Korean Guidelines for Diagnosis and Management of Interstitial Lung Diseases
Article information
, Yoomi Yeo2,*, A La Woo3, Jung Wan Yoo4, Goohyeon Hong5, Jong Wook Shin6, Sung Woo Park,7, on Behalf of the Korean Interstitial Lung Disease Study GroupAbstract
Interstitial lung disease (ILD) comprises a heterogeneous group of disorders characterized by interstitial compartment proliferation, inflammatory infiltration, and potential fibrosis with abnormal collagen deposition. Diagnosis requires a multidisciplinary consensus integrating clinical, radiological, and pathological findings. Idiopathic interstitial pneumonia (IIP) includes idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia, desquamative interstitial pneumonia, acute interstitial pneumonia, and respiratory bronchiolitis-ILD, each exhibiting distinct prognostic and therapeutic implications. Some non-IPF ILDs progress despite standard treatment, classified as progressive fibrosing-ILD or progressive pulmonary fibrosis (PPF), diagnosed by worsening symptoms, physiological decline, and radiological progression. Nintedanib is conditionally recommended for refractory PPF cases. Combined pulmonary fibrosis and emphysema is characterized by upper-lobe predominant emphysema and lower-lobe fibrosis, frequently complicated by pulmonary hypertension and lung cancer. Interstitial lung abnormality, observed in both smokers and the general population, is associated with increased mortality and disease risk, warranting further research. Despite advancements, refinement in classification, diagnostic criteria, and therapeutic strategies remains crucial for improving patient outcomes.
Introduction and Idiopathic Interstitial Pneumonia
1. Classification of idiopathic interstitial pneumonia
1) Introduction
Interstitial lung disease (ILD) refers to a group of disorders characterized by proliferation of the lung interstitial compartment, accompanied by the infiltration of various inflammatory cells and, in some cases, fibrosis, leading to abnormal collagen accumulation. There are various opinions regarding the classification and scope of ILD; however, it can generally be divided into two main categories: those with known and those with unknown etiologies. Cases with identifiable causal etiologies can be further subdivided into four major categories based on the underlying cause (Figure 1) [1].
Classification of interstitial lung disease. *Myositis: Polymyositis (PM)/dermatomyositis (DM)/anti-synthetase syndrome, which may be considered amyopathic, is a part of myositis. †RB-ILD: While almost all patients are known to have RB-ILD, which is a result of cigarette smoke exposure, RB-ILD and desquamative interstitial pneumonia (DIP) usually coexist. DIP is present in some patients with connective tissue disease, without exposure to cigarette smoke, and for unknown cause, even though it is also associated with cigarette smoke exposure in a majority of patients. ILD: interstitial lung disease; IIP: idiopathic interstitial pneumonia; iNSIP: idiopathic nonspecific interstitial pneumonia; iPPFE: idiopathic pleuroparenchymal fibroelastosis; iDIP: idiopathic desquamative interstitial pneumonia; AFOP: acute fibrinous and organizing pneumonia; IPF: idiopathic pulmonary fibrosis; COP: cryptogenic organizing pneumonia; iLIP: idiopathic lymphoid interstitial pneumonia; AIP: acute interstitial pneumonia; RA: rheumatoid arthritis; SSc: systemic sclerosis; MCTD: mixed connective tissue disease; SLE: systemic lupus erythematosus; HP: hypersensitivity pneumonitis; RB-ILD: respiratory bronchiolitis-associated interstitial lung disease; LCH: Langerhans cell histiocytosis; PAP: pulmonary alveolar proteinosis; LAM: lymphangioleiomyomatosis.
First, environmental ILD encompasses occupational conditions such as silicosis, asbestosis, and berylliosis, as well as hypersensitivity pneumonitis (HP). Second, iatrogenic ILD refers to lung diseases induced by radiation or medications including chemotherapeutic agents and antiarrhythmic drugs. Third, autoimmune ILD includes conditions associated with connective tissue or autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). Additionally, lymphangioleiomyomatosis (LAM), pulmonary Langerhans cell histiocytosis (PLCH), and pulmonary alveolar proteinosis are classified as ILD. ILD without a determinate causative etiology is defined as idiopathic interstitial pneumonia (IIP). Various types of IIP are classified based on histological findings, each with markedly different prognoses and treatments [1]. Diagnosis requires a comprehensive approach that integrates radiological findings, histopathological evidence, and clinical assessments. These guidelines specifically address IIP among various types of ILD.
2) Classification of IIP
This classification was established based on the 2022 American Thoracic Society/European Respiratory Society (ATS/ERS) classification [2] (Table 1) and is based on a multidisciplinary diagnosis (MDD), a decision-making process that involves clinicians, radiologists, and pathologists, as well as clinical data, including smoking history, exposure to hazardous materials (drugs), occupational history, other medical history, and results of pulmonary function tests (PFTs). Patients with a known cause of IIP, such as inhalation of hazardous materials, drugs, or connective tissue diseases (CTD), are excluded from the IIP category [1].
(1) Important differential diagnostic considerations
Hypersensitivity pneumonitis
In some cases of chronic HP, differentiation from idiopathic pulmonary fibrosis (IPF) and idiopathic nonspecific interstitial pneumonia (NSIP) can be challenging, even with high-resolution computed tomography (HRCT) of the chest and lung biopsy. A detailed exposure history of potential causative agents and serum-specific immunoglobulin G antibody testing may aid in diagnosis. However, no causative agent can be identified in approximately 30% of the cases.
Connective tissue disease
CTD is a common cause of interstitial pneumonia, especially NSIP [1]. Clinical and serological evaluations are crucial for differentiating it from IIPs. Various forms of ILDs are commonly observed in RA, SLE, systemic sclerosis, and Sjögren’s syndrome [3].
Familial interstitial pneumonia
Family history is reported in 2% to 20% of IIP cases, with heterozygous mutations in surfactant protein C (SFTPC), surfactant protein A2 (SFTPA2), telomerase reverse transcriptase (TERT), and telomerase RNA component (TERC) accounting for approximately 20% of all familial interstitial pneumonias [4,5]. More recently, a mucin 1B subunit (MUCB) promoter variant was identified as a genetic factor associated with the development of both familial and sporadic IPF [1,6].
Coexisting patterns
Multiple pathologic and/or HRCT patterns may be found in the same patient. In smokers, PLCH, respiratory bronchiolitis-ILD (RB-ILD), desquamative interstitial pneumonia, usual interstitial pneumonia (UIP), and emphysema may coexist. Combined pulmonary fibrosis and emphysema (CPFE) is an example of this coexistence. Such coexisting patterns may be evaluated based on the clinical significance of the individual patterns through MDD [1].
(2) Rare IIPs
Idiopathic lymphoid interstitial pneumonia
Most cases are related to autoimmune diseases or lymphoproliferative disorders (lymphoma, post-bone marrow transplant state, human immunodeficiency virus [HIV], Epstein-Barr virus, etc.) and are rarely idiopathic [1].
Idiopathic pleuroparenchymal fibroelastosis
Pleuroparenchymal fibroelastosis is a rare condition that consists of fibrosis involving the pleura and subpleural lung parenchyma, predominantly in the upper lung lobes. Histologically, it is characterized by alveolar elastosis and fibrosis of the surrounding lung parenchyma. It is clinically associated with a high incidence of pneumothorax and recurrent infections [1,7].
(3) Unclassifiable IIP
IIP may remain unclassified despite MDD, owing to overlapping histological and chest HRCT findings and contradictory clinical, radiological, and pathological findings. This can also occur in CTD and in cases in which a biopsy is performed after pharmacological treatment is initiated. Clear classification criteria and comprehensive data on the clinical presentation of unclassifiable IIP are yet to be established [1].
2. Diagnosis of IIP
1) Medical history
(1) Sex
Among the different types of ILD, LAM usually occurs in women, particularly those of reproductive age. ILD associated with CTD, except for RA, usually occur in women. In contrast, pneumoconiosis, PLCH, and IPF occur more frequently in men [1].
(2) Pattern of onset
If ILD presents with an acute onset (days to weeks), potential causes such as infection, acute interstitial pneumonia, acute eosinophilic pneumonia, HP, or diffuse alveolar hemorrhage (DAH) should be considered. Subacute onset (weeks to months) suggests differential diagnoses including cryptogenic organizing pneumonia (COP), sarcoidosis, chronic eosinophilic pneumonia (CEP), and drug-induced lung disease. In cases with chronic onset (months to years), IPF, pneumoconiosis, sarcoidosis, and PLCH should be considered [1].
(3) Occupational history
It is essential to consider not only the patient’s current occupation, but also the type, duration, and work environment of all previous occupations, as well as the patient’s role and work environment [1].
(4) Hobbies and other environmental history
For HP, a detailed history of environmental exposures, including contact with pets, is crucial. Exposure may occur not only from pets kept at home but also in outdoor settings such as parks. A history of symptom improvement several days after the cessation of exposure, followed by recurrence upon re-exposure, can provide valuable diagnostic clues.
(5) Medication history
Both past and current medication histories are important. Gastric juice aspiration owing to gastroesophageal reflux disease slowly leads to ILD development. The use of mineral oil as a laxative or oily nose drops at night may also contribute to the development of ILD. The sequence and duration of drug exposure in relation to symptom onset are important; however, ILD may manifest weeks or years after drug use. In addition, a history of radiation therapy or high-concentration oxygen therapy is important [1].
(6) Smoking history
Smoking history is significant. More than 90% of PLCH patients have a positive smoking history at the time of diagnosis. Patients with RB-ILD or Goodpasture syndrome have been observed to have a prominent history of smoking. Among patients who have been exposed to asbestos, interstitial fibrosis occurs 13 times more frequently in smokers than in nonsmokers. Sarcoidosis and HP usually occur in nonsmokers [1].
(7) Family history
Family history is important for identifying various genetic and metabolic disorders, although they are rare in Korea. Familial incidence can be observed in sarcoidosis or IIP [1].
(8) Travel and other history
Travel history is important because parasitic infections can cause eosinophilia in the lungs. A history of risk factors for HIV infection is also important [1].
2) Symptoms
Symptoms of ILD can occur over months to years and manifest at various levels of progression. Major symptoms include gradually progressing shortness of breath and coughing. Wheezing sounds rarely occur in CEP and HP, whereas substernal chest pain rarely occurs in sarcoidosis. Pleuritic pain can accompany CTD and drug-induced ILD. A spontaneous pneumothorax can cause acute pleuritic chest pain in patients with PLCH, LAM, tuberous sclerosis, or neurofibromatosis. Hemoptysis typically occurs in DAH, LAM, and pulmonary veno-occlusive disease. In ILD, the presence of hemoptysis raises the suspicion of an underlying malignancy [1].
3) Physical examination
Crackles are typically auscultated in the lower lobes of both lungs. Clubbing is commonly associated with progressive fibrotic lung diseases, whereas pulmonary hypertension (PH) or cor pulmonale resulting from chronic hypoxemia may develop in the advanced stages.
4) Radiologic findings
(1) Chest X-ray
Although chest radiography is less sensitive than HRCT for diagnosing ILD, it serves as an initial screening tool. ILD typically manifests as a reticular pattern, nodular pattern, ground-glass opacities, or consolidation predominantly in the bilateral lower lobes on chest X-rays. Chest radiographic findings may be unremarkable during the early stages of ILD [1].
(2) HRCT
Chest HRCT can assess the presence of interstitial pneumonia; the distribution, characteristics, and severity of lung lesions; and the presence of other lung disease combinations [1].
5) Laboratory findings
In patients with suspected ILD, the role of autoimmune antibody testing for CTD remains unclear. However, autoimmune antibody testing is recommended if CTD-related symptoms are present. In the 2011 guideline, screening for rheumatoid factor (RF), anti-cyclic citrullinated peptide, and antinuclear antibody (ANA) is advised, even without symptoms suggestive of CTD [1,3].
In a study conducted in the United States, 22% of patients with IPF tested positive for autoimmune antibodies, and these patients showed better prognoses than autoimmune antibody-negative patients. Additionally, a recent study reported that, among patients with a UIP pattern, those who tested positive for one or more autoimmune antibodies or exhibited one or more symptoms or signs of CTD without meeting the criteria for a definitive CTD diagnosis had better prognoses than patients with IPF without these findings.
(1) Specific antibodies
Positivity for antibodies against organic dust or proteins only indicate prior exposure and cannot be used alone for the diagnosis of HP [2]. However, specific antibodies such as anti-glomerular basement membrane antibody or anti-neutrophil cytoplasmic antibody may be useful in certain diagnostic contexts [1].
6) PFT and arterial gas analysis
The characteristic PFT findings in ILD include decreased lung compliance and restrictive ventilatory defects characterized by reduced lung volumes, particularly forced vital capacity (FVC) and total lung capacity (TLC), whereas the forced expiratory volume in 1 second (FEV1)/FVC ratio and airway resistance remain normal. In most patients, the diffusion capacity is reduced, and arterial blood gas analysis in the stable phase may be normal or indicate hypoxemia and respiratory alkalosis, primarily due to ventilation/perfusion mismatch [1].
7) Bronchoalveolar lavage
Bronchoalveolar lavage (BAL) is performed by advancing a flexible bronchoscope into the bronchial branch and instilling 30 to 50 mL of sterile physiological saline solution to retrieve cells and materials from the bronchioles and alveoli. In healthy nonsmokers, the recovered cellular composition consists of approximately 90% macrophages, 10% lymphocytes, and <1% neutrophils. The predominance of specific cell types varies by disease and may aid in the differential diagnosis of ILD. Lymphocyte predominance is observed in conditions such as cellular NSIP, HP, and COP, whereas neutrophilic infiltration is characteristic of IPF. However, given the nonspecific nature and limited diagnostic value of BAL findings, routine BAL is not required for all patients and should be performed at the discretion of the treating clinician [1,8].
8) Lung biopsy
Lung biopsy is the most definitive diagnostic tool and includes transbronchial lung biopsy (TBLB), transbronchial lung cryobiopsy (TBLC), and surgical lung biopsy (SLB) (via open thoracotomy and video-assisted thoracoscopic biopsy) [1].
(1) TBLB
Conditions commonly diagnosed with TBLB include lung sarcoidosis, malignant tumors (bronchoalveolar carcinoma), lymphangitic carcinomatosis, alveolar proteinosis, infections such as Pneumocystis jirovecii pneumonia or tuberculosis, and eosinophilic pneumonia [1].
(2) TBLC
Surgical biopsy is the standard histological investigation method; however, its use is limited by high costs and procedural risks. A recent study has demonstrated that TBLC using a cryoprobe can obtain lung tissue samples measuring 40 to 50 mm², with a diagnostic yield comparable to that of surgical biopsy in patients with a high suspicion of IIP [8]. TBLC allows for the acquisition of adequate lung tissue, enabling pathologists to establish a definitive histological diagnosis. Notably, the interobserver agreement among pathologists in identifying UIP is also high. Pneumothorax is a common complication, with a reported incidence rate of up to 28%. However, the diagnostic yield of ILD using TBLC remains high (79%). In cases in which definite UIP features are not clearly identified, histopathological evaluation using TBLC can aid in the diagnosis of IPF [2].
(3) Video-assisted thoracoscopic surgery
SLB is the most useful diagnostic tool for ILDs but must be performed selectively with consideration for patient age, systemic status, comorbidities, and complications [2,8]. Indications for SLB include progressive lesions with inconclusive chest HRCT, predictable drug reactions to therapies with high rates of adverse events, such as immunosuppressant use, or cases requiring differentiation between ILD progression and malignancy or infection [1,2,9]. Relative contraindications include diffuse end-stage lung disease (with honeycomb lesions) due to the high probability of obtaining only fibrotic lung tissue, accompanying severe emphysema, <35% predictive value of lung diffusion capacity, severe hypoxia, and severe heart disease [1,9,10]. The optimal biopsy site is determined using chest HRCT, with tissue samples taken from areas most representative of the disease while avoiding late-stage honeycombing. To improve diagnostic accuracy, at least two adequately sized specimens should be obtained from different lobes. Biopsy of the right middle lobe or the lingular segment of the left upper lobe is generally avoided because of the frequent presence of nonspecific inflammation and passive congestion in these regions. Although histopathological evaluation plays a crucial role in the diagnosis of ILD, SLB alone is insufficient for definitive diagnosis. A multidisciplinary approach incorporating clinical, radiological, and pathological findings is essential [1].
9) Biomarkers
Researchers have shown great interest in identifying biomarkers of IIP, leading to several notable findings regarding the diagnosis, treatment, and prognosis of ILD. Elevated serum levels of proteins associated with epithelial cells or macrophages, such as surfactant protein (SP)-A, SP-D, Krebs von den Lungen-6, chemokine ligand (CCL)-18, and matrix metalloproteinase-7 have been linked to a rapid decline in pulmonary function and reduced survival rate. These proteins can be used as clinically useful biomarkers to identify patients at a high risk of disease progression [11]. Serum SP-A levels are significantly higher in patients with IPF than in those with NSIP or COP, whereas SP-D levels are significantly higher in patients with CTD-associated ILD than in those with IPF. Additionally, BAL fluid reveals distinct immunological patterns, with NSIP exhibiting a helper T-cell type 1–dominant response, whereas IPF is characterized by a helper T-cell type 2–skewed response, along with increased expression of chemokine receptor-7 and CCL7 [1].
10) Multidisciplinary discussion
The diagnosis of ILD is often challenging owing to overlapping differential diagnoses, unclear diagnostic criteria for certain conditions, and low interobserver agreement among clinical, radiological, and pathological experts.
A precise diagnosis is essential for determining the prognosis and guiding appropriate treatment. Many international ILD diagnostic guidelines recommend a consensus diagnosis in which pulmonology, thoracic radiology, and pulmonary pathology specialists integrate clinical data, blood tests, chest HRCT findings, and lung biopsy results to reach a comprehensive diagnostic agreement [12]. Additionally, in cases in which CTD-ILD is suspected or requires exclusion, the involvement of a rheumatology specialist is beneficial in MDD [13]. A key study on the utility of MDD demonstrated that implementing MDD improved diagnostic concordance among experts from multiple centers in cases of IPF and CTD-ILD (k value=0.7) [14]. Several studies have also reported significant discrepancies between ILD diagnoses made through MDD and those made solely by individual clinical experts [15-17]. Furthermore, MDD has been found to be particularly beneficial in diagnosing non-IPF ILDs compared with IPF [18]. However, research validating ILD diagnoses established through MDD remains limited, and further studies are needed to assess its impact on final diagnosis and treatment decisions. In summary, MDD has already been recognized as an essential and validated diagnostic tool for ILD, particularly for non-IPF ILD.
Progressive Pulmonary Fibrosis
1. Definition and diagnostic criteria
Among non-IPF ILDs, some exhibit characteristics of progressive fibrosing interstitial lung disease (PF-ILD), demonstrating clinical, radiological, and physiological progression despite standard treatment. However, the definitions and diagnostic criteria for PF-ILD vary across studies.
The 2022 ATS/ERS/Japanese Respiratory Society (JRS)/Asociación Latinoamericana de Tórax (ALAT) clinical guidelines standardized terminology by redefining diseases previously referred to as PF-ILD as progressive pulmonary fibrosis (PPF) [2]. This term now applies to non-IPF ILD in which fibrosis progresses rapidly despite appropriate treatment.
PPF is defined as the occurrence of at least two of the following three criteria within the past year with no alternative explanation: (1) worsening respiratory symptoms; (2) physiological evidence of disease progression, as defined below; and (3) radiological evidence of disease progression, as defined below.
1) Physiological criteria
There is a paucity of published data on physiological measurements in patients with PPF. Therefore, the committee derived the physiological criteria for PPF by extrapolating data from patients with IPF because the disease behavior and prognosis of IPF and PPF are comparable [2,19]. The committee defined physiological evidence of disease progression as the presence of either of the following findings, if the findings are attributable to worsening fibrosis:
(1) absolute decline in FVC of >5% within 1 year of follow-up;
(2) absolute decline in diffusing capacity of the lungs for carbon monoxide (DLCO, corrected for hemoglobin) of >10% within 1 year of follow-up [2].
2) Radiologic criteria
(1) Visual determination of PPF
Progression of fibrosis is typically assessed visually, relying on the percentage of lung volume containing fibrotic features in the upper, mid, and lower lung zones. Transverse, coronal, and sagittal contiguous HRCT sections from the initial and follow-up computed tomography (CT) examinations are compared side-by-side after adjusting for lung volume changes [2] (Figure 2).
High-resolution computed tomography (HRCT) of progressive pulmonary fibrosis: a patient with nonspecific interstitial pneumonia (A, B) and a patient with polymyositis-interstitial lung disease (C, D). (A) Initial axial computed tomography (CT) image showing ground-glass opacity with mild reticulation in both lungs, predominantly in the dorsolateral areas of both lower lobes and subpleural areas of both upper lobes. (B) On follow-up HRCT obtained 8 years after the initial study, the progression of pulmonary fibrosis is clearly demonstrated with traction bronchiolectasis, subpleural honeycombing, and architectural distortion with volume loss in the lower lungs and lingula. (C) Initial axial CT image of a patient with polymyositis showing peribronchial and peripheral distribution of air space consolidation with air bronchograms in the lower lungs, suggesting an organizing pneumonia pattern. (D) On follow-up HRCT obtained 4 years after the initial study, significant progression of pulmonary fibrosis is evident, with diffuse and peribronchial distribution of coarse reticulation and traction bronchiectasis.
Follow-up HRCT is indicated when there is clinical suspicion of worsening fibrosis. However, the optimal interval for follow-up HRCT to determine disease progression remains unknown. Limited data suggest that in patients with systemic sclerosis and stable pulmonary function, repeated chest HRCT within 12 to 24 months from baseline could be useful to promptly detect progression and possibly influence prognosis [20].
It is difficult to predict the proportion of patients with non-IPF ILDs who will develop a progressive fibrotic pattern; however, some HRCT findings in individual patients are considered predictors of disease progression. For example, in addition to the presence of honeycombing and traction bronchiectasis, which are associated with worse prognosis, a greater extent of fibrotic changes is known to be predictive of mortality in IPF, RA-related ILD, systemic sclerosis-related ILD, fibrotic HP, pulmonary sarcoidosis, and unclassified ILD [2,21].
CT features of early lung fibrosis include fine reticulation, intralobular lines, and architectural distortion (irregular, tortuous pulmonary vessels and airways or distorted lobular anatomy), seen either in isolation or superimposed on ground-glass opacities. This pattern, suggestive of interstitial changes in the early phase, may be observed incidentally on thoracic or abdominal CT scans obtained for other purposes, including screening for lung cancer, and is often associated with histological evidence of fibrosis. Incidentally identified interstitial lung abnormalities (ILAs) are independent risk factors for mortality. At least 40% of subjects with ILAs show progression of CT changes when followed up for 4 to 6 years [2,22,23].
(2) Quantitative assessment of the progression of pulmonary fibrosis
Computer-based quantitative CT (QCT) provides a more objective and reproducible measure of disease progression than visual assessmen [24,25]. Further validation and the adoption of standardized protocols are necessary before QCT can be widely used in the community [2].
2. Evidence-based recommendations for treatment of PPF, other than IPF
Research has been conducted on the possibility that antifibrotic agents that slow the progression of IPF can also delay the progression of PPF [2]. The two antifibrotic agents recommended for the treatment of IPF are pirfenidone, which exhibits anti-inflammatory, antioxidant, and antiproliferative effects, and nintedanib, an intracellular tyrosine kinase inhibitor that suppresses fibrosis.
1) Pirfenidone
A phase 2 randomized clinical trial (uILD, RELIEF study) was conducted to evaluate the effects of pirfenidone [26,27]. Both studies were randomized; however, their interpretations were limited. The studies were small in scale, and the RELIEF study was prematurely terminated owing to insufficient patient enrollment, whereas the uILD study was only conducted on a subset of progressive uILD patients within the PPF cohort. Considering these factors, the 2022 ATS/ERS/ALAT clinical guidelines for PPF recommended additional research to investigate the efficacy, effectiveness, and safety of pirfenidone in PPF patients [2].
2) Nintedanib
A randomized clinical trial (INBUILD) was conducted to evaluate the effects of nintedanib in PPF [28]. The trial showed that the average decline in FVC, a measure of disease progression, was significantly lower in the nintedanib group (107 mL/year), and the progression of ILD was 2.4 times lower in the nintedanib group. However, the effects of nintedanib on the progression of ILD to PPF were not consistent. Based on these findings, the 2022 ATS/ERS/ALAT clinical guidelines for PPF recommend nintedanib as a treatment for PPF in patients with failed standards (conditional recommendation, low evidence level). Further research on the efficacy, effectiveness, and safety of nintedanib in individual ILDs progressing to PPF is recommended [27].
Combined Pulmonary Fibrosis and Emphysema
1. Introduction
Despite its clinical significance and substantial research interest, CPFE remains poorly understood. This disease encompasses a spectrum of fibrotic and emphysematous changes, necessitating differentiation from conditions such as alveolar expansion associated with pulmonary fibrosis and smoking-related interstitial fibrosis (SRIF) [29]. CPFE is not synonymous with IPF because pulmonary fibrosis in CPFE is not always classified as IPF. The lack of consensus on the diagnostic criteria makes it challenging to draw consistent conclusions regarding its clinical features, prognosis, and optimal management [30]. Moreover, whether CPFE should be considered as a distinct disease entity or syndrome remains debatable.
2. Definition
CPFE is defined radiologically as the presence of pulmonary fibrosis in the lower zones and subpleural areas, coexisting with upper-lobe predominant emphysema. While quantification of emphysema is often not feasible, emphysema in CPFE is identified on HRCT as low-attenuation areas with well-defined thin walls or no walls, encompassing at least 5% of the total lung volume. Pulmonary fibrosis is characterized by traction bronchiectasis, honeycombing, volume loss, and ground-glass opacities on HRCT [31].
3. Prevalence
The prevalence of CPFE among patients with IPF is estimated to range from 8% to 67%, depending on the population studied and definitions used (Table 2) [32-35]. Higher rates have been reported in Asia and Greece than in the United States. CPFE is observed in 26% to 54% of patients with IIP, with higher rates among hospitalized patients (45% to 71%) [34]. CPFE is also frequently associated with lung cancer (55% to 58%) [35]. The prevalence of CPFE in the general population is unknown because most data are derived from patients undergoing chest CT for clinical indications.
4. Etiology
1) Exposures and diseases
CPFE is strongly associated with smoking and male sex, with male patients showing a nine-fold higher prevalence than female patients. However, nonsmokers, particularly those with CTDs, may also develop CPFE. Approximately 5% to 10% of patients with systemic sclerosis-associated ILD [36] and 27% of RA-associated ILD cases in nonsmokers demonstrate radiological features of CPFE [37]. Additionally, CPFE has been observed in systemic vasculitis, particularly in microscopic polyangiitis. Environmental and occupational exposure to asbestos and silica has also been implicated.
2) Genetic predisposition and aging
Genetic susceptibility combined with environmental exposure, such as smoking and air pollution, may contribute to the development of both emphysema and fibrosis. Mutations in genes associated with surfactant production and telomerase have been reported in patients with CPFE [38].
5. Clinical features and comorbidities
The mean age of patients with CPFE is approximately 65 to 70 years, with 73% to 100% being male [29]. Primary symptoms include exertional dyspnea and cough. Patients with PH often experience severe dyspnea during physical activity, with the majority classified as New York Heart Association functional class III or IV [39].
The two most notable comorbidities of CPFE are lung cancer and PH. Other comorbid conditions include coronary artery disease, peripheral vascular disease, and diabetes mellitus. However, it is unclear whether these are more common in CPFE than in IPF without emphysema.
6. Radiologic characteristics
1) Overview
CPFE is defined as the coexistence of emphysema and fibrosis, which can present as overlapping features on HRCT. Differentiating honeycomb cysts from mixed emphysema-fibrosis lesions can be challenging, especially given the high prevalence of a UIP pattern among patients with CPFE (Figure 3). The co-occurrence of emphysema and fibrosis often produces radiologic patterns of thick-walled cystic lesions.
Combined pulmonary fibrosis and emphysema in a heavy smoker (A, B). High-resolution computed tomography axial images show upper-lobe predominant emphysema with peripheral bullae (A) and concurrent pulmonary fibrosis with honeycombing predominantly involving the subpleural areas of both basal lungs (B).
2) Quantification of HRCT abnormalities
HRCT enables semiquantitative evaluation of the extent of the disease, focusing on the relative areas of emphysema and fibrosis. However, standardization of this assessment is lacking.
3) Emphysema quantification
Emphysema in CPFE is primarily evaluated using imaging rather than PFTs. Although visual assessments by experienced radiologists are commonly used, these methods often fail to capture the diversity of emphysema patterns.
4) ILD quantification
Despite its clinical relevance, a minimal threshold extent of pulmonary fibrosis on HRCT has not yet been established for CPFE. Ground-glass opacities, which may reflect inflammation rather than fibrosis, remain a point of contention regarding whether they should be included in fibrosis scoring. Further research is required to clarify this issue.
7. Pulmonary function characteristics
Patients with CPFE exhibit limited exercise capacity and severely reduced DLCO, while airflow and lung volume are relatively preserved [40]. Most patients show an increased FVC/DLCO ratio [36].
Patients with CPFE show higher lung volumes (FVC and TLC), similar FEV1, increased residual volume (RV), lower DLCO, and lower arterial oxygen partial pressure (PaO2) than patients with IPF. FEV1/FVC ratios are generally normal or slightly reduced but may increase with disease progression.
Severe oxygen desaturation during exercise and exertional hypoxemia are common in CPFE, particularly in patients with severe PH [29]. Hypercapnia typically occurs only in the late disease stages.
Currently, no optimal parameters for monitoring CPFE progression have been identified. Changes in FVC, which are often used to track IPF progression, are not reliable indicators of CPFE. Parameters such as DLCO, composite physiologic index, and FEV1/FVC have been suggested, but require further validation. The ATS Clinical Guideline Committee recommends incorporating clinical, radiologic, and functional findings to monitor CPFE progression (Table 3) [29].
8. Pathological features
CPFE is primarily defined based on clinical, functional, and HRCT findings, and lung biopsies are often impractical because of the associated risks (Table 4). Histologically, CPFE combined with emphysema is characterized by distal airway destruction without obvious fibrosis, with features such as patchy fibrotic changes, fibroblast foci, and honeycombing. Smoking-related bronchiolitis and SRIF are frequently observed in CPFE patients [41].
9. Diagnostic criteria
1) Clinical criteria
There are no clear clinical diagnostic criteria for CPFE. However, in patients diagnosed with chronic obstructive pulmonary disease (COPD), significant reductions in DLCO, despite mild-to-moderate airflow limitations, should prompt HRCT evaluation for CPFE (Table 5).
2) Radiologic criteria
HRCT is the cornerstone for identifying CPFE, allowing the assessment of both emphysema and fibrosis. Differentiating between honeycomb cysts and emphysema can be challenging in some cases [40].
3) Functional criteria
No definitive functional criteria are available for the diagnosis of CPFE. Typical findings include severely reduced DLCO and transfer coefficient (Kco), with relatively preserved airflow and lung volumes. Compared to IPF, CPFE shows higher lung volumes, lower DLCO and Kco values, and increased RV. Relative to COPD, patients with CPFE demonstrate less hyperinflation and lower DLCO [32].
10. Treatment
1) General management
No treatment modalities for CPFE have been established in clinical trials. General management includes smoking cessation, regular exercise, pulmonary rehabilitation, and oxygen therapy [42].
2) Treatment of pulmonary fibrosis
Antifibrotic agents such as nintedanib are effective in slowing the progression of fibrosis, as shown in subanalyses of the INPULSIS and INBUILD trials [43,44]. Therefore, these drugs should be considered in patients with progressive fibrosis.
3) Treatment of emphysema
Bronchodilators and inhaled corticosteroids may be used in accordance with COPD management guidelines, although supporting clinical trial data are limited. Surgical and bronchoscopic interventions for emphysema are generally contraindicated because of severe DLCO reductions.
4) Treatment of PH
PH management includes oxygen supplementation, timely referral for lung transplantation, and supportive therapies. Clinical trials of oral medications for PH, such as endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and soluble guanylate cyclase stimulators, have shown unsatisfactory results [45].
5) Treatment of lung cancer
Approaches to lung cancer management in CPFE are similar to those in other lung cancer patients but have higher complication and mortality rates. Surgery, chemotherapy, and radiation should be tailored to the severity of the underlying ILD and emphysema [46].
11. Prognosis and complications
1) Pulmonary hypertension
PH is reported in 15% to 55% of patients with CPFE [29], with variability attributed to differences in diagnostic methods and patient populations. Estimated systolic pulmonary artery pressures are higher in patients with CPFE than in those with IPF alone [32]. The additional hemodynamic burden imposed by emphysema exacerbates the risk of PH beyond what is attributable to fibrosis severity alone.
2) Lung cancer
The prevalence of lung cancer in patients with CPFE ranges from 2% to 52% [29], depending on the study design. Compared with patients with IPF alone, CPFE patients have an approximately 2.7 times higher lung cancer risk. Squamous cell carcinoma and adenocarcinoma are the most frequently observed histological subtypes, with squamous cell carcinoma more common in CPFE than in the general non-small cell lung cancer population. Most cancers are located in the lower lobes and tend to be diagnosed at advanced stages with invasive features [46]. The presence of CPFE adversely affects the prognosis, with poor outcomes associated with honeycombing, advanced tumor stages, and reduced surgical candidacy. Standard cancer treatments are often limited in CPFE, contributing to increased morbidity and mortality rates.
3) Acute exacerbations
Acute exacerbations similar to those observed in IPF have been reported in patients with CPFE at varying frequencies. Risk factors include higher Gender- Age-Physiology scores, the presence of lung cancer, and post-surgical status [47]. HRCT findings of diffuse ground-glass opacities and/or consolidation can help differentiate exacerbations of fibrosis from emphysema. The prognosis following acute exacerbation of CPFE is better than that following IPF.
4) Mortality and prognostic factors
Patients with CPFE exhibit worse survival rates than those with emphysema alone. Comparisons with IPF have yielded mixed results, with survival reported as worse, similar, or better, depending on the study [29]. FVC declines more slowly in CPFE than in IPF because of the emphysema-induced preservation of lung volume. However, larger emphysematous lesions are associated with poorer outcomes. Mortality predictors include DLCO, physiological indices, age, and the presence of specific complications such as PH and lung cancer [29].
Interstitial Lung Abnormality
1. Definition
ILA is defined as an incidentally detected radiological abnormality on chest CT. Various definitions have been proposed; however, in 2020, the Fleischner Society issued a position paper defining ILA as non-dependent abnormalities occupying at least 5% of any lung region (six zones: upper, middle, or lower lobes) [48,49].
ILA is not simply a radiologic abnormality but is accompanied by a decline in pulmonary function [50] or clinical symptoms [5]. Therefore, ILA should be distinguished from subclinical ILD detected in high-risk individuals (e.g., those with environmental exposure, CTDs, or a family history of ILD) and preclinical ILD that has yet to manifest symptoms.
2. Prevalence
HRCT is a sensitive modality for detecting ILA. Studies using chest CT for purposes other than ILD screening have reported a prevalence of ILA ranging from 4% to 17%, depending on smoking status [51]. This prevalence is significantly higher than that of lung nodules detected during lung cancer screening [52].
3. Risk factors
Commonly reported risk factors for ILA include advanced age and smoking. Environmental factors such as asbestos exposure [53], occupational exposure [54], and air pollution [55], have also been identified as risk factors. Additionally, genetic factors such as mucin 5B subunit (MUC5B) promoter polymorphisms have been linked to familial interstitial pneumonia and IPF.
4. Radiologic findings
Radiologic findings associated with ILA include ground-glass opacities, reticular abnormalities, diffuse centrilobular nodularity, traction bronchiectasis, honeycombing, and non-emphysematous cysts (Table 6 and Figure 4) [49]. Initially, centrilobular nodularity was considered an ILA feature, but the 2020 Fleischner Society position paper excluded it from the definition [49]. Local or unilateral ground-glass opacities, dependent atelectasis that does not persist in the prone position, and pleuropulmonary fibroelastosis are not included in ILA imaging findings (Figure 5).
Interstitial lung abnormality (ILA). (A) Non-subpleural nonfibrotic ILA, screening low-dose chest computed tomography (CT) axial image showing non-subpleural patchy ground-glass opacities in both lower lobes with no reticulation, traction bronchiolectasis, or bronchiectasis. (B) Subpleural nonfibrotic ILA, Screening low-dose chest CT axial image showing subpleural subtle ground-glass opacities in the dorsolateral areas of both lower lobes, with no reticulation, traction bronchiolectasis, or bronchiectasis. (C) On baseline staging workup for colon cancer, a chest CT axial image showed subpleural reticulation in both basal lungs, associated with traction bronchiolectasis and mild lung parenchymal distortion.
Imaging abnormalities that do not represent interstitial lung abnormalities (ILAs). (A) Focal paraspinal fibrosis (not representative of ILA), chest computed tomography (CT) axial (red arrow) and coronal (short red arrow) images showing a curvilinear fibrotic band in the medial right lower lobe, closely related to osteophytes. (B) Centrilobular nodularity (respiratory bronchiolitis) in a heavy smoker (not representative of ILA). High-resolution CT axial image showing poorly defined ground-glass centrilobular nodules (yellow circle) and mild emphysema in both upper lobes without other f indings of interstitial abnormalities. (C) Unilateral focal abnormality (not representative of ILA) in chest CT axial image showing focal reticulation, mild traction bronchiectasis, and architectural distortion in the right lower lobe associated with adjacent pleural thickening, which is thought to be a sequela of pneumonia.
5. Pathologic features
Because ILA is primarily a radiologic concept, there are limited pathological studies. The predominant histopathological findings included nonspecific fibrosis, UIP, SRIF, and NSIP [56,57].
6. Diagnosis
The most widely accepted definition of ILA is based on the 2020 Fleischner Society position paper [49]. ILA is defined as non-dependent abnormalities that involve at least 5% of any part of the lung in an individual who has not previously suspected ILD. Table 6 summarizes the imaging findings included and not included in ILA.
If the examination performed is insufficient (e.g., abdominal CT findings of ILA), a chest CT scan can help evaluate the properties of the ILA. Chest CT should be performed with moderate edge-enhancing thin-section reconstruction (<1.5 mm). Prone-position CT helps to identify dependent opacities (Table 7).
7. Clinical presentation and prognosis
Patients with ILA may present with chronic cough, dyspnea, and reduced exercise capacity in test such as in the 6-minute walking test [6,58,59]. It was also confirmed that progression on imaging was associated with a decrease in FVC. The progression of ILA varies across studies, with some reporting a 20% progression over 2 years [60] and others showing 48% progression over 5 years (Figure 6) [23]. However, not all ILAs progress; therefore, it is necessary to identify the risk factors that predict their progression.
Interstitial lung abnormality (ILA) and long-term progression. (A) Screening low-dose chest computed tomography (CT) axial image showing subtle subpleural reticulation with ground-glass opacities in the dorsolateral areas of both basal lungs, indicating a subpleural ILA. (B) On the follow-up CT obtained 10 years after the initial study, the progression of pulmonary fibrosis iss evident, with increased reticulation, traction bronchiolectasis, and mild architectural distortion in both subpleural basal lungs. Upon clinical review, the patient showed no respiratory symptoms or spirometric abnormalities.
Radiologic predictors of disease progression include subpleural reticulation, predominant lower-lobe changes, traction bronchiectasis, and honeycombing. Elevated blood monocyte levels [61] and advanced age [60] have also been associated with progression to ILD.
The association between ILA and mortality was consistently confirmed in each related study, including a long-term follow-up study in South Korea [62]. Radiologic features such as traction bronchiectasis [63] and a UIP pattern [60], as well as biomarkers such as growth differentiation factor 15 [64], are associated with a higher mortality risk. Moreover, ILA is a poor prognostic factor in lung cancer treatment, increasing the risk of immune checkpoint inhibitor-related pneumonitis [65], radiation pneumonitis [66], and systemic chemotherapy-related pulmonary complications [67]. ILA is also associated with postoperative pulmonary complications in lung cancer surgery [68], especially in case of fibrotic ILA [69]. ILA is linked to higher mortality rates after aortic valve replacement [70] and an increased risk of acute respiratory distress syndrome in sepsis [71]. Therefore, patients with ILA may require close evaluation and monitoring of complications before treatments such as chemotherapy or surgery.
8. Evaluation and monitoring
Owing to limited evidence, the evaluation and monitoring of ILA are primarily based on expert opinions from the Fleischner Society [49]. If initial imaging is insufficient, HRCT should be considered. Identified ILA cases should be evaluated for contributing factors such as smoking, systemic diseases, inhalational exposure, drug toxicity, and aspiration. Patients with respiratory symptoms, pulmonary function abnormalities, or extensive disease on imaging should be referred to a pulmonologist for a multidisciplinary ILD evaluation and standard management. Follow-up monitoring should be tailored to each patient’s risk level. High-risk individuals should be closely monitored. If ILD is excluded, follow-up should be considered based on the risk of ILA progression. PFT (3 to 12 months) and imaging follow-up (12 to 24 months) are considered for active monitoring, and early follow-up may be considered depending on the accompanying risk factors (imaging findings, PFT results, and clinical symptoms). In particular, according to the Framingham Heart Study [50] and the AGES-Reikjavik Study [23], follow-up for high-risk groups (Table 8) is clinically important because imaging progression is associated with increased mortality.
Notes
Authors’ Contributions
Conceptualization: Park SW. Methodology: Park C, Yeo Y, Woo AL, Park SW. Formal analysis: Park C, Yeo Y, Park SW. Data curation: Park C, Yeo Y, Woo AL, Yoo JW, Hong G, Shin JW. Funding acquisition: Park SW. Software: Park C, Yeo Y. Validation: Park C, Yeo Y. Writing - original draft preparation: all authors. Writing - review and editing: Park C, Yeo Y. Approval of final manuscript: all authors.
Conflicts of Interest
No potential conflict of interest relevant to this article was reported.
Funding
This study was supported by the National research Foundation of Korea (NRF) grant fundede by the Korea government (MSIT) (RS-2023-00274884).