self-reported fever87.6 (84.1–90.4)75.9 (68.1–82.3)0.001
      Rhinorrhea63.3 (57.2–69.1)62.8 (52.7–71.9)0.926
      Audible wheezing50.8 (38.6–62.9)55.6 (42.4–68.0)0.612
      Sore throat63.4 (54.6–71.4)36.7 (25.6–49.3)0.001
      Myalgia69.9 (60.9–77.6)32.7 (21.2–46.6)<0.001
      Alteration of consciousness24.1 (19.9–28.8)25.4 (18.7–33.5)0.767
      Nausea/vomiting26.8 (20.4–34.2)15.5 (9.3–24.7)0.047
      Diarrhea17.0 (12.7–22.3)10.8 (5.9–18.7)0.159
      Physical exam
      Fever (BT ≥ 37.5°C) at admission70.8 (66.3–74.9)53.9 (45.7–61.9)<0.001
      Peak BT (°C)
      Within 48 hours after admission ¶Peripheral oxygen saturation (SpO2) ≤ 92% and required oxygen at admission
      , mean ± SD
      38.2 ± 0.938.0 ± 0.90.016
      Initial hypoxemia
      Symptoms (n/total of patients with influenza and RSV who their symptoms were recorded in the medical record): cough (388/404 vs 128/134); sputum (325/381 vs 125/134); dyspnea (281/337 vs 113/126); self-reported fever (368/420 vs 104/137); rhinorrhea (157/248 vs 59/94); audible wheezing (31/61 vs 30/54); sore throat (78/123 vs 22/60); myalgia (79/113 vs 16/49); alteration of consciousness (85/353 vs 33/130); nausea/vomiting (42/157 vs 13/84); diarrhea (39/230 vs 10/93)
      44.7 (40.0–49.5)49.6 (41.5–57.8)0.312
      Wheezing
      Wheezing was found in 177 influenza and 92 RSV
      42.0 (37.4–46.8)65.2 (57.1–72.6)<0.001
      Wheezing excluding COPD or asthma
      After excluding 30 COPD and 21 asthma in influenza; 13 COPD and 16 asthma in RSV
      34.1 (29.4–39.0)56.3 (47.0–65.1)<0.001
      Complete blood counts
      After excluding hematologic malignancy or on immunosuppressive drugs or with bacterial coinfection: 336 influenza, 107 RSV Abbreviations: RSV, respiratory syncytial virus; CI, confidence interval; IQR, interquartile range; BT, body temperature;°C, degrees Celsius; SD, standard deviation; WBC, white blood cells
      WBC (cells/mm3), median (IQR)7,910 (5610–11 120)8,750 (6210–11 880)0.135
      Lymphocytes < 1000 cells/mm351.2 (45.9–56.5)34.6 (26.2–44.0)0.003
      Antibiotic treatment on admission88.8 (85.5–91.5)91.5 (85.7–95.1)0.374
      Oseltamivir treatment on admission98.6 (96.9–99.3)69.5 (61.5–76.5)<0.001
      Data presented as % (95% CI) unless otherwise indicated
      Combined influenza A and influenza B
      Duration from symptoms to specimen collection (days), median, IQR
      Symptoms (n/total of patients with influenza and RSV who their symptoms were recorded in the medical record): cough (388/404 vs 128/134); sputum (325/381 vs 125/134); dyspnea (281/337 vs 113/126); self-reported fever (368/420 vs 104/137); rhinorrhea (157/248 vs 59/94); audible wheezing (31/61 vs 30/54); sore throat (78/123 vs 22/60); myalgia (79/113 vs 16/49); alteration of consciousness (85/353 vs 33/130); nausea/vomiting (42/157 vs 13/84); diarrhea (39/230 vs 10/93)
      Within 48 hours after admission¶Peripheral oxygen saturation (SpO2) ≤ 92% and required oxygen at admission
      a Wheezing was found in 177 influenza and 92 RSV
      b After excluding 30 COPD and 21 asthma in influenza; 13 COPD and 16 asthma in RSV
      low asterisk After excluding hematologic malignancy or on immunosuppressive drugs or with bacterial coinfection: 336 influenza, 107 RSVAbbreviations: RSV, respiratory syncytial virus; CI, confidence interval; IQR, interquartile range; BT, body temperature;°C, degrees Celsius; SD, standard deviation; WBC, white blood cells
      Most respiratory specimens for PCR testing (549; 97.7%) were ordered after admission. Among patients with RSV, the median time interval between admission to reported result was 40.5 hours (IQR 35.9–47.6 hours), and from laboratory receipt of the specimen to result was 32.8 hours (IQR 22.0–38.2 hours) (supplementary Table S2). On admission, 98 (69.5%) of patients with RSV received oseltamivir and 129 (91.5%) received antibiotics (Table 2). When a diagnosis of RSV was established, oseltamivir was stopped in 80.6% (79 of 98) of patients and 19.4% of the patients continued treatment for a 5-day course. However, antibiotic treatment was continued in 58.9% (76 of 129) of patients, with a median duration of 7 days (IQR 5–8 days), with only 13.1% (10 of 76) having a culture-confirmed bacterial infection. Length of stay in patients with RSV was significantly longer than those in patients with influenza, with medians of 9 days (IQR 5–15 days) and 7 days (IQR 4–15 days), respectively; p = 0.037 (Table 3).
      Table 3Complications and mortality compared among adult hospitalized patients with influenza
      Combined influenza A and influenza B
      and RSV infections (n = 562)
      VariablesInfluenza (n = 421)RSV (n = 141)p-value
      n
      Number of patients in a given category
      %(95%CI)n
      Number of patients in a given category
      % (95%CI)
      CXR within 24 h of admission41398.1 (96.3–99.0)14099.3(96.1- 99.9)0.462
      Pulmonary complications
      Includes pneumonia, acute bronchitis, exacerbation of COPD, and asthma
      40095.0 (92.5–96.7)13897.9 (94.0–99.3)0.146
      Pneumonia29570.1 (65.5–74.3)11078.0 (70.5–84.1)0.069
      Acute bronchitis10524.9 (21.1–29.3)2618.4(12.9–25.7)0.114
      COPD exacerbation
      Some patients had exacerbation and pneumonia
      276.4 (4.4–9.2)117.8(4.4–13.4)0.570
      Asthma exacerbation
      Some patients had exacerbation and pneumonia
      184.3 (2.3–6.7)1510.6(6.6–16.8)0.005
      CXR findings of pneumonia
      Number of CXR: influenza pneumonia, 295; RSV pneumonia, 110
      Interstitial infiltrations17459.0 (53.3–64.4)6559.1(49.6–67.8)0.984
      Interstitial and alveolar8328.1 (23.3–33.5)3229.1(21.4–38.2)0.850
      Alveolar infiltrations3812.9 (9.5–17.2)1311.8(7.0–19.2)0.774
      Initial coinfection with bacteria317.4 (5.2 –10.3)107.1 (3.9–12.6)0.915
      Hypoxemia during admission
      eripheral oxygen saturation (SpO2) ≤ 92% and requiring oxygen during admission
      24458.0 (53.2–62.6)8862.4(54.2–70.0)0.352
      On non-invasive ventilation (NIV)102.4 (1.3–4.3)42.8 (1.1–7.1)0.758
      On invasive mechanical ventilation13231.4 (27.1–35.9)3927.7 (20.9–35.6)0.409
      HAP194.5 (2.9–6.9)32.1 (0.7–6.1)0.206
      VAP5813.8 (10.8–17.4)1510.6 (6.6–16.8)0.337
      Cardiovascular complications
      Includes CHF, acute MI, myocarditis, new-onset AF, SVT, VT, VF, and sinus bradyarrhythmia a+bSome patients had both pulmonary and cardiovascular complications *Acute MI had concomitant CHF in 16 of 22 (72.7%) of influenza, 8 of 11 (72.7%) of RSV
      9622.8 (19.1–27.0)3021.3 (15.3–28.8)0.707
      Congestive heart failure (CHF)7016.6 (13.4–20.5)2517.7 (12.3–24.9)0.762
      Worsening of CHF4210.0 (7.5–13.2)1611.3 (7.1–17.6)0.643
      New onset of CHF286.7 (4.6–9.4)96.4 (3.4 –11.7)0.912
      Acute MI
      Number of patients in a given category
      225.2(3.5–7.8)117.8 (4.4–13.4)0.260
      First diagnosis of MI174.0 (2.5–6.4)42.8 (1.1–7.1)0.617
      Acute MI with CHF163.8 (2.4–6.1)85.7 (2.9–10.8)0.341
      Cardiac arrhythmia
      Cardiac arrhythmia included new-onset AF, SVT, VT, VF, and sinus bradyarrhythmia Abbreviations: RSV, respiratory syncytial virus; CXR, chest X-ray; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; MI, myocardial infarction; AF, atrial fibrillation; SVT, supraventricular tachycardia; VT, ventricular tachycardia; VF, ventricular fibrillation; LOS, length of stay; VAP, ventilator-associated pneumonia; HAP, hospital-acquired pneumonia
      307.1 (5.0-10.0)53.6 (1.5–8.0)0.159
      New onset AF163.8 (2.4–6.1)21.4 (0.4–5.0)0.267
      SVT81.9 (1.0–3.7)10.7 (0.1–3.9)0.462
      Acute kidney injury10925.9 (21.9–30.3)2819.9 (14.1–27.2)0.149
      Septic shock4610.9 (8.3–14.3)117.8 (4.4–13.4)0.287
      LOS, days, median (IQR)7 (4, 15)9 (5, 15)0.043
      Mortality rate6014.3 (11.2–17.9)1712.1 (7.7–18.5)0.512
      VAP3558.3 (45.7–69.9)847.1 (26.2–69.0)0.409
      HAP711.7 (5.8–22.2)15.9 (1.1–27.0)0.676
      Cardiac death1321.7 (13.1–33.6)211.8 (3.3–34.3)0.499
      Combined influenza A and influenza B
      low asterisk Number of patients in a given category
      a Includes pneumonia, acute bronchitis, exacerbation of COPD, and asthma
      Some patients had exacerbation and pneumonia
      Number of CXR: influenza pneumonia, 295; RSV pneumonia, 110
      eripheral oxygen saturation (SpO2) ≤ 92% and requiring oxygen during admission
      b Includes CHF, acute MI, myocarditis, new-onset AF, SVT, VT, VF, and sinus bradyarrhythmiaa+bSome patients had both pulmonary and cardiovascular complications*Acute MI had concomitant CHF in 16 of 22 (72.7%) of influenza, 8 of 11 (72.7%) of RSV
      low asterisklow asterisk Cardiac arrhythmia included new-onset AF, SVT, VT, VF, and sinus bradyarrhythmiaAbbreviations: RSV, respiratory syncytial virus; CXR, chest X-ray; COPD, chronic obstructive pulmonary disease; CHF, congestive heart failure; MI, myocardial infarction; AF, atrial fibrillation; SVT, supraventricular tachycardia; VT, ventricular tachycardia; VF, ventricular fibrillation; LOS, length of stay; VAP, ventilator-associated pneumonia; HAP, hospital-acquired pneumonia

      Pulmonary complications

      Pulmonary complications did not differ between patients with RSV (138; 97.9%) and those with influenza (400; 95.0%) (p = 0.146) (Table 3). Pneumonia was the most common complication, and the predominant finding on chest X-ray was interstitial infiltration — 59.1% (65 of 110) had interstitial infiltration alone and 29.1% (32 of 110) had mixed interstitial and alveolar infiltration. Ten (7.1%) of the RSV infections had bacterial coinfection on admission, all of which were confirmed by sputum Gram stain and culture for bacteria (Table 3; supplementary Table S3). Hypoxemia (SpO2 ≤ 92%) requiring oxygen supplement during admission was found in 91 (64.5%) of patients. Patients with RSV required invasive mechanical ventilation in 39 (27.7%) and non-invasive ventilation (NIV) in 4 (2.8%) cases. Hospital-acquired pneumonia (HAP) occurred in 3 (2.1%) patients, and ventilator-associated pneumonia (VAP) developed in 15 (10.6%) patients (Table 3). All patients with HAP and VAP had sputum Gram's stain, bacterial culture, and hemoculture for bacteria performed (supplementary Table S4). The most common secondary bacterial cause of HAP, VAP, and septic shock was Acinetobacter baumannii.

      Cardiovascular complications

      Cardiovascular complications did not differ between patients with RSV (30; 21.3%) and those with influenza (96; 22.8%) (p = 0.707) (Table 3). Patients with cardiovascular complications had high rates of pre-existing cardiovascular diseases — 80% (24 of 30) for RSV vs 60.4% (58 of 96) for influenza (p = 0.050). Worsening or new onset of cardiovascular complications was the reason for admission in 15 (10.6%) of RSV patients and 50 (11.9%) of influenza cases. CHF was the most common cause of admission, followed by acute MI, in both groups.
      In patients with RSV, CHF was the most common cardiovascular complication (25; 17.7%), followed by acute MI (11; 7.8%), and cardiac arrhythmia (5; 3.6%) (Table 3). All acute MI in patients with RSV was non-ST-segment elevation MI (NSTEMI). Acute MI with concomitant CHF was found in 72.7% (8 of 11) of acute MI patients. All first acute MI in patients with RSV had known risk factors of coronary arterial disease (DM, HT, and/or DLP).

      Factors associated with in-hospital mortality

      In-hospital mortality of patients with RSV did not differ from that in those with influenza — 17 (12.1%) and 60 (14.3%), respectively; p = 0.512 (Table 3), with mean ages 75.9 ± 11.6 years (range 58−95) for RSV and 70.6 ± 16.6 years (range 21−96) for influenza; p = 0.222. The most common cause of death in patients with RSV was pulmonary complications (47.1% VAP and 5.9% HAP) followed by 11.8% cardiac complications, with similar results for those with influenza.
      The multivariate analyses (Table 4) found that in patients with influenza or RSV who had pulmonary complications, septic shock, and cardiac complications were associated with increased mortality. Patients with pneumonia on admission (adjusted OR [aOR]: 3.69, 95% CI: 1.11−12.34, p = 0.034), HAP (aOR: 3.81, 95% CI: 1.26−11.49, p = 0.018), on a mechanical ventilator but without VAP (aOR: 2.48, 95% CI: 1.05−5.84, p = 0.038), on a mechanical ventilator and with VAP (aOR: 15.02, 95% CI: 6.46−34.92, p < 0.001), septic shock during admission (aOR: 4.88, 95% CI: 2.28−10.43, p < 0.001), and new onset of cardiac arrhythmia (aOR: 2.51, 95% CI: 1.20−5.26, p = 0.015) were significantly associated with increased mortality. Patients aged ≥ 55 years were associated with mortality on univariate analyses, but not on multivariate analyses (aOR: 1.82, 95% CI: 0.68−4.90, p = 0.234).
      Table 4Univariate and multivariate analyses for factors associated with mortality in adult hospitalized patients with influenza and RSV infections (total n = 562)
      VariablesUnivariate analysisMultivariate analyses
      OR (95% CI)p-value
      Variables with a p-value < 0.2 in univariate analysis were included in multivariate analysis A p-value < 0.05 in multivariate analysis indicates statistical significance
      Adjusted OR (95% CI)p-value
      Age ≥ 55 years2.44 (1.14–5.24)0.0221.82 (0.68–4.90)0.234
      Sex, male1.36 (0.84–2.21)0.210
      Underlying diseases
      Pulmonary diseases
      Includes chronic obstructive pulmonary disease, asthma, bronchiectasis, and old pulmonary tuberculosis
      1.69 (1.03–2.78)0.040
      COPD1.76 (0.86–3.58)0.121
      Bronchiectasis1.70 (0.62–4.70)0.304
      Old pulmonary tuberculosis1.97 (0.86–4.50)0.110
      Cardiovascular disease1.64 (1.01–2.65)0.046
      Coronary artery disease1.48 (0.85–2.58)0.169
      Congestive heart failure1.90 (1.04–3.46)0.036
      Hematologic malignancy
      Includes leukemia, lymphoma, and multiple myeloma
      1.70 (0.75–3.85)0.204
      Bedridden2.01 (0.83–4.86)0.121
      Blood lymphocytes < 1000 cells/mm31.84 (1.12–3.03)0.016
      Pulmonary complications
      Pneumonia on admission8.33 (2.99–23.21)< 0.0013.69 (1.11–12.34)0.034
      Hypoxemia4.42 (2.33–8.40)< 0.0012.29 (0.79–6.61)0.126
      HAP3.90 (1.58–9.64)0.0033.81 (1.26–11.49)0.018
      No MV, no VAP11
      MV without VAP7.93 (3.81–16.52)< 0.0012.48 (1.05–5.84)0.038
      MV with VAP41.68 (20.22–85.90)< 0.00115.02 (6.46–34.92)< 0.001
      Septic shock19.40 (10.38– 36.27)< 0.0014.88 (2.28–10.43)<0.001
      Cardiovascular complications
      New cardiac arrhythmia
      Includes new atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and sinus bradyarrhythmia
      5.50 (3.18–9.52)< 0.0012.51 (1.20–5.26)0.015
      New atrial fibrillation5.51 (2.10–14.43)0.001
      SVT3.24 (0.79–13.22)0.102
      VT or VF9.79 (1.61–59.58)0.013
      Acute MI2.13 (0.93–4.92)0.075
      CHF
      Worsening or new-onset congestive heart failure Abbreviations: RSV, respiratory syncytial virus; COPD, chronic obstructive pulmonary disease; VAP, ventilator-associated pneumonia; HAP, hospital-acquired pneumonia; SVT, supraventricular tachycardia; VT, ventricular tachycardia; VF, ventricular fibrillation; MI, myocardial infarction; CHF, congestive heart failure; OR, odds ratio; 95% CI, 95% confidence interval
      1.92 (1.09–3.38)0.024
      # Variables with a p-value < 0.2 in univariate analysis were included in multivariate analysisA p-value < 0.05 in multivariate analysis indicates statistical significance
      Includes chronic obstructive pulmonary disease, asthma, bronchiectasis, and old pulmonary tuberculosis
      low asterisk Includes leukemia, lymphoma, and multiple myeloma
      Includes new atrial fibrillation, supraventricular tachycardia, ventricular tachycardia, ventricular fibrillation, and sinus bradyarrhythmia
      Worsening or new-onset congestive heart failureAbbreviations: RSV, respiratory syncytial virus; COPD, chronic obstructive pulmonary disease; VAP, ventilator-associated pneumonia; HAP, hospital-acquired pneumonia; SVT, supraventricular tachycardia; VT, ventricular tachycardia; VF, ventricular fibrillation; MI, myocardial infarction; CHF, congestive heart failure; OR, odds ratio; 95% CI, 95% confidence interval

      RSV vs influenza subtypes

      Clinical characteristics, complications, and outcomes of RSV and influenza subtype [A(H1N1pdm09), A(H3N2) and B] infections were compared (Table 5). Most patients with RSV were aged ≥ 65 years (104; 73.8%). The mean age of patients with RSV (72 ± 15 years) did not differ from that for influenza A(H3N2) (70 ± 18 years) (p = 1.000), and was significantly older than patients with influenza B (65 ± 18 years; p = 0.005) and influenza A(H1N1pdm09) (60 ± 17 years, p < 0.001). Patients with RSV had a significantly higher rate of underlying diseases, less myalgia, and less fever (BT ≥ 37.5°C), but more wheezing than those with influenza subtypes A(H1N1pdm09), A(H3N2), and B. Pneumonia, cardiovascular complications, and mortality rates for RSV and influenza subtypes were not significantly different.
      Table 5Clinical characteristics, complications, and outcomes for adult hospitalized patients with RSV and influenza subtype infections (total n = 562).
      CharacteristicsInfluenza subtype (total n = 421)RSV (n = 141)p-value
      B (n=97)H1N1 (n=108)H3N2 (n=216)All
      Compared among four groups: influenza B, influenza A(H1N1pdm09), influenza A(H3N2), and RSV
      vs RSV
      RSV compared with influenza subtype (influenza B, influenza A(H1N1pdm09), influenza A(H3N2))
      BH1N1H3N2
      Age (years), mean ± SD65±1860±1770±1872±15<0.0010.005<0.0011.000
      Age, years<0.001
      18–4919 (19.6%)27 (25.0%)29 (13.4%)12 (8.5%)0.013<0.0010.154
      50–6419 (19.6%)37 (34.3%)38 (17.6%)25 (17.7%)0.7170.0030.973
      65–7935 (36.1%)30 (27.8%)67 (31.0%)53 (37.6%)0.8130.1040.199
      ≥ 8024 (24.7%)14 (13.0%)82 (38.0%)51 (36.2%)0.062<0.0010.732
      Underlying diseases90 (92.8%)95 (88.0%)200 (92.6%)139 (98.6%)0.0100.034<0.0010.011
      Cardiovascular diseases
      Includes coronary artery disease, congestive heart failure, atrial fibrillation, and valvular heart diseases
      30 (30.9%)30 (27.8%)89 (41.2%)70 (49.6%)0.0010.004<0.0010.117
      Pulmonary diseases
      Includes COPD, asthma, bronchiectasis, and old pulmonary tuberculosis
      26 (26.8%)32 (29.6%)57 (26.4%)48 (34.0%)0.4400.2360.4600.121
      Diabetes mellitus45 (46.4%)43 (39.8%)81 (37.5%)41 (29.1%)0.0490.0060.0760.101
      Hematologic malignancy
      Includes leukemia, lymphoma, and multiple myeloma
      5 (5.2%)7 (6.5%)7(3.2%)15 (10.6%)0.0390.1350.2520.004
      Symptoms
      Symptoms (n/total of patients with influenza subtype and RSV whose symptoms were found in the medical record): - B: cough (89/95); sputum (77/93); dyspnea (62/77); reported fever (76/96); sore throat (20/28); myalgia (14/21); N/V (7/33) - H1N1: cough (97/101); sputum (79/98); dyspnea (77/87); reported fever (92/108); sore throat (17/32); myalgia (26/34); N/V (13/29) - H3N2: cough (202/208); sputum (169/190); dyspnea (142/173); reported fever (200/216); sore throat (41/63); myalgia (39/58); N/V (22/95) - RSV: cough (128/134); sputum (125/134); dyspnea (113/126); reported fever (104/137); sore throat (22/60); myalgia (16/49); N/V (13/84)
      Cough93.7%96.0%97.1%95.5%0.5290.5390.8460.434
      Sputum82.8%80.6%88.9%93.3%0.0150.0130.0030.185
      Dyspnea80.5%88.5%82.1%89.7%0.1450.0660.7860.067
      Reported fever79.2%85.2%92.6%75.9%<0.0010.4350.046<0.001
      Sore throat71.4%53.1%65.1%36.7%0.0030.0020.1280.002
      Myalgia66.7%76.5%67.2%32.7%<0.0010.008<0.001<0.001
      Nausea/vomiting (N/V)21.2%44.8%23.2%15.5%0.0140.4580.0010.196
      Physical examination
      BT ≥ 37.5°C at admission66 (68.0%)75 (69.4%)157 (72.7%)76 (53.9%)0.0030.0290.013<0.001
      Wheezing41 (42.3%)41 (38.0%)95 (44.0%)92 (65.2%)<0.001<0.001<0.001<0.001
      Wheezing excluding COPD and asthma, % (n/total)33.3% (28/84)28.7% (27/94)37.0% (71/192)56.3% (63/112)<0.0010.001<0.0010.001
      Blood lymphocytes < 1000 cells/mm333 (44.0%)49 (59.0%)90 (50.6%)37 (34.6)0.0060.1990.0010.009
      Complications
      Pneumonia65 (67.0%)81 (75.0%)150 (69.4%)110 (78.0%)0.1780.0590.5770.075
      Cardiovascular complications
      Includes worsening or new-onset CHF, acute MI, new AF, SVT, ventricular tachycardia or fibrillation, cardiogenic shock Abbreviations: B, influenza B; H1N1, influenza A(H1N1pdm09); H3N2, influenza A(H3N2); RSV, respiratory syncytial virus; BT, body temperature; COPD, chronic obstructive pulmonary disease
      25 (25.8%)20 (18.5%)51 (23.6%)30 (21.3%)0.6030.4190.5900.607
      Mortality rate17 (17.5%)18 (16.7%)25 (11.6%)17 (12.1%)0.3690.2360.3000.890
      Data presented as number and percentage unless otherwise indicated
      Compared among four groups: influenza B, influenza A(H1N1pdm09), influenza A(H3N2), and RSV
      RSV compared with influenza subtype (influenza B, influenza A(H1N1pdm09), influenza A(H3N2))
      a Includes coronary artery disease, congestive heart failure, atrial fibrillation, and valvular heart diseases
      b Includes COPD, asthma, bronchiectasis, and old pulmonary tuberculosis
      c Includes leukemia, lymphoma, and multiple myeloma
      Symptoms (n/total of patients with influenza subtype and RSV whose symptoms were found in the medical record):- B: cough (89/95); sputum (77/93); dyspnea (62/77); reported fever (76/96); sore throat (20/28); myalgia (14/21); N/V (7/33)- H1N1: cough (97/101); sputum (79/98); dyspnea (77/87); reported fever (92/108); sore throat (17/32); myalgia (26/34); N/V (13/29)- H3N2: cough (202/208); sputum (169/190); dyspnea (142/173); reported fever (200/216); sore throat (41/63); myalgia (39/58); N/V (22/95)- RSV: cough (128/134); sputum (125/134); dyspnea (113/126); reported fever (104/137); sore throat (22/60); myalgia (16/49); N/V (13/84)
      Includes worsening or new-onset CHF, acute MI, new AF, SVT, ventricular tachycardia or fibrillation, cardiogenic shockAbbreviations: B, influenza B; H1N1, influenza A(H1N1pdm09); H3N2, influenza A(H3N2); RSV, respiratory syncytial virus; BT, body temperature; COPD, chronic obstructive pulmonary disease

      Discussion

      RSV was detected by RT-PCR in 5.0% of 2836 adult hospitalized patients with suspected respiratory viral infection during a 4-year period (2014−2017), which was significantly lower than for influenza (14.8%, p < 0.001). Our result was consistent with a prospective study conducted in two rural provinces of Thailand during a 3-year period (2003−2005) (
      • Olsen SJ
      • Thamthitiwat S
      • Chantra S
      • et al.
      Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.
      ). That study reported an incidence of RSV of 2.9% (63 of 2177 patients), which was lower than for influenza A and B, at 13.4% (293 of 2177 patients) in adult (aged ≥ 18 years) hospitalized patients with pneumonia diagnosed by clinical symptoms or chest X-ray. According to the literature, the reported rate of adult hospitalized patients ranges from 2.3% to 13.0% for RSV, and from 6.5% to 39.0% for influenza (
      • Chittaganpitch M
      • Waicharoen S
      • Yingyong T
      • et al.
      Viral etiologies of influenza-like illness and severe acute respiratory infections in Thailand.
      ;
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Falsey AR
      • McElhaney JE
      • Beran J
      • et al.
      Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness.
      ;
      • Kestler M
      • Munoz P
      • Mateos M
      • et al.
      Respiratory syncytial virus burden among adults during flu season: an underestimated pathology.
      ;
      • Loubet P
      • Lenzi N
      • Valette M
      • et al.
      Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.
      ;
      • Malosh RE
      • Martin ET
      • Callear AP
      • et al.
      Respiratory syncytial virus hospitalization in middle-aged and older adults.
      ;
      • Olsen SJ
      • Thamthitiwat S
      • Chantra S
      • et al.
      Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.
      ;
      • Widmer K
      • Zhu Y
      • Williams JV
      • et al.
      Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults.
      ). These differences are probably due to different study populations, age groups, study years, geographical regions, and laboratory methods (
      • Chittaganpitch M
      • Waicharoen S
      • Yingyong T
      • et al.
      Viral etiologies of influenza-like illness and severe acute respiratory infections in Thailand.
      ;
      • Haynes AK
      • Manangan AP
      • Iwane MK
      • et al.
      Respiratory syncytial virus circulation in seven countries with Global Disease Detection Regional Centers.
      ;
      • Olsen SJ
      • Thamthitiwat S
      • Chantra S
      • et al.
      Incidence of respiratory pathogens in persons hospitalized with pneumonia in two provinces in Thailand.
      ).
      Winter peaks of RSV infection have been reported in temperate countries, and during the rainy season in tropical countries (
      • Chadha M
      • Hirve S
      • Bancej C
      • et al.
      Human respiratory syncytial virus and influenza seasonality patterns — early findings from the WHO global respiratory syncytial virus surveillance.
      ;
      • Haynes AK
      • Manangan AP
      • Iwane MK
      • et al.
      Respiratory syncytial virus circulation in seven countries with Global Disease Detection Regional Centers.
      ;
      • Obando-Pacheco P
      • Justicia-Grande AJ
      • Rivero-Calle I
      • et al.
      Respiratory syncytial virus seasonality: a global overview.
      ;
      • Pangesti KNA
      • El Ghany MA
      • Kesson AM
      • et al.
      Respiratory syncytial virus in the Western Pacific region: a systematic review and meta-analysis.
      ). Our study showed that RSV circulated during the rainy season with a unimodal peak in either September or October, which was similar to other surveillance studies in Thailand (
      • Chittaganpitch M
      • Waicharoen S
      • Yingyong T
      • et al.
      Viral etiologies of influenza-like illness and severe acute respiratory infections in Thailand.
      ;
      • Naorat S
      • Chittaganpitch M
      • Thamthitiwat S
      • et al.
      Hospitalizations for acute lower respiratory tract infection due to respiratory syncytial virus in Thailand, 2008–2011.
      ;
      • Thongpan I
      • Vongpunsawad S
      • Poovorawan Y
      Respiratory syncytial virus infection trend is associated with meteorological factors.
      ). Seasonality during the rainy season was similar to many others tropical countries of Asia and America (
      • Chadha M
      • Hirve S
      • Bancej C
      • et al.
      Human respiratory syncytial virus and influenza seasonality patterns — early findings from the WHO global respiratory syncytial virus surveillance.
      ;
      • Haynes AK
      • Manangan AP
      • Iwane MK
      • et al.
      Respiratory syncytial virus circulation in seven countries with Global Disease Detection Regional Centers.
      ;
      • Obando-Pacheco P
      • Justicia-Grande AJ
      • Rivero-Calle I
      • et al.
      Respiratory syncytial virus seasonality: a global overview.
      ;
      • Pangesti KNA
      • El Ghany MA
      • Kesson AM
      • et al.
      Respiratory syncytial virus in the Western Pacific region: a systematic review and meta-analysis.
      ).
      The interval time from admission to PCR-confirmed diagnosis of RSV was 40.5 hours (IQR 35.9–47.6 hours), which was longer than found in a previous study, which reported a mean (SD) of 16.4 (13.7) hours (
      • Lee N
      • Walsh EE
      • Sander I
      • et al.
      Delayed diagnosis of respiratory syncytial virus infections in hospitalized adults: individual patient data, record review analysis and physician survey in the United States.
      ). Our study found the slowest part of the process to be PCR assays performed in batches on a once-a-day schedule. This led to prolonged and unnecessary antiviral and antibiotic prescriptions.

      Clinical characteristics

      Consistent with previous studies (
      • Ackerson B
      • Tseng HF
      • Sy LS
      • et al.
      Severe morbidity and mortality associated with respiratory syncytial virus versus influenza infection in hospitalized older adults.
      ;
      • Chen L
      • Han X
      • Bai L
      • et al.
      Clinical characteristics and outcomes in adult patients hospitalized with influenza, respiratory syncytial virus and human metapneumovirus infections.
      ;
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ), adult hospitalized patients with RSV were older and had higher rates of comorbidities than those with influenza (Table 1). However among the influenza subtypes, the age of patients with influenza A(H3N2) was similar to those with RSV, which were both significantly older than those with influenza A(H1N1pdm09) and influenza B (Table 5). Similarly to previous studies, RSV cases had less myalgia (
      • Chen L
      • Han X
      • Bai L
      • et al.
      Clinical characteristics and outcomes in adult patients hospitalized with influenza, respiratory syncytial virus and human metapneumovirus infections.
      ) and less fever (
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ;
      • Kwon YS
      • Park SH
      • Kim MA
      • et al.
      Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ;
      • Walsh EE
      • Peterson DR
      • Falsey AR
      Is clinical recognition of respiratory syncytial virus infection in hospitalized elderly and high-risk adults possible?.
      ), but more wheezing (
      • Dowell SF
      • Anderson LJ
      • Gary Jr, HE
      • et al.
      Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults.
      ;
      • Falsey AR
      • McElhaney JE
      • Beran J
      • et al.
      Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ;
      • Walsh EE
      • Peterson DR
      • Falsey AR
      Is clinical recognition of respiratory syncytial virus infection in hospitalized elderly and high-risk adults possible?.
      ) than those with influenza. These clinical manifestations were significantly different between RSV and influenza subtypes [A(H1N1pdm09), A(H3N2), and B]. However, these clinical characteristics are not specific for RSV and laboratory confirmation is needed. In our study, most physicians ordered PCR testing for both influenza and RSV. However, in some cases the physician ordered only an influenza test to confirm the clinical diagnosis, but the laboratory result indicated that the patient was RSV-positive (supplementary Table S1). In addition, the physicians rarely ordered RSV testing alone (0.4%), which was similar to a report by Lee et al. (
      • Lee N
      • Walsh EE
      • Sander I
      • et al.
      Delayed diagnosis of respiratory syncytial virus infections in hospitalized adults: individual patient data, record review analysis and physician survey in the United States.
      ) in which only 17 of 379 (4.5%) RSV patients had been tested only for RSV. This could be due to a lack of incentive for RSV diagnosis, because no specific treatments exist for this virus. In order to improve awareness and to recognize the burdens of RSV infection in clinical practice, a bundled PCR assay that includes both influenza and RSV may be desirable.

      Pulmonary complications

      The percentage of pneumonia in patients with RSV (78.0%) and influenza (70.1%) was not significantly different and was higher than previous studies (30%−44% of RSV and 20%−54% of influenza) (
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ;
      • Dowell SF
      • Anderson LJ
      • Gary Jr, HE
      • et al.
      Respiratory syncytial virus is an important cause of community-acquired lower respiratory infection among hospitalized adults.
      ;
      • Falsey AR
      • Cunningham CK
      • Barker WH
      • et al.
      Respiratory syncytial virus and influenza A infections in the hospitalized elderly.
      ;
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Kwon YS
      • Park SH
      • Kim MA
      • et al.
      Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ;
      • Loubet P
      • Lenzi N
      • Valette M
      • et al.
      Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.
      ). The rates of acute respiratory failure requiring mechanical ventilation in patients with RSV (30.5%) and influenza (33.5%) were also higher than previous studies that ranged from 3.4% to 20.0% for RSV and 2.2% to 10.0% for influenza (
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ;
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Kwon YS
      • Park SH
      • Kim MA
      • et al.
      Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ).

      Cardiovascular complications

      The prevalences of cardiovascular complications in patients with RSV (21.3%) and influenza (22.8%) infections were not significantly different (Table 3), which was in line with previous studies — 14.3–29.4% for RSV and 13.3–22.2% for influenza (
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ). Cardiovascular complications can develop in patients with or without pre-existing cardiovascular diseases (
      • Ivey KS
      • Edwards KM
      • Talbot HK
      Respiratory syncytial virus and associations with cardiovascular disease in adults.
      ). Patients with cardiovascular complications were found to have high rates of pre-existing cardiovascular diseases (80.0% for RSV vs 60.4% for influenza), while earlier studies have reported 45.3–63.4% for RSV and 41.0–63.0% for influenza patients (
      • Falsey AR
      • Cunningham CK
      • Barker WH
      • et al.
      Respiratory syncytial virus and influenza A infections in the hospitalized elderly.
      ;
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Loubet P
      • Lenzi N
      • Valette M
      • et al.
      Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.
      ;
      • Widmer K
      • Zhu Y
      • Williams JV
      • et al.
      Rates of hospitalizations for respiratory syncytial virus, human metapneumovirus, and influenza virus in older adults.
      ). CHF was the most common cardiovascular complication, with no difference between RSV and influenza (17.7% of RSV vs 16.6% of influenza; p = 0.762); this was in line with most other studies, which have reported 12.9–20.0% for RSV vs 10.4–16.2% for influenza (
      • Falsey AR
      • Cunningham CK
      • Barker WH
      • et al.
      Respiratory syncytial virus and influenza A infections in the hospitalized elderly.
      ;
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Loubet P
      • Lenzi N
      • Valette M
      • et al.
      Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.
      ). In contrast, Cohen et al. (
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ) reported a significantly higher percentage of CHF in patients with RSV (14.1% for RSV vs 7.5% for influenza (A and B); p = 0.04).

      Factors associated with in-hospital mortality

      In-hospital mortality rates were not significantly different between patients with RSV (12.1%) and those with influenza (14.3%), and were similar to those found in previous studies (
      • Falsey AR
      • Hennessey PA
      • Formica MA
      • et al.
      Respiratory syncytial virus infection in elderly and high-risk adults.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ;
      • Loubet P
      • Lenzi N
      • Valette M
      • et al.
      Clinical characteristics and outcome of respiratory syncytial virus infection among adults hospitalized with influenza-like illness in France.
      ). However, some studies have reported higher mortality rates in RSV patients than in those with influenza (
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ;
      • Kestler M
      • Munoz P
      • Mateos M
      • et al.
      Respiratory syncytial virus burden among adults during flu season: an underestimated pathology.
      ;
      • Kwon YS
      • Park SH
      • Kim MA
      • et al.
      Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.
      ;
      • Pastula ST
      • Hackett J
      • Coalson J
      • et al.
      Hospitalizations for respiratory syncytial virus among adults in the United States, 1997–2012.
      ). These findings confirm that adult patients with RSV infection have a mortality rate at least as high as patients with influenza infection. Previous studies have demonstrated that advanced age, hematologic malignancy, pneumonia, and being on mechanical ventilation were associated with mortality (
      • Cohen R
      • Babushkin F
      • Geller K
      • et al.
      Characteristics of hospitalized adult patients with laboratory documented Influenza A, B and respiratory syncytial virus — a single center retrospective observational study.
      ;
      • Kwon YS
      • Park SH
      • Kim MA
      • et al.
      Risk of mortality associated with respiratory syncytial virus and influenza infection in adults.
      ;
      • Lee N
      • Lui GC
      • Wong KT
      • et al.
      High morbidity and mortality in adults hospitalized for respiratory syncytial virus infections.
      ). However, our study found that patients with complications (pneumonia on admission, developing HAP, receiving mechanical ventilation with or without VAP, and developing septic shock), and presenting with new cardiac arrhythmia, were significantly associated with mortality. Multivariate analyses showed no association between patients with advanced age and mortality.

      Limitations

      Our study had some limitations. First, the retrospective design of our study rendered it vulnerable to incomplete data, especially for clinical symptoms. Second, our data were from a single center — a national tertiary referral center in Bangkok — which may not be representative of other parts of Thailand. Third, the specimens included in our study were sent only for influenza and RSV detection. As a result, other viruses could have been involved, although they should not have a major effect on the comparisons between influenza and RSV.

      Conclusion

      RSV cocirculated with influenza during the rainy season in Thailand. Patients with RSV had significantly fewer myalgias, less fever, and more wheezing than patients with influenza. Pulmonary and cardiovascular complications in patients with RSV were common, and were causes of in-hospital mortality rates similar to those found with influenza. However, the clinical presentations of RSV and influenza cannot be reliably distinguished, and laboratory confirmation is needed to guide management.

      Declaration of Competing Interest

      All authors declare they have no personal or professional conflicts of interest, and have not received financial support from the companies that produce or distribute the drugs, devices, or materials described in this report.

      Acknowledgements

      The authors gratefully acknowledge Professor Emeritus Khun Nanta Maranetra for proofreading the article. They would also like to thank Miss Khemajira Karaketklang and Mr Suthipol Udompunthurak for their assistance with statistical analysis.

      Contributions

      Benjamas Chuaychoo: conceptualization, study design, data collection, data analysis, writing — original draft, reviewing, and editing. All authors: study design, data collection, data analysis, reviewing, and editing.

      Funding disclosure

      This research did not receive any specific grants from funding agencies in the public, commercial, or not-for-profit sectors.

      Ethical approval

      The study protocol was approved by the Institutional Review Board of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Informed consent was not required due to the retrospective nature of the study.

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