Results
Patient characteristics
In this study, 148 (58.0%) of 255 patients with viral pneumonia were
male with a median age of 67.0 (54.0-81.0) years (Table 1). One hundred
and eight (42.4%) patients had a smoking history. A total of
201
(85.5%) patients had one or more coexisting illnesses. Hypertension,
cardiovascular diseases, diabetes, and COPD were the most common
coexisting conditions. Cough, fever, and sputum production were the most
common symptoms. Chest pain/tightness was reported in 24.3% of the
patients. On admission, the leukocyte count was normal or slightly
increased in most patients. Elevated levels of C-reactive protein (CRP)
were observed in most patients. Hypoxemia
(PaO2/FiO2 < 300 mmHg) was
found in 97 (38.0%) of the patients. All patients underwent chest
radiography on admission, 180 (70.6%), and 72 (28.2%) of patients had
findings of multi-lobular infiltration and pleural effusion,
respectively. Generally,
79
(31.0%) patients had a bacterial infection, and
9 (3.6%) had a fungal infection.
Common complications included respiratory failure (68 [26.7%] of
patients), followed by acute cardiac injury and acute kidney injury.
There were 136 (57.9%) patients who had received antiviral medication,
and 211 (89.8%) were administrated with antibiotic treatment.
Additionally, 59 (25.1%) patients were given systemic corticosteroids.
Eighty-eight (34.5%) patients were diagnosed with severe pneumonia. The
median length of hospital stay was 13.0 (8.0-21.0) days, and the 120-day
mortality was 11.0%.
Most baseline characteristics, mixed bacterial/fungal infections,
complications, risk assessment, and clinical outcomes were comparable
among influenza, non-influenza, and mixed viral pneumonia.
Patients
with influenza had the highest rate of antiviral use (111, 68.1%) and
the shortest length of hospital stay (12, IQR 7-17 days) compared to the
remainder. Other significant differences were summarized in Table 1.
Pathogens distribution
Low respiratory tract specimens for viral identification were obtained
in 238 (93.3%) patients (117 for
sputum, 53 for ETA, and 68 for BALF respectively). Among all viral
patients, Flu A was the first ranking viral pathogen by the detection
rate of 49% (126/255), followed by Flu B, 15%; SARS-CoV-2, 8%; HRV,
7%; PIV and CoV, 4%; AdV, 3%; RSV, 2%; HMPV, 1%. No bocavirus was
detected. Mixed viral infections were observed in 18 (7%) cases (Figure
1).
Approximately
forty percent of patients had
bacterial/fungal superinfection
(ranging from 38%-50%), except for patients with HMPV and SARS-CoV-2
(5%). Notably, there were no significant differences in the rate of
bacterial/fungal infection by the viral pathogen (χ2=11.490, P = 0.244).
For the 88 (34.5%) patients involving mixed
bacterial/fungal infection, the
diagnosis was confirmed with blood
culture (in 6 cases), pleural fluid (3 cases), low respiratory specimens
culture or PCR (91 cases). Especially, the detection rate of specific
bacteria/fungi etiology were similar among influenza, non-influenza and
mixed viral infection group (Table S1). A total of 129 strains of
pathogens were isolated from 88 patients, and 27 cases of superinfection
were caused by dual or more pathogens.P. aeruginosa (20.5%, 18/88)
and K. pneumonia (19.3%, 17/88) were the most commonly detected
pathogens, followed by A. baumannii (18.2%) and H.
influenza (17.0%). Of note, fungal infections were documented 9
(10.2%) patients (Figure 2). Up to 75% (6/8) of S. aureus were
methicillin-resistant, 53% (9/17) of K. pneumonia resistant to
β-lactam antibiotics, including third-generation cephalosporins and
carbapenems, 33% (6/18) of P. aeruginosa and 31% (5/11) ofA. baumannii resistant to carbapenem. Other details were shown in
Figure 2. Furthermore,
58.1%
(18/31) of antibiotic-resistant bacteria were documented from patients
with ventilation, 83.9% (26/31) from patients with severe pneumonia,
and 48.4% (15/31) from those who died in 120-days after admission.
Severe clinical outcome of bacterial/fungal
superinfection
Clinical and laboratory parameters were compared between
hospitalizations involving viral infection alone to those
with mixed viral-bacterial/fungal
infections.
A
battery of clinical features was profoundly different between the two
groups as indicated in Table 2. Patients with mixed
viral-bacterial/fungal infections had more males, higher rates of
coexisting illness, especially for hypertension, liver disease, and
cancer. These individuals also had a higher incidence of cough, dyspnea
and rales, higher respiratory rate, worse laboratory findings, more
common abnormalities on chest CT of multi-lobular infiltration and
pleural effusion, and worse clinical admission characteristics. Immune
examinations between two groups demonstrated that serum levels of T
cells were decreased in the bacterial/fungal superinfection group (P =
0.003), and the subset of CD8+ T cells declined
further (P = 0.005). There were no differences in antiviral or
antibiotic treatments between patients with or without
bacterial/fungal superinfection.
However, patients with bacterial/fungal superinfection revealed a
dramatic increase in the use of antifungal drugs, systematic
corticosteroids and mechanical ventilation, incidence of complications,
and length of hospital stay as compared with those who suffered viral
infection alone (Table 3). The in-hospital mortality was strikingly
higher in patients with mixed viral-bacterial/fungal infections than in
those without (22.7% vs 2.4%, P < 0.001), especially when
they came from non-ICU wards (non-ICU: 15.8% vs 1.3%, P <
0.001; ICU: 45.2% vs 17.6%, P = 0.057, Figure 3). The Kaplan−Meier
survival curves for patients with and without bacterial/fungal
superinfection showed that the incidence of death within 120 days after
admission was significantly higher in patients with bacterial/fungal
superinfection (HR = 9.708 P < 0.0001) than in those without.
Risk factors of bacterial/fungal
superinfection
To explore the risk factors associated with superinfection, we initially
evaluated each variable that displayed statistical significance with P
< 0.05 in the difference between
patients with and without
superinfection using univariate analysis, and candidate variables were
shown in
Table
2. Considering the total number of
patients with superinfection (N = 88 ) in our study and to avoid
overfitting in the model, ten variables were chosen for further
multivariable analysis based on previous findings and clinical
constraints, namely PaO2/FiO2, BUN,
leukocytosis, lymphocytopenia, ICU
admission within 24 h after hospitalization, need for mechanical
ventilation on admission, comorbidity, D-dimer, rales, and age. Finally,
PaO2/FiO2 < 300 (OR: 2.570,
95% CI: 1.370-4.821, P = 0.003), BUN ≥ 7.1 mmol/L (OR: 4.016, 95% CI:
2.148-7.509, P < 0.001), leukocytosis (OR: 2.769, 95% CI:
1.335-5.741, P = 0.006) and lymphocytopenia (OR: 1.998, 95% CI:
1.086-3.675, P = 0.026) were independent risk factors of superinfection
(Table 4).