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Clinical features and risk factors of invasive pulmonary aspergillosis in interstitial lung disease patients

BMC Pulmonary Medicine volume 24, Article number: 602 (2024) Cite this article

Abstract

Background

The prevalence of invasive pulmonary aspergillosis (IPA) among patients with interstitial lung disease (ILD) is steadily increasing, leading to high mortality. The purpose of this study is to analyze the clinical features and risk factors of IPA in patients with ILD.

Methods

353 hospitalized ILD patients admitted in Nanjing Drum Tower Hospital from March 2023 and April 2024 were enrolled. The enrolled patients were divided into the IPA group (proven and probable IPA) and non-IPA group, and the clinical characteristics and prognosis were compared between the two groups.

Results

Among 353 patients with ILD, 58 who suffered from IPA were identified. Among them, 2 (3.4%) episodes of proven IPA and 56 (96.6%) of probable IPA were diagnosed. The median age was 68.4 ± 8.6 years, and 35 patients were men. The forms of ILD included idiopathic pulmonary fibrosis (n = 21), interstitial pneumonia with autoimmune features (n = 13), rheumatoid arthritis related interstitial pneumonia (n = 11) and Sjögren′s syndrome (n = 4). The clinical features of IPA in ILD were cough (100.0%), dyspnea (93.1%) and fever (55.2%). Chest CT images showed reticulation (87.9%), traction bronchiectasis (84.5%), GGO (77.6%), honeycombing (69.0%), consolidation (44.8%) and pleural effusion (24.1%). The incidence of honeycombing and consolidation were higher in ILD patients with IPA compared to control group (P < 0.05). The main pathogens were A. fumigatus (50.0%) and A. flavus (29.3%). Following the diagnosis of IPA, all patients were treated with antifungal drugs. The overall survival rate after 90 days was 74.1%. Multivariate conditional Logistic regression analysis showed that lymphopenia (OR = 2.745, 95% CI 1.344–5.607) and honeycombing (OR = 2.915, 95% CI 1.429–5.949) were the risk factors of ILD with IPA (P < 0.05).

Conclusion

IPA is one of the major complications of ILD and its prognosis is poor. Lymphopenia and honeycombing increased the risk of IPA in ILD patients.

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Introduction

Invasive pulmonary aspergillosis (IPA) primarily occurs in severely immunocompromised patients, including those with neutropenia, a history of hematopoietic stem-cell transplantation, solid-organ transplantation or prolonged and/or high dose corticosteroid treatment [1]. IPA progresses rapidly, and the mortality rate is high. Underlying lung disease like chronic obstructive pulmonary disease (COPD) is a well-known risk factor of IPA [2]; however, interstitial lung disease (ILD) has not been recognized as a risk factor of IPA.

Several case reports on ILD with aspergillosis have been published recently [3,4,5]. The comorbid occurrence of IPA in patients with ILD severely impacts their short-term outcomes. Unfortunately, reports of these cases are few, the clinical presentation and imaging features of such patients are relatively rare. Therefore, we conducted a retrospective study of patients diagnosed with IPA associated with ILD in order to investigate the clinical features and risk factors of this condition.

Methods

Subjects and study design

Medical records of all patients treated for ILD with or without IPA, who were admitted to Nanjing Drum Tower Hospital due to both worsening of existing symptoms and the emergence of new symptoms between March 2023 and April 2024 were retrospectively reviewed. This study was approved from the institutional review board of Nanjing Drum Tower Hospital, which waived the need for patient approval or informed consent because the study involved a retrospective review of clinical records.

To diagnose ILD, we used the American Thoracic Society (ATS)/European Respiratory Society (ERS) consensus classification [6]. In patients with histological evidence, the diagnosis of ILD was dependent on pathological findings. In patients without histological evidence, the diagnosis was based on the findings of high-resolution computed tomography (HRCT) scans of the chest, medical history taking and physical examinations. Laboratory data and HRCT image were collected on the second day of admission.

IPA was diagnosed according to the European Organization for the Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group (EORTC) and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (MSG) criteria [7, 8]. Diagnostic criteria for IPA included the following items: (a) host factors such as solid-organ transplant, hereditary immunodeficiencies, connective tissue disorders (CTD) and use of immunosuppressive agents. Critically, acute respiratory distress syndrome, COPD, influenza, pneumonia, burns, severe bacterial infection, surgery, diabetes and malnutrition were included; (b) Clinical manifestations, including fever, cough, sputum, hemoptysis, dyspnea or other symptoms of lower respiratory tract infection that were not relieved with broad-spectrum antibacterial treatment; (c) radiological data such as nodule(s) > 1 cm, which may be surrounded by a halo of ground-glass attenuation, pleural based wedge-shaped areas of consolidation, alveolar consolidations, masses, internal low attenuation, reverse halo sign, cavity or air-crescent sign and ground-glass opacities and pleural effusion; (d) mycological evidence, such as a positive aspergillus culture from qualified specimens (sputum and BALF) or a positive serum galactomannan (GM) result; and (e) histological evidence of aspergillus hyphae in lung biopsy specimens or a positive aspergillus culture from lung biopsy specimens. A proven diagnosis was made with histological evidence, and a probable diagnosis was made on the basis of host risk factors, clinical and radiological manifestations and microbiological evidence.

Finally, we extracted 58 patients who had IPA with ILD and then collected data from these patients’ medical records that included characteristics, laboratory data, pulmonary function results, and chest HRCT findings at the time of the IPA diagnosis. Each subject’s radiological findings were reviewed by 2 independent radiologists. HRCT patterns were classified as usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP). Honeycombing pattern was defined as clustered cystic air spaces with well-defined walls and typically comparable diameters of 3 to 10 mm in subpleural and lower lobes. Survival was defined as the time from the date of either the IPA diagnosis or ILD diagnosis to the date of death or date of censoring (See Fig. 1).

Fig. 1
figure 1

Recruitment flowchart

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Statistical analysis

Categorical variables were compared using the chi-square test and continuous variables were compared using Student’s t-test or the Mann-Whitney test based on the distribution of the data. Fisher’s exact test was used to compare qualitative variables. Survival curves were generated using the Kaplan-Meier method. Differences in survival were compared using the log-rank test. The Cox proportional hazards model was used to assess the associations between clinical variables and survival. Variables with a P value < 0.1 in univariate analysis were included into the multivariate model. Finally, only variables with P value < 0.05 were retained in the multivariate model. Statistical analysis was performed using SPSS Statistics 23.0 (SPSS Inc., Chicago, IL, USA), and statistical significance was defined as a two-tailed P value < 0.05.

Results

Patient characteristics

The patient characteristics are summarized in Table 1. Among the patients with ILD, we identified a total of 58 patients suffered from IPA, with a median age of 68.4 ± 8.6 years. 35 patients (60.3%) were male. History of smoking was present in 17 cases (29.3%). There were no significant differences in sex, underlying disease and its smoke status between IPA group and non-IPA group. The subtypes of ILD were as follows: 21 patients had idiopathic pulmonary fibrosis (IPF), 13 patients had interstitial pneumonia with autoimmune features, 11 patients had rheumatoid arthritis (RA) associated ILD, 4 patients had primary Sjögren′s syndrome (pSS), 5 patients with antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis, 3 patients with idiopathic inflammatory myopathy and 1 patient with systemic sclerosis. Our study showed that IPA develops more often in patients with RA-ILD (19.0% vs. 5.1%, P < 0.001), as well as in patients with ANCA-ILD (8.6% vs. 2.0%, P = 0.021). IPA developed less frequently in pSS-ILD patients (6.9% vs. 19.3%, P = 0.022). The average length of time from initial ILD diagnosis to onset of IPA was 30.0 ± 33.8 months. Of the 58 patients, 32 patients (55.2%) received corticosteroid over the last 3 weeks, 16 patients (27.6%) received immunosuppressive agents (i.e., cyclosporin, tacrolimus, methotrexate, and abatacept), and 27 patients (46.6%) received antifibrotic agents (i.e., pirfenidone or nintedanib). IPA developed more often at corticosteroid exposure (55.2% vs. 37.3%, P = 0.011) and nintedanib use (36.2% vs. 22.0%, P = 0.022).

Table 1 Characteristics of ILD patients in the IPA and non-IPA groups
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The clinical features of IPA in ILD were cough (100.0% vs. 99.0%, p = 1.000), dyspnea (93.1% vs. 98.0%, p = 0.064), fever (55.2% vs. 29.5%, P < 0.001) and hemoptysis (8.6% vs. 2.9%, P = 0.043). In terms of clinical symptoms, the IPA group displayed significantly greater proportions of fever (55.2% vs. 29.5%, P < 0.001) and hemoptysis (8.6% vs. 2.9%, P = 0.043). No significant differences were observed in cough, dyspnea or chest pain between the two groups. White blood cell count (median 11.1 × 109 vs. 8.3 × 109, P < 0.001), neutrophil count (median 9.6 × 109 vs. 6.2 × 109, P < 0.001) and NLR (median 16.3 vs. 6.4, P < 0.001) were significantly greater in the IPA group. While lymphocyte count (median 1.0 × 109 vs. 1.5 × 109, P < 0.001), eosinophils count (median 0.06 × 109 vs. 0.12 × 109, P = 0.004), hemoglobin (median 116.8 vs. 124.2, P = 0.006) and albumin (median 32.3 vs. 35.3, P < 0.001) were significantly lower in the IPA group. Blood gas analysis indicated significantly smaller PaO2/FiO2 (P/F) ratio in the IPA group (median 238.6 vs. 307.4 mmol/L, P = 0.005). Significant differences were observed between the IPA and non-IPA groups for CRP (median 84.8 mg/L vs. 28.1 mg/L, P < 0.001), PCT (median 1.06 ng/mL vs. 0.14 ng/mL, P = 0.001), LDH (median 379.2 U/L vs. 290.4 U/L, P < 0.001), ESR (median 45.7 mm/h vs. 37.1 mm/h, P = 0.038) and IL-6 (median 76.2 g/L vs. 24.8 g/L, P < 0.001). Compared with ILD patients without IPA, CD4+% (median 30.4 vs. 35.6, P = 0.005) and CD4+/CD8 + ratio (median 1.2 vs. 1.5, P = 0.048) were significantly lower in ILD patients with IPA.

CRP, IL-6, PCT, ESR and NLR were found to be common inflammatory biomarkers of IPA [9, 10]. ROC curves were generated to evaluate the diagnostic performance of these inflammatory biomarkers for IPA in ILD patients. WBC was not included due to glucocorticoid used to treat ILD often interfere with WBC counts [11]. The area under the curve (AUC), cutoff values, sensitivity and specificity for each biomarker are summarized in Table 2. The AUC values for CRP, IL-6, PCT, ESR, and NLR were 0.731, 0.624, 0.707, 0.608, and 0.738, respectively. The corresponding cutoff values were 45.4, 11.1, 0.06, 31.5, and 7.33 g/L, respectively. The sensitivity and specificity were as follows: CRP (56.9%, 80.0%), IL-6 (61.5%, 64.8%), PCT (70.0%, 66.7%), ESR (65.9%, 48.9%), and NLR (65.5%, 72.9%) (See Fig. 2).

Table 2 Area under the curve (AUC), cutoff value, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for the diagnosis of ILD combined with IPA by each biomarker
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Fig. 2
figure 2

Receiver operating characteristic (ROC) curve for each biomarker in the IPA and non-IPA groups (A-E)

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Chest CT findings

The CT findings are summarized in Table 3. The HRCT patterns at the time of ILD diagnosis were UIP in 36 patients (62.1%), NSIP in 16 patients (27.6%), OP in 3 patients (5.2%), and NSIP-OP in 3 patients (5.2%). The most frequent abnormal finding was reticulation (n = 51, 87.9%), traction bronchiectasis (n = 49, 84.5%), GGO (n = 45, 77.6%), honeycombing (n = 40, 69.0%), consolidation (n = 26, 44.8%) and pleural effusion (n = 14, 24.1%). Radiographic findings revealed significantly more honeycombing (69.0% vs. 48.8%, p = 0.005) in the IPA group. Notably, typical IPA signs were rare in the IPA group, with only 1.7% each for the halo sign and air crescent sign.

Table 3 The microbiological, laboratory, and CT thorax findings of ILD patients in the IPA and non-IPA groups
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Microbiological analysis

During the study period, respiratory cultures were collected from 257 patients with ILD and Aspergillus was detected in 30 patients (30/56, 53.6%). The most common species were A. fumigatus with 23 strains, A. flavus with 12 strains, A. niger with 3 strains and A. terreus with 2 strains were isolated. Moreover, GM was positive in 19 patients (33.9%). BAL fluid analyses were performed in 96 episodes (29 in the IPA group and 69 in the non-IPA group). In the 29 episodes in the IPA group, there were 20 (66.7%) cases of positive BAL fluid GMI and only 11 (36.7%) episode of positive BAL fluid culture for Aspergillus spp.

Table 4 Species and treatments
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Treatments and outcomes

The treatments and outcomes are summarized in Table 4. Of the 58 patients with IPA associated with ILD, all patients received antifungal treatment regardless of the duration of treatment. The basic treatment was voriconazole as monotherapy or in combination with other antifungals in 86.2% of patients. Isavuconazole was used in 12.1% of patients; amphotericin B (1.7%) was rarely used. Kaplan-Meier survival curves and log-rank test showed a significant difference in overall survival rate after 90 days between the IPA patients (70.2%) and non-IPA patients (84.0%) from the viewpoints of the follow-up period from the ILD diagnosis (See Fig. 3).

Fig. 3
figure 3

The overall 90-days survival of IPA patients

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Multivariate analysis

To further analyze the independent risk factors affecting the occurrence of IPA, a positive diagnosis was set as the dependent variable. Based on the ILD-IPA susceptibility factor analysis and univariate analysis results, we included age, steroid before admission, lymphopenia, IL-6, CRP, NLR and honeycombing in the logistic regression model [12,13,14]. The multivariate analysis summarized in Table 5 indicates that lymphopenia (OR = 2.745, 95% CI 1.344–5.607) and honeycombing (OR = 2.915, 95% CI 1.429–5.949) were independent risk factors for ILD-IPA. (P < 0.05). Additionally, it cannot be proven that CRP or NLR level is correlated with survival (See Fig. 4).

Table 5 Logistic regression analysis of risk factors for the occurrence of ILD-IPA
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Fig. 4
figure 4

Forest plot of Logistic regression analysis of risk factors for the occurrence of ILD-IPA

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Discussion

IPA is a common opportunistic infection. Aspergillus infection is usually seen in those with underlying respiratory disease. However, the report of its association with ILD is rare. Therefore, we focused on the correlations between IPA and ILD in the present study and then investigated both the patient characteristics and the prognosis or mortality risk of IPA in patients with ILD. In this retrospective study, we included 58 patients with proven (3.4%) and probable (96.6%) IPA.

Neutrophils play a key role of the first line defense against aspergillus infection. To eliminate aspergillus germinating spores, neutrophils produce extracellular traps, release antimicrobial proteases by degranulation, and activate the toll-like receptor pathway [15]. Our study presents the results of neutrophil-to-lymphocyte ratio (NLR) comparison between surviving and deceased ILD patients suffering from IPA infections.

Except for neutropenia, the increased risk for opportunistic infection in ILD is predominantly related to lymphocyte deficiency [16]. Immunosuppressive regimens have a lymphocyte reducing effect, a marker of poor prognosis for the patients [17]. The decreasing number of lymphocytes predicts impairing immune defense. Lymphopenia is found to be associated with IPA in many medical backgrounds. Elderly patients with lymphopenia are prone to develop co-infections [18]. The study indicates that a simple parameter such as lymphopenia may predict mortality risk for mold infection following ILD. On immunosuppressive therapy, the lymphocytes are depressed, leading to suppression of the natural defense system, including inflammatory response. Lymphopenia was associated with a higher risk of infection and adverse outcome [19]. Our findings also suggested that lymphopenia was the risk factor of ILD patients with IPA.

Our experience also suggests that radiologic signs of IPA are non-specific. In the previous study, UIP pattern with honeycombing (40.6%) and smoking-related ILD (28.1%) accounted for the majority of cases of Aspergillus infection [3]. Wide-spread cystic lesions and emphysema as destructive changes in lung tissue can be colonized by Aspergillus [20]. The extensive honeycomb-like changes in the lungs caused structural damage to the lungs. Thus this UIP patient lacked the essential resistance to aspergillus, and aspergillus was much likely to colonize the lungs. According to the published reports, UIP that is diagnosed upon radiologic examination accounts for 80.4% of all patients with ILD plus IPA [21]. Moreover, a Japanese study has shown that UIP patients are inclined to have aspergillosis, indicating, from another perspective, the potential role of structural lesions of the lungs in the development or pathogenesis of aspergillosis [22]. The most common radiologic manifestation of RA-ILD is the UIP pattern [23]. This may also explain IPA develops more often in patients with RA-ILD (19.0% vs. 5.1%, P < 0.001) in our study.

Unfortunately, the clinical presentation and imaging features of such patients lack specificity, posing a great challenge for the early diagnosis of ILD-IPA. In studies carried out on patients with hematologic malignancy from our country, GM antigen test sensitivity was found as 56–61% and its specificity as 21–84% [14]. In addition, it has been indicated that GM positivity in COPD patients with IPA development in intensive care and the isolation of Aspergillus species in respiratory samples may be significant in terms of mortality [10]. As for our study, the GM value was found to be positive in 14 (25.9%) cases, and 11 of them (20.7%) died. This gives further support to the belief that GM positivity in ILD cases with the development of IPA is a significant parameter to be considered in terms of mortality.

Glucocorticoids and immunosuppressants are the main medications for ILD, though they may increase the risk of aspergillosis [24]. Prolonged immunosuppressive therapy is a risk factor for IPA [25, 26]. Corticosteroid have often been used in non-IPF patients, and in fact, it was used in 51.9% of the patients in the present study. Patients treated with steroid therapy require special attention regarding the potential for Aspergillus infection. In recent years, it has been shown that corticosteroid use plays a significant role in terms of increasing the rate of IPA incidence in ILD cases [5, 27].

It was determined that IPA leads to increased mortality of ILD patients. Early antifungal therapy is mandatory for the successful treatment of IPA [28, 29]. All our patients received antifungal therapy. Voriconazole was mainly used for IPA treatment in 89.6% patients.

There are some limitations to the present study. First, it is a single-center retrospective study, which can introduce referral bias and limit the ability to generalize our findings. Moreover, the rate of positivity of mycological proof was low, although the diagnosis of IPA was made according to commonly used criteria. Randomized controlled trials are needed to evaluate the efficacy and safety of primary antifungal prophylaxis in these patients.

Conclusions

IPA with atypical manifestations can occur in patients with ILD. Constantly considering the potential presence of IPA can aid in the prompt diagnosis of such atypical IPA. As the complication of IPA may lead to a poor prognosis for any ILD, clinicians should be aware of the importance of a prompt. Lymphopenia and honeycombing, as a simple parameter of very basic blood and CT feature analysis, may be of predictive value in the estimation of mortality risk among patients with IPA following ILD.

Data availability

The datasets used and/or analysed during this study are available from the corresponding author upon reasonable request.

Abbreviations

ATS:

American Thoracic Society

ANCA:

Antineutrophil cytoplasmic antibody

BALF:

Bronchoalveolar lavage fluid

COPD:

Chronic obstructive pulmonary disease

CTD:

Connective tissue disorders

EORTC:

the European Organization for the Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group

ERS:

European Respiratory Society

GM:

Galactomannan

HRCT:

High-resolution computed tomography

IPA:

Invasive pulmonary aspergillosis

IPF:

Idiopathic pulmonary fibrosis

ILD:

Interstitial lung disease

MSG:

the National Institute of Allergy and Infectious Diseases Mycoses Study Group

UIP:

Usual interstitial pneumonia

NLR:

Neutrophil-to-lymphocyte ratio

NSIP:

Nonspecific interstitial pneumonia

RA:

Rheumatoid arthritis

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Acknowledgements

Not applicable.

Funding

This study was funded by National Natural Science Foundation of China (82270019), Fundings for Clinical Trials from the Affiliated Drum Tower Hospital, Medical School of Nanjing University (2023-LCYJ-MS-18). The funder played no role in the study design, data collection, analysis and interpretation of data, or the writing of this manuscript.

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Authors and Affiliations

  1. Department of Respiratory and Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China

    Yin Liu, Hanyi Jiang, Tingting Zhao, Min Cao, Yonglong Xiao & Xin Su

  2. Department of Nuclear Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China

    Jian He

  3. Department of Medical Imaging, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, 210008, China

    Rongfeng Qi

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  1. Yin Liu
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  2. Hanyi Jiang
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  4. Min Cao
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  7. Yonglong Xiao
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  8. Xin Su
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Contributions

LY, and SX conceived and designed the analysis. LY, JHY, ZTT, and CM collected the data. NYL, LY, YX, and ZTT contributed to the analysis. XYL, QRF, ZTT, and HJ performed the analysis. LY and SX wrote the paper. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Xin Su.

Ethics declarations

Ethics approval and consent to participate

The study protocol was approved by the Ethics Committee of Nanjing Drum Tower Hospital, with the ethics application number 2021–390-01. Due to the retrospective nature of the study using anonymous claims data, the requirement for informed consent was waived.

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Not Applicable.

Competing interests

The authors declare no competing interests.

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Liu, Y., Jiang, H., Zhao, T. et al. Clinical features and risk factors of invasive pulmonary aspergillosis in interstitial lung disease patients. BMC Pulm Med 24, 602 (2024). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12890-024-03430-x

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  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s12890-024-03430-x

Keywords

BMC Pulmonary Medicine

ISSN: 1471-2466

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