Background
Invasive Pulmonary Aspergillosis (IPA) commonly occurs in immunocompromised individuals. Traditional risk factors include hematopoietic stem cell transplantation, solid organ transplantation, hematologic malignancies, previous exposure to corticosteroids, and neutropenia.1 Severe viral pneumonias increase susceptibility to Aspergillus fumigatus due to disruption of the alveolar epithelial barrier, secretion of pro-inflammatory factors, and immune dysfunction.2 IPA is now recognized as a significant complication of severe respiratory viral infections,3 with influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) being particularly notable In 2021, the EORTC/MSGERC introduced definitions for invasive fungal diseases applicable to ICU, recognizing severe viral pneumonia as a high-risk host factor.4 These conditions are characterized by a high prevalence, insidious onset, atypical clinical manifestations, elevated mortality, and a lack of classic host factors.1,5 Previous studies have suggested that the incidence of IAPA ranges from 14% to 32%,6,7 with a mortality rate of 45% to 51%.6,8 The incidence of CAPA ranges from 1.7% to 26.8%,9–12 with a mortality rate of 38% to 59%.9,11,12 A retrospective study from China, found an IAPA incidence rate of 20% among influenza pneumonia patients and a CAPA incidence rate of 15% among COVID-19 patients in respiratory wards.13 Significant heterogeneity in reported IPA incidence rates arises from variations in environmental Aspergillus spore loads across regions, host genetic factors among ethnic groups, vaccination coverage rates, and disparities in diagnostic capabilities—including bronchoscopy, galactomannan testing, and NGS (Next-generation sequencing).3 Existing studies largely focus on risk factors for the onset of IAPA and CAPA, lacking analysis of factors associated with mortality, our study investigates these mortality-related risk factors.
This study collected the clinical data of 50 IAPA and 56 CAPA inpatients from four hospitals in Zhejiang Province between January 2018 and March 2024, and retrospectively analyzed their clinical characteristics, prognosis, and mortality risk factors.
Methods
Research Subjects
This study is a multicenter retrospective case-control study that included 50 patients with IAPA and 56 patients with CAPA who were hospitalized at four hospitals in Zhejiang Province, China, between January 2018 and March 2024. Clinical data were obtained from these patients. Imaging data were determined by consensus among two experienced respiratory physicians and one radiologist. This retrospective study was performed in compliance with the Declaration of Helsinki and was approved by the medical ethics committee of the First Affiliated Hospital Zhejiang University School of Medicine (Ethics approval No. IIT20230650A). The requirement for informed consent was waived by the Ethics Commission due to the retrospective and anonymous characteristics of the study.
Inclusion and Exclusion Criteria
Inclusion Criteria
① Age≥18 years; ② Positive nucleic acid test for influenza virus or SARS‑CoV‑2 from nasopharyngeal swabs or bronchoalveolar lavage fluid, accompanied by clinical and radiological evidence of pneumonia; ③ Diagnosis of invasive pulmonary aspergillosis, either confirmed or clinically suspected, based on the diagnostic criteria jointly proposed by the European Organization for Research and Treatment of Cancer (EORTC) and the Mycology Study Group (MSG) in 2020.
Exclusion Criteria
① Incomplete medical records; ② Patients with baseline chest CT images showing cavities, masses, and other features that may interfere with the diagnosis of pulmonary aspergillosis; ③ Patients with a confirmed diagnosis of pulmonary aspergillosis prior to viral infection.
Diagnostic Criteria
In this study, patients with confirmed or clinically diagnosed IPA were included, with the following specific diagnostic criteria: (1) confirmation: presence of Aspergillus hyphae observed in tissue examination accompanied by evidence of tissue destruction, or a positive tissue culture for Aspergillus. (2) clinical diagnosis: fulfillment of all three criteria of host factors, clinical features, and microbiological evidence. Host factors include hematopoietic stem cell transplantation or solid organ transplantation, hematological malignancies, previous exposure to corticosteroids, neutropenia, use of T-cell immunosuppressants, or other severe inherited immune deficiencies. However, given that multiple studies have demonstrated that a significant portion of patients infected with the influenza virus or SARS-CoV-2 lack classic immunosuppressive factors when infected with Aspergillus, viral infection can increase susceptibility to Aspergillus.5 Furthermore, severe viral infection itself is a high-risk factor for fungal infection in the host.5,6,14,15 Therefore, host factors are not included in the diagnostic criteria of this study. Clinical features must include at least one of the following three signs on chest CT: ① solid, well-defined nodular shadows, with or without the halo sign, ② the air crescent sign, ③ a cavity. Microbiological evidence includes the detection of fungal components or positive Aspergillus culture in sputum, bronchoalveolar lavage fluid, or bronchoscopy brush specimens; positive galactomannan (GM) test in serum or bronchoalveolar lavage fluid; or a positive result using the Aspergillus polymerase chain reaction (PCR) / next-generation sequencing (NGS)16 in bronchoalveolar lavage fluid or blood.
Collection of Clinical Data
Collect general patient information, including underlying diseases, and medication history (such as corticosteroids, immunosuppressants, and cytotoxic drugs). Document the interval between viral infection and the onset of IPA, ICU admission during the disease course, the use of advanced supportive therapies, including high-flow nasal cannula (HFNC), extracorporeal membrane oxygenation (ECMO), invasive mechanical ventilation, and continuous renal replacement therapy (CRRT). Record clinical manifestations, laboratory test results, chest CT imaging, and bronchoscopy findings when secondary aspergillosis occurs. Also collect data on the use of antiviral agents, antibiotics, and antifungal drugs before and during the treatment course, the administration of glucocorticoids, the occurrence of complications throughout the illness, and the final clinical outcome.
Statistical Methods
Statistical analysis was performed using SPSS version 27.0 software (IBM SPSS Inc., Chicago, Illinois, USA). Categorical data were described as frequency and proportion, and normally distributed quantitative variables were described as mean ± standard deviation. Non-normally distributed quantitative variables were presented as median (interquartile range). T-tests were used for comparisons between groups for normally distributed quantitative data, and Mann–Whitney U-tests were applied for non-normally distributed data. Chi-square tests, adjusted chi-square tests, or Fisher’s exact tests were used for comparisons between groups for categorical data. In univariate analyses, variables with p < 0.05 were included in the Cox proportional hazards regression model for multivariate analysis. Survival status comparisons between groups were made using the Kaplan-Meier method, and survival rates were compared using the Log rank test. The significance level (α) for all statistical tests was set at 0.05, unless otherwise specified. The sample size was determined based on all eligible patients identified during the current study period. Missing data were identified and excluded from analysis prior to conducting relevant statistical analyses.
Results
General Clinical Characteristics at Admission
This study included a total of 106 patients, with 50 IAPA patients and 56 CAPA patients, with mean ages of 63.4±12.3 and 64.1±13.1 years, respectively. There were no statistically significant differences between the two groups in terms of age, BMI, and gender (P> 0.05). The proportion of patients with a history of solid organ transplantation was higher in the CAPA group than in the IAPA group (25.0% vs 4.0%, p = 0.003), whereas the proportion of COPD was lower (5.4% vs 34.0%, p < 0.001), as shown in Table 1. The IAPA group had higher level of white blood cells (11.7×109/L vs 7.4×109/L), neutrophils (10.2×109/L vs 6.0×109/L), T lymphocytes (519.0 cells/μL vs 180.0 cells/μL), B lymphocytes (70.0 cells/μL vs 23.0 cells/μL), absolute CD4+ T lymphocytes (256.0 cells/μL vs 92.2 cells/μL), CD4/CD8 ratios (1.92 vs 1.26), and C-reactive protein (42.1mg vs.71.0mg) compared to the CAPA group (P< 0.05), as shown in Table 1. Additionally, the proportion of patients with concurrent bacterial infections during the disease course was higher in the CAPA group than in the IAPA group (50.0% vs 24.0%, p < 0.05), as shown in Figure 1. The most commonly combined infection bacterium in CAPA was Klebsiella pneumoniae, while Pseudomonas aeruginosa was the most common in the IAPA group.
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Table 1 Clinical Characteristics at Admission
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Figure 1 Comparative analysis of Aspergillus species distribution and coinfection with pathogens during the disease course in IAPA and CAPA.
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Clinical Features of Confirmed Aspergillosis
Patients in the CAPA group had a longer interval from viral infection to the onset of aspergillosis compared to those in the IAPA group (mean duration: 23.0 days vs 4.0 days, p < 0.001). Before the confirmation of pulmonary aspergillosis, a higher proportion of patients in the CAPA group received glucocorticoid therapy (94.6% vs 47.9%, P<0.001) and at higher cumulative doses (all glucocorticoid doses converted to methylprednisolone equivalents: 786.7mg vs 177.3mg, P <0.001), as shown in Table 2.
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Table 2 Clinical Features of Confirmed Aspergillosis
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When concurrent Aspergillus infection was confirmed, the CAPA group exhibited significantly higher rates of respiratory failure (67.9% vs 46.0%), invasive mechanical ventilation (35.7% vs 16.0%), ICU admission (42.9% vs 24.0%), and baseline sepsis-related organ failure assessment (SOFA) scores (7.0 vs 3.0) than the IAPA group (p < 0.05), as presented in Table 2.
The most frequently identified species in both the CAPA and IAPA groups were Aspergillus fumigatus, followed by Aspergillus flavus, with no significant difference between the two groups, as shown in Figure 1. Regarding imaging findings, the CAPA group predominantly showed masses and areas of consolidation, whereas the IAPA group mainly showed masses and nodular opacities. Additionally, the CAPA group had a higher proportion of ground-glass opacities (33.9% vs 12.0%), interstitial changes (17.9% vs 4.0%), and pleural effusion (44.6% vs 26.0%) compared to the IAPA group (p <0.05), as shown in Figure 2.
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Figure 2 Radiographic findings on chest CT at the time of IPA diagnosis.
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Clinical Status After Diagnosis of Aspergillus Infection
After a confirmed diagnosis of Aspergillus infection, the proportion of patients receiving glucocorticoids was higher in the CAPA group (98.2% vs 76.0%), the duration of treatment (39.0 days vs 9.0 days) and the total glucocorticoid dose (all glucocorticoids converted to methylprednisolone equivalents: 1541.1mg vs 260.0mg) were higher than in the IAPA group. Additionally, the CAPA group had a significantly longer total hospital stay was longer (average 38.0 days vs.16.5 days, p <0.001), as shown in Table 2.
Regarding complications involving other organ systems following diagnosis and during treatment, the CAPA group had a significantly higher incidence of lower extremity deep vein thrombosis (33.9% vs 10.0%), gastrointestinal bleeding (35.7% vs 6.0%), and heart failure (23.2% vs 8.0%) compared to the IAPA group (p < 0.05), as detailed in Table 2.
Survival and Prognosis
Based on the Log rank test, the IAPA group had significantly better survival compared to the CAPA group (χ2 = 4.718, p = 0.030). The survival rates of the two groups were analyzed as follows: 30-day survival rate (74.0% vs 64.3%, p=0.281), 60-day survival rate (62.0% vs 51.8%, p = 0.290), and 120-day survival rate (40.0% vs 30.4%, p=0.298), as shown in Figure 3.
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Figure 3 Kaplan-Meier survival curves.
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In patients with IAPA, those in the mortality group had a higher proportion of confirmed respiratory failure, invasive mechanical ventilation, ICU admission, and shock at diagnosis compared to the survival group. The SOFA score, white blood cell count, neutrophil count, and procalcitonin (PCT) level were also significantly higher in the mortality group (p <0.05), as shown in Supplementary 1. Variables with statistically significant differences in univariate analysis were included in the Cox regression analysis, which identified ICU admission at diagnosis as a risk factor for IAPA-related mortality (OR = 9.578; 95% CI: 1.778–51.603; p = 0.009), as shown in Table 3.
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Table 3 Univariate and Cox Regression Analyses of High-Risk Factors for Mortality in IAPA
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In patients with CAPA, the mortality group had a lower prevalence of baseline hypertension compared to the survival group at diagnosis. They also had higher rates of confirmed respiratory failure, ICU admissions, and invasive mechanical ventilation, along with higher levels of IL-6, increased incidences of new-onset gastrointestinal bleeding and deep vein thrombosis during the disease course (p <0.05), as shown in Supplementary 2. Based on a literature review, hypertension was not identified as a protective factor for CAPA mortality and was therefore excluded from further analysis. The remaining variables with statistically significant differences in univariate analysis were then subjected to a multivariate Cox proportional hazards regression model, but no risk factors for CAPA-related death were identified, as shown in Table 4 (26 survivors, 30 deaths).
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Table 4 Univariate and Cox Regression Analyses of High-Risk Factors for Mortality in CAPA
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Discussion
Viral infections can lead to a reduction in lymphocyte counts,17 thereby impairing both T-cell- and B-cell-mediated immune responses. This results in diminished immune function and an increased risk of Aspergillus infection. In this study, both influenza and SARS-CoV-2 infections were associated with reduced absolute counts of T lymphocytes, B lymphocytes, and CD4+ T lymphocytes. The CAPA group showed more significant immune suppression than the IAPA group, this alteration may be associated with the extensive use of cortisol during therapeutic management of COVID-19,18 which is consistent with previous studies.13 In this study, individuals in the CAPA group often had classic IPA risk factors before viral infection, whereas most patients in the IAPA group were individuals without immunodeficiency, consistent with previous reports indicating that about half of IAPA patients lack classic immunosuppressive factors.7 Multiple previous studies have demonstrated that severe influenza virus infection is a significant risk factor for Aspergillus infection.6,14,15 Regarding CAPA, research has shown that 36.8% of affected individuals have classic risk factors for Aspergillus infection.12 In our study, 55.4% of CAPA patients had classic fungal infection host factors; however, whether COVID-19 is a risk factor for Aspergillus infection remains to be confirmed and requires further research and validation.10 IL-6 receptor antagonist use19 and elevated IL-6 levels post-COVID-19 infection20 have been reported as risk factors for CAPA. Our univariate analysis of IAPA mortality revealed significantly higher IL-6 levels in non-survivors compared to survivors, although this difference was not observed in the CAPA group. Overall, larger sample sizes may be required to robustly analyze associations between cytokine changes and the incidence and mortality of both IAPA and CAPA.
In our study, the median time from influenza virus infection to confirmed aspergillosis was 4 days, while for COVID-19 infection, it was 23 days. Previous literature has reported that patients with influenza virus infection can develop invasive aspergillosis within 2 to 5 days,7,8,15 and the median time from COVID-19 symptom onset to CAPA diagnosis is 14 (11–22) days.10,12 In severe COVID-19 patients, CAPA typically develops 8 (4–15) days after ICU admission.9,10,12 The discrepancy in the timing of CAPA aspergillosis diagnosis in this study may be attributable to differences in calculation methods. We measured the interval from COVID-19 symptom onset to confirmed fungal infection, whereas most international studies use the interval from ICU admission or initiation of mechanical ventilation to confirmed fungal infection. COVID-19 typically progresses to viral pneumonia in 10 days (range 2–21).12
In our study, the incidence of deep vein thrombosis and gastrointestinal bleeding was higher in the CAPA group than in the IAPA group. Previous studies have indicated that the rate of thromboembolic complications in patients with COVID-19 ranges from 10.9% to 45%,21–23 while the incidence of venous thromboembolism in hospitalized influenza patients is 5.3% to 11%. The risk of venous thromboembolism in COVID-19 pneumonia is higher than that in influenza pneumonia.21,22 Multiple reports have shown that the incidence of gastrointestinal bleeding in patients infected with COVID-19 ranges from 1.8% to 3.1%,24,25 whereas in this study, the proportion of gastrointestinal bleeding was 35.7%, which may be attributed to the more severe condition of the patients enrolled and the extensive use of medications such as corticosteroids and anticoagulants. Studies have confirmed that the use of corticosteroids and anticoagulants during COVID-19 treatment increases the risk of gastrointestinal bleeding.25,26 The higher incidence of gastrointestinal bleeding in CAPA compared to IAPA may also be related to the binding of SARS-CoV-2 to angiotensin-converting enzyme 2 receptors in the gastrointestinal tract, leading to inflammation and hemorrhage.27
In this study, the primary causes of death in IAPA and CAPA were septic shock and multiple organ failure, consistent with the pathophysiology of sepsis. Therefore, the use of the SOFA score has been proposed to predict short-term mortality in patients. Previous studies have confirmed that for infected patients admitted to the ICU, an increase of two or more points in the SOFA score within a short period is predictive of in-hospital mortality.28 Based on this, this study conducts a correlation analysis between changes in SOFA scores and patient outcomes. By comparing SOFA scores between the deceased and surviving groups in IAPA and CAPA in this study, we found that SOFA scores increased in both groups after one week and two weeks. These findings suggest that changes in SOFA scores after one week may be useful in predicting the prognosis of IAPA and CAPA. Future large-scale studies are warranted to validate the predictive value of this indicator.
However, this study still has some limitations. First, the retrospective nature of the study results in missing information, such as the inability to accurately assess the total amount and duration of corticosteroids and antibiotics used before hospitalization, which may introduce confounding bias. Second, since influenza and SARS-CoV-2 are highly contagious, many patients did not undergo invasive procedures, such as bronchoscopy, to improve diagnostic accuracy. Therefore, the cases included in this study are primarily confirmed or clinically diagnosed, which could result in the exclusion of some IAPA and CAPA patients. Third, the small sample size may affect the authenticity of the research results.
Conclusion
Patients in the IAPA group were more likely to have underlying lung disease and exhibited a more acute onset. The median time of infection was 4 days after viral infection. Admission to the ICU at diagnosis was identified as a risk factor for IAPA-related mortality. In contrast, CAPA patients exhibited greater immune dysfunction, a more insidious onset, and a longer treatment duration. The median time of infection was 23 days after viral infection, making these patients more susceptible to complications such as bacterial infections, thrombosis, and gastrointestinal bleeding. The overall prognosis for CAPA is poor, with a high risk of death. In terms of therapeutic management, early diagnosis and identification, coupled with the timely initiation of antifungal therapy, are critical determinants of clinical outcomes, additionally, corticosteroid administration in CAPA patients requires particular caution to avoid immunosuppression that may trigger secondary infections.
Ethics Statement
This retrospective study has been approved by the Medical Ethics Committee of the First Affiliated Hospital, Zhejiang University School of Medicine, and informed consent had been waived. Ethics approval number: IIT20230650A.
Funding
This work was supported by research grants, including the Research and Development Program of Zhejiang Province (2023C03068), the National Natural Science Foundation of China (82272338). The funders had no involvement in the study design, data collection and analysis, the decision to publish, or the preparation of the manuscript.
Disclosure
The authors declared no conflicts of interest in this work.
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