Patient identification
In total, 3405 hospitalized patients who tested positive for influenza viral RNA over the course of this study were assessed for eligibility, of whom 1191 were identified as immunocompetent adults with laboratory-confirmed, community-acquired Flu-p and were enrolled in the present study, of whom 64.4% were infected with influenza A virus 64.4% (767/1191) and 35.6% were infected with influenza B virus 35.6% (464/1191) (Figure 1).
Patient overview
Flu-p patients in the present study had a median age of 61.0 yrs old (interquartile range [IQR]: 49.0-78.0 yrs) and were 54.5% male (649/1191). The most common comorbidities in these patients included hypertension (25.9%, 309/1191), coronary artery disease (24.6%, 293/1191), and diabetes mellitus (12.4%, 148/1191), while mental confusion and respiratory rates ≥ 30 breaths/min were present in 14.0% (167/1191) and 13.4% (159/1191) of patients at the time of admission, respectively. Just 1.4% (17/1191) of patients exhibited a systolic blood pressure < 90 mmHg, while a lymphocyte count < 0.8×109/L and PaO2/FiO2 < 300 mmHg were respectively observed in 45.8% (537/1173) and 47.9% (542/1132) of patients (Table 1).
Coinfections with other community-acquired respiratory pathogens were detected in 34.0% (405/1191) of patients, with Klebsiella pneumoniae (32.8%, 133/405), Streptococcus pneumoniae (29.9%, 121/405), and Staphylococcus aureus (20.7%, 84/405) being the most common causative pathogens (Supplementary Material 4).
Early NAI therapy was performed in 36.7% (437/1191) of patients, whereas 24.4% were treated with systemic corticosteroids. ACEIs/ARBs, statins, anticoagulants, antiplatelet agents, and β-receptor blockers were administrated to 40.1% (478/1191), 41.4% (493/1191), 10.1% (120/1191), 29.3% (349/1191), and 19.2% (229/1191) of patients, respectively. Noninvasive and invasive ventilation were conducted for 25.7% (306/1191) and 17.7% (211/1191) of patients, respectively. Of these patients, 22.4% (267/1191) were admitted to ICU, and the all-cause 30-day mortality rate for this patient cohort was 20.3% (242/1191) (Table 1).
Type, incidence, and timing of CVEs in Flu-p patients
At least one type of CVE occurred in 24.6% (293/1191) of Flu-p patients, with the most common CVEs being arrhythmia (17.4%, 207/1191), heart failure (15.5%, 185/1191), myocardial infarction (4.6%, 55/1191), stroke (4.2%, 50/1191), and pulmonary embolism (1.0%, 12/1191) (Figure 2).
The median times between admission and the incidence of each CVE type were as follows: arrhythmia (2.0 days, IQR: 1.0-5.0 days), heart failure (3.0 days, IQR:2.0-4.0 days), MI (2.0 days, IQR: 1.0-3.0 days), stroke (7.0 days, 5.0-8.0 days), and PE (11.5 days, IQR: 10.0-14.0 days) (Figure 3).
Risk factors associated with CVE incidence in Flu-p patients
Relative to patients without CVEs, those with CVEs were more likely to suffer from hypertention (31.1% vs 24.3%, p = 0.021), coronary artery disease (42.3% vs 18.8%, p < 0.001), preexistingheart failure (7.8% vs 1.8%, p < 0.001), cerebrovascular disease (13.7% vs 8.2%, p = 0.006), and chronic kidney disease (7.2% vs 1.6%, p < 0.001). Mental confusion (35.2% vs 7.1%, p < 0.001), respiratory rates ≥ 30 breaths/min (25.6% vs 9.4%, p < 0.001), leukocyte counts > 10×109/L (30.4% vs 24.5, p = 0.046), lymphocytes < 0.8×109/L (83.3% vs 33.3%, p < 0.001), hemoglobin (HB) levels < 100 g/L (39.9% vs 17.5%, p < 0.001), blood urea nitrogen (BUN) > 7 mmol/L (65.9% vs 33.3%, p < 0.001), and PaO2/FiO2 < 300 mmHg (54.9% vs 45.4, p = 0.005) at time of admission were more frequently observed in patients with CVEs than in patients without CVEs. Patients with CVEs were more likely to be treated with systemic corticosteroids (50.9% vs 15.8%, p < 0.001), ACEIs/ARBs (54.6% vs 35.4%, p < 0.001), statins (54.9% vs 37.0%,bp < 0.001), anticoagulants (19.1% vs 7.1%, p < 0.001), and β-receptor blockers (27.6% vs 16.5%, p < 0.001), and were less likely to have undergone early NAI therapy (15.4% vs 43.7%, p < 0.001) (Table 1).
Multivariate logistic regression analyses revealed hypertension (OR 4.038, 95% CI 2.023-8.062, p < 0.001), cerebrovascular disease (OR 4.716, 95% CI 2.175-10.229, p < 0.001), coronary artery disease (OR 5.554, 95% CI 2.447-12.604, p < 0.001), preexisting heart failure (OR 5.634, 95% CI 1.919-16.538, p = 0.002), systolic blood pressure < 90 mmHg (OR 6.178, 95% CI 1.626-23.476, p = 0.008), respiratory rates ≥ 30 breaths/min (OR 6.870, 95% CI 3.803-12.409, p < 0.001), a lymphocyte count < 0.8×109/L (OR 7.604, 95% CI 4.499-12.853, p < 0.001), PaO2/FiO2 < 300 mmHg (OR 2.057, 95% CI 1.348-3.140, p = 0.001), systemic corticosteroid administration (OR 3.708, 95% CI 2.306-5.962, p < 0.001), early NAI treatment (OR 0.402, 95% CI 0.158-0.780, p < 0.001), and ACEIs/ARBs treatment (OR 0.383, 95% CI 0.153-0.960, p = 0.041) to be independently associated with CVE incidence (Figure 4).
The relationship between CVEs and Flu-p patient outcomes
In univariate analyses, CVEs were related to higher rates of 30-day Flu-p patient mortality (OR 5.733, 95% CI 4.230-7.772, p < 0.001), with CVE-specific odds ratios for arrhythmia, heart failure, MI, stroke, and PE of 4.448 (95% CI 3.215-6.154, p < 0.001), 5.482 (95% CI 3.917-7.672, p < 0.001), 16.872 (95% CI 8.739-32.577, p < 0.001), 7.881 (95% CI 4.340-14.312, p < 0.001), and 3.996 (95% CI 1.277-12.501, p = 0.012), respectively (Table 2).
Following adjustment for age, sex, comorbidities, obesity, pregnancy, smoking history, early NAI treatment, and systemic corticosteroid administration, CVEs were linked to an elevated risk of 30-day mortality (OR 3.307, 95% CI 2.198-4.975, p < 0.001) in Flu-p patients. Similarly, arrhythmia (OR 2.465, 95% CI 1.586-3.830, p < 0.001), heart failure (OR 2.997, 95% CI 1.938-4.637, p < 0.001), MI (OR 15.017, 95% CI 6.857-32.887, p < 0.001), stroke (OR 4.507, 95% CI 1.790-11.346, p = 0.001), and PE (OR 4.557, 95% CI 1.051-19.755, p = 0.043) were all associated with higher 30-day mortality risk (Table 2).
Comparable associations were also observed with respect to the relationships between CVEs and invasive ventilation (Supplementary Material 5) and ICU admission (Supplementary Material 6).
Relative to patients that did not experience CVEs, the survival rates of patients that experienced one (Hazard ratio [HR] 2.059, 95% CI 1.355-3.130, p = 0.001), two (HR 2.727, 95% CI 1.893-3.929, p < 0.001), and three types of CVEs (HR 5.832, 95% CI 3.600-9.446, p < 0.001) within 30 days following admission were significantly lower (Figure 5).