Clinical classification of chronic obstructive pulmonary disease with invasive pulmonary aspergillosis: a retrospective study

Abstract

Background

Patients with chronic obstructive pulmonary disease (COPD) complicated by invasive pulmonary aspergillosis (IPA) have high mortality and significant clinical heterogeneity. However, systematic classification criteria are currently lacking. To address this, our study proposes a clinical classification system specifically for COPD-IPA, based on its distinct clinical manifestations and pulmonary imaging features.

Methods

We performed a retrospective analysis of clinical and radiological features in patients diagnosed with COPD-IPA during hospitalization from 2008 to 2024 to develop a novel clinical classification system. Demographic characteristics, laboratory parameters, radiologic manifestations, and prognosis were compared across the identified subtypes.

Results

The study cohort comprised 63 COPD-IPA patients, who were predominantly elderly males (mean age: 70.9±8.7 years; 95.2% male). A novel classification system defined five distinct subtypes: (I) the fulminant type (3/63, 4.8%), which progressed rapidly to respiratory failure [partial pressure of arterial oxygen (PaO₂)/fraction of inspired oxygen (FiO₂): 204.0±36.2 mmHg], was associated with hemodynamic instability (2/3, 66.7%), and had a high mortality rate (2/3, 66.7%); (II) the pneumonic type (35/63, 55.5%), presenting primarily as lobar or segmental consolidation (26/35, 74.3%) and frequently misdiagnosed as bacterial pneumonia; (III) the tuberculosis-like type (14/63, 22.2%), typically exhibiting upper-lobe fibro-proliferative lesions (13/14, 92.9%); (IV) the asthma-like type (7/63, 11.1%), characterized by mucoid impaction (5/7, 71.4%) and steroid-refractory trait; (V) the tumor-like type (3/63, 4.8%), manifesting in all cases as solitary ground-glass opacity (GGO) nodules or mixed solid lesions. Additionally, one patient (1/63, 1.6%) presented with diuretic-unresponsive, diffuse GGOs in both lower lungs, suggesting a potential heart failure-like type. Critical differences emerged between the subtypes: the fulminant subtype had the most severe oxygenation impairment (lowest PaO₂/FiO₂, P<0.05) and universally required mechanical ventilation (100.0%), while the tumor-like subtype presented with the most insidious symptoms (PaO₂/FiO₂: 517.0±110.0 mmHg).

Conclusions

The five-subtype classification system established in this study delineates the heterogeneity of COPD-IPA and provides a novel framework to guide precise clinical management.

Highlight box.

Key findings

• This study establishes a novel five-subtype classification system for chronic obstructive pulmonary disease with invasive pulmonary aspergillosis (COPD-IPA) that captures the disease’s broad clinical and radiological spectrum, ranging from a fulminant type with high mortality to an indolent tumor-like type.

What is known and what is new?

• COPD‑IPA is associated with high mortality and marked clinical heterogeneity, but systematic clinical classification criteria have been lacking.

• This study proposes the first dedicated clinical classification system for COPD-IPA, which delineates five distinct phenotypes based on their specific manifestations and prognoses.

What is the implication, and what should change now?

• This framework supports a shift toward precision medicine in COPD-IPA by enabling subtype recognition to guide diagnostics evaluation and inform individualized management strategies.

Introduction

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic respiratory disorder characterized by persistent and progressive airflow limitation, with key pathological features including small airway inflammation, luminal narrowing, and mucus hypersecretion (1). Infectious complications represent a major challenge in COPD management. Underlying structural lung disease and frequent corticosteroid use render COPD patients a high-risk population for invasive pulmonary aspergillosis (IPA) (2). A 2020 worldwide systematic review synthesizing data from 2000–2019 estimated the annual incidence of IPA among hospitalized COPD patients at 1.3–3.9% (3). Accumulating evidence indicates that COPD complicated by IPA (COPD-IPA) is associated with markedly worse clinical outcomes, including accelerated lung function decline, reduced quality of life, and increased mortality (4-6). For instance, an analysis of a U.S. national inpatient database showed that acute exacerbations of COPD (AECOPD) patients with IPA had a significantly higher in-hospital mortality rate (14.5%) than those without IPA (3.6%) (5). This elevated mortality is closely linked to delays in diagnosis and treatment (6,7).

Clinically, COPD-IPA typically manifests with cough, sputum production, dyspnea, and fever, whereas hemoptysis and chest pain occur less frequently (8). Radiologically, classic signs of vascular invasion (e.g., halo sign, air-crescent sign) are often absent. Instead, imaging findings frequently align with airway-invasive aspergillosis (AIA) and demonstrate dynamic changes as the disease progresses (9,10). These nonspecific symptoms and atypical imaging features are often obscured by the underlying COPD in early stages, contributing to diagnostic delay. Consequently, patients with COPD-IPA can deteriorate rapidly, with severe cases progressing to respiratory failure and hemodynamic instability, which may result in fatal outcomes (8).

To date, systematic analyses of the clinical and radiological characteristics of COPD-IPA patients remain limited. Therefore, this retrospective study aims to: (I) delineate distinct clinical and radiological phenotypes through a comprehensive analysis of patient data; (II) characterize the specific profiles to each subtype; and (III) enhance diagnostic recognition to facilitate early intervention and improve clinical outcomes. We present this article in accordance with the STROBE reporting checklist (available at https://jtd.amegroups.com/article/view/10.21037/jtd-2025-1932/rc).

Methods

Study design

This single-center retrospective study hypothesized that patients with COPD-IPA present with distinct clinico-radiological phenotypes associated with divergent prognostic outcomes. Analyzing these differences aimed to provide more targeted guidance for clinical diagnosis and treatment. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (No. SYSKY-2025-615-01). Medical records from prior clinical care have been used for this study, and the waiver of informed consent has been granted.

Study subjects

We screened patients hospitalized at Sun Yat-sen Memorial Hospital, Sun Yat-sen University between January 1, 2008 and December 30, 2024. Data were extracted from the hospital’s electronic medical record system, laboratory/information system, and imaging system. Enrollment was limited to patients with a diagnosis of COPD-IPA. Inclusion required meeting the specific diagnostic criteria for COPD-IPA, detailed subsequently. The diagnosis of IPA was established according to the Bulpa criteria (9,11,12), which classify cases as proven, probable, or possible. Patients were excluded for: (I) concurrent active pulmonary tuberculosis (TB), lung cancer, or other invasive fungal infections; (II) a history of hematological malignancies, solid organ transplantation, or human immunodeficiency virus (HIV) infection; (III) the absence of more than 30% of key data, particularly thoracic computed tomography (CT) scans or chest radiographs.

Diagnostic criteria

COPD was diagnosed according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) guidelines (13), which require a post-bronchodilator ratio of forced expiratory volume in one second to forced vital capacity (FEV₁/FVC) <0.7 and GOLD stage III–IV. IPA was defined using the Bulpa criteria (9,11,12). Proven IPA required histopathological or cytopathological evidence of Aspergillus hyphae in lung biopsy tissue, or a positive tissue polymerase chain reaction (PCR) for Aspergillus, accompanied by signs of tissue damage attributable to infection, plus at least one of the following microbiological criterion: (I) a positive culture or direct microscopy for Aspergillus from a lower respiratory tract specimen; (II) a positive serum or bronchoalveolar lavage fluid (BALF) galactomannan (GM) antigen test, or a positive serum Aspergillus immunoglobulin G (IgG) antibody; (III) detection of Aspergillus by PCR or other validated mycological methods in serum or BALF. To improve specificity, a positive GM test was defined as: a single serum or plasma GM index ≥1.0; a BALF GM index ≥1.0; or both a serum/plasma GM index >0.7 and a BALF GM index ≥0.8 (14). Probable IPA required host factors (COPD GOLD stage III–IV, prolonged corticosteroid therapy), clinical features (symptoms of an acute COPD exacerbation with poor response to conventional management, plus new pulmonary radiological abnormalities consistent with IPA), and microbiological evidence. Possible IPA was defined by the presence of host factors and clinical features but an absence of microbiological evidence. This study included patients with proven or probable IPA. Additionally, patients with possible IPA who responded to antifungal therapy were also included. All enrolled patients showed symptomatic improvement and resolution of pulmonary lesions following antifungal therapy against Aspergillus.

Clinical classification of COPD-IPA

All cases were independently reviewed by a panel of two to three board-certified radiologists or pulmonologists. Integrated clinico-radiological profiles were evaluated, and final phenotypic classification was determined by consensus. Based on preliminary analysis, COPD-IPA patients were classified into five subtypes: fulminant, pneumonia-like, TB-like, asthma-like, tumor-like. A sixth distinct subtype, termed heart failure-like, was identified. The fulminant type was defined by a severe and rapidly progressive clinical course, with deterioration occurring within 72 hours and necessitating intensive care unit (ICU) admission. The other subtypes (namely, pneumonia-like, TB-like, asthma-like, tumor-like, and heart failure-like) exhibited clinical and imaging features that closely resembled their respective mimicked diseases prior to the definitive diagnosis of IPA.

Data collection

Clinical symptoms were obtained from institutional medical records. Relevant chest imaging and laboratory data, including complete blood count, artery blood gas analysis, and C-reactive protein (CRP) were retrieved from hospital databases. The most abnormal values recorded from symptom onset until the initiation of targeted therapy were collected to reflect peak disease severity.

Statistical analysis

We employed IBM SPSS Statistics (RRID:SCR_016479) for all statistical analyses. The Chi-squared test was used to analyze the distribution of proven, probable, and possible IPA cases across the different phenotypes to assess potential associations between diagnostic certainty and phenotype. Differences in laboratory parameters among different phenotypes—including white blood cell (WBC) count, neutrophil percentage, lymphocyte count, CRP level, the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen [partial pressure of arterial oxygen (PaO₂)/fraction of inspired oxygen (FiO₂)], and partial pressure of arterial carbon dioxide (PaCO₂)—were analyzed using one-way analysis of variance (ANOVA) or the Kruskal-Wallis test, as appropriate. Additionally, the Chi-squared test was employed to compare the proportions of patients requiring mechanical ventilation and mortality rates across phenotypes, providing an assessment of disease severity and prognostic outcomes.

Results

Diagnostic and demographic characteristics of the patients

A total of 63 patients with COPD-IPA were enrolled. The mean age was 70.9±8.7 years, and the cohort comprised 3 females and 60 males. All patients had COPD classified as GOLD stage III or IV. Specifically. A history of long-term (>3 months) inhaled corticosteroid use was documented in 28 patients. Thirty patients had recently received broad-spectrum antibiotics and/or systemic corticosteroids, though the specific dosage and duration were unavailable from records, while prior medication history was unknown for 5 patients due to missing documentation.

According to diagnostic criteria, the cohort included 1 case (1.6%) of proven IPA, 47 cases (74.6%) of probable IPA, and 15 cases (23.8%) of possible IPA. Comorbidities and relevant medical history included previous pulmonary TB (n=10), bronchiectasis (n=1), asthma (n=1), recent viral infections such as severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and influenza A/B virus (n=11), prior pulmonary surgery (n=2), and diabetes mellitus (n=6) (Table 1).

Table 1. Basic information.

Characteristics	Value (N=63)
Age (years)	70.9±8.7
Gender
Female	3
Male	60
Diagnostic classification of IPA
Proven diagnosis	1 (1.6)
Probable diagnosis	47 (74.6)
Possible diagnosis	15 (23.8)
Complication in disease
Old tuberculosis	10 (15.9)
Bronchiectasis	1 (1.6)
Asthma	1 (1.6)
Viral infections	11 (17.5)
Lung surgery	2 (3.2)
Diabetes mellitus	6 (9.5)

Data are presented as number (percent) or mean ± SD. IPA, invasive pulmonary aspergillosis; SD, standard deviation.

Clinical features of each phenotypes of COPD-IPA

Fulminant type

Three patients (3/63, 4.8%) were classified into this subtype, all with probable IPA. BALF analysis incorporating direct microscopy, culture, GM antigen testing, or next-generation sequencing (NGS) yielded positive results in all three cases. Sputum culture was positive for Aspergillus in only 1 patient (1/3, 33.3%), and serum GM was positive in 1 patient (1/3, 33.3%). These patients exhibited rapidly progressive respiratory failure, severe hypoxemia (PaO₂/FiO₂ ratio: 204.0±36.2), and hypercapnia (PaCO₂: 78.4±9.7 mmHg), necessitating invasive mechanical ventilation in all cases. Fever was present in 2 patients (2/3, 66.7%). Hemodynamic instability, including hypotension and shock, occurred in 2 patients (2/3, 66.7%), both of whom died. Radiologically, this subtype was characterized by diffuse bronchial wall thickening, frequently involving the trachea and main bronchi (Figure 1). Chest CT showed scattered streaky, patchy, or nodular opacities in all patients. Peribronchial patchy or ground-glass consolidation with surrounding centrilobular nodules was seen in 2 patients (2/3, 66.7%), and bronchiectasis was noted in 1 (1/3, 33.3%).

Figure 1.

Chest CT manifestations of the early stage of the fulminant-type of COPD-IPA. Images are from a 77-year-old male COPD-IPA patient, admitted for “worsening cough, sputum production, and dyspnea for 1 day”. Despite timely antifungal therapy, he developed severe respiratory and circulatory failure and ultimately died. The CT image (A-C) showed thickened bronchial walls with a beaded appearance, surrounded by areas of ground-glass consolidation and tree-in-bud opacities. Early-stage CT manifestations in this phenotype often lack pathognomonic findings, thus complicating initial diagnosis. COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis; CT, computed tomography.

Pneumonia-like type

This was the most common subtype (n=35, 55.5%), comprising 1 proven (2.9%), 27 probable (77.1%), and 7 possible (20.0%) IPA cases. Aspergillus was cultured from sputum in 9 patients (25.7%), while serum GM or IgG was positive in 13 (37.1%). Of the 24 patients who underwent BALF analysis, 20 (83.3%) had positive microbiological findings. Clinical presentation included prominent cough, sputum, and progressive dyspnea (PaO₂/FiO₂: 304.8±98.3; PaCO₂: 44.3±9.2 mmHg). Fever was present in 10 patients (10/35, 28.6%), chest pain in 1 (1/35, 2.9%), and hemoptysis in 1 (1/35, 2.9%). Radiologically, 26 patients (26/35, 74.3%) exhibited single or multiple patchy opacities and lobar or segmental consolidation (Figure 2A,2B). Cavitary lesions within areas of consolidation were observed in 5 patients (5/35, 14.3%). Imaging also revealed bronchial wall thickening in 18 (18/35, 51.4%), bronchial stenosis or obstruction in 4 (4/35, 11.4%), and bronchiectasis in 10 (10/35, 28.6%). The halo sign or air-crescent sign was evident in only 2 patients (Figure 2C,2D).

Figure 2.

Chest CT manifestations of the pneumonia-like COPD-IPA. (A) Image is from a 71-year-old COPD-IPA patient, admitted for “worsening cough and dyspnea for 20 days”. It showed chronic inflammation in the right upper lobe of the lung. (B) Image is from a 63-year-old COPD-IPA patient who was admitted to the hospital primarily due to worsening cough and shortness of breath accompanied by fever. It indicates lobar pneumonia in the middle lobe of the right lung. (C) Image obtained from a 56-year-old patient with COPD-IPA reveals a “halo sign” in the right upper lobe of the lung (white arrow). (D) Image from a 74-year-old patient with COPD-IPA shows a cavitary lesion in the right lower lobe, which demonstrates an “air crescent sign” (white arrow). COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis; CT, computed tomography.

TB-like type

Fourteen patients (22.2%) were classified into this subtype, comprising 10 probable and 4 possible IPA cases. Sputum culture was positive for Aspergillus in 5 patients (5/14, 35.7%), while serum GM or IgG was positive in 3 (3/14, 21.4%). Among the seven patients who underwent BALF analysis, five was positive (71.4%). Common symptoms included cough, sputum, and progressive dyspnea (PaO₂/FiO₂: 336.6±103.4; PaCO₂: 46.1±10.1 mmHg). Fever was present in 4 patients (4/14, 28.6%), hemoptysis in 3 (3/14, 21.4%), and chest pain in 1 (1/14, 7.1%). All tested negative for TB via purified protein derivative (PPD) skin testing, Mycobacterium tuberculosis polymerase chain reaction (PCR), and acid-fast bacilli (AFB) staining. Imaging revealed a predominance of lesions in the upper lobes or dorsal segments of the lower lobes. Multiple fibrotic, proliferative, and exudative lesions were seen in 13 patients (92.9%). Two patients exhibited cavitary lesions with irregular inner walls and surrounding satellite nodules (Figure 3). Additionally, bronchial wall thickening was noted in 6 patients (6/14, 42.9%), and bronchiectasis was present in 4 (4/14, 28.6%).

Figure 3.

Chest CT manifestations of the tuberculosis-like COPD-IPA. Images are from a 77-year-old COPD-IPA patient who was admitted to the hospital presenting with “cough and shortness of breath for 1 month” and has no history of pulmonary tuberculosis. CT scans (A-C) show diffusely distributed patchy and nodular opacities in both lungs, with upper lobe predominance. The lesions demonstrate ill-defined margins, with some developing cavitary lesions containing small patchy and nodular opacities within the cavities. Additionally, irregular pleural thickening is observed bilaterally. Follow-up CT after 3 weeks of antifungal therapy demonstrates marked improvement of the lung lesions (A1-C1). COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis; CT, computed tomography.

Asthma-like type

This subtype comprised seven patients (11.1%), including 5 with probable and 2 with possible IPA. Sputum culture was positive in 1 patient (1/7, 14.3%), while serum GM and IgG antibody was positive in 3 (3/7, 42.9%). BALF analysis (n=6) was positive in 3 (50.0%). Prominent wheezing and auscultatory rhonchi were characteristic during physical examination Patients had progressive dyspnea (PaO₂/FiO₂: 343.2±78.7; PaCO₂: 47.5±10.2 mmHg), and responded poorly to bronchodilators and corticosteroids. Cough and sputum production were common, but no fever was observed. Radiologically, chest CT scans revealed diffuse or focal bronchial wall thickening in 4 patients (4/7, 57.1%) and mucoid impaction in 5 (71.4%). Central bronchiectasis was present in 2 (2/7, 28.6%). Ground-glass opacities (GGOs) or patchy infiltrates were observed, likely secondary to distal infection or inflammation beyond the obstructing mucoid plugs (Figure 4).

Figure 4.

Chest CT manifestations of the asthma-like COPD-IPA. Images are from a 45-year-old female with COPD-IPA admitted for “recurrent cough with sputum production for over 3 months and dyspnea for 1 week”. Pulmonary function tests revealed moderate -severe obstructive ventilatory impairment. Bronchoscopy showed diffuse nodular mucosal lesions in the bronchi. Chest CT (A-C) demonstrated multiple bronchial mucus plugs causing obstruction and central bronchiectasis. Additionally, ground-glass opacities and patchy shadows are seen surrounding the distal airways (white arrow, C). COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis; CT, computed tomography.

Tumor-like type

Three patients (4.8%) were classified into this subtype (2 probable, 1 possible IPA). Serum GM/IgG antibody was positive in 1 patient (1/3, 33.3%). Of the two patients who underwent BALF analysis, one tested positive (50.0%). The clinical presentation was insidious, characterized primarily by cough and sputum production without prominent dyspnea (PaO₂/FiO₂: 517.0±110.0; PaCO₂: 39.5±3.9 mmHg). Fever, chest pain, and hemoptysis were absent. The patients failed to respond to conventional anti-infective therapy. Imaging revealed solitary pulmonary nodules or mass-like opacities with well-defined borders, spiculation, and heterogeneous density, which resolved rapidly after antifungal therapy (Figure 5). Additionally, bronchial wall thickening was noted in 2 patients (2/3, 66.7%), while one patient exhibited bronchial stenosis or obstruction in 1 (1/3, 33.3%) and another (1/3, 33.3%) had bronchiectasis.

Figure 5.

Chest CT manifestations of the tumor-like COPD-IPA. Representative CT images from two male patients with COPD-IPA (aged 57 and 73 years) demonstrate solitary pulmonary nodules or mass-like lesions with spiculated margins and heterogeneous attenuation (A,B). Follow-up imaging after antifungal therapy demonstrates marked improvement in the pulmonary lesions in both patients (A1,B1). COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis; CT, computed tomography.

Unusual phenotype: heart failure-like type

A single patient (1.6%) with possible IPA represented this rare phenotype. The patient presented with progressive dyspnea (PaO₂/FiO₂ 348.6), orthopnea, and blood-streaked sputum despite treatment with empirical antibiotics, bronchodilators, and systemic corticosteroids. Bibasilar crackles were audible. Chest imaging showed diffuse, bilateral ground-glass opacities and patchy consolidations, which were most predominant in the mid-to-lower lung zones and perihilar regions and lacked typical airway abnormalities of the other subtypes. Bothe symptoms and radiographic opacities improved only after initiation of anti-Aspergillus therapy (Figure 6).

Figure 6.

Chest X-ray manifestations of the heart failure-like COPD-IPA. Images are from an 82-year-old male COPD patient admitted for “worsening cough, sputum production, and shortness of breath over 7 days”. During hospitalization, he developed progressively worsening dyspnea, orthopnea, and blood-streaked sputum. (A) Chest X-ray prior to symptom onset demonstrated patchy opacities in both lower lung fields with clearly defined hila. (B) Chest X-ray following symptom onset revealed large opacities in both lower lungs, showing increased extent compared to the previous study. The hila appeared obscured, notable for newly developed pleural effusion. (C) After 4 weeks of antifungal therapy, the lung lesions showed marked improvement compared to previous studies. COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis.

Statistical analysis of phenotype differences

No statistically significant difference was observed in the distribution of diagnostic certainty levels (proven, probable, possible IPA) among the different phenotypes (P=0.85). As shown in Table 2, the Fulminant type exhibited more severe respiratory failure than the other phenotypes, characterized by a significantly lower PaO₂/FiO₂ ratio (P<0.05) and a significantly higher PaCO₂ (P<0.01). Furthermore, this phenotype required mechanical ventilation more frequently (P<0.05) and had a significantly higher mortality rate (P<0.01). Laboratory parameters, including WBC count, neutrophil percentage, CRP level, and lymphocyte count, showed no statistically significant differences across all phenotypes (P>0.05). Similarly, the PaO₂/FiO₂ ratio and PaCO₂ were also comparable among the pneumonia-like, TB-like, and asthma-like type (P>0.05). Among these groups, the pneumonic-like type had the second-highest rate of mechanical ventilation requirement (28.6%). In contrast, patients with the tumor-like type exhibited no significant respiratory failure compared to other phenotypes (Table 2).

Table 2. Comparison among different phenotypes of COPD-IPA.

Characteristics	Fulminant type (N=3)	Pneumonia-like type (N=35)	Tuberculosis-like type (N=14)	Asthma-like type (N=7)	Tumor-like type (N=3)	Heart failure-like type (unusual phenotype) (N=1)
Age (years)	75.0±6.2	71.3±8.5	72.4±8.0	64.4±10.7	67.0±8.7	82
Diagnostic classification of IPA
Proven diagnosis	0	1 (2.9)	0	0	0	0
Probable diagnosis	3 (100.0)	27 (77.1)	10 (71.4)	5 (71.4)	2 (66.7)	0
Possible diagnosis	0	7 (20.0)	4 (28.6)	2 (28.6)	1 (33.3)	1 (100.0)
Clinical manifestations
Fever	2 (66.7)	10 (28.6)	4 (28.6)	0	0	0
Chest pain	0	1 (2.9)	1 (7.1)	0	0	0
Hemoptysis	0	1 (2.9)	3 (21.4)	0	0	1 (100.0)
Imaging features
Bronchial wall thickening	2 (66.7)	18 (51.4)	6 (42.9)	4 (57.1)	2 (66.7)	–
Bronchial obstruction or stenosis	0	4 (11.4)	0	5 (71.4)	1 (33.3)	–
Bronchiectasis	1 (33.3)	10 (28.6)	4 (28.6)	2 (28.6)	1 (33.3)	–
Cavity	0	5 (14.3)	2 (14.3)	0	1 (33.3)	–
Halo sign	0	1 (2.9)	0	0	0	–
Air crescent	0	1 (2.9)	0	0	0	–
Laboratory indicators
WBC count (109/L)	11.5±1.5	10.9±5.5	11.2±6.7	10.9±2.2	7.0±2.5	11.1
Neutrophil percentage (%)	87.5±7.7	80.6±11.9	77.4±11.3	80.4±13.2	74.1±8.6	84.2
Lymphocyte count (109/L)	0.5±0.1	1.0±0.5	1.1±0.6	1.2±0.9	1.1±0.3	0.45
CRP (mg/L)	36.4±14.5	52.2±54.1	55.5±49.3	19.2±19.1	24.9±31.0	–
PaCO2 (mmHg)	78.4±9.7**	44.3±9.2	46.1±10.1	47.5±10.2	39.5±3.9	36.2
PaO2/FiO2 ratio	204.0±36.2*	304.8±98.3	336.6±103.4	343.2±78.7	517.0±110.0	348.6
Prognosis and outcomes
Received mechanical ventilation	3 (100.0)*	10 (28.6)	1 (7.1)	1 (14.3)	0	0
Death toll	2 (66.7)**	0	0	0	0	0

Data are presented as number (percent) or mean ± SD. Asterisks indicates statistical significance (*, P<0.05; **, P<0.01) compared to other groups. The heart failure-like type was included as an unusual phenotype for comparison. COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis; CRP, C-reactive protein; FiO₂, fraction of inspired oxygen; PaCO₂, partial pressure of arterial carbon dioxide; PaO₂, partial pressure of arterial oxygen; SD, standard deviation; WBC, white blood cell.

Discussion

The high mortality rate of COPD-IPA is closely linked to its insidious clinical presentation and frequent diagnostic delays. In this study, we propose a novel clinico-radiological classification system, categorizing COPD-IPA into five primary subtypes and one additional special type. This framework systematically reveals, for the first time, the heterogeneous nature of this condition. The classification not only deepens the understanding of its underlying pathophysiology but also provides a critical basis for precise diagnosis and therapeutic intervention.

Characteristics and diagnostic challenges in COPD-IPA

Demographic profile and diagnostic dilemmas

This cohort was characterized by advanced age (70.9±8.7 years) and a male predominance (95.2%), aligning with COPD epidemiology. Diagnosis of IPA followed the Bulpa criteria, which are particularly applicable to COPD patients (12). All enrolled subjects had GOLD stage III–IV COPD, and the vast majority had a documented history of corticosteroid exposure, though this could not be definitively confirmed for a small number due to incomplete medical records. Comorbidities such as diabetes mellitus (n=6) and recent viral infections (SARS-CoV-2 or influenza A/B, n=11) were present, both contributing to varying degrees of immunosuppression.

Notably, only one case (1.6%) was histopathologically proven, while clinically diagnosed probable IPA cases predominated (74.6%), highlighting the difficulty in obtaining pathological confirmation in COPD-IPA (15). This challenge stems from the severe dyspnea in these patients, which often precludes tolerance for invasive procedures. Furthermore, the absence of invasive hyphae in a limited biopsy sample does not rule out invasion at other sites. An additional 15 patients (23.8%) were classified as possible IPA based on clinical presentation combined with a positive response to antifungal therapy.

The serum GM assay is a critical diagnostic tool for IPA. However, COPD-IPA is associated with lower serum GM positivity rates, attributable to a lower fungal burden and limited angioinvasion. Unlike in systemic immunodeficiencies, the pathological basis of IPA in COPD involves pulmonary structural damage and localized immunodeficiency from inhaled corticosteroids. Aspergillus tends to colonize structural lesions (e.g., bullae, fibrosis) before slowly invading surrounding tissue, resulting in localized and mild angioinvasion that contributes to low serum GM positivity (7,16). In contrast, BALF GM testing demonstrates superior sensitivity compared to serum GM assays (14,17), a finding corroborated by our data.

However, obtaining BALF is often challenging in critically ill COPD-IPA patients due to severe respiratory distress and intolerance to bronchoscopy. Therefore, the diagnosis of COPD-IPA requires an integrated model that synthesizes three key elements: host risk factors (COPD exacerbation and corticosteroid use), clinical deterioration, and microbiological/radiological evidence (17). Negative microbiological results alone cannot exclude IPA.

Atypical clinical presentation and complex radiological features

Clinical manifestations primarily involved worsening baseline respiratory symptoms (cough, sputum production, dyspnea), which significantly overlapped with those of AECOPD, complicating differentiation. Fever occurred in only 25.4% (16/63) of our cohort, in contrast to its higher frequency in IPA complicating hematological malignancies (18). This blunted inflammatory response may stem from impaired innate immunity in COPD [e.g., reduced alveolar macrophage phagocytosis and suppressed Toll-like receptor (TLR) signaling] (19,20) along with corticosteroid-mediated suppression of pro-inflammatory cytokines such as IL-1β and TNF-α (21,22).

Radiological presentations were highly heterogeneous. Classic angioinvasive features like the halo sign or air-crescent sign were rare (3.2%), a prevalence substantially lower than in IPA patients with hematological malignancies (18). A retrospective study analyzing imaging findings in 20 COPD-IPA cases revealed that characteristic signs such as the halo sign, wedge-shaped consolidation, and air-crescent sign were in only 19%, 19%, and 28.5% of cases, respectively (23). Instead, airway-invasive patterns predominated, featuring bronchial wall thickening, luminal stenosis or obstruction, mucoid impaction, bronchiectasis, and parenchymal infiltrates such as patchy consolidation, ground-glass opacities, or cavitation. This heterogeneity relates to the underlying pathophysiology in COPD, encompassing structural abnormalities and localized immunodeficiency. This airway-centered pattern with mixed inflammatory features aligns with the chronic airway inflammation and structural destruction in COPD (19-25). Aspergillus spores colonize damaged airways, forming biofilms and penetrating the basement membrane, leading to intertwined airway and parenchymal lesions that mask typical angioinvasive signs. Concurrent bacterial infections may further obscure characteristic radiographic features.

Characteristics and differential diagnosis of the six clinical subtypes

Fulminant type

The concept of fulminant COPD-IPA was first proposed in a 2018 case report by Ohara et al. (26). In our study, patients with this subtype exhibited rapidly progressive respiratory failure (mean PaO₂/FiO₂ 204.0±36.2), refractory hypercapnia (mean PaCO₂ 78.4±9.7 mmHg), and hemodynamic instability (66.7%). Chest CT findings in this subtype indicated extensive tracheobronchial involvement, characterized by bronchial wall thickening, luminal narrowing or obstruction, and peribronchial consolidation. In one case, significant bronchial wall thickening was absent, which may be related to the timing of imaging—the CT scan may have been performed prior to disease onset or at a very early stage before typical feature developed. All three patients with either succumbed or transitioned to comfort care within days of presentation, which precluded the acquisition of serial chest imaging. The severe ventilatory failure in this context likely stems from destruction of bronchial architecture and extensive intra-alveolar exudates, which decrease lung compliance, increase intrapulmonary shunt, and elevate airway resistance. These pathophysiological alterations ultimately progress to hypercapnic respiratory failure, multiple organ failure, and death. Notably, two patients had a recent history of infection with either SARS-CoV-2 or influenza A virus. We hypothesize that the rapid and extensive invasion by Aspergillus observed in this subtype may be linked to virus-induced immune dysregulation (27,28). Mechanistically, respiratory viral infections can compromise the integrity of the respiratory mucosal barrier and induce a state of localized immunosuppression or inflammatory dysregulation, potentially facilitating the rapid transition and dissemination of Aspergillus within bronchopulmonary tissues. In clinical practice, COPD patients with a recent viral infection who develop acute and rapidly progressive respiratory failure should raise strong suspicion for fulminant COPD-IPA. This subtype requires differentiation from other causes of acute respiratory distress syndrome (ARDS), septic shock, and pulmonary embolism (29-31). Given its rapid progression and exceedingly high mortality, early initiation of combination antifungal therapy alongside aggressive hemodynamic support is imperative.

Pneumonia-like type

This was the most prevalent subtype (n=35, 55.5%). Pathologically, Aspergillus hyphae invade compromised bronchial walls, triggering peribronchial inflammation and alveolar flooding. Patients presented with acute exacerbation symptoms and relatively mild hypoxemia (mean PaO₂/FiO₂ 304.8±98.3). Radiographic features comprised bronchial wall thickening (51.4%), bronchiectasis (28.6%), unifocal or multifocal patchy opacities with lobar/segmental consolidation (74.3%), and cavitation (14.3%). Given its clinical and imaging features, this subtype necessitates differentiation from bacterial pneumonia such as community-acquired pneumonia (CAP) as well as organizing pneumonia (OP). Importantly, a lack of response to conventional antibiotic therapy should prompt immediate suspicion for IPA.

TB-like type

Owing to the characteristic bronchoangioinvasive nature of Aspergillus, COPD-IPA lesions predominantly propagate along bronchovascular bundles, with a predilection for the upper lobes and peripheral zones, and typically exhibit a bilateral multifocal distribution (8,10). Although IPA and pulmonary TB represent pathologically distinct entities, they share overlapping radiographic features, including nodular opacities, cavitation, consolidation, or patchy exudates (32). Crucially, all cases were definitively excluded as active TB through negative PPD tests, PCR assays, and mycobacterial cultures. Given this striking resemblance to TB imaging characteristics, we designated this variant the TB-like type. Notably, structural lung damage secondary to prior TB constitutes a recognized predisposing factor for IPA (33). Five patients with a documented TB history—all having completed full anti-TB regimens—exhibited residual fibrotic changes on CT. These sequelae obscured characteristic IPA lesions and complicated radiological diagnosis.

In addition to pulmonary TB, this subtype must also be differentiated from chronic fibrosing pulmonary aspergillosis (CFPA). CFPA typically represents the end-stage sequela of untreated or inadequately treated chronic cavitary pulmonary aspergillosis (CCPA). Its imaging features typically include upper lobe predominance, extensive pulmonary fibrosis, lobar volume loss, multiple thick-walled cavities, and pleural thickening with adhesions—characteristics that substantially overlap with those of TB-like IPA (34). However, a key distinguishing factor lies in the therapeutic response, as CFPA is often refractory to antifungal therapy. In the present study, patients with TB-like IPA exhibited short-term imaging improvement following antifungal treatment, providing important evidence for distinguishing IPA from non-invasive forms.

Asthma-like type

This subtype primarily manifests as acute airway obstruction, characterized by sudden-onset wheezing with diffuse bilateral wheezes in all cases. Only one patient in this group had a documented history of bronchial asthma. Although the clinical presentation resembles an acute COPD exacerbation or an asthma attack, this subtype proved refractory to conventional anti-infective therapy, bronchodilators, and systemic corticosteroids, suggesting a distinct underlying pathophysiology from typical COPD exacerbations or asthma episodes. Pathologically, this phenotype corresponds to tracheobronchial invasive aspergillosis. CT imaging reveals central airway mucoid impaction causing distal obstructive pneumonitis, which appears radiographically as ground-glass opacities or segmental atelectasis. This pattern indicates Aspergillus hyphae invading bronchial walls and inducing hypersecretion of viscous mucus from tracheobronchial mucosa, ultimately resulting in luminal occlusion (21,22). It should be noted, however, that such imaging patterns are not specific to invasive disease.

This phenotype closely resembles allergic bronchopulmonary aspergillosis (ABPA) in both clinical presentation and radiographic findings. ABPA typically develops in patients with asthma or cystic fibrosis, and is pathologically characterized by a hypersensitivity reaction to colonizing Aspergillus, which drives remarkable eosinophilic inflammation and bronchial damage (35,36). Its hallmark diagnostic features are markedly elevated serum immunoglobulin E (IgE) levels and a favorable response to systemic corticosteroid therapy (37). In contrast, the asthma-like type responded poorly to corticosteroids. Only one patient exhibited elevated serum IgE, and this same individual also had a positive serum GM assay (index >1), a finding consistent with invasive aspergillosis. Differentiating IPA from ABPA is critical in clinical practice, for misdiagnosing IPA as ABPA and administering high-dose corticosteroids may accelerate fungal dissemination.

Tumor-like type

Solitary GGO nodules or masses represent a relatively uncommon yet diagnostically significant imaging manifestation of COPD-IPA. This pattern likely results from multifactorial interactions. The characteristic pulmonary architectural destruction and chronic airway inflammation in COPD patients establish a pathological foundation for Aspergillus colonization and subsequent invasion (19-24). Fungal infections frequently initiate at sites of severe structural compromise or impaired local defenses, such as pulmonary bullae. Concurrently, diminished vascular perfusion in emphysematous regions combined with the anti-inflammatory and hemorrhage-suppressing effects of corticosteroid, contains both inflammatory and hemorrhagic responses within the initial focus (38). Consequently, these early foci remain confined to the initial site of infection and may be incidentally detected on CT examinations prior to dissemination, potentially mimicking primary lung neoplasms (39). This phenotype presents subtle symptoms (afebrile, no hemoptysis) and mild dyspnea (mean PaO₂/FiO₂ 517.0±110.0). Following antifungal therapy, these patients exhibited symptomatic improvement with rapid radiological resolution of the pulmonary lesions. This favorable treatment response serves as a key feature distinguishing it from chronic non-IPA, such as aspergilloma or fungal nodules, which typically do not improve promptly with antifungal agents. In clinical practice, CT-guided biopsy demonstrating hyphal invasion remains a critical diagnostic tool. Although its sensitivity is limited, it provides definitive pathological evidence for differentiating this condition from primary lung carcinoma, metastatic tumors, and inflammatory pseudotumors.

Heart failure-like type (unusual phenotype)

Only one patient presented with heart failure-like manifestations, including progressive dyspnea and bilateral basal crackles, with chest radiography demonstrating diffuse ground-glass opacities predominantly in the hilar regions and mid-to-lower lung zones. This presentation is easily mistaken as acute heart failure. However, unlike typical heart failure, this patient had a normal N-terminal pro-brain natriuretic peptide level, displayed no imaging signs of interlobar edema, and failed to respond to conventional anti-heart failure therapy. Following the initiation of antifungal treatment, the patient’s dyspnea improved rapidly, and follow-up chest imaging demonstrated resolution of the pulmonary lesions. We propose that the clinical manifestations in this phenotype likely result from diffuse alveolar hemorrhage secondary to angioinvasive aspergillosis, aggravated by gravitational pooling of blood in dependent lung areas. The rarity of this phenotype may be related to the pathological features of COPD: emphysematous regions are typically characterized by capillary bed destruction and hypoperfusion, which may partially restrict the opportunity for Aspergillus to disseminate extensively via vasculature. Given that it involved only one patient, this subtype was categorized as a special form. Future studies are needed to identify additional cases to support the establishment of this subtype.

We have summarized the clinical features and differential diagnosis of each phenotype of COPD-IPA (Table 3).

Table 3. Clinical features and differential diagnosis of each phenotypes of COPD-IPA.

Characteristics	Fulminant type (N=3)	Pneumonia-like type (N=35)	Tuberculosis-like type (N=14)	Asthma-like type (N=7)	Tumor-like type (N=3)	Heart failure-like type (unusual phenotype) (N=1)
Clinical manifestations	Rapidly progressive respiratory failure, refractory hypercapnia, hemodynamic instability	Resembles severe pneumonia, dominant acute exacerbation symptoms (cough, sputum, dyspnea)	Cough, sputum, possible hemoptysis, negative TB tests	Asthma-like sudden wheezing, poor treatment response to conventional bronchodilators and steroids	Cough with no obvious dyspnea and no response to conventional antibiotic therapy	Progressive dyspnea, orthopnea, Bilateral lower lung wet rales, poor response to cardiotonics and diuretics
Imaging features	Predominant tracheal invasion, early stage: Bronchial wall thickening, Bronchial obstruction, Bronchiectasis	Lobar/segmental consolidation, cavitary lesions	Upper lobe lesions, multiple fibrous, proliferative, exudative lesions, possible cavities and satellite lesions	Mucus plug obstructing central airways, distal obstructive pneumonia (ground-glass opacity or atelectasis)	Solitary nodule or mass with spiculation	Diffuse or bilateral asymmetric ground-glass opacities located in the mid-lower lung fields or perihilar regions
Differential diagnosis	Septic shock, ARDS, pulmonary embolism	CAP, OP	TB	Asthma, ABPA	Primary lung cancer, metastatic tumor, inflammatory pseudotumor	Cardiogenic pulmonary edema and interstitial pneumonia caused by other reasons such as viral

ABPA, allergic bronchopulmonary aspergillosis; ARDS, acute respiratory distress syndrome; CAP, community-acquired pneumonia; COPD-IPA, chronic obstructive pulmonary disease with invasive pulmonary aspergillosis; OP, organizing pneumonia; TB, tuberculosis.

Clinical implications of the classification system for diagnosis and management

The clinical and radiological heterogeneity of COPD-IPA, coupled with its resemblance to other pulmonary disorders, frequently leads to missed or delayed diagnoses, which increases mortality risk. Our cohort study synthesizes these complex manifestations into six distinct syndromic patterns to improve the recognition of COPD-IPA phenotypes. Clinicians should maintain a high index of suspicion for IPA in severe COPD patients receiving long-term glucocorticoid therapy. Fungal screening is warranted in patients who fail to respond to conventional antimicrobials and bronchodilators, even when radiological features suggestive of fungal infection are absent. Two patterns merit particular vigilance: steroid-refractory wheezing exacerbations (indicative of asthma-like IPA) and upper-lobe cavitary lesions unresponsive to anti-TB therapy (suggestive of TB-like IPA); both scenarios necessitate expedited diagnostic evaluation.

When IPA is clinically suspected, bronchoscopy with BALF analysis should be performed urgently when feasible (17,40). In COPD patients with suspected IPA and refractory respiratory failure, prompt initiation of antifungal therapy is imperative following CT pulmonary angiography (CTPA) to exclude pulmonary embolism (41). Fulminant COPD-IPA necessitates ICU admission, invasive mechanical ventilation, intravenous voriconazole of loading doses, and hemodynamic support. For pneumonia-like and asthma-like type, aggressive antifungal therapy should be initiated alongside rigorous respiratory monitoring; ICU transfer is indicated if hypoxemia or hypercapnia worsens. In TB-like and tumor-like type, antifungals must be commenced, with biopsies performed under antifungal coverage to prevent diagnostic delay. This stratified management strategy ensures that interventions are appropriately calibrated to disease severity.

Study limitations

This study has several limitations inherent to its retrospective single-center design. Conclusions regarding rare subtypes (heart failure-like type) must be interpreted with caution due to small sample sizes. The low rate of histopathological confirmation (only one proven case) reflects diagnostic dependence on clinical criteria. Furthermore, the lack of treatment-outcome correlation analysis precludes evaluation of subtype-specific therapeutic efficacy.

Conclusions

The classification system proposed delineates substantial clinical-radiological heterogeneity in COPD-IPA patients, characterized by a predominant airway-invasive pattern with mixed inflammatory-consolidative features and infrequent classic angioinvasive signs. This framework bridges non-specific presentations to earlier diagnosis, thereby enhancing clinical vigilance and guiding precision management. Specific applications include aggressive cardiorespiratory support in the ICU for fulminant subtypes, pathological verification to prevent misdiagnosis in tumor-like presentations, and dedicated airway clearance assessment for asthma-like variants. Collectively, this stratification approach may improve clinical practice in this high-risk population. Future prospective multicenter studies are required to validate and refine these criteria and to establish optimized subtype-specific antifungal regimens and management pathways.

Supplementary

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Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. This study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of Sun Yat-sen Memorial Hospital, Sun Yat-sen University (No. SYSKY-2025-615-01). Medical records from prior clinical care have been used for this study, and the waiver of informed consent has been granted.

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DOI: 10.21037/jtd-2025-1932