Screening process
We screened 2,187 hospitalised patients who tested positive for influenza A RNA. Overall, 693 immunocompetent adults and adolescent patients hospitalised with FluA-p were included in the final analysis (Fig.1). Among these patients, 38.1% (264/693) were infected with A(H1N1) pdm09 and 11.0% (76/693) were infected with A(H3N2), while 50.9% (353/693) of patients were infected with an unclassified subtype. All patients received NAIs during the course of the disease, and 33.5% (232/693) were early NAI users.
Overview of patients with FluA-p
Overall, the median age of the patients was 61.0 years and 65.1% (451/693) were males. Fifty-eight percent of patients (402/693) had at least one underlying disease. Only 4.6% (32/693) of patients had a consciousness disorder on admission. Respiratory rates ≥30 times/min and hypotension were identified in 17.5% (121/693) and 1.2% (8/693) of patients, respectively and 26.9% (172/639) of patients had pO2/FiO2 ≤250 mmHg. Multilobar infiltrate and pleural effusion in chest radiology was observed in 78.8% (546/693) and 16.6% (115/693) of patients, respectively (Table 1).
As shown in Appendix file 4, 38.2% (265/693) of FluA-p patients were coinfected with other community-acquired respiratory pathogens, with Streptococcus pneumoniae (33.2%) as the most common etiology, followed by Klebsiella pneumoniae (30.6%) and Staphylococcus aureus (20.4%).
All patients were treated with antibiotics and 19% of patients (132/693) received systemic corticosteroids during hospitalisation. The 30-day mortality was 19.6% (136/693) (Table 1).
Table 1 The baseline characteristics of patients in the deceased and survival groups.
Variables
|
Total
(n = 693)
|
Deceased group
(n = 136)
|
Survival group
(n = 557)
|
p-value
|
Male (n, %)
|
461(66.5)
|
92 (67.6)
|
369 (66.2)
|
0.757
|
Age (median, IQR, years)
|
61.0 (36.0-73.0)
|
61.5 (28.0-76.0)
|
59.0 (36.0-72.0)
|
0.963
|
BMI ≥ 30 kg/m2 (n, %)#
|
48 (6.9)
|
0 (0.0)
|
48 (8.6)
|
<0.001
|
Comorbidities (n, %)
|
|
|
|
|
Hypertension
|
252 (36.4)
|
48 (35.3)
|
204 (36.6)
|
0.772
|
Cardiovascular disease#
|
136 (19.6)
|
48 (35.3)
|
88 (15.8)
|
<0.001
|
Diabetes mellitus
|
92 (13.3)
|
14 (10.3)
|
78 (14.0)
|
0.253
|
Cerebrovascular disease
|
72 (10.4)
|
10 (7.4)
|
62 (11.1)
|
0.195
|
COPD#
|
40 (5.8)
|
3 (2.2)
|
37 (6.6)
|
0.047
|
Asthma
|
19 (2.7)
|
2 (1.5)
|
17 (3.1)
|
0.222
|
Chronic kidney disease
|
16 (2.3)
|
6 (4.4)
|
10 (1.8)
|
0.133
|
Malignant solid tumor
|
16 (2.3)
|
0 (0.0)
|
16 (2.9)
|
0.193
|
Smoking history#
|
243 (35.1)
|
68 (50.0)
|
175 (31.4)
|
<0.001
|
Clinical and radiologic characteristics (n, %)
|
|
|
|
|
Respiratory rates ≥30 times/min
|
121 (17.5)
|
25 (18.4)
|
96 (17.2)
|
0.752
|
Confusion#
|
32 (4.6)
|
32 (23.5)
|
0 (0.0)
|
<0.001
|
SBP < 90 mmHg
|
8 (1.2)
|
0 (0.0)
|
8 (1.4)
|
0.338
|
Leukocytes > 10×109/L #
|
118 (17.0)
|
42 (30.9)
|
76 (13.6)
|
<0.001
|
Lymphocytes < 0.8×109/L #
|
299/677 (44.2)
|
120 (88.2)
|
179/541 (33.1)
|
<0.001
|
Hb < 100 g/L#
|
69 (10.0)
|
34 (25.0)
|
35 (6.3)
|
<0.001
|
ALB < 35 g/L
|
58/639 (9.1)
|
12/131 (9.2)
|
46/508 (9.1)
|
0.970
|
BUN > 7 mmol/L#
|
183/685 (26.7)
|
97 (71.3)
|
86/549 (15.7)
|
<0.001
|
BG > 11 mmol/L
|
48 (6.9)
|
8 (5.9)
|
40 (7.2)
|
0.397
|
Arterial pH < 7.35#
|
120/639 (18.8)
|
60/136 (44.1)
|
60/503 (11.9)
|
<0.001
|
pO2/FiO2 ≤ 250 mmHg #
|
172/639 (26.9)
|
28/136 (20.6)
|
144/503 (28.6)
|
0.061
|
Pleural effusion#
|
120 (17.3)
|
36 (26.5)
|
84 (15.1)
|
<0.001
|
Early NAI usea (n, %)#
|
232 (33.5)
|
60 (43.4)
|
172 (30.9)
|
0.003
|
Duration from illness onset to NAI use
(days, median, IQR)#
|
3.0 (1.0-4.0)
|
2.5 (1.0-3.0)
|
3.0 (1.0-4.0)
|
0.004
|
Systemic corticosteroid use (n, %)#
|
132 (19.0)
|
60 (44.1)
|
72 (12.9)
|
<0.001
|
Coinfection with other pathogens (n, %)#
|
265 (38.2)
|
84 (61.8)
|
181 (32.5)
|
<0.001
|
#Variables cited in the table above were the candidates which were entered into the multivariate logistic regression model. The bolded values are p-values < 0.05, which represent significant differences between survival group and deceased group. IQR: interquartile range; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SBP: systolic blood pressure; Hb: hemoglobin; BG: blood glucose; ALB: albumin; BUN: blood urea nitrogen; pO2/FiO2: arterial pressure of oxygen/fraction of inspiration oxygen; NAIs: neuraminidase inhibitors; a: Neuraminidase inhibitor refers to any dose of oseltamivir, zanamivir or peramivir.
The risk factors for 30-day mortality in FluA-p patients
According to the survival status at 30 days after admission, the patients were divided into survival and deceased groups. The baseline characteristics of the patients in the survival and deceased groups are shown in the Table 1. There were no significant differences in terms of age and sex between the two groups. Cardiovascular disease, smoking history, confusion, leukocytes > 10×109/L, lymphocytes < 0.8×109/L, Hb < 100 g/L, BUN > 7 mmol/L, arterial pH < 7.35 on admission, early use of NAIs and systemic corticosteroids during hospitalization were more common in the deceased group compared with the survival group, while BMI ≥ 30 kg/m2 and COPD were less common. Although more patients in the deceased group were coinfected with other pathogens, there was no significant differences in the spectrum of etiologies (Appendix file 4).
The multivariate logistic regression model confirmed early NAI therapy [odds ratio (OR) 0.415, 95% confidence interval (CI) 0.195-0.858, p = 0.001], cardiovascular disease (OR 3.189, 95% CI 1.300-7.892, p < 0.001), smoking history (OR 3.294, 95% CI 1.151-9.429, p < 0.001), lymphocytes < 0.8×109/L (OR 4.080, 95% CI 1.321–12.596, p < 0.001), BUN > 7 mmol/L (OR 2.158, 95% CI 1.084-4.690, p < 0.001) and pO2/FiO2 ≤ 250 mmHg (OR 4.344, 95% CI 2.050-9.203, p < 0.001) were independent risk factors for 30-day mortality in FluA-p patients (Table 2).
Table 2 The risk factors for the 30-day mortality in FluA-CAP patients.
Variable
|
OR (95% CI)
|
p-value
|
Cardiovascular disease
|
3.189 (1.300-7.892)
|
<0.001
|
Smoking history
|
3.294 (1.151-9.429)
|
<0.001
|
Lymphocytes < 0.8×109/L
|
4.080 (1.321–12.596)
|
<0.001
|
BUN > 7 mmol/L
|
2.158 (1.084-4.690)
|
<0.001
|
pO2/FiO2 ≤ 250 mmHg
|
4.344 (2.050-9.203)
|
<0.001
|
Early NAI therapy
|
0.415 (0.195–0.858)
|
0.001
|
OR: odd ratio; CI: confidence interval
The impact of early NAI use on the clinical outcomes of FluA-p patients
In the univariate analysis, early NAI therapy was associated with increased risk for 30-day mortality, but not with invasive ventilation or 14-day mortality.
After adjusting for WPs for treatment, systemic corticosteroid and antibiotic use, a multivariate logistic regression model showed that early use of NAI was associated with decreased risk of invasive ventilation (OR 0.511, 95% CI 0.312–0.835, p = 0.007), 14-day mortality (OR 0.477, 95% CI 0.124–0.744, p < 0.001) and 30-day mortality (OR 0.533, 95% CI 0.210–0.807, p < 0.001) in FluA-p patients (Table 3).
Table 3 The impact of early NAI therapy on the clinical outcomes of FluA-CAP patients.
Variable
|
Patients (n, %)
|
Univariate logistic analysis
|
Multivariate logistic analysis
|
Early NAI use group (n = 232)
|
Control group (n = 461)
|
OR (95% CI)
|
p-value
|
*aOR (95% CI)
|
p-value
|
Invasive ventilation
|
52 (22.4)
|
106 (23.0)
|
0.897 (0.612–1.317)
|
0.577
|
0.511 (0.312–0.835)
|
0.007
|
14-day mortality
|
32 (13.8)
|
48 (10.4)
|
1.377 (0.853–2.221)
|
0.190
|
0.477 (0.124–0.744)
|
<0.001
|
30-day mortality
|
60 (25.9)
|
76 (16.5)
|
1.767 (1.205–2.592)
|
0.004
|
0.533 (0.210–0.807)
|
<0.001
|
*: Adjusted for weighted propensity scores for treatment, systemic corticosteroid and antibiotic use.
Figure 2 shows association between early NAI therapy and the outcomes of FluA-p patients before and after adjusting for confounders.
The risk factors for early NAI administration prescribed by clinicians
Logistic regression analysis allowed us to further explore the factors predictive of NAI use in FluA-p patients. All the potential factors screened in the univariate analysis with p < 0.1 variables were included in the regression model: male, age ≥ 65 years old, cardiovascular disease, diabetes mellitus, cerebrovascular disease, COPD, asthma, chronic kidney disease, malignant solid tumor, axillary temperature ≥ 38℃, cough, chest pain, confusion, SBP < 90 mmHg, leukocytes > 10×109/L, leukocytes < 4.0×109/L, lymphocytes < 0.8×109/L, PO2/FiO2 ≤ 250 mmHg, pleural effusion and positive for RIDTs (Appendix file 5).
A multivariate logistic regression model suggested that positive RIDTs (OR 6.504, 95% CI 1.671–25.323, p = 0.007) was the only predictor for early NAI administration by clinicians in the FluA-p patients (Table 4).
Table 4 The risk factors for early NAI administration by the clinicians
Variable
|
p-value
|
OR (95% CI)
|
Positive for RIDTs
|
<0.001
|
3.586 (1.259-10.219)
|
RIDTs: rapid influenza diagnostic tests
Figure 3 shows similar proportions of early NAI administration and positive RIDT in FluA-p patients treated during the study period, both of which fluctuated up and down by 30%.