Invasive pulmonary aspergillosis in immunocompetent patients hospitalised with influenza A-related pneumonia: a multicenter retrospective study

Invasive pulmonary aspergillosis in immunocompetent patients hospitalised with influenza A-related pneumonia: a multicenter retrospective study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Invasive pulmonary aspergillosis in immunocompetent patients hospitalised with influenza A-related pneumonia: a multicenter retrospective study Liang Chen, Xiudi Han, YanLi Li, Chunxiao Zhang, Xiqian Xing This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-20930/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 09 Sep, 2020 Read the published version in BMC Pulmonary Medicine → Version 1 posted 9 You are reading this latest preprint version Abstract Background Increasing cases of pulmonary aspergillosis (IPA) in immunocompetent patients with severe influenza have been reported. Howevere, the risk factors for occurence and death are largely unknown. Methods Data of hospitalised patients with influenza A-related pneumonia (FluA-p) obtained from five teaching hospitals from 2031 to 2018, were reviewed. Univariate and multivariate logistical regression analyses were performed to determine the risk factors involved in the acquisition and 60-day mortality in IPA patients. Results Of the 693 FluA-p patients included in the study, 3.0% (21/693) were IPA patients with a 60-day mortality of 42.9% (9/21). Adjusted for confounders, a Cox proportional hazard model showed that IPA was associated with increased risk for 60-day mortality [hazard ratio ( HR) 4.336, 95% confidence interval (CI) 1.191-15.784, p = 0.026] in FluA-p patients. A multivariate logistic regression model confirmed that age (odd ratio ( OR) 1.147, 95% CI 1.048-1.225, p = 0.003), systemic corticosteroids use before IPA diagnosis ( OR 33.773, 95% CI 5.681-76.764, p 10×10 9 /L ( OR 1.988, 95% CI 1.028-6.454, p = 0.029) and lymphocytes < 0.8×10 9 /L on admission ( OR 34.813, 95% CI 1.676-73.006, p = 0.022), were related with the acquisition of IPA. Early neuraminidase inhibitor use ( OR 0.290, 95% CI 0.002-0.584, p = 0.021) was associated with a decreased risk for a 60-day mortality in IPA patients. Conclusions Our results showed that IPA worsen the clinical outcomes of FluA-p patients. The risk factors for the acquisition and death were helpful for the clinicians in preventing and treating IPA. Pulmonology Influenza A Pneumonia Invasive pulmonary aspergillosis Risk factor Figures Figure 1 Figure 2 Background Influenza is a respiratory infectious disease, caused by influenza viruses, and which can present seasonal epidemics and pandemics [ 1 – 2 ]. Despite the progress in medical technologies and economic development, influenza still causes considerate complications and mortality [ 3 ]. Following infection by influenza viruses, patients can show a broad spectrum of clinical symptoms, ranging from self-limited upper respiratory tract illness to severe pneumonia and acute respiratory distress syndrome (ARDS) [ 4 ]. It was estimated that every year, 10–20% of the global population experienced symptomatic influenza, including 3–5 million severe illnesses and 260–640 thousand deaths [ 5 ]. Nearly half of severe influenza patients present with pneumonia, which is mostly caused by influenza A [ 6 ]. Influenza pneumonia is often coinfected with other pathogens and this worsen the clinical symptoms and deteriorates the outcomes [ 7 – 8 ]. Previous studies found, that Streptococcus pneumoniae, Staphylococcus aureus and Haemophilus influenzae , were the most common etiologies in coinfected influenza [ 9 ]. The Chinese and American guidelines recommend empiric antibiotics use to fight the pathogens associated with severe influenza [ 10 – 11 ]. Invasive pulmonary aspergillosis mostly and traditionally occurs in immunocompromised hosts, such as patients with hematopoietic stem cell transplantation, granulocyte deficiency and organ transplant recipients; but rarely in those with normal immune function [ 12 – 13 ]. In recent years, more cases of IPA have been reported in severe influenza patients and with increased mortality [ 14 – 16 ]. The most notable was that over 30% of these cases had no classic immunocompromised factors. However, there are limited data on influenza-associated pulmonary aspergillosis (IAPA), especially in prior immunocompetent patients. The incidence and disease characteristics were largely unknown. Identifying those patients with high risk for IPA, remains challenging. We carried out this multicenter retrospective study with the following purposes: ⅰ) to investigate the incidence and risk factors for IPA acquisition in immunocompetent patients hospitalised with influenza A-related pneumonia (FluA-p); ⅱ) to explore the risk factors associated with a 60-day mortality in IAPA patients. Methodology Study Design and Population We screened hospitalised patients for positive influenza A virus RNA using respiratory specimens by reverse transcription polymerase chain reaction (RT-PCR) from microbiology laboratories of five teaching hospitals in Beijing, Shandong and Yunnan Provinces and during the period from 1st January to 31st December 2018 (the details of the five centers are shown in Appendix file 1). From this data, we retrieved all cases had both influenza and radiograph proven pneumonia. Patients were excluded if [ 17 ] (1) age < 14 years; (2) pneumonia onset ≥ 48 hours after admission and not been hospitalised within the last 28 days, because the consensus of nosocomial pneumonia caused by influenza was difficult; (3) Immunocompromised status, including HIV (+),chemotherapy/radiotherapy within 6 months, immunosuppressive therapy, organ/bone marrow transplantation, splenectomy, hematological neoplasms. Immunosuppressive therapy: was defined as systmatic glucocorticosteroid (such as prednisone ≥ 10 mg/d for more than 3 weeks in the last month); cyclosporine or azathioprine use within 3 months, and methotrexate use ≥ 12.5 mg/week within 3 months; biological modifiers such as etanercept and infiximab within 3 weeks. Group Division We divided the patients into two groups: the case group included patients with FluA-p, who subsequently became infected with proven and/or probable invasive pulmonary aspergillosis (IPA group); and the control group that included patients with FluA-p and who showed no evidence of Aspergillus infection while hospitalised. Study Definitions Patients with FluA-p were defined as patients with respiratory symptoms and a new pulmonary infiltrate on the chest radiograph, combined with positive influenza virus A RT-PCR testing during the influenza seasons. A Proven IPA was defined as the microscopic evidence of dichotomous branching hyphae with a positive culture for Aspergillus through an endobronchial biopsy, irrespective of host factors or clinical features [ 18 ]. According to the revised definitions of invasive fungal diseases from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) in 2019 [ 18 ], a probable IPA required a host factor, clinical features and mycological evidence of aspergillosis. However, these criteria were created for immunosuppressed hosts and influenza-related aspergillosis may occur in previously normal hosts. Thus, the host factors were not required in our study. The clinical features included one of the following signs or symptoms: refractory fever to at least 3 days of appropriate antibiotic treatment; recrudescent fever after a period of defervescence of at least 48 h, while still on antibiotics and without other apparent cause; dyspnea; hemoptysis; pleural friction rub or chest pain; worsening respiratory insufficiency in spite of appropriate antibiotic therapy and ventilatory support. The radiological criteria included any infiltrates on pulmonary imaging detected by chest x-ray or CT scan of the lungs. The mycological evidence included: a positive Aspergillus culture from a bronchoalveolar lavage (BAL); a galactomannan (GM) optical index on BAL of ≥ 1.0; a GM optical index on serum of ≥ 1.0; GM optical index on single serum of ≥ 0.7 and BAL of ≥ 0.8. Early neuraminidase inhibitor (NAI) treatment was defined as any NAI (e.g., oseltamivir, zanamivir and peramivir) administered within 2 days after disease onset [ 10 – 11 ]. The coinfection with other Aspergillus pathogens was defined by community-acquired respiratory co-pathogens that was identified within 2 days of hospital admission [ 19 ]. The conditions of a community-acquired respiratory co-pathogen was defined as the definite or probable etiology (Appendix 3). Immunocompetent hosts were defined as patients without immunocompromised factors described above. Data Collection: Data was retrospectively collected and included demographic information, underlying disease (Appendix 2), clinical manifestations, laboratory and radiological findings, microbiologic diagnosis, treatment (use of antiviral agents, corticosteroids, vasopressors and mechanical ventilation), clinical outcomes (complications during hospitalisation, admittance to the intensive care unit (ICU) and a 60-day mortality). Statistical analysis All data were analyzed with SPSS 22.0 and measurement data were tested for normality by Kolmogorov-Smirnov. The measurement data of normal distributions were reported as mean ± standard deviation. Measurements data of non-normal distributions were reported as median. The categorical variables were analyzed by the Chi-square test or Fisher’s exact test, and continuous variables were analyzed by the student t-test or the Mann–Whitney U-test. A p-value of < 0.05 was considered statistically significant and all probabilities were two-tailed. A Cox proportional hazard model was performed to evaluate the effect of IPA on a 60-day mortality in FluA-p patients. The model was adjusted by age, gender, comorbidities, leukocytes > 10 × 10 9 /L, serum procalcitonin > 0.1 ng/ml, coinfection with non- Aspergillus pathogens and early use of neuraminidase inhibitors. The clinical characteristics were compared between patients in the IPA and control groups (Table 1 ). Variables with p-values of ≤ 0.05 on univariate analysis were subsequently entered into the backward stepwise logistic regression analysis to identify risk factors for the acquisition and death in IPA patients. Table 1 Demographic and clinical characteristics between the two groups Variables Total ( n = 693) IPA group ( n = 21) Control group ( n = 672) p - value # Age (years, median, IQR) 61.0 (36.0–76.0) 67.0 (61.0–82.0) 60.0 (36.0–76.0) < 0.001 Male ( n , %) 461(66.5) 18 (85.7) 443 (65.9) 0.058 BMI (kg/m 2 , mean ± SD) 24.4 ± 3.6 21.5 ± 0.4 24.5 ± 3.6 0.014 Comorbidities ( n , %) 402 (58.0) 18 (85.7) 384 (57.1) 0.009 Diabetes mellitus 92 (13.3) 15 (71.4) 77 (11.5) < 0.001 Cerebrovascular disease 72 (10.4) 4 (19.0) 68 (10.1) 0.338 COPD 40 (5.8) 6 (28.6) 34 (5.1) 0.999 Chronic congestive heart failure 3 (0.4) 3 (14.3) 0 (0.0) < 0.001 Smoking history ( n , %) 243 (35.1) 7 (33.3) 236 (35.1) 0.866 Alcoholism history ( n , %) 92 (13.3) 0 (0.0) 92 (13.7) 0.135 Antibiotics use before admission ( n , %) 587 (84.7) 15 (71.4) 572 (85.1) 0.159 Clinical characteristics ( n , %) Confusion 32 (4.6) 0 (0.0) 32 (4.8) 0.620 SBP 10 × 10 9 /L 118 (17.0) 15 (71.4) 103 (15.3) < 0.001 Lymphocytes < 0.8 × 10 9 /L 299/677 (44.2) 15 (71.4) 284/656 (43.3) 0.011 HB < 100 g/L 69 (10.0) 5 (23.8) 64 (9.5) 0.075 Albumin 11 mmol/L 48 (6.9) 0 (0.0) 48 (7.1) 0.405 BUN > 7 mmol/L 183/685 (26.7) 9 (42.9) 174/664 (26.2) 0.090 Serum PCT > 0.1 ng/ml 248/541 (45.8) 2 (9.5) 246/520 (47.3) 0.001 PO 2 /FiO 2 < 300 mmHg 340/639 (53.2) 16 (76.2) 324/618 (52.4) 0.032 Radiology ( n , %) Cavity 19 (2.7) 3 (14.3) 16 (2.4) 0.009 Multiple nodules 151 (21.8) 8 (38.1) 143 (21.3) 0.116 ICs use before IPA diagnosis ( n , %) 3 (0.4) 3 (14.3) 0 (0.0) < 0.001 Systemic corticosteroids use before IPA diagnosis ( n ,%) 132 (19.0) 18 (85.7) 114 (17.0) < 0.001 Dose of systemic corticosteroids a (mg/kg, mean ± SD) 0.6 ± 0.3 0.6 ± 0.3 0.6 ± 0.3 0.853 Early NAIs b use ( n , %) 232 (33.3) 10 (47.6) 222 (33.0) 0.163 Coinfection with other community-acquired pathogens ( n , %) 265 (38.2) 3 (14.3) 262 (39.0) 0.016 IQR: interquartile range; SD: standard deviation; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SBP: systolic blood pressure; RR: respiratory rates; WBC: white blood cell count; HB: hemoglobin; BG: blood glucose; BUN: blood urea nitrogen; PCT: procalcitonin; PO 2 /FiO 2 : arterial pressure of oxygen/fraction of inspiration oxygen; ICs: inhaled corticosteroids; NAIs: neuraminidase inhibitors; a: methylprednisolone or its equivalent; b: Neuraminidase inhibitors refer to any dose of oseltamivir, zanamivir, and peramivir; # : IPA group vs control group. The bolded values are p-values < 0.05, which represent significant differences between subgroups. Results Screening Process We screened 2187 hospitalised patients with positive influenza A RNA. Overall, 693 immunocompetent adults and adolescent patients hospitalised with FluA-p onset in the community were entered into the final analysis. The proportion of patients who developed IPA during hospitalisation was 3.0% (21/693) (Fig. 1 ). Overview Of Patients With FluA-p Overall, the median age was 61.0 years old and the male accounted for 66.5% (461/693). Fifty-eight percent of patients (402/693) had at least one underlying disease with the top three being diabetes mellitus 13.3% (92/693), cerebrovascular disease 10.4% (72/693) and chronic obstructive pulmonary disease 5.8% (40/693). The proportion of patients with PO 2 /FiO 2 < 300 mmHg was 53.2% (340/639). Cavities and multiple nodules in chest radiology were seen in 2.7% (19/693) and 21.8% (151/693) of patients, respectively. Nineteen percent (132/693) of FluA-p patients used a systemic dose of 0.6 ± 0.3 mg/kg corticosteroids before IPA diagnosis. All patients were administrated with NAI during the disease course, while 33.3% (231/693) received NAIs within the 48hrs after illness onset. 24.1% (167/693) of patients had complications with respiratory failure, 21.2% (147/693) had heart failure, 5.2% (36/693) had septic shocks during hospitalisation, 26.3% (182/693) of patients were admitted to intensive care unit (ICU) and the 60-day mortality was 20.9% (145/693) (Table 1 ). Comparisons Between The IPA And Control Patients Compared with control patients, the IPA patients were older (67.0 yrs vs. 60.0 yrs, p < 0.001), had more frequency of diabetic (71.4% vs. 11.5%, p < 0.001), chronic pulmonary disease (28.6% vs 5.1%, p < 0.001), asthma (14.3% vs. 2.4%, p = 0.009) and chronic heart failure (14.3% vs. 0.0%, p 10 × 10 9 /L (71.4% vs. 15.3%, p < 0.001), lymphocytes < 0.8 × 10 9 /L (71.4% vs. 43.3%, p = 0.011), albumin < 35 g/L (28.6% vs. 8.4%, p = 0.006), PO 2 /FiO 2 0.1 ng/ml (9.5% vs. 47.3%, p = 0.001) was more common in the control patients. More IPA patients used corticosteroids inhalers (14.3% vs. 0.0%, p < 0.001 ) and systemic corticosteroids (85.7% vs. 17.0%, p < 0.001) before IPA diagnosis. However, no significant differences in the dose of systemic corticosteroids was observed. Complications of respiratory failure (100.0% vs. 21.7%, p < 0.001), heart failure (42.9% vs. 20.5%, p = 0.028) and septic shock (85.7% vs. 2.7%, p < 0.001 ) were more frequent in IPA patients. The proportion of patients needing noninvasive ventilation (42.9% vs. 22.3%, p = 0.014), invasive ventilation (85.7% vs. 20.8%, p < 0.001) and vasopressor use (52.4% vs. 2.4%, p < 0.001), were higher in IPA patients. More IPA patients were admitted to ICU (71.4% vs. 24.9%, p < 0.001) and had a higher 60-day mortality rate (42.9% vs. 18.9%, p = 0.015) (Table 2 ). Table 2 Supportive treatments and clinical outcomes between the two groups Variables Total ( n = 693) IPA group ( n = 21) Control group ( n = 672) p-value # Vasopressor use ( n , %) 27 (3.9) 11 (52.4) 16 (2.4) < 0.001 Length of vasopressor use (days, median, IQR) 1.0 (0.5-3.0) 2.0 (0.5–4.5) 1.5 (1.0–2.0) 0.185 Noninvasive ventilation ( n , %) 159 (22.9) 9 (42.9) 150 (22.3) 0.014 Length of noninvasive ventilation (days, median, IQR) 4.0 (1.0–8.0) 2.0 (2.0–10.0) 5.0 (1.0–8.0) 0.009 Invasive ventilation ( n , %) 158 (22.8) 18 (85.7) 140 (20.8) < 0.001 Length of invasive ventilation (days, median, IQR) 4.0 (1.0–9.0) 9.0 (7.0–11.0) 4.0 (1.0–9.0) 0.003 Complications during hospitalisation ( n , %) Respiratory failure 167 (24.1) 21 (100.0) 146 (21.7) < 0.001 Heart failure 147 (21.2) 9 (42.9) 138 (20.5) 0.028 Septic shock 36 (5.2) 18 (85.7) 18 (2.7) 0.999 Admittance to ICU (n, %) 176 (26.3) 15 (71.4) 161 (24.0) < 0.001 Length of stay in ICU (days, median, IQR) 8.0 (6.0–13.0) 9.0 (7.0–11.0) 8.0 (6.0–13.0) 0.473 LOS (days, median, IQR) 10.0 (8.0–14.0) 24.0 (11.0–42.0) 10.0 (7.0–13.0) < 0.001 60-day mortality ( n , %) 136 (19.6) 9 (42.9) 127 (18.9) 0.015 LOS: length of stay in hospital; ICU: intensive care unit; # : IPA group vs control group. The bolded values are p-values < 0.05, which represent significant differences between subgroups. Diagnosis Of IPA The mean duration from the diagnosis of IPA to the day of admission was 6.4 ± 4.8 days, with a range of 2–18 days. A serum GM test was performed in 15 of the 21 IPA patients. Seventeen IPA patients were subjected to a GM test in BAL. Only one patient had a GM optical index on serum of ≥ 1.0; while, 12 patients had a GM optical index on BAL of ≥ 1.0, six patients a GM optical index of single serum of ≥ 0.7 and BAL of ≥ 0.8. In all 21 IPA patients, a BAL culture was performed that led to the identification of Aspergillus in 6 patients’ cultures. Two patients were diagnosed as proven IPA by trans-bronchial lung biopsy (both were Aspergillus fumigatus ). A probable IPA diagnosis was performed in 19 of the 21 IPA patients (Table 3 ). Table 3 Diagnosis of IPA Variables IPA group ( n = 21) Control group ( n = 672) Serum GM test ( n , %) 15 (71.4) 322 (47.9) BAL GM test ( n , %) 17 (81.0) 167 (24.9) Serum GM ≥ 1.0 1 (4.8) 0 (0.0) BAL GM ≥ 1.0 12 (60.0) 0 (0.0) Single serum GM ≥ 0.7 and BAL GM ≥ 0.8 6 (28.6) 0 (0.0) BAL Aspergillus culture ( n , %) 21 (100.0) 146 (21.7) Positive 6 (28.6) 0 (0.0) Lung tissue microscopy ( n , %) 4 (19.0) 18 (2.7) Positive 2 (9.5) 0 (0.0) Proven IPA ( n , %) 2 (9.5) 0 (0.0) Probable IPA ( n , %) 19 (90.5) 0 (0.0) GM: galactomannan; BAL: bronchoalveolar lavage Coinfection with non- Aspergillus pathogens isolated in FluA-p patients Coinfection with other community-acquired pathogens was diagnosed in only 3 of 21 IPA patients and 1 patient was diagnosed with S. pneumoniae , 1 patient with P. aeruginosa and 1 with K. pneumoniae . While, 39.0% (262/672) of control patients were diagnosed with non- Aspergillus etiologies, S. pneumoniae was the most common diagnosed pathogen with 33.2% (87/262), followed by K. pneumoniae 30.5% (80/262) and Staphylococcus aureus 20.6% (54/262) (Appendix file 4). Effect of IPA on the 60-day mortality of FluA-p patients Adjusted for age, gender, comorbidities, blood leukocyte counts > 10 × 10 9 /L, serum PCT > 0.1 ng/ml, coinfection with other pathogens and early NAIs use, a Cox proportional hazard model showed that IPA was associated with an increased risk in the 60-day mortality of FluA-p patients [hazard ratio ( HR) 4.336, 95% confidence interval (CI) 1.191–15.784, p = 0.026) (Table 4 ). Table 4 The impact of IPA on the 60-day mortality in FluA-p patients Variable Univariate Cox regression Multivariate Cox regression HR (95% CI) p - value *adjusted HR (95%CI) p - value IPA 3.219 (1.328–7.803) 0.010 4.336 (1.191–15.784) 0.026 HR: hazard ratio; CI: interval confidence *adjusted by age, gender, comorbidities( chronic pulmonary disease, cerebrovascular disease, asthma, diabetes mellitus, chronic kidney disease, malignant solid tumor, chronic congestive heart failure), leukocytes > 10 × 10 9 /L, serum procalcitonin > 0.1 ng/ml, coinfection with non- Aspergillus other pathogens, early NAIs use. Kaplan-Meier survival curve showed that the 60-day mortality of the IPA patients was significantly higher than that of the control patients ( p = 0.006 for the log rank test) (Fig. 2 ). Risk Factors Associated With Ipa Occurrence In FluA-p Patients To explore the risk factors for IPA acquisition, the following variables were entered into the backstep logistic regression model: age, BMI, diabetes mellitus, asthma, chronic congestive heart failure, leukocytes > 10 × 10 9 /L, lymphocytes < 0.8 × 10 9 /L, albumin 0.1 ng/ml, cavity on chest radiology, use of inhaled corticosteroids and systemic corticosteroids before IPA diagnosis, and coinfection with other community-acquired pathogens, and the analyses led to the following results: age ( OR 1.147, 95% CI 1.048–1.225, p = 0.003), systemic corticosteroids use before IPA diagnosis ( OR 33.773, 95% CI 5.681–76.764, p 10 × 10 9 /L ( OR 1.988, 95% CI 1.028–6.454, p = 0.029) and lymphocytes < 0.8 × 10 9 /L on admission ( OR 34.813, 95% CI 1.676–73.006, p = 0.022). These results were proven to be independently related to the IPA acquisition in FluA-p patients (Table 5 ). Table 5 Predictors for acquisition and 60-day mortality of IPA in FluA-p patients Predictors for IPA acquisition p - value OR (95% CI) Age 0.003 1.147 (1.048–1.225) Systemic corticosteroids use before IPA diagnosis 10 × 10 9 /L 0.029 1.988 (1.028–6.454) Lymphocyts < 0.8 × 10 9 /L 0.022 34.813 (1.676–73.006) Predictors for 60-day mortality of IPA patients Early NAIs use 0.021 0.290 (0.002–0.584) OR: odd ratio Predictors for a 60-day mortality of IPA in FluA-p patients The demographic features and comorbidities were similar between the survival and deceased patients with IPA. Of the 21 patients that received an antifungal treatment within 24 hours after IPA diagnosis, 18 patients used voriconazole and 3 patients used a combination treatment (voriconazole + echinocandin). However, no significant difference was found in antifungal therapy between the two groups. Compared with the survival group, the deceased patients’ group had a higher proportion of lymphocytes < 0.8 × 10 9 /L (100.0% vs 50.0%, p = 0.043) and lower proportion of early NAIs use (11.1% vs 75.0%, p = 0.014) (Appendix file 5). A multivariate logistic regression model confirmed early NAIs use ( OR 0.290, 95% CI 0.002–0.584, p = 0.021) and that was the only predictor for the 60-day mortality in IPA patients (Table 5 ). Discussion Our study has two important findings: 1) the prevalence of IPA in immunocompetent adult and adolescent patients hospitalised with FluA-p, was 3.0%. However, it was associated with increased mortality; 2) we identified age, leukocytes, lymphocytes and systemic corticosteroids use as risk factors for IPA diagnosis. Early NAIs use was related to better outcomes, which were helpful in the prevention and treatment of IPA patients with severe influenza. There are rare data on the incidence of IPA among all hospitalised FluA-p patients and previous studies were limited to patients admitted to ICU. In our study, the incidence of IPA in ICU patients was 8.2%, which was consistent with the 7.2–8.8% reported by Rice [ 20 ] and Martin-Loeches [ 21 ]; but, this was lower than the reported 19.2% in the Schauwvlieghe’s study [ 22 ]. Further analysis revealed that all IPA patients had respiratory failure complications and an IPA incidence of 12.6%. This observation is very close to that of the Schauwvlieghe’s study, in which the IPA incidence was 14.2% in non-immunocompromised severe influenza patients. The difference in reported IPA incidences could be explained by the severity of influenza illness, the detection capability of IPA and the discrepancy in ICU admission criteria in the different medical systems. Although the IPA incidence in our study was not high, the 60-day mortality was as high as 42.9%, which was in accordance with previous reports of 33–71% [ 12 , 14 – 16 , 19 , 22 – 24 ]. The prevalence of respiratory failure and septic shock complications was also significantly higher than that of patients without IPA. In addition to the genetic background, there were at least two reasons for the difference in mortality among those studies: 1) the influence of the patients’ immunity status before influenza onset. In the Schauwvlieghe’s study [ 22 ], the 90-day mortality in immunocompetent patients with IPA, was 33%; while, it was 71% in patients with immunocompromised factors. Among Huang’s research population [ 24 ], 24% received immunosuppressive agents and the overall ICU mortality was 41.3%. All the patients in our study were previously immunocompetent and the mortality was lower than that in the previously reported immunocompromised patients’ studies. 2) the outcomes were profoundly affected by the awareness, timing and approach of pathogenic testing that were performed for invasive aspergillosis, leading to a delayed IPA diagnosis and treatment. For example, a center in the Schauwvlieghe’s [ 22 ] study paid more attention to IPA because of several previous reports. As a result, the diagnostic and survival rate of IPA were much higher than that in other centers. Adjusted by age, sex, comorbidities, early use of NAIs and probable co-infection with other etiologies, a Cox proportional hazard model showed, that IPA independently increases the risk for 60-day mortality in FluA-p patients, by 3 times. Our results implied the importance of IPA screening in patients with severe influenza pneumonia, regardless of their previous immunity status. This allows an early diagnosis in patients, that prompts carrying out an antifungal treatment, as soon as possible. In our study, IPA patients were older in age and with frequent comorbidities. Diabetes and chronic airway diseases (such as COPD and asthma) were the most common underlying diseases. Hypoproteinemia was common, suggesting that their nutritional statuses were poor. When the radiological findings of IPA patients were reviewed, it showed mainly pulmonary infiltrates, with a slightly higher proportion of cavities than the control patients; but, no obvious halo sign was found. Previous studies also showed that the halo sign was only seen in less than 5% of patients with secondary IPA influenza [ 25 – 26 ]. The multivariate logistic regression analysis confirmed, that age, increased leukocyte counts, decreased lymphocyte counts and systemic corticosteroids use, were independent risk factors for the acquisition of IPA in immunocompetent patients hospitalised with FluA-p. It is believed that the pathogenesis of invasive aspergillosis, in the setting of influenza infection, may be due to both local and systemic effects of the virus. Local effects include influenza and inflammation damage of the bronchoalveolar epithelial cells, that lead to the impairment of the barrier function and dysfunction of ciliary motility and clearance [ 27 ]. Systemically, influenza alters the Th1/Th2 balance and causes lymphopenia. The immune function of the elderly patients significantly decreased, and their resistance to infection was poor. Previous studies also showed that elderly influenza patients, were more vulnerable to secondary infections [ 28 ]. Elevated leukocyte counts in influenza pneumonia patients is usually associated with bacterial or fungal coinfection; while, serum PCT is a relatively specific biomarker of bacterial infection [ 29 ]. In our study, more than 90% of IPA patients had a serum PCT of < 0.1 ng/ml, indicating that the coinfection with bacteria was not common. Therefore, the elevated leukocytes with normal serum PCT level, strongly suggested fungal infection. Lymphocytes reflected the function of cellar immunity, which was the main anti-viral mechanism in humans. The suppression of cellar immunity delays the clearance of the virus, along with a more serious damage of airway, thus creating conditions for an invasive Aspergillus infection. The steroids are the most common immunomodulators in clinic, with powerful depressive effects on both cellar immunity and humoral immunity. Corticosteroids use often causes secondary fungal infection [ 30 ]. Our study confirmed the association of systemic corticosteroids use and occurrence of IPA as previously reported [ 22 , 24 ]. Meanwhile, we found, that even a low-to-moderate dose and short-term systemic corticosteroids use, would increase the risk for of IPA acquisition in the predisposition to immune suppression, caused by severe influenza. Traditionally, it was believed that a prolonged use of steroids (at least 3 weeks and a prednisone equivalent of > 0.3 mg/kg/d) was related to IPA occurrence [ 31 ]. It should be noted that there may be overuse of systemic steroids in influenza patients. In numerous reports, more than 50% of influenza patients received systemic corticosteroids, which were proven to be associated with poor outcomes [ 32 – 33 ]. In our study, 19% of FluA-p patients received systemic steroids during hospitalisation. Although in severe influenza, uncontrolled immune response is involved in organic damage and increased mortality. In animal models, corticosteroid treatment was found to decrease mortality and ameliorate acute lung injury induced by influenza [ 34 ]. By now, except for septic shock patients with vasopressor-dependence or adrenal insufficiency, there is no consensus on steroids use in the treatment of severe influenza. Our study confirmed, that the systemic steroids use, was associated with increased risk for IPA and with an unacceptable high mortality, and even in prior immunocompetent FluA-p patients. Therefore, we thought that it was urgent to regulate the use of systemic corticosteroids in the influenza setting. In our study, early NAIs use was proven to be the only predictor associated with better outcomes in IAPA patients, by decreasing the risk of more than 70% for a 60-day mortality. Previous studies also proved that the sooner NAIs were used, the better were the outcomes in severe influenza patients [ 35 – 36 ]. According to the mechanism of IAPA, it is reasonable that early inhibition of viral duplication and alleviation of lung damage, caused by virus and inflammation, can create favorable conditions for controlling the occurrence and development of IAPA. However, why early use of NAIs had not shown a decrease in the risk for IAPA incidence, was still unclear. Apart from the small size of the population, our study implies that there is a complex pathogenesis for IPA occurrence in severe influenza patients. As far as we know, this was the only investigation focused on IPA in immunocompetent patients hospitalised with FluA-p. Unlike other studies that were limited to ICU patients, our study included, not only patients in ICU, but also patients from general wards. IPA patients, that were not admitted to ICU in other studies and for some reasons, could be included into our population; which, reduced the selective bias. In addition, the population in our study had no classic immunocompromised factors. The occurrence of IPA in these patients was most likely to be neglected. Therefore, the results of our study provide a great significance for clinicians as it allows to identify patients with increased risk for IPA acquisition and at an early stage, advocating therefore, a prompt prevention and treatment. There were some limitations specific to our study: 1) Besides the nature of the retrospective study, the relatively small sample size along with some missing data, might limit the accuracy of the results; 2) Though the latest diagnostic criteria of IPA was used, the proportion of the microbiologic examinations for IPA in the control patients, was low. Especially, BAL samples were only performed in less than 25%; while, a serum GM testing was performed in 47% of control patients. A study by Zhou et al [ 37 ] showed that in nonneutropenic patients, even at a cutoff value of ≥ 1.0, the sensitivity of serum GM detection was still much lower than that of BAL GM detection (24.32% versus 64.86%; p < 0.001). In addition, the triggers to perform BAL were not clarified due to the restrospective study design, and IPA complicating influenza might develope post-admission. This may have limited the number of true cases found and caused selective bias. Therefore, the actual IPA incidence in our study might be under-detected; 3) more than 1/3 of the patients had not performed influenza subtype testing and other respiratory tract viruses were not routinely detected. Thus, we could not exclude coinfection with other viruses. Conclusions Our study showed that there is approximatively 3.0% of IPA incidence with an increased mortality that was observed even in immunocompetent patients, hospitalised with FluA-p. Additionally, we identified age, elevated leukocytes, reduced lymphocytes, on the day of admission and systemic corticosteroids use, as risk factors for IPA acquisition, and that early NAIs use was a predictor of better outcome. Meanwhile, it is suggested that these results should be confirmed using prospective and large sample studies to further verify these conclusions. Abbreviations Flu-p: Influenza-related pneumonia; IPA: Invasive pulmonary aspergillosis; NAI: Neuraminidase inhibitor; OR: Odds ratio; HR: Hazard ratio; 95% IC: 95% Interval confidence; FluA-p: Influenza A-related pneumonia; RT-PCR: Reverse transcription polymerase chain reaction; EORTC/MSG: European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group; BAL: Bronchoalveolar lavage; GM: galactomannan; 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; PH: Hydrogen ion index；pO2/FiO2: Arterial pressure of oxygen/fraction of inspiration oxygen; ICs: inhaled corticosteroid; PCT: procalcitonin; ICU: Intensive care unit. Declarations Ethics approval and consent to participate The study design was approved by the Ethics Committee of Beijing Jishuitan Hospital (No.201911-15). Given the retrospective nature of the study, the Ethics Committee determined that an informed consent was not necessary. Consent for publication Not applicable Availability of data and materials All data generated or analysed during this study are included in this published article and its supplementary information files. Competing interests The authors declare that they have no competing interests. Funding This study is founded by Beijing JST research (ZR-201921). Authors' contributions Study concept and design: LC, XdH. Acquisition of data: LC, XdH, YlL, CxZ, XqX. Statistical analysis of data: LC. Drafting of the manuscript: LC. Critical revision of the manuscript for important intellectual content: XdH, XqX. All authors agree with the article submission. All authors read and approved the final manuscript. Acknowledgments We thank Dr. Bai and Dr. Zhang (Infectious Disease Department, Beijing Jishuitan Hospital) for their valuable comments on the manuscript. Authors' information Department of Infectious Disease, Beijing Jishuitan Hospital, 4th Medical College of Peking University, Beijing, China. 2. Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao City, Shandong Province, China. 3. Department of Infectious Diseases and Clinical Microbiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. 4. Department of Pulmonary and Critical Care Medicine, Beijing Huimin Hospital, Beijing, China. 5. Department of Pulmonary and Critical Care Medicine, the 2 nd People’s Hospital of Yunnan Province, Kunming City, Yunnan Province, China. Conflicts of Interest None. References Peteranderl C, Herold S, Schmoldt C. Human Influenza Virus Infections. Semin Respir Crit Care Med. 2006;37(4):487–500. Neuzil KM, Bresee JS, de la Hoz F, Johansen K, Karron RA, Krishnan A, et al. Data and product needs for influenza immunization programs in low- and middle-income countries: Rationale and main conclusions of the WHO preferred product characteristics for next-generation influenza vaccines. Vaccine. 2017;35(43):5734–37. Dahal S, Jenner M, Dinh L, Mizumoto K, Viboud C, Chowell G. Excess mortality patterns during 1918–1921 influenza pandemic in the state of Arizona, USA. Ann Epidemiol. 2016;28(5):273–80. Kumar V. Influenza in Children. Indian J Pediatr. 2017;84(2):139–43. Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analfor the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095–128. Li M, Bolker BM, Dushoff J, Ma J, Earn DJD. Patterns of seasonal and pandemic influenza-associated health care and mortality in Ontario, Canada. BMC Public Health. 2019;19(1):1237. Klein EY, Monteforte B, Gupta A, Jiang W, May L, Hsieh YH, Dugas A. The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza Other Respir Viruses. 2016;10(5):394–403. Kylla H, Dutta TK, Roychoudhury P, Subudhi PK. Coinfection of diarrheagenic bacterial and viral pathogens in piglets of Northeast region of India.Vet World. 2019; 12(2): 224–30. Brundage JF. Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness. The Lancet Infectious diseases. 2016;6(5):303–12. Harper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG, et al. Seasonal influenza in adults and children–diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2019;48(8):1003–32. Cao B, Huang Y, She DY, Cheng QJ, Fan H, Tian XL, et al. Diagnosis and treatment of community-acquired pneumonia in adults: 2016 clinical practice guidelines by the Chinese Thoracic Society, Chinese Medical Association. Clin Respir J. 2018;12(4):1320–60. Cadena J, Thompson GR 3rd, Patterson TF. Invasive Aspergillosis: Current Strategies for Diagnosis and Management. Infect Dis Clin North Am. 2016;30(1):125–42. Solano C, Vázquez L. Invasive aspergillosis in the patient with oncohematologic disease. Rev Iberoam Micol. 2018;35(4):198–205. Alshabani K, Haq A, Miyakawa R, Palla M, Soubani AO. Invasive pulmonary aspergillosis in patients with influenza infection: report of two cases and systematic review of the literature. Expert Rev Respir Med. 2015;9(1):89–96. Kim SH, Kim MN, Lee SO, Choi SH, Kim YS, Woo JH, et al. Fatal pandemic influenza A/H1N1 infection complicated by probable invasive pulmonary aspergillosis. Mycoses. 2012;55(2):189–92. Lat A, Bhadelia N, Miko B, Furuya EY, Thompson GR 3rd. Invasive aspergillosis after pandemic (H1N1) 2009. Emerging infectious diseases. 2010; 16(6): 971–3. Chen L, Zhou F, Li H, Xing X, Han X, Wang Y, et al. Disease characteristics and management of hospitalised adolescents and adults with community-acquired pneumonia in China: a retrospective multicentre survey. BMJ Open. 2018;8(2):e018709. Donnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2019; pii, ciz1008. Ku YH, Chan KS, Yang CC, Tan CK, Chuang YC, Yu WL, et al. Higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections. J Formos Med Assoc. 2017;116(9):660–70. Rice TW, Rubinson L, Uyeki TM, Vaughn FL, John BB, Miller RR 3rd, et al. Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States. Crit Care Med. 2012;40(5):1487–98. Martin-Loeches I, Schultz J, Vincent M, Alvarez-Lerma JL, Bos F, Solé-Violán LD. J,, et al. Increased incidence of co-infection in critically ill patients with influenza. Intensive Care Med. 2017;43(1):48–58. Schauwvlieghe AFAD, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med. 2018;6(10):782–92. Cattaneo C, Gramegna D, Malagola M, Pagani C, Borlenghi E, Cerqui E, et al. Invasive pulmonary aspergillosis in acute leukemia: a still frequent condition with a negative impact on the overall treatment outcome. Leuk Lymphoma. 2019;60(12):3044–50. Huang L, Zhang N, Huang X, Xiong S, Feng Y, Zhang Y, et al. Invasive pulmonary aspergillosis in patients with influenza infection: A retrospective study and review of the literature. Clin Respir J. 2019;13(4):202–11. Vandewoude KH, Blot SI, Depuydt P, Benoit D, Temmerman W, Colardyn F, Vogelaers D. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Crit Care. 2006;10(1):R31. Park SY, Lim C, Lee SO, Choi SH, Kim YS, et al. Computed tomography findings in invasive pulmonary aspergillosis in non-neutropenic transplant recipients and neutropenic patients, and their prognostic value. J Infect. 2011;63(6):447–56. Crum-Cianflone NF. Invasive Aspergillosis Associated With Severe Influenza Infections. Open Forum Infect Dis. 2016;3(3):ofw171. Rosano A, Bella A, Gesualdo F, Acampora A, Pezzotti P, Marchetti S, et al. Investigating the impact of influenza on excess mortality in all ages in Italy during recent seasons (2013/14-2016/17 seasons). Int J Infect Dis. 2019;88:127–34. Choi JJ, McCarthy MW. Novel applications for serum procalcitonin testing in clinical practice. Expert Rev Mol Diagn. 2018;18(1):27–34. Lionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet. 2003;362(9398):1828–38. Karthaus M, Buchheidt D. Invasive aspergillosis: new insights into disease, diagnostic and treatment. Curr Pharm Des. 2013;19(20):3569–94. Ni YN, Chen G, Sun J, Liang BM, Liang ZA. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care. 2019;23(1):99. Li H, Yang SG, Gu L, Zhang Y, Yan XX, Liang ZA, et al. Effect of low-to-moderate-dose corticosteroids on mortality of hospitalised adolescents and adults with influenza A(H1N1)pdm09 viral pneumonia. Influenza Other Respir Viruses. 2017;11(4):345–54. Ghoneim HE, McCullers JA. Adjunctive corticosteroid therapy improves lung immunopathology and survival during severe secondary pneumococcal pneumonia in mice. J Infect Dis. 2014;209(9):1459–68. Osthoff M, Erb S. Neuraminidase Inhibitors and Influenza Infection. JAMA Intern Med. 2016;176(3):415. Muthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Lim WS, Al Mamun A, et al. Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an individual participant data meta-analysis. Influenza Other Respir Viruses. 2016;10(3):192–204. Zhou W, Li H, Zhang Y, Huang M, He Q, Li P, et al. Diagnostic Value of Galactomannan Antigen Test in Serum and Bronchoalveolar Lavage Fluid Samples from Patients with Nonneutropenic Invasive Pulmonary Aspergillosis. J Clin Microbiol. 2017;55(7):2153–61. Supplementary Files Appendix.docx Cite Share Download PDF Status: Published Journal Publication published 09 Sep, 2020 Read the published version in BMC Pulmonary Medicine → Version 1 posted Review # 2 received at journal 26 Apr, 2020 Review # 1 received at journal 26 Apr, 2020 Reviewer # 2 agreed at journal 25 Apr, 2020 Reviewer # 1 agreed at journal 22 Apr, 2020 Reviewers invited by journal 21 Apr, 2020 Editor assigned by journal 15 Apr, 2020 Submission checks completed at journal 08 Apr, 2020 Editor invited by journal 08 Apr, 2020 First submitted to journal 02 Apr, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-20930","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":478316,"identity":"52dff37d-4360-491d-8f39-29aa4f5b1085","order_by":1,"name":"Liang Chen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA90lEQVRIiWNgGAWjYDACCSB+YAAkmJkPPv5RwcBDnJYEkBZ2tmRjhjNEawEx+HnMpBnbiHAX/+zmYw8SCuzy5J2BWgrn1cmYsx9g/PAxB48ld46lGyQYJBcbHmYrtp657TCPZU8Cs+TMbbi1GEjkmEkkGDAnbmxm3niDd9sBHoMDCWzMvHi15H8DaqkHagGyeefU8Ricf0BISw4bUMvhxPnMLEbSvA3MPAY3CNgicSMN5LDjiRuY2ZINZxw7DNTysBmvX/hnJD+T+PCnOnF+/+GDDz7U1NkbnE8++OEjHi0IFx6AMxkbiFAPBPJEqhsFo2AUjIIRCAAjgE8l0P3slAAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-3147-5688","institution":"Beijing JISHUITAN Hospital, China","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Liang","middleName":"","lastName":"Chen","suffix":""},{"id":478317,"identity":"0a6750e4-4212-4e8b-a641-9e80c7c0797a","order_by":2,"name":"Xiudi Han","email":"","orcid":"","institution":"Qingdao Municipal Hospital Group","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiudi","middleName":"","lastName":"Han","suffix":""},{"id":478318,"identity":"b97f0127-87a3-4c9a-8b5f-29e44c7c384c","order_by":3,"name":"YanLi Li","email":"","orcid":"","institution":"Beijing Chaoyang Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"YanLi","middleName":"","lastName":"Li","suffix":""},{"id":478319,"identity":"9ef475ae-d820-4b50-b4e9-3150b91a1754","order_by":4,"name":"Chunxiao Zhang","email":"","orcid":"","institution":"Beijing HUimin Hospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Chunxiao","middleName":"","lastName":"Zhang","suffix":""},{"id":478320,"identity":"e9889e1d-cb62-4ebb-b5b1-7eb0d2f896c0","order_by":5,"name":"Xiqian Xing","email":"","orcid":"","institution":"2nd people's Hospital of Yunnan Province","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Xiqian","middleName":"","lastName":"Xing","suffix":""}],"badges":[],"createdAt":"2020-04-02 11:36:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-20930/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-20930/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12890-020-01257-w","type":"published","date":"2020-09-09T12:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":881570,"identity":"bf9be553-e71b-4c6e-b66a-43b7280696fb","added_by":"auto","created_at":"2020-04-10 19:02:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":95459,"visible":true,"origin":"","legend":"Patient screening algorithm for FluA-p","description":"","filename":"fig1.png","url":"https://assets-eu.researchsquare.com/files/rs-20930/v1/fig1.png"},{"id":881571,"identity":"12af0d1f-f761-467c-907a-d1f521334d84","added_by":"auto","created_at":"2020-04-10 19:02:35","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":38327,"visible":true,"origin":"","legend":"Kaplan-Meier survival graph for FluA-p patients with and without IPA (censored at 60d).","description":"","filename":"fig2.png","url":"https://assets-eu.researchsquare.com/files/rs-20930/v1/fig2.png"},{"id":13497964,"identity":"30efb9c6-0c65-48e1-86bc-bdf71a7e6268","added_by":"auto","created_at":"2021-09-16 22:55:59","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":629145,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-20930/v1/645c9335-cd51-4160-9b60-8a1782ab6057.pdf"},{"id":881569,"identity":"0e0295cf-f880-4e0c-87e5-eafd5cf2fb9c","added_by":"auto","created_at":"2020-04-10 19:02:35","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":25071,"visible":true,"origin":"","legend":"","description":"","filename":"Appendix.docx","url":"https://assets-eu.researchsquare.com/files/rs-20930/v1/Appendix.docx"}],"financialInterests":"","formattedTitle":"Invasive pulmonary aspergillosis in immunocompetent patients hospitalised with influenza A-related pneumonia: a multicenter retrospective study","fulltext":[{"header":"Background","content":" \u003cp\u003eInfluenza is a respiratory infectious disease, caused by influenza viruses, and which can present seasonal epidemics and pandemics [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Despite the progress in medical technologies and economic development, influenza still causes considerate complications and mortality [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Following infection by influenza viruses, patients can show a broad spectrum of clinical symptoms, ranging from self-limited upper respiratory tract illness to severe pneumonia and acute respiratory distress syndrome (ARDS) [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. It was estimated that every year, 10\u0026ndash;20% of the global population experienced symptomatic influenza, including 3\u0026ndash;5\u0026nbsp;million severe illnesses and 260\u0026ndash;640 thousand deaths [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eNearly half of severe influenza patients present with pneumonia, which is mostly caused by influenza A [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Influenza pneumonia is often coinfected with other pathogens and this worsen the clinical symptoms and deteriorates the outcomes [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Previous studies found, that \u003cem\u003eStreptococcus pneumoniae, Staphylococcus aureus\u003c/em\u003e and \u003cem\u003eHaemophilus influenzae\u003c/em\u003e, were the most common etiologies in coinfected influenza [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. The Chinese and American guidelines recommend empiric antibiotics use to fight the pathogens associated with severe influenza [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Invasive pulmonary aspergillosis mostly and traditionally occurs in immunocompromised hosts, such as patients with hematopoietic stem cell transplantation, granulocyte deficiency and organ transplant recipients; but rarely in those with normal immune function [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. In recent years, more cases of IPA have been reported in severe influenza patients and with increased mortality [\u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. The most notable was that over 30% of these cases had no classic immunocompromised factors.\u003c/p\u003e \u003cp\u003eHowever, there are limited data on influenza-associated pulmonary aspergillosis (IAPA), especially in prior immunocompetent patients. The incidence and disease characteristics were largely unknown. Identifying those patients with high risk for IPA, remains challenging. We carried out this multicenter retrospective study with the following purposes: ⅰ) to investigate the incidence and risk factors for IPA acquisition in immunocompetent patients hospitalised with influenza A-related pneumonia (FluA-p); ⅱ) to explore the risk factors associated with a 60-day mortality in IAPA patients.\u003c/p\u003e "},{"header":"Methodology","content":" \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Design and Population\u003c/h2\u003e \u003cp\u003eWe screened hospitalised patients for positive influenza A virus RNA using respiratory specimens by reverse transcription polymerase chain reaction (RT-PCR) from microbiology laboratories of five teaching hospitals in Beijing, Shandong and Yunnan Provinces and during the period from 1st January to 31st December 2018 (the details of the five centers are shown in Appendix file 1). From this data, we retrieved all cases had both influenza and radiograph proven pneumonia.\u003c/p\u003e \u003cp\u003ePatients were excluded if [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] (1) age\u0026thinsp;\u0026lt;\u0026thinsp;14 years; (2) pneumonia onset\u0026thinsp;\u0026ge;\u0026thinsp;48 hours after admission and not been hospitalised within the last 28 days, because the consensus of nosocomial pneumonia caused by influenza was difficult; (3) Immunocompromised status, including HIV (+),chemotherapy/radiotherapy within 6 months, immunosuppressive therapy, organ/bone marrow transplantation, splenectomy, hematological neoplasms. Immunosuppressive therapy: was defined as systmatic glucocorticosteroid (such as prednisone\u0026thinsp;\u0026ge;\u0026thinsp;10\u0026nbsp;mg/d for more than 3 weeks in the last month); cyclosporine or azathioprine use within 3 months, and methotrexate use\u0026thinsp;\u0026ge;\u0026thinsp;12.5\u0026nbsp;mg/week within 3 months; biological modifiers such as etanercept and infiximab within 3 weeks.\u003c/p\u003e \u003c/div\u003e \n\u003ch2\u003eGroup Division\u003c/h2\u003e\n \u003cp\u003eWe divided the patients into two groups: the case group included patients with FluA-p, who subsequently became infected with proven and/or probable invasive pulmonary aspergillosis (IPA group); and the control group that included patients with FluA-p and who showed no evidence of \u003cem\u003eAspergillus\u003c/em\u003e infection while hospitalised.\u003c/p\u003e \n\u003ch2\u003eStudy Definitions\u003c/h2\u003e\n \u003cp\u003ePatients with FluA-p were defined as patients with respiratory symptoms and a new pulmonary infiltrate on the chest radiograph, combined with positive influenza virus A RT-PCR testing during the influenza seasons.\u003c/p\u003e \u003cp\u003eA Proven IPA was defined as the microscopic evidence of dichotomous branching hyphae with a positive culture for \u003cem\u003eAspergillus\u003c/em\u003e through an endobronchial biopsy, irrespective of host factors or clinical features [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAccording to the revised definitions of invasive fungal diseases from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) in 2019 [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e], a probable IPA required a host factor, clinical features and mycological evidence of aspergillosis. However, these criteria were created for immunosuppressed hosts and influenza-related aspergillosis may occur in previously normal hosts. Thus, the host factors were not required in our study. The clinical features included one of the following signs or symptoms: refractory fever to at least 3 days of appropriate antibiotic treatment; recrudescent fever after a period of defervescence of at least 48\u0026nbsp;h, while still on antibiotics and without other apparent cause; dyspnea; hemoptysis; pleural friction rub or chest pain; worsening respiratory insufficiency in spite of appropriate antibiotic therapy and ventilatory support. The radiological criteria included any infiltrates on pulmonary imaging detected by chest x-ray or CT scan of the lungs. The mycological evidence included: a positive \u003cem\u003eAspergillus\u003c/em\u003e culture from a bronchoalveolar lavage (BAL); a galactomannan (GM) optical index on BAL of \u0026ge;\u0026thinsp;1.0; a GM optical index on serum of \u0026ge;\u0026thinsp;1.0; GM optical index on single serum of \u0026ge;\u0026thinsp;0.7 and BAL of \u0026ge;\u0026thinsp;0.8.\u003c/p\u003e \u003cp\u003eEarly neuraminidase inhibitor (NAI) treatment was defined as any NAI (e.g., oseltamivir, zanamivir and peramivir) administered within 2 days after disease onset [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. The coinfection with other \u003cem\u003eAspergillus\u003c/em\u003e pathogens was defined by community-acquired respiratory co-pathogens that was identified within 2 days of hospital admission [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The conditions of a community-acquired respiratory co-pathogen was defined as the definite or probable etiology (Appendix 3). Immunocompetent hosts were defined as patients without immunocompromised factors described above.\u003c/p\u003e \n\u003ch2\u003eData Collection:\u003c/h2\u003e\n \u003cp\u003eData was retrospectively collected and included demographic information, underlying disease (Appendix 2), clinical manifestations, laboratory and radiological findings, microbiologic diagnosis, treatment (use of antiviral agents, corticosteroids, vasopressors and mechanical ventilation), clinical outcomes (complications during hospitalisation, admittance to the intensive care unit (ICU) and a 60-day mortality).\u003c/p\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eAll data were analyzed with SPSS 22.0 and measurement data were tested for normality by Kolmogorov-Smirnov. The measurement data of normal distributions were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Measurements data of non-normal distributions were reported as median. The categorical variables were analyzed by the Chi-square test or Fisher\u0026rsquo;s exact test, and continuous variables were analyzed by the student t-test or the Mann\u0026ndash;Whitney U-test. A p-value of \u0026lt;\u0026thinsp;0.05 was considered statistically significant and all probabilities were two-tailed. A Cox proportional hazard model was performed to evaluate the effect of IPA on a 60-day mortality in FluA-p patients. The model was adjusted by age, gender, comorbidities, leukocytes\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L, serum procalcitonin\u0026thinsp;\u0026gt;\u0026thinsp;0.1\u0026nbsp;ng/ml, coinfection with non-\u003cem\u003eAspergillus\u003c/em\u003e pathogens and early use of neuraminidase inhibitors. The clinical characteristics were compared between patients in the IPA and control groups (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Variables with p-values of \u0026le;\u0026thinsp;0.05 on univariate analysis were subsequently entered into the backward stepwise logistic regression analysis to identify risk factors for the acquisition and death in IPA patients.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eDemographic and clinical characteristics between the two groups\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eVariables\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eTotal\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;693)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eIPA group\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eControl group\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;672)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003ep\u003cem\u003e-\u003c/em\u003evalue\u003csup\u003e#\u003c/sup\u003e\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAge (years, median, IQR)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e61.0 (36.0\u0026ndash;76.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e67.0 (61.0\u0026ndash;82.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e60.0 (36.0\u0026ndash;76.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMale (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e461(66.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (85.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e443 (65.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.058\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBMI (kg/m\u003csup\u003e2\u003c/sup\u003e, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e24.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e24.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eComorbidities (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e402 (58.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (85.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e384 (57.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eDiabetes mellitus\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e92 (13.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e15 (71.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e77 (11.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCerebrovascular disease\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e72 (10.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e4 (19.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e68 (10.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.338\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCOPD\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e40 (5.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e6 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e34 (5.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAsthma\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e19 (2.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (2.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eChronic kidney disease\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (2.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (9.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e14 (2.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.134\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMalignant solid tumor\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (2.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (2.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026gt;\u0026thinsp;0.999\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eChronic congestive heart failure\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (0.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSmoking history (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e243 (35.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e7 (33.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e236 (35.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.866\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAlcoholism history (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e92 (13.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e92 (13.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.135\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAntibiotics use before admission (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e587 (84.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e15 (71.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e572 (85.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.159\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eClinical characteristics (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eConfusion\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e32 (4.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e32 (4.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.620\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSBP\u0026thinsp;\u0026lt;\u0026thinsp;90\u0026nbsp;mmHg\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e8 (1.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (4.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e7 (1.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.593\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLeukocytes\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e118 (17.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e15 (71.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e103 (15.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLymphocytes\u0026thinsp;\u0026lt;\u0026thinsp;0.8\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e299/677 (44.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e15 (71.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e284/656 (43.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.011\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHB\u0026thinsp;\u0026lt;\u0026thinsp;100\u0026nbsp;g/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e69 (10.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e5 (23.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e64 (9.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.075\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAlbumin\u0026thinsp;\u0026lt;\u0026thinsp;35\u0026nbsp;g/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e58/639 (9.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e6 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e52/618 (8.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBG\u0026thinsp;\u0026gt;\u0026thinsp;11\u0026nbsp;mmol/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e48 (6.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e48 (7.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.405\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBUN\u0026thinsp;\u0026gt;\u0026thinsp;7\u0026nbsp;mmol/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e183/685 (26.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (42.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e174/664 (26.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.090\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSerum PCT\u0026thinsp;\u0026gt;\u0026thinsp;0.1\u0026nbsp;ng/ml\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e248/541 (45.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (9.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e246/520 (47.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;300\u0026nbsp;mmHg\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e340/639 (53.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (76.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e324/618 (52.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.032\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eRadiology (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCavity\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e19 (2.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (2.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eMultiple nodules\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e151 (21.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e8 (38.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e143 (21.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.116\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eICs use before IPA diagnosis (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (0.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSystemic corticosteroids use\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003ebefore IPA diagnosis (\u003cem\u003en\u003c/em\u003e,%)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e132 (19.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (85.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e114 (17.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eDose of systemic corticosteroids \u003csup\u003ea\u003c/sup\u003e\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(mg/kg, mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.853\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eEarly NAIs \u003csup\u003eb\u003c/sup\u003e use (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e232 (33.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e10 (47.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e222 (33.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.163\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eCoinfection with other community-acquired pathogens (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e265 (38.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e262 (39.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.016\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eIQR: interquartile range; SD: standard deviation; BMI: body mass index; COPD: chronic obstructive pulmonary disease; SBP: systolic blood pressure; RR: respiratory rates; WBC: white blood cell count; HB: hemoglobin; BG: blood glucose; BUN: blood urea nitrogen; PCT: procalcitonin; PO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e: arterial pressure of oxygen/fraction of inspiration oxygen; ICs: inhaled corticosteroids; NAIs: neuraminidase inhibitors; a: methylprednisolone or its equivalent; b: Neuraminidase inhibitors refer to any dose of oseltamivir, zanamivir, and peramivir; \u003csup\u003e#\u003c/sup\u003e: IPA group vs control group. The bolded values are p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05, which represent significant differences between subgroups.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e "},{"header":"Results","content":" \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eScreening Process\u003c/h2\u003e \u003cp\u003eWe screened 2187 hospitalised patients with positive influenza A RNA. Overall, 693 immunocompetent adults and adolescent patients hospitalised with FluA-p onset in the community were entered into the final analysis. The proportion of patients who developed IPA during hospitalisation was 3.0% (21/693) (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \n\u003ch2\u003eOverview Of Patients With FluA-p\u003c/h2\u003e\n \u003cp\u003eOverall, the median age was 61.0\u0026nbsp;years old and the male accounted for 66.5% (461/693). Fifty-eight percent of patients (402/693) had at least one underlying disease with the top three being diabetes mellitus 13.3% (92/693), cerebrovascular disease 10.4% (72/693) and chronic obstructive pulmonary disease 5.8% (40/693). The proportion of patients with PO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;300\u0026nbsp;mmHg was 53.2% (340/639). Cavities and multiple nodules in chest radiology were seen in 2.7% (19/693) and 21.8% (151/693) of patients, respectively.\u003c/p\u003e \u003cp\u003eNineteen percent (132/693) of FluA-p patients used a systemic dose of 0.6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.3\u0026nbsp;mg/kg corticosteroids before IPA diagnosis. All patients were administrated with NAI during the disease course, while 33.3% (231/693) received NAIs within the 48hrs after illness onset. 24.1% (167/693) of patients had complications with respiratory failure, 21.2% (147/693) had heart failure, 5.2% (36/693) had septic shocks during hospitalisation, 26.3% (182/693) of patients were admitted to intensive care unit (ICU) and the 60-day mortality was 20.9% (145/693) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\n\u003ch2\u003eComparisons Between The IPA And Control Patients\u003c/h2\u003e \n \u003cp\u003eCompared with control patients, the IPA patients were older (67.0 yrs vs. 60.0 yrs, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), had more frequency of diabetic (71.4% vs. 11.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), chronic pulmonary disease (28.6% vs 5.1%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), asthma (14.3% vs. 2.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009) and chronic heart failure (14.3% vs. 0.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and lower levels of body mass index (BMI) [(21.5\u0026thinsp;\u0026plusmn;\u0026thinsp;0.4) kg/m\u003csup\u003e2\u003c/sup\u003e vs. (24.5\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6) kg/m\u003csup\u003e2\u003c/sup\u003e, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014]. The proportion of leukocytes\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L (71.4% vs. 15.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), lymphocytes\u0026thinsp;\u0026lt;\u0026thinsp;0.8\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L (71.4% vs. 43.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.011), albumin\u0026thinsp;\u0026lt;\u0026thinsp;35\u0026nbsp;g/L (28.6% vs. 8.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006), PO\u003csub\u003e2\u003c/sub\u003e/FiO\u003csub\u003e2\u003c/sub\u003e\u0026thinsp;\u0026lt;\u0026thinsp;300\u0026nbsp;mmHg (76.2% vs 52.4%, p\u0026thinsp;=\u0026thinsp;0.032) and radiologic cavities (14.3% vs. 2.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.009), were significantly higher in the IPA patients; while, serum procalcitonin (PCT)\u0026thinsp;\u0026gt;\u0026thinsp;0.1\u0026nbsp;ng/ml (9.5% vs. 47.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.001) was more common in the control patients. More IPA patients used corticosteroids inhalers (14.3% vs. 0.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 ) and systemic corticosteroids (85.7% vs. 17.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) before IPA diagnosis. However, no significant differences in the dose of systemic corticosteroids was observed.\u003c/p\u003e \u003cp\u003eComplications of respiratory failure (100.0% vs. 21.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), heart failure (42.9% vs. 20.5%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.028) and septic shock (85.7% vs. 2.7%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001 ) were more frequent in IPA patients. The proportion of patients needing noninvasive ventilation (42.9% vs. 22.3%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014), invasive ventilation (85.7% vs. 20.8%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and vasopressor use (52.4% vs. 2.4%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), were higher in IPA patients. More IPA patients were admitted to ICU (71.4% vs. 24.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and had a higher 60-day mortality rate (42.9% vs. 18.9%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.015) (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eSupportive treatments and clinical outcomes between the two groups\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eVariables\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eTotal\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;693)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eIPA group\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eControl group\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;672)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003ep-value\u003csup\u003e#\u003c/sup\u003e\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eVasopressor use (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e27 (3.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e11 (52.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e16 (2.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLength of vasopressor use\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(days, median, IQR)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.0 (0.5-3.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2.0 (0.5\u0026ndash;4.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.5 (1.0\u0026ndash;2.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.185\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eNoninvasive ventilation (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e159 (22.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (42.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e150 (22.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLength of noninvasive ventilation\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(days, median, IQR)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e4.0 (1.0\u0026ndash;8.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e2.0 (2.0\u0026ndash;10.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e5.0 (1.0\u0026ndash;8.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eInvasive ventilation (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e158 (22.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (85.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e140 (20.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLength of invasive ventilation\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(days, median, IQR)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e4.0 (1.0\u0026ndash;9.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9.0 (7.0\u0026ndash;11.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e4.0 (1.0\u0026ndash;9.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eComplications during hospitalisation (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eRespiratory failure\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e167 (24.1)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e21 (100.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e146 (21.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eHeart failure\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e147 (21.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (42.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e138 (20.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.028\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSeptic shock\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e36 (5.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (85.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (2.7)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAcute kidney failure\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e27 (3.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e3 (14.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e24 (3.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.054\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBloodstream infection\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e8 (1.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e8 (1.2)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026gt;\u0026thinsp;0.999\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAdmittance to ICU (n, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e176 (26.3)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e15 (71.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e161 (24.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLength of stay in ICU\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(days, median, IQR)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e8.0 (6.0\u0026ndash;13.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9.0 (7.0\u0026ndash;11.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e8.0 (6.0\u0026ndash;13.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.473\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLOS (days, median, IQR)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e10.0 (8.0\u0026ndash;14.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e24.0 (11.0\u0026ndash;42.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e10.0 (7.0\u0026ndash;13.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e60-day mortality (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e136 (19.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e9 (42.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e127 (18.9)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e0.015\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eLOS: length of stay in hospital; ICU: intensive care unit; \u003csup\u003e#\u003c/sup\u003e: IPA group vs control group. The bolded values are p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05, which represent significant differences between subgroups.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \n\u003ch2\u003eDiagnosis Of IPA\u003c/h2\u003e\n \u003cp\u003eThe mean duration from the diagnosis of IPA to the day of admission was 6.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8 days, with a range of 2\u0026ndash;18 days. A serum GM test was performed in 15 of the 21 IPA patients. Seventeen IPA patients were subjected to a GM test in BAL. Only one patient had a GM optical index on serum of \u0026ge;\u0026thinsp;1.0; while, 12 patients had a GM optical index on BAL of \u0026ge;\u0026thinsp;1.0, six patients a GM optical index of single serum of \u0026ge;\u0026thinsp;0.7 and BAL of \u0026ge;\u0026thinsp;0.8.\u003c/p\u003e \u003cp\u003eIn all 21 IPA patients, a BAL culture was performed that led to the identification of \u003cem\u003eAspergillus\u003c/em\u003e in 6 patients\u0026rsquo; cultures. Two patients were diagnosed as proven IPA by trans-bronchial lung biopsy (both were \u003cem\u003eAspergillus fumigatus\u003c/em\u003e). A probable IPA diagnosis was performed in 19 of the 21 IPA patients (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eDiagnosis of IPA\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eVariables\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eIPA group\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;21)\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003eControl group\u003c/div\u003e \u003cdiv class=\"SimplePara\"\u003e(\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;672)\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSerum GM test (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e15 (71.4)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e322 (47.9)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBAL GM test (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e17 (81.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e167 (24.9)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSerum GM\u0026thinsp;\u0026ge;\u0026thinsp;1.0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e1 (4.8)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBAL GM\u0026thinsp;\u0026ge;\u0026thinsp;1.0\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e12 (60.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSingle serum GM\u0026thinsp;\u0026ge;\u0026thinsp;0.7 and BAL GM\u0026thinsp;\u0026ge;\u0026thinsp;0.8\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e6 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eBAL \u003cem\u003eAspergillus\u003c/em\u003e culture (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e21 (100.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e146 (21.7)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePositive\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e6 (28.6)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLung tissue microscopy (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e4 (19.0)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e18 (2.7)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePositive\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (9.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eProven IPA (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e2 (9.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eProbable IPA (\u003cem\u003en\u003c/em\u003e, %)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e19 (90.5)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0 (0.0)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eGM: galactomannan; BAL: bronchoalveolar lavage\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eCoinfection with non-\u003c/b\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eAspergillus\u003c/span\u003e \u003cb\u003epathogens isolated in FluA-p patients\u003c/b\u003e\u003c/p\u003e \u003cp\u003eCoinfection with other community-acquired pathogens was diagnosed in only 3 of 21 IPA patients and 1 patient was diagnosed with \u003cem\u003eS. pneumoniae\u003c/em\u003e, 1 patient with \u003cem\u003eP. aeruginosa\u003c/em\u003e and 1 with \u003cem\u003eK. pneumoniae\u003c/em\u003e. While, 39.0% (262/672) of control patients were diagnosed with non-\u003cem\u003eAspergillus\u003c/em\u003e etiologies, \u003cem\u003eS. pneumoniae\u003c/em\u003e was the most common diagnosed pathogen with 33.2% (87/262), followed by \u003cem\u003eK. pneumoniae\u003c/em\u003e 30.5% (80/262) and \u003cem\u003eStaphylococcus aureus\u003c/em\u003e 20.6% (54/262) (Appendix file 4).\u003c/p\u003e \u003cp\u003e \u003cb\u003eEffect of IPA on the 60-day mortality of FluA-p patients\u003c/b\u003e \u003c/p\u003e \u003cp\u003eAdjusted for age, gender, comorbidities, blood leukocyte counts\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L, serum PCT\u0026thinsp;\u0026gt;\u0026thinsp;0.1\u0026nbsp;ng/ml, coinfection with other pathogens and early NAIs use, a Cox proportional hazard model showed that IPA was associated with an increased risk in the 60-day mortality of FluA-p patients [hazard ratio (\u003cem\u003eHR)\u003c/em\u003e 4.336, \u003cem\u003e95% confidence interval (CI)\u003c/em\u003e 1.191\u0026ndash;15.784, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.026) (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003eThe impact of IPA on the 60-day mortality in FluA-p patients\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cdiv class=\"SimplePara\"\u003eVariable\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003eUnivariate Cox regression\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003eMultivariate Cox regression\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eHR (95% CI)\u003c/span\u003e\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003ep\u003c/b\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003e-\u003c/span\u003e\u003cb\u003evalue\u003c/b\u003e\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003e*adjusted\u003c/b\u003e \u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003eHR (95%CI)\u003c/span\u003e\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003ep\u003c/b\u003e\u003cspan type=\"BoldItalic\" class=\"BoldItalic\" name=\"Emphasis\"\u003e-\u003c/span\u003e\u003cb\u003evalue\u003c/b\u003e\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eIPA\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e3.219 (1.328\u0026ndash;7.803)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.010\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cdiv class=\"SimplePara\"\u003e4.336 (1.191\u0026ndash;15.784)\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.026\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eHR: hazard ratio; CI: interval confidence\u003c/td\u003e\u003c/tr\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003e*adjusted by age, gender, comorbidities( chronic pulmonary disease, cerebrovascular disease, asthma, diabetes mellitus, chronic kidney disease, malignant solid tumor, chronic congestive heart failure), leukocytes\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L, serum procalcitonin\u0026thinsp;\u0026gt;\u0026thinsp;0.1\u0026nbsp;ng/ml, coinfection with non-\u003cem\u003eAspergillus\u003c/em\u003e other pathogens, early NAIs use.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eKaplan-Meier survival curve showed that the 60-day mortality of the IPA patients was significantly higher than that of the control patients (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.006 for the log rank test) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \n\u003ch2\u003eRisk Factors Associated With Ipa Occurrence In FluA-p Patients\u003c/h2\u003e\n \u003cp\u003eTo explore the risk factors for IPA acquisition, the following variables were entered into the backstep logistic regression model: age, BMI, diabetes mellitus, asthma, chronic congestive heart failure, leukocytes\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L, lymphocytes\u0026thinsp;\u0026lt;\u0026thinsp;0.8\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L, albumin\u0026thinsp;\u0026lt;\u0026thinsp;35\u0026nbsp;g/L, serum PCT\u0026thinsp;\u0026gt;\u0026thinsp;0.1\u0026nbsp;ng/ml, cavity on chest radiology, use of inhaled corticosteroids and systemic corticosteroids before IPA diagnosis, and coinfection with other community-acquired pathogens, and the analyses led to the following results: age (\u003cem\u003eOR\u003c/em\u003e 1.147, \u003cem\u003e95% CI\u003c/em\u003e 1.048\u0026ndash;1.225, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.003), systemic corticosteroids use before IPA diagnosis (\u003cem\u003eOR\u003c/em\u003e 33.773, \u003cem\u003e95% CI\u003c/em\u003e 5.681\u0026ndash;76.764, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001), leukocytes\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L (\u003cem\u003eOR\u003c/em\u003e 1.988, \u003cem\u003e95% CI\u003c/em\u003e 1.028\u0026ndash;6.454, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.029) and lymphocytes\u0026thinsp;\u0026lt;\u0026thinsp;0.8\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L on admission (\u003cem\u003eOR\u003c/em\u003e 34.813, \u003cem\u003e95% CI\u003c/em\u003e 1.676\u0026ndash;73.006, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.022). These results were proven to be independently related to the IPA acquisition in FluA-p patients (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cdiv class=\"SimplePara\"\u003ePredictors for acquisition and 60-day mortality of IPA in FluA-p patients\u003c/div\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003ePredictors for IPA acquisition\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003ep\u003cem\u003e-\u003c/em\u003evalue\u003c/div\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cem\u003eOR (95% CI)\u003c/em\u003e\u003c/div\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eAge\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.003\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.147 (1.048\u0026ndash;1.225)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eSystemic corticosteroids use before IPA diagnosis\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u0026lt;\u0026thinsp;0.001\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e33.773 (5.681\u0026ndash;76.764)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLeukocytes\u0026thinsp;\u0026gt;\u0026thinsp;10\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.029\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e1.988 (1.028\u0026ndash;6.454)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eLymphocyts\u0026thinsp;\u0026lt;\u0026thinsp;0.8\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.022\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e34.813 (1.676\u0026ndash;73.006)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003e\u003cb\u003ePredictors for 60-day mortality of IPA patients\u003c/b\u003e\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cdiv class=\"SimplePara\"\u003eEarly NAIs use\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.021\u003c/div\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cdiv class=\"SimplePara\"\u003e0.290 (0.002\u0026ndash;0.584)\u003c/div\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"3\"\u003eOR: odd ratio\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003ePredictors for a 60-day mortality of IPA in FluA-p patients\u003c/b\u003e \u003c/p\u003e \u003cp\u003eThe demographic features and comorbidities were similar between the survival and deceased patients with IPA. Of the 21 patients that received an antifungal treatment within 24 hours after IPA diagnosis, 18 patients used voriconazole and 3 patients used a combination treatment (voriconazole\u0026thinsp;+\u0026thinsp;echinocandin). However, no significant difference was found in antifungal therapy between the two groups. Compared with the survival group, the deceased patients\u0026rsquo; group had a higher proportion of lymphocytes\u0026thinsp;\u0026lt;\u0026thinsp;0.8\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L (100.0% vs 50.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.043) and lower proportion of early NAIs use (11.1% vs 75.0%, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.014) (Appendix file 5).\u003c/p\u003e \u003cp\u003eA multivariate logistic regression model confirmed early NAIs use (\u003cem\u003eOR\u003c/em\u003e 0.290, \u003cem\u003e95% CI\u003c/em\u003e 0.002\u0026ndash;0.584, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.021) and that was the only predictor for the 60-day mortality in IPA patients (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eOur study has two important findings: 1) the prevalence of IPA in immunocompetent adult and adolescent patients hospitalised with FluA-p, was 3.0%. However, it was associated with increased mortality; 2) we identified age, leukocytes, lymphocytes and systemic corticosteroids use as risk factors for IPA diagnosis. Early NAIs use was related to better outcomes, which were helpful in the prevention and treatment of IPA patients with severe influenza.\u003c/p\u003e \u003cp\u003eThere are rare data on the incidence of IPA among all hospitalised FluA-p patients and previous studies were limited to patients admitted to ICU. In our study, the incidence of IPA in ICU patients was 8.2%, which was consistent with the 7.2\u0026ndash;8.8% reported by Rice [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e] and Martin-Loeches [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]; but, this was lower than the reported 19.2% in the Schauwvlieghe\u0026rsquo;s study [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Further analysis revealed that all IPA patients had respiratory failure complications and an IPA incidence of 12.6%. This observation is very close to that of the Schauwvlieghe\u0026rsquo;s study, in which the IPA incidence was 14.2% in non-immunocompromised severe influenza patients. The difference in reported IPA incidences could be explained by the severity of influenza illness, the detection capability of IPA and the discrepancy in ICU admission criteria in the different medical systems.\u003c/p\u003e \u003cp\u003eAlthough the IPA incidence in our study was not high, the 60-day mortality was as high as 42.9%, which was in accordance with previous reports of 33\u0026ndash;71% [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan additionalcitationids=\"CR15\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan additionalcitationids=\"CR23\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. The prevalence of respiratory failure and septic shock complications was also significantly higher than that of patients without IPA. In addition to the genetic background, there were at least two reasons for the difference in mortality among those studies: 1) the influence of the patients\u0026rsquo; immunity status before influenza onset. In the Schauwvlieghe\u0026rsquo;s study [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], the 90-day mortality in immunocompetent patients with IPA, was 33%; while, it was 71% in patients with immunocompromised factors. Among Huang\u0026rsquo;s research population [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e], 24% received immunosuppressive agents and the overall ICU mortality was 41.3%. All the patients in our study were previously immunocompetent and the mortality was lower than that in the previously reported immunocompromised patients\u0026rsquo; studies. 2) the outcomes were profoundly affected by the awareness, timing and approach of pathogenic testing that were performed for invasive aspergillosis, leading to a delayed IPA diagnosis and treatment. For example, a center in the Schauwvlieghe\u0026rsquo;s [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e] study paid more attention to IPA because of several previous reports. As a result, the diagnostic and survival rate of IPA were much higher than that in other centers. Adjusted by age, sex, comorbidities, early use of NAIs and probable co-infection with other etiologies, a Cox proportional hazard model showed, that IPA independently increases the risk for 60-day mortality in FluA-p patients, by 3 times. Our results implied the importance of IPA screening in patients with severe influenza pneumonia, regardless of their previous immunity status. This allows an early diagnosis in patients, that prompts carrying out an antifungal treatment, as soon as possible.\u003c/p\u003e \u003cp\u003eIn our study, IPA patients were older in age and with frequent comorbidities. Diabetes and chronic airway diseases (such as COPD and asthma) were the most common underlying diseases. Hypoproteinemia was common, suggesting that their nutritional statuses were poor. When the radiological findings of IPA patients were reviewed, it showed mainly pulmonary infiltrates, with a slightly higher proportion of cavities than the control patients; but, no obvious halo sign was found. Previous studies also showed that the halo sign was only seen in less than 5% of patients with secondary IPA influenza [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. The multivariate logistic regression analysis confirmed, that age, increased leukocyte counts, decreased lymphocyte counts and systemic corticosteroids use, were independent risk factors for the acquisition of IPA in immunocompetent patients hospitalised with FluA-p. It is believed that the pathogenesis of invasive aspergillosis, in the setting of influenza infection, may be due to both local and systemic effects of the virus. Local effects include influenza and inflammation damage of the bronchoalveolar epithelial cells, that lead to the impairment of the barrier function and dysfunction of ciliary motility and clearance [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Systemically, influenza alters the Th1/Th2 balance and causes lymphopenia. The immune function of the elderly patients significantly decreased, and their resistance to infection was poor. Previous studies also showed that elderly influenza patients, were more vulnerable to secondary infections [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]. Elevated leukocyte counts in influenza pneumonia patients is usually associated with bacterial or fungal coinfection; while, serum PCT is a relatively specific biomarker of bacterial infection [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. In our study, more than 90% of IPA patients had a serum PCT of \u0026lt;\u0026thinsp;0.1\u0026nbsp;ng/ml, indicating that the coinfection with bacteria was not common. Therefore, the elevated leukocytes with normal serum PCT level, strongly suggested fungal infection. Lymphocytes reflected the function of cellar immunity, which was the main anti-viral mechanism in humans. The suppression of cellar immunity delays the clearance of the virus, along with a more serious damage of airway, thus creating conditions for an invasive \u003cem\u003eAspergillus\u003c/em\u003e infection.\u003c/p\u003e \u003cp\u003eThe steroids are the most common immunomodulators in clinic, with powerful depressive effects on both cellar immunity and humoral immunity. Corticosteroids use often causes secondary fungal infection [\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e]. Our study confirmed the association of systemic corticosteroids use and occurrence of IPA as previously reported [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Meanwhile, we found, that even a low-to-moderate dose and short-term systemic corticosteroids use, would increase the risk for of IPA acquisition in the predisposition to immune suppression, caused by severe influenza. Traditionally, it was believed that a prolonged use of steroids (at least 3 weeks and a prednisone equivalent of \u0026gt;\u0026thinsp;0.3\u0026nbsp;mg/kg/d) was related to IPA occurrence [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. It should be noted that there may be overuse of systemic steroids in influenza patients. In numerous reports, more than 50% of influenza patients received systemic corticosteroids, which were proven to be associated with poor outcomes [\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. In our study, 19% of FluA-p patients received systemic steroids during hospitalisation. Although in severe influenza, uncontrolled immune response is involved in organic damage and increased mortality. In animal models, corticosteroid treatment was found to decrease mortality and ameliorate acute lung injury induced by influenza [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. By now, except for septic shock patients with vasopressor-dependence or adrenal insufficiency, there is no consensus on steroids use in the treatment of severe influenza. Our study confirmed, that the systemic steroids use, was associated with increased risk for IPA and with an unacceptable high mortality, and even in prior immunocompetent FluA-p patients. Therefore, we thought that it was urgent to regulate the use of systemic corticosteroids in the influenza setting.\u003c/p\u003e \u003cp\u003eIn our study, early NAIs use was proven to be the only predictor associated with better outcomes in IAPA patients, by decreasing the risk of more than 70% for a 60-day mortality. Previous studies also proved that the sooner NAIs were used, the better were the outcomes in severe influenza patients [\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e]. According to the mechanism of IAPA, it is reasonable that early inhibition of viral duplication and alleviation of lung damage, caused by virus and inflammation, can create favorable conditions for controlling the occurrence and development of IAPA. However, why early use of NAIs had not shown a decrease in the risk for IAPA incidence, was still unclear. Apart from the small size of the population, our study implies that there is a complex pathogenesis for IPA occurrence in severe influenza patients.\u003c/p\u003e \u003cp\u003eAs far as we know, this was the only investigation focused on IPA in immunocompetent patients hospitalised with FluA-p. Unlike other studies that were limited to ICU patients, our study included, not only patients in ICU, but also patients from general wards. IPA patients, that were not admitted to ICU in other studies and for some reasons, could be included into our population; which, reduced the selective bias. In addition, the population in our study had no classic immunocompromised factors. The occurrence of IPA in these patients was most likely to be neglected. Therefore, the results of our study provide a great significance for clinicians as it allows to identify patients with increased risk for IPA acquisition and at an early stage, advocating therefore, a prompt prevention and treatment.\u003c/p\u003e \u003cp\u003eThere were some limitations specific to our study: 1) Besides the nature of the retrospective study, the relatively small sample size along with some missing data, might limit the accuracy of the results; 2) Though the latest diagnostic criteria of IPA was used, the proportion of the microbiologic examinations for IPA in the control patients, was low. Especially, BAL samples were only performed in less than 25%; while, a serum GM testing was performed in 47% of control patients. A study by Zhou et al [\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e] showed that in nonneutropenic patients, even at a cutoff value of \u0026ge;\u0026thinsp;1.0, the sensitivity of serum GM detection was still much lower than that of BAL GM detection (24.32% versus 64.86%; p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In addition, the triggers to perform BAL were not clarified due to the restrospective study design, and IPA complicating influenza might develope post-admission. This may have limited the number of true cases found and caused selective bias. Therefore, the actual IPA incidence in our study might be under-detected; 3) more than 1/3 of the patients had not performed influenza subtype testing and other respiratory tract viruses were not routinely detected. Thus, we could not exclude coinfection with other viruses.\u003c/p\u003e "},{"header":"Conclusions","content":" \u003cp\u003eOur study showed that there is approximatively 3.0% of IPA incidence with an increased mortality that was observed even in immunocompetent patients, hospitalised with FluA-p. Additionally, we identified age, elevated leukocytes, reduced lymphocytes, on the day of admission and systemic corticosteroids use, as risk factors for IPA acquisition, and that early NAIs use was a predictor of better outcome. Meanwhile, it is suggested that these results should be confirmed using prospective and large sample studies to further verify these conclusions.\u003c/p\u003e "},{"header":"Abbreviations","content":"Flu-p: Influenza-related pneumonia; IPA: Invasive pulmonary aspergillosis; NAI: Neuraminidase inhibitor; OR: Odds ratio; HR: Hazard ratio; 95% IC: 95% Interval confidence; FluA-p: Influenza A-related pneumonia; RT-PCR: Reverse transcription polymerase chain reaction; EORTC/MSG: European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group; BAL: Bronchoalveolar lavage; GM: galactomannan; 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; PH: Hydrogen ion index；pO2/FiO2: Arterial pressure of oxygen/fraction of inspiration oxygen; ICs: inhaled corticosteroid; PCT: procalcitonin; ICU: Intensive care unit. "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study design was approved by the Ethics Committee of Beijing Jishuitan Hospital (No.201911-15). Given the retrospective nature of the study, the Ethics Committee determined that an informed consent was not necessary.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article and its supplementary information files.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study is founded by Beijing JST research (ZR-201921).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eStudy concept and design: LC, XdH. Acquisition of data: LC, XdH, YlL, CxZ, XqX. Statistical analysis of data: LC. Drafting of the manuscript: LC. Critical revision of the manuscript for important intellectual content: XdH, XqX. All authors agree with the article submission. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr. Bai and Dr. Zhang (Infectious Disease Department, Beijing Jishuitan Hospital) for their valuable comments on the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' information \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDepartment of Infectious Disease, Beijing Jishuitan Hospital, 4th Medical College of Peking University, Beijing, China. \u003csup\u003e2.\u003c/sup\u003e Department of Pulmonary and Critical Care Medicine, Qingdao Municipal Hospital, Qingdao City, Shandong Province, China. \u003csup\u003e3.\u003c/sup\u003e Department of Infectious Diseases and Clinical Microbiology, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China. \u003csup\u003e4.\u003c/sup\u003e Department of Pulmonary and Critical Care Medicine, Beijing Huimin Hospital, Beijing, China. \u003csup\u003e5. \u003c/sup\u003eDepartment of Pulmonary and Critical Care Medicine, the 2\u003csup\u003end\u003c/sup\u003e People\u0026rsquo;s Hospital of Yunnan Province, Kunming City, Yunnan Province, China.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of Interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e \u003cspan\u003ePeteranderl C, Herold S, Schmoldt C. Human Influenza Virus Infections. Semin Respir Crit Care Med. 2006;37(4):487\u0026ndash;500.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eNeuzil KM, Bresee JS, de la Hoz F, Johansen K, Karron RA, Krishnan A, et al. Data and product needs for influenza immunization programs in low- and middle-income countries: Rationale and main conclusions of the WHO preferred product characteristics for next-generation influenza vaccines. Vaccine. 2017;35(43):5734\u0026ndash;37.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eDahal S, Jenner M, Dinh L, Mizumoto K, Viboud C, Chowell G. Excess mortality patterns during 1918\u0026ndash;1921 influenza pandemic in the state of Arizona, USA. Ann Epidemiol. 2016;28(5):273\u0026ndash;80.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKumar V. Influenza in Children. Indian J Pediatr. 2017;84(2):139\u0026ndash;43.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eLozano R, Naghavi M, Foreman K, Lim S, Shibuya K, Aboyans V, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analfor the Global Burden of Disease Study 2010. Lancet. 2012;380(9859):2095\u0026ndash;128.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eLi M, Bolker BM, Dushoff J, Ma J, Earn DJD. Patterns of seasonal and pandemic influenza-associated health care and mortality in Ontario, Canada. BMC Public Health. 2019;19(1):1237.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKlein EY, Monteforte B, Gupta A, Jiang W, May L, Hsieh YH, Dugas A. The frequency of influenza and bacterial coinfection: a systematic review and meta-analysis. Influenza Other Respir Viruses. 2016;10(5):394\u0026ndash;403.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKylla H, Dutta TK, Roychoudhury P, Subudhi PK. Coinfection of diarrheagenic bacterial and viral pathogens in piglets of Northeast region of India.Vet World. 2019; 12(2): 224\u0026ndash;30.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eBrundage JF. Interactions between influenza and bacterial respiratory pathogens: implications for pandemic preparedness. The Lancet Infectious diseases. 2016;6(5):303\u0026ndash;12.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHarper SA, Bradley JS, Englund JA, File TM, Gravenstein S, Hayden FG, et al. Seasonal influenza in adults and children\u0026ndash;diagnosis, treatment, chemoprophylaxis, and institutional outbreak management: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2019;48(8):1003\u0026ndash;32.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eCao B, Huang Y, She DY, Cheng QJ, Fan H, Tian XL, et al. Diagnosis and treatment of community-acquired pneumonia in adults: 2016 clinical practice guidelines by the Chinese Thoracic Society, Chinese Medical Association. Clin Respir J. 2018;12(4):1320\u0026ndash;60.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eCadena J, Thompson GR 3rd, Patterson TF. Invasive Aspergillosis: Current Strategies for Diagnosis and Management. Infect Dis Clin North Am. 2016;30(1):125\u0026ndash;42.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eSolano C, V\u0026aacute;zquez L. Invasive aspergillosis in the patient with oncohematologic disease. Rev Iberoam Micol. 2018;35(4):198\u0026ndash;205.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eAlshabani K, Haq A, Miyakawa R, Palla M, Soubani AO. Invasive pulmonary aspergillosis in patients with influenza infection: report of two cases and systematic review of the literature. Expert Rev Respir Med. 2015;9(1):89\u0026ndash;96.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKim SH, Kim MN, Lee SO, Choi SH, Kim YS, Woo JH, et al. Fatal pandemic influenza A/H1N1 infection complicated by probable invasive pulmonary aspergillosis. Mycoses. 2012;55(2):189\u0026ndash;92.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eLat A, Bhadelia N, Miko B, Furuya EY, Thompson GR 3rd. Invasive aspergillosis after pandemic (H1N1) 2009. Emerging infectious diseases. 2010; 16(6): 971\u0026ndash;3.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eChen L, Zhou F, Li H, Xing X, Han X, Wang Y, et al. Disease characteristics and management of hospitalised adolescents and adults with community-acquired pneumonia in China: a retrospective multicentre survey. BMJ Open. 2018;8(2):e018709.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eDonnelly JP, Chen SC, Kauffman CA, Steinbach WJ, Baddley JW, Verweij PE, et al. Revision and Update of the Consensus Definitions of Invasive Fungal Disease From the European Organization for Research and Treatment of Cancer and the Mycoses Study Group Education and Research Consortium. Clin Infect Dis. 2019; pii, ciz1008.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKu YH, Chan KS, Yang CC, Tan CK, Chuang YC, Yu WL, et al. Higher mortality of severe influenza patients with probable aspergillosis than those with and without other coinfections. J Formos Med Assoc. 2017;116(9):660\u0026ndash;70.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eRice TW, Rubinson L, Uyeki TM, Vaughn FL, John BB, Miller RR 3rd, et al. Critical illness from 2009 pandemic influenza A virus and bacterial coinfection in the United States. Crit Care Med. 2012;40(5):1487\u0026ndash;98.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eMartin-Loeches I, Schultz J, Vincent M, Alvarez-Lerma JL, Bos F, Sol\u0026eacute;-Viol\u0026aacute;n LD. J,, et al. Increased incidence of co-infection in critically ill patients with influenza. Intensive Care Med. 2017;43(1):48\u0026ndash;58.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eSchauwvlieghe AFAD, Rijnders BJA, Philips N, Verwijs R, Vanderbeke L, Van Tienen C, et al. Invasive aspergillosis in patients admitted to the intensive care unit with severe influenza: a retrospective cohort study. Lancet Respir Med. 2018;6(10):782\u0026ndash;92.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eCattaneo C, Gramegna D, Malagola M, Pagani C, Borlenghi E, Cerqui E, et al. Invasive pulmonary aspergillosis in acute leukemia: a still frequent condition with a negative impact on the overall treatment outcome. Leuk Lymphoma. 2019;60(12):3044\u0026ndash;50.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eHuang L, Zhang N, Huang X, Xiong S, Feng Y, Zhang Y, et al. Invasive pulmonary aspergillosis in patients with influenza infection: A retrospective study and review of the literature. Clin Respir J. 2019;13(4):202\u0026ndash;11.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eVandewoude KH, Blot SI, Depuydt P, Benoit D, Temmerman W, Colardyn F, Vogelaers D. Clinical relevance of Aspergillus isolation from respiratory tract samples in critically ill patients. Crit Care. 2006;10(1):R31.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003ePark SY, Lim C, Lee SO, Choi SH, Kim YS, et al. Computed tomography findings in invasive pulmonary aspergillosis in non-neutropenic transplant recipients and neutropenic patients, and their prognostic value. J Infect. 2011;63(6):447\u0026ndash;56.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eCrum-Cianflone NF. Invasive Aspergillosis Associated With Severe Influenza Infections. Open Forum Infect Dis. 2016;3(3):ofw171.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eRosano A, Bella A, Gesualdo F, Acampora A, Pezzotti P, Marchetti S, et al. Investigating the impact of influenza on excess mortality in all ages in Italy during recent seasons (2013/14-2016/17 seasons). Int J Infect Dis. 2019;88:127\u0026ndash;34.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eChoi JJ, McCarthy MW. Novel applications for serum procalcitonin testing in clinical practice. Expert Rev Mol Diagn. 2018;18(1):27\u0026ndash;34.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eLionakis MS, Kontoyiannis DP. Glucocorticoids and invasive fungal infections. Lancet. 2003;362(9398):1828\u0026ndash;38.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eKarthaus M, Buchheidt D. Invasive aspergillosis: new insights into disease, diagnostic and treatment. Curr Pharm Des. 2013;19(20):3569\u0026ndash;94.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eNi YN, Chen G, Sun J, Liang BM, Liang ZA. The effect of corticosteroids on mortality of patients with influenza pneumonia: a systematic review and meta-analysis. Crit Care. 2019;23(1):99.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eLi H, Yang SG, Gu L, Zhang Y, Yan XX, Liang ZA, et al. Effect of low-to-moderate-dose corticosteroids on mortality of hospitalised adolescents and adults with influenza A(H1N1)pdm09 viral pneumonia. Influenza Other Respir Viruses. 2017;11(4):345\u0026ndash;54.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eGhoneim HE, McCullers JA. Adjunctive corticosteroid therapy improves lung immunopathology and survival during severe secondary pneumococcal pneumonia in mice. J Infect Dis. 2014;209(9):1459\u0026ndash;68.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eOsthoff M, Erb S. Neuraminidase Inhibitors and Influenza Infection. JAMA Intern Med. 2016;176(3):415.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eMuthuri SG, Venkatesan S, Myles PR, Leonardi-Bee J, Lim WS, Al Mamun A, et al. Impact of neuraminidase inhibitors on influenza A(H1N1)pdm09-related pneumonia: an individual participant data meta-analysis. Influenza Other Respir Viruses. 2016;10(3):192\u0026ndash;204.\u003c/span\u003e \u003c/li\u003e \u003cli\u003e \u003cspan\u003eZhou W, Li H, Zhang Y, Huang M, He Q, Li P, et al. Diagnostic Value of Galactomannan Antigen Test in Serum and Bronchoalveolar Lavage Fluid Samples from Patients with Nonneutropenic Invasive Pulmonary Aspergillosis. J Clin Microbiol. 2017;55(7):2153\u0026ndash;61.\u003c/span\u003e \u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Influenza A, Pneumonia, Invasive pulmonary aspergillosis, Risk factor","lastPublishedDoi":"10.21203/rs.3.rs-20930/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-20930/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eBackground\u0026nbsp;\u003c/p\u003e\u003cp\u003eIncreasing cases of pulmonary aspergillosis (IPA) in immunocompetent\u0026nbsp;patients with severe influenza have been reported. Howevere, the risk factors for occurence and death are largely unknown.\u003c/p\u003e\u003cp\u003eMethods\u0026nbsp;\u003c/p\u003e\u003cp\u003eData of\u0026nbsp;hospitalised\u0026nbsp;patients with influenza A-related pneumonia (FluA-p)\u0026nbsp;obtained from five teaching hospitals from\u0026nbsp;2031 to 2018, were reviewed. Univariate and multivariate logistical regression analyses were performed to determine the risk factors involved in the acquisition and 60-day mortality in IPA patients.\u0026nbsp;\u003c/p\u003e\u003cp\u003eResults\u0026nbsp;\u003c/p\u003e\u003cp\u003eOf the 693 FluA-p\u0026nbsp;patients included in the study, 3.0% (21/693) were IPA patients with a 60-day mortality of 42.9% (9/21). Adjusted for confounders, a Cox proportional hazard model showed that IPA was associated with increased risk for 60-day mortality [hazard ratio ( HR)\u0026nbsp;4.336, 95% confidence interval (CI)\u0026nbsp;1.191-15.784, p\u0026nbsp;= 0.026] in FluA-p\u0026nbsp;patients. A multivariate logistic regression model confirmed that age (odd ratio ( OR)\u0026nbsp;1.147, 95% CI\u0026nbsp;1.048-1.225, p\u0026nbsp;= 0.003), systemic corticosteroids use before IPA diagnosis ( OR\u0026nbsp;33.773, 95% CI 5.681-76.764, p\u0026nbsp;\u0026lt; 0.001), leukocytes \u0026gt; 10×10 9 /L ( OR\u0026nbsp;1.988, 95% CI 1.028-6.454, p\u0026nbsp;= 0.029) and lymphocytes\u0026nbsp;\u0026lt; 0.8×10 9 /L on admission ( OR\u0026nbsp;34.813, 95% CI 1.676-73.006, p\u0026nbsp;= 0.022), were related with the acquisition of IPA. Early neuraminidase inhibitor\u0026nbsp;use ( OR\u0026nbsp;0.290, 95% CI\u0026nbsp;0.002-0.584, p\u0026nbsp;= 0.021) was associated with a decreased risk for a 60-day mortality in IPA patients.\u0026nbsp;\u003c/p\u003e\u003cp\u003eConclusions\u0026nbsp;\u003c/p\u003e\u003cp\u003eOur results showed\u0026nbsp;that IPA worsen the clinical outcomes of FluA-p\u0026nbsp;patients. The risk factors for the acquisition and death were helpful for the clinicians in preventing and treating IPA.\u003c/p\u003e","manuscriptTitle":"Invasive pulmonary aspergillosis in immunocompetent patients hospitalised with influenza A-related pneumonia: a multicenter retrospective study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-04-10 19:02:32","doi":"10.21203/rs.3.rs-20930/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2020-04-26T12:00:00+00:00","index":2,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"editorInvitedReview","content":"","date":"2020-04-26T12:00:00+00:00","index":1,"fulltext":"Recommendation: Reviewer's comments unavailable pending editorial decision\n"},{"type":"reviewerAgreed","content":"","date":"2020-04-25T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-04-22T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-04-21T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-04-15T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-04-08T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-04-08T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-04-02T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-pulmonary-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"pulm","sideBox":"Learn more about [BMC Pulmonary Medicine](http://bmcpulmmed.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/pulm/default.aspx","title":"BMC Pulmonary Medicine","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b07ffdc5-40ca-4d5b-8297-20103c98ac6a","owner":[],"postedDate":"April 10th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":82099,"name":"Pulmonology"}],"tags":[],"updatedAt":"2020-09-13T15:02:30+00:00","versionOfRecord":{"articleIdentity":"rs-20930","link":"https://doi.org/10.1186/s12890-020-01257-w","journal":{"identity":"bmc-pulmonary-medicine","isVorOnly":false,"title":"BMC Pulmonary Medicine"},"publishedOn":"2020-09-09 12:00:00","publishedOnDateReadable":"September 9th, 2020"},"versionCreatedAt":"2020-04-10 19:02:32","video":"","vorDoi":"10.1186/s12890-020-01257-w","vorDoiUrl":"https://doi.org/10.1186/s12890-020-01257-w","workflowStages":[]},"version":"v1","identity":"rs-20930","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-20930","identity":"rs-20930","version":["v1"]},"buildId":"uwybb5PU2iWlRI8EIam5Y","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}