Study population
Over the course of the study period, 1491 patients with ILI were identified, of whom 594 were enrolled in the present study. These patients included 421 cases of influenza (303 cases with influenza A, and 118 cases with influenza B), 92 cases of RSV infection, and 81 cases of hMPV infection (Fig. 1).
The median age of this study cohort was 64.0 years old, with 48.3% (287/594) of patients being ≥ 65 years old. Of these patients, 53.5% (318/594) were male. The most prevalent comorbidities in these patients included COPD (52.7%, 313/594), cardiovascular disease (44.8%, 266/594), and cerebrovascular disease (16.3%, 97/594), while just 3.0% (18/594) of patients were immunocompromised. The most common symptoms at time of admission included cough (98.1%, 583/594), fever (71.9%, 427/594), sore throat (54.2%, 322/594), and dyspnea (38.6%, 229/594) (Table 1).
Table 1
Demographic and baseline clinical characteristics of patients with the three viruses infections
Variable
|
Total
(n = 594)
|
Flu
(n = 421)
|
RSV
(n = 92)
|
P1 value
|
hMPV
(n = 81)
|
P2 value
|
Male (n, %)
|
318 (53.5)
|
217 (51.5)
|
49 (53.3)
|
0.765
|
52 (64.2)
|
0.037#
|
Age (median, IQR, years)
|
64.0 (56.8–77.0)
|
60.0 (55.0–67.0)
|
70.0 (64.0–72.0)
|
< 0.001
|
69.0 (63.5–77.0)
|
< 0.001
|
≥ 65 years old (n, %)
|
287 (48.3)
|
163 (38.7)
|
68 (73.9)
|
< 0.001#
|
56 (69.1)
|
< 0.001#
|
Days from illness onset to admission (median, IQR)
|
3.0 (2.0–5.0)
|
2.5 (1.0–3.0)
|
4.0 (3.0–6.0)
|
< 0.001
|
3.0 (2.0–5.0)
|
< 0.001
|
Influenza vaccination in the past year (n, %)
|
64 (10.8)
|
34 (8.1)
|
16 (17.4)
|
0.006
|
14 (17.3)
|
0.010
|
Comorbidities (n, %)
|
|
|
|
|
|
|
COPD
|
313 (52.7)
|
210 (49.9)
|
57 (62.0)
|
0.036#
|
46 (56.8)
|
0.255
|
Cardiovascular disease
|
266 (44.8)
|
196 (46.6)
|
39 (42.4)
|
0.468
|
31 (38.3)
|
0.170
|
Cerebrovascular disease
|
97 (16.3)
|
66 (15.7)
|
17 (18.5)
|
0.509
|
14 (17.3)
|
0.717
|
Diabetes mellitus
|
96 (16.2)
|
64 (15.2)
|
22 (23.9)
|
0.043#
|
10 (12.3)
|
0.507
|
Chronic kidney disease
|
36 (6.1)
|
20 (4.8)
|
11 (12.0)
|
0.009#
|
5 (6.2)
|
0.795
|
Solid malignant tumor
|
38 (6.4)
|
21 (5.0)
|
12 (13.0)
|
0.004#
|
5 (6.2)
|
0.867
|
Asthma
|
30 (5.1)
|
22 (5.2)
|
1 (1.1)
|
0.144
|
7 (8.6)
|
0.344
|
Immunocompromised status (n, %)
|
18 (3.0)
|
11 (2.6)
|
3 (3.3)
|
1.000
|
4 (4.9)
|
0.260
|
Obesity (n,%)
|
46 (7.7)
|
31 (7.4)
|
4 (4.3)
|
0.299
|
11 (13.6)
|
0.064
|
Smoking history (n, %)
|
256 (43.1)
|
172 (40.9)
|
42 (45.7)
|
0.398
|
42 (51.9)
|
0.067
|
Baseline clinical features (n, %)
|
|
|
|
|
|
|
Fever ≥ 38℃
|
427 (71.9)
|
311 (73.9)
|
62 (67.4)
|
0.206
|
54 (66.7)
|
0.182
|
Nosal congestion
|
133 (22.4)
|
85 (20.2)
|
35 (38.0)
|
< 0.001#
|
17 (21.0)
|
0.870
|
Rhinorrhea
|
153 (25.8)
|
113 (26.8)
|
23 (25.0)
|
0.717
|
17 (21.0)
|
0.271
|
Sore throat
|
322 (54.2)
|
236 (56.1)
|
48 (52.2)
|
0.497
|
38 (46.9)
|
0.130
|
Myalgia
|
203 (34.2)
|
176 (41.8)
|
26 (28.3)
|
0.016#
|
16 (19.8)
|
< 0.001#
|
Cough
|
583 (98.1)
|
416 (98.8)
|
90 (97.8)
|
0.460
|
77 (95.1)
|
0.061
|
Sputum production
|
169 (28.5)
|
85 (20.2)
|
12 (13.0)
|
0.113
|
26 (32.1)
|
0.575
|
Chest pain
|
147 (24.7)
|
102 (24.2)
|
23 (25.0)
|
0.876
|
22 (27.2)
|
0.859
|
Dyspnea
|
229 (38.6)
|
133 (31.6)
|
62 (67.4)
|
< 0.001
|
34 (42.0)
|
0.069
|
Leukocytes > 10 × 109/L
|
76 (12.8)
|
54 (12.8)
|
11 (12.0)
|
0.820
|
11 (13.6)
|
0.853
|
Leukocytes < 4 × 109/L
|
44 (7.4)
|
28 (6.7)
|
7 (7.6)
|
0.741
|
9 (11.1)
|
0.159
|
Lymphocytes < 0.8 × 109/L
|
150 (25.3)
|
124 (29.5)
|
15 (16.3)
|
0.010#
|
11 (13.6)
|
0.003#
|
Coinfection (n, %)
|
162 (27.3)
|
107 (25.4)
|
18 (19.6)
|
0.236
|
22 (27.2)
|
0.742
|
Flu: influenza; RSV: respiratory syncytial virus; hMPV: human metapneumovirus; IQR:; COPD: chronic obstructive pulmonary disease; #: The values were entered into the multivariate logistic regression model; p1: patients with RSV infection versus patients with Flu; p2: patients with hMPV infection versus patients with Flu; The bolded values are p-values < 0.05, which represented significant differences between two groups. |
Coinfection with other community-acquired respiratory pathogens was detected in 27.3% (162/594) of patients (Table 1). The most common coinfecting pathogen was Klebsiella pneumoniae (25.3%, 41/162), followed by Streptococcus pneumoniae (23.5%, 38/162) and Staphylococcus aureus (17.9%, 29/162) (Supplementary material 2).
A total of 97.8% (581/594) of patients suffered from LRT complications at time of admission, including pneumonia (47.1%, 280/594) and acute exacerbation of COPD (AECOPD) (40.4%, 240/594). Of these patients, 13.6% (81/594) had baseline cardiovascular complications. Antibiotics and systemic corticosteroids were administrated to 98.0% (98.0%, 582/594) and 48.0% (285/594) of patients, respectively. Overall, 12.0% (71/594) of patients underwent invasive ventilation, and 14.1% (84/594) of patients were admitted to ICU. The all-cause 30-day mortality rate in these patients was 8.4% (50/594). The most common cause of death was severe pneumonia 62.0% (31/50), followed by heart failure 28.0% (14/50), acute renal failure 4.0% (2/50), septic shock 4.0% (2/50), and acute myocardial infarction 1.0% (1/50) (Table 2).
Table 2
Clinical management and outcomes of patients with the three viruses infections
Variable
|
Total
(n = 594)
|
Flu
(n = 421)
|
RSV
(n = 92)
|
P1 value
|
hMPV
(n = 81)
|
P2 value
|
Baseline lower respiratory tract complications (n, %)
|
581 (97.8)
|
413 (98.1)
|
89 (96.7)
|
0.675
|
79 (97.5)
|
1.000
|
Pneumonia
|
280 (47.1)
|
184 (43.7)
|
49 (53.3)
|
0.095
|
47 (58.0)
|
0.018
|
AECOPD
|
240 (40.4)
|
187 (44.4)
|
30 (32.6)
|
0.038
|
23 (28.4)
|
0.010
|
bronchitis
|
40 (6.7)
|
23 (5.5)
|
9 (9.8)
|
0.121
|
8 (9.9)
|
0.131
|
Athma exacerbation
|
21 (3.5)
|
19 (4.5)
|
1 (1.1)
|
0.215
|
1 (1.2)
|
0.284
|
Baseline cardiovascular complications (n, %)
|
81 (13.6)
|
52 (12.4)
|
15 (16.3)
|
0.306
|
14 (17.3)
|
0.229
|
Decompensated heart failure
|
75 (12.6)
|
49 (11.6)
|
14 (15.2)
|
0.009
|
12 (14.8)
|
0.002
|
Acute myocardial infarction
|
6 (1.0)
|
3 (0.7)
|
1 (1.1)
|
0.548
|
2 (2.5)
|
0.185
|
Early NAI administration (n, %)
|
148 (24.9)
|
101 (24.0)
|
25 (27.2)
|
0.520
|
22 (27.2)
|
0.544
|
Antibiotics use (n, %)
|
582 (98.0)
|
411 (97.6)
|
92 (100.0)
|
0.282
|
79 (97.5)
|
1.000
|
Systemic corticosteroid use (n, %)
|
285 (48.0)
|
215 (51.1)
|
29 (31.5)
|
0.001
|
41 (50.6)
|
0.941
|
Noninvasive ventilation (n, %)
|
76 (12.8)
|
44 (10.5)
|
18 (19.6)
|
0.015
|
14 (17.3)
|
0.078
|
Invasive ventilation (n, %)
|
71 (12.0)
|
39 (9.3)
|
15 (16.3)
|
0.046
|
17 (21.0)
|
0.002
|
Admittance to ICU (n, %)
|
84 (14.1)
|
45 (10.7)
|
19 (20.7)
|
0.009
|
20 (24.7)
|
0.001
|
Length of stay in hospital
(median, IQR, days)
|
10.0 (8.0–14.0)
|
9.0 (8.0–13.0)
|
14.0 (10.0–19.0)
|
< 0.001
|
10.0 (9.0–16.0)
|
0.003
|
30-day mortality (n, %)
|
50 (8.4)
|
26 (6.2)
|
10 (10.9)
|
0.110
|
14 (17.3)
|
0.001
|
Direct cause of death
|
|
|
|
< 0.001
|
|
< 0.001
|
Severe pneumonia
|
32 (64.0)
|
21 (80.8)
|
6 (60.0)
|
|
5 (35.7)
|
|
Heart failure
|
11 (22.0)
|
2 (7.7)
|
3 (30.0)
|
|
6 (42.9)
|
|
Acute renal failure
|
2 (4.0)
|
0 (0.0)
|
0 (0.0)
|
|
2 (14.3)
|
|
Septic shock
|
3 (6.0)
|
3 (11.5)
|
0 (0.0)
|
|
0 (0.0)
|
|
AMI
|
2 (4.0)
|
0 (0.0)
|
1 (10.0)
|
|
1 (7.1)
|
|
AECOPD: acute exacerbation of chronic obstructive pulmonary disease; ICU: intensive care unit; AMI: Acute myocardial infarction. The bolded values are p-values < 0.05, which represented significant differences between two groups. |
Predictors Of Demographic And Clinical Features Of RSV Infection
Relative to patients infected with influenza, patients infected with RSV tended to be older (median: 70.0 vs. 60.0 years old), with significantly more of these patients being ≥ 65 years old (73.9% vs 38.7%). In addition, more patients with RSV had COPD (62.0% vs 49.9%), diabetes mellitus (23.9% vs 15.2%), chronic kidney disease (12.0% vs 4.8%), and solid malignant tumors (13.0% vs 5.0%) relative to patients with influenza. Nasal congestion (38.0% vs 20.2%) and dyspnea (67.4% vs 31.6%) were more common in RSV patients, whereas myalgia (28.3% vs 41.8%) and lymphocytes < 0.8 × 109/L (16.3% vs 29.5%) were more common in influenza patients relative to RSV patients (Table 1).
A multivariate logistic regression model revealed that relative to influenza, age ≥ 65 years old [odds ratio (OR) 3.972, 95% confidence interval (CI) 2.330–6.769, p < 0.001; sensitivity 66.30%, specificity 61.28%, AUROC = 0.638], solid malignant tumors (OR 2.883, 95% CI 1.203–6.907, p = 0.018; sensitivity 13.04%, specificity 95.10%, AUROC = 0.540), nasal congestion (OR 1.868, 95% CI 1.064–3.279, p = 0.030; sensitivity 40.22%, specificity 79.81%, AUROC = 0.600), and dyspnea (OR 4.834, 95% CI 2.671–8.750, p < 0.001; sensitivity 67.39%, specificity 64.80%, AUROC = 0.679) were positively associated with RSV infection, while myalgia (OR 0.494, 95% CI 0.275–0.888, p = 0.018; sensitivity 73.91%, specificity 41.81%, AUROC = 0.579), and lymphocytes < 0.8 × 109/L (OR 0.411, 95% CI 0.211-0.800, p = 0.009; sensitivity 83.70%, specificity 29.45%, AUROC = 0.566) were negatively associated with RSV infections to RSV infection (Fig. 2).
Predictors Of Demographic And Clinical Features Of HBPV Infection
Relative to patients with influenza, those infected with hMPV were more often male (64.2% vs 51.5%) and were older on average (median: 69.0 yrs vs 60.0 yrs), with an age ≥ 65 years old being more common in these hMPV patients (69.1% vs 38.7%). In contrast, myalgia (19.8% vs 41.8%) and lymphocytes < 0.8 × 109/L (13.6% vs 29.5%) were less commonly observed in patients with hMPV infections relative to patients with influenza (Table 1).
Multivariate logistic regression analysis indicated that relative to influenza, age ≥ 65 years old (OR 4.075, 95% CI 2.394–6.938, p < 0.001; sensitivity 69.14%, specificity 61.28%, AUROC = 0.652) was positively correlated with hMPV infection, whereas myalgia (OR 0.280, 95% CI 0.151–0.522, p < 0.001; sensitivity 80.25%, specificity 41.81%, AUROC = 0.610) and lymphocytes < 0.8 × 109/L (OR 0.339, 95% CI 0.166–0.692, p = 0.003; sensitivity 86.42%, specificity 29.45%, AUROC = 0.579) were all negatively correlated with hMPV infections (Fig. 3).
The impact of RSV, hMPV, and influenza on clinical outcomes in patients with pneumonia
In patients with pneumonia, univariate analyses indicated that relative to influenza, RSV infections were associated with similar risks of invasive ventilation (OR 0.929, 95% CI 0.379–2.274, p = 0.871), ICU admission (OR 1.429, 95% CI 0.659–3.099, p = 0.366), and 30-day mortality (OR 1.367, 95% CI 0.542–3.447, p = 0.508). In addition, these analyses revealed that relative to influenza, hMPV infections in pneumonia patients were associated with similar risks of invasive ventilation (OR 1.506, 95% CI 0.672–3.372, p = 0.320) and ICU admission (OR 1.887, 95% CI 0.894–3.982, p = 0.096), but were associated with an increased risk of 30-day mortality (OR 2.811, 95% CI 1.259–6.278, p = 0.012) (Table 3).
Table 3
Impact of specific virus type on the clinical outcomes among patients with pneumonia
Clinical outcome
|
Virus type
|
Cases
(n, %)
|
Univariate logistic analysis
|
Multivariate logistic analysis
|
OR (95% CI)
|
P value
|
*aOR (95% CI)
|
P value
|
Invasive ventilation
|
Flu
|
28/184 (15.2)
|
ref
|
|
ref
|
|
RSV
|
7/49 (14.3)
|
0.929 (0.379–2.274)
|
0.871
|
0.783 (0.231–2.656)
|
0.695
|
hMPV
|
10/47 (21.3)
|
1.506 (0.672–3.372)
|
0.320
|
0.206 (0.044–0.959)
|
0.044
|
ICU admission
|
Flu
|
31/189 (16.4)
|
ref
|
|
ref
|
|
RSV
|
11/49 (22.4)
|
1.429 (0.659–3.099)
|
0.366
|
1.368 (0.470–3.978)
|
0.565
|
hMPV
|
13/47 (27.7)
|
1.887 (0.894–3.982)
|
0.096
|
0.311 (0.075–1.298)
|
0.109
|
30-day mortality
|
Flu
|
20/184 (10.9)
|
ref
|
|
ref
|
|
RSV
|
7/49 (14.3)
|
1.367 (0.542–3.447)
|
0.508
|
1.016 (0.267–3.856)
|
0.982
|
hMPV
|
12/47 (25.5)
|
2.811 (1.259–6.278)
|
0.012
|
0.144 (0.027–0.780)
|
0.025
|
*: adjusted for age, sex, comorbidities, obesity, smoking history, influenza vaccination and early neuraminidase inhibitor therapy in patients with Flu, antibiotics and systemic corticosteroids use in hospitalzation and coinfections. OR: odd ratio; CI: confidence interval. |
After adjusting for confounding variables, multivariate logistic regression analyses suggested that RSV and influenza infections were associated with similar risks of invasive ventilation (OR 0.783, 95% CI 0.231–2.656, p = 0.695), ICU admission (OR 1.368, 95% CI 0.470–3.978, p = 0.565), and 30-day mortality (OR 1.016, 95% CI 0.267–3.856, p = 0.982), whereas hMPV infections were associated with a similar risk of ICU admission (OR 0.311, 95% CI 0.075–1.298, p = 0.109), but with decreased risk of invasive ventilation (OR 0.206, 95% CI 0.044–0.959, p = 0.044) and 30-day mortality (OR 0.144, 95% CI 0.027–0.780, p = 0.025) relative to influenza (Table 3).
Among patients with pneumonia, 30-day mortality rates were comparable in patients infected with RSV and influenza, and rates in both of these patient groups were significantly higher than those in patients with hMPV infections after adjusting for confounders (Fig. 4).
The impact of RSV, hMPV, and influenza on clinical outcomes in patients without pneumonia
In patients without pneumonia, univariate analyses revealed that RSV infection was associated with increased risks of invasive ventilation (OR 4.696, 95% CI 1.766–12.485, p = 0.002) and ICU admission (OR 3.641, 95% CI 1.424–9.310, p = 0.007), but with a similar risk for 30-day mortality (OR 2.887, 95% CI 0.694–12.017, p = 0.145) relative to influenza infection. Similarly, hMPV infection was associated with an increased risk of invasive ventilation (OR 5.327, 95% CI 1.905–14.894, p < 0.001) and ICU admission (OR 4.130, 95% CI 1.532–11.128, p = 0.005), but with a similar risk of 30 day mortality (OR 2.406, 95% CI 0.466–12.435, p = 0.295) relative to influenza infection (Table 4).
Table 4
Impact of specific virus type on the clinical outcomes among patients without pneumonia
Clinical outcome
|
Virus type
|
Cases
(n, %)
|
Univariate logistic analysis
|
Multivariate logistic analysis
|
OR (95% CI)
|
P value
|
*aOR (95% CI)
|
P value
|
Invasive ventilation
|
Flu
|
11/237 (4.6)
|
ref
|
|
ref
|
|
RSV
|
8/43 (18.6)
|
4.696 (1.766–12.485)
|
0.002
|
2.904 (0.795–10.606)
|
0.107
|
hMPV
|
7/34 (20.6)
|
5.327 (1.905–14.894)
|
< 0.001
|
2.878 (0.798–10.375)
|
0.106
|
ICU admission
|
Flu
|
14/237 (5.9)
|
ref
|
|
ref
|
|
RSV
|
8/43 (18.6)
|
3.641 (1.424–9.310)
|
0.007
|
2.533 (0.747–8.595)
|
0.136
|
hMPV
|
7/34 (20.6)
|
4.130 (1.532–11.128)
|
0.005
|
2.329 (0.680–7.977)
|
0.178
|
30-day mortality
|
Flu
|
6/237 (2.5)
|
ref
|
|
ref
|
|
RSV
|
3/43 (7.0)
|
2.887 (0.694–12.017)
|
0.145
|
1.268 (0.172–9.355)
|
0.816
|
hMPV
|
2/34 (5.9)
|
2.406 (0.466–12.435)
|
0.295
|
1.128 (0.122–10.419)
|
0.916
|
*: adjusted for age, sex, comorbidities, obesity, smoking history, influenza vaccination and early neuraminidase inhibitor therapy in patients with Flu, antibiotics and systemic corticosteroids use in hospitalzation and coinfections. |
After adjusting for confounding variables, multivariate logistic regression analyses suggested that RSV and influenza infections were associated with similar risks of invasive ventilation (OR 2.904, 95% CI 0.795–10.606, p = 0.107), ICU admission (OR 2.533, 95% CI 0.747–8.595, p = 0.136), and 30-day mortality (OR 1.268, 95% CI 0.172–9.355, p = 0.816) in patients without pneumonia. Similarly, hMPV and influenza infections were associated with comparable risks for invasive ventilation (OR 2.878, 95% CI 0.798–10.375, p = 0.106), ICU admission (OR 2.329, 95% CI 0.680–7.977, p = 0.178), and 30-day mortality (OR 1.128, 95% CI 0.122–10.419, p = 0.916) in patients without pneumonia (Table 4).
Rates of 30-day mortality were similar in all patients without pneumonia infected with influenza, RSV, and hMPV infections after adjusting for confounders (Fig. 5).
The impact of RSV, hMPV, and influenza on clinical outcomes in all patients
Relative to influenza infection, univariate analyses revealed that RSV infection was associated with an increased risk of invasive ventilation (OR 1.908, 95% CI 1.002–3.633, p = 0.049) and ICU admission (OR 2.175, 95% CI 1.203–3.931, p = 0.010), but with a similar risk of 30-day mortality (OR 1.853, 95% CI 0.806–3.990, p = 0.115) in the overall patient population. In contrast, hMPV infection was associated with an increased risk of invasive ventilation (OR 2.602, 95% CI 1.905–14.894, p = 0.003), ICU admission (OR 2.740, 95% CI 1.515–4.953, p = 0.001), and 30-day mortality (OR 3.175, 95% CI 1.577–6.389, p = 0.001) relative to influenza infection in the overall patient population (Supplementary material 3).
Relative to influenza infection, risks of invasive ventilation (OR 1.553, 95% CI 0.702–3.436, p = 0.277; OR 1.616, 95% CI 0.733–3.564, p = 0.234; respectively), ICU admission (OR 1.951, 95% CI 0.949–4.013, p = 0.069; OR 1.983, 95% CI 0.953–4.129, p = 0.067; respectively), and 30-day mortality (OR 1.658, 95% CI 0.665–4.132, p = 0.278; OR 2.193, 95% CI 0.914–5.262, p = 0.079; respectively) associated with RSV and hMPV infections were similar in the overall patient population after adjusting for potential confounding variables (Supplementary material 3).
Rates of 30-day mortality were similar in all patients without pneumonia infected with influenza, RSV, and hMPV infections after adjusting for confounders (Supplementary Fig. 1).