Introduction
Interstitial lung disease (ILD) comprises over 200 diverse lung disorders that are grouped together due to common clinical, radiological, and pathological characteristics [1]. Idiopathic interstitial pneumonias (IIPs) are a subset of ILDs with an unknown cause, marked by inflammation and fibrosis of the lung interstitium, the tissue surrounding the alveoli. The updated IIP classification separates major IIPs from rare and unclassifiable cases. Major IIPs are categorized into chronic fibrosing, smoking-related, and acute/subacute types, which include cryptogenic organizing pneumonia and acute interstitial pneumonia (AIP) [1].
The Korean Guidelines for Diagnosis and Management of ILD, including IIPs and connective tissue disease-associated ILD (CTD-ILD), were developed by the Clinical Practice Guideline Development Committee and officially released by the Korean Academy of Tuberculosis and Respiratory Disease in April 2018, with the guidelines published in Korean. Research findings published after 2018 were incorporated, and idiopathic pleuroparenchymal fibroelastosis (IPPFE), which was not included in the 2018 guidelines, was added. The recommendations and their levels were determined through a vote by the guideline committee members. In this section, due to the lack of sufficient randomized controlled trials, recommendations were based on expert consensus. The recommendation levels were classified as Strong for recommendation, Conditional for recommendation, Strong against, Conditional against, and Inconclusive. The 2023 update of the Korean clinical guidelines for ILD was written in Korean and published in November 2023.
This article presents the Korean guidelines for diagnosing and managing ILD, focusing on respiratory bronchiolitis-associated ILD (RB-ILD) and desquamative interstitial pneumonia (DIP), which are smoking-related diseases; AIP, which presents acutely; and lymphoid interstitial pneumonia (LIP) and IPPFE, which are considered rare forms of IIP.
Respiratory Bronchiolitis-Associated Interstitial Lung Disease (RB-ILD)
1. Recommendation
Smoking cessation is strongly recommended as a firstline strategy for the treatment of RB-ILD. (Level of evidence, Expert consensus; Grade of recommendation, Strong for recommendation)
Voting: Strong for recommendation 6/6
Corticosteroids may be considered in cases with functional decline. (Level of evidence, Expert consensus; Grade of recommendation, Conditional for recommendation)
Voting: Strong for recommendation 1/6, Conditional for recommendation 5/6
2. Summary
RB-ILD is a relatively uncommon form of IIP seen in smokers. It is diagnosed when chest computed tomography (CT) scans show diffuse centrilobular ground-glass nodules and opacities, and bronchoalveolar lavage fluid contains increased pigmented macrophages. Smoking cessation is the most important treatment, and if there is no improvement, corticosteroids may be considered. While the clinical course and response to treatment vary, the disease generally has a good prognosis with long-term survival.
As the name suggests, RB-ILD is a condition where ILD occurs alongside RB. RB is a histological finding in the lungs related to smoking and has been observed in up to 89% of smokers who had lung biopsies for reasons unrelated to RB, indicating its common presence among smokers [2-4]. Most people with RB are asymptomatic, and it is characterized by mild inflammation with an accumulation of pigmented macrophages in the terminal bronchioles. RB can persist for years after smoking cessation, and the extent of pigmentation in alveolar macrophages and peribronchiolar fibrosis is linked to total smoking exposure [2].
RB-ILD is a rare form of IIP found in smokers and differs from RB. Some researchers suggest that RB-ILD represents a more advanced stage of RB, with more extensive fibrosis in the peribronchiolar interstitium [5-7]. However, others argue that RB and RB-ILD cannot be histologically distinguished and should be differentiated based on clinical evidence of ILD [2].
Large-scale studies on RB-ILD are limited, and most of the existing knowledge comes from five case series [4,5,7-9]. As a result, the exact prevalence and incidence remain unclear. One epidemiological study in Greece reported a prevalence of 0.07 per 100,000 individuals and an incidence of 0.04 per 100,000 individuals [10]. In studies on IIP, the proportion of RB-ILD among IIPs has been reported to range from 2% to 13% [2,11-13].
3. Clinical features
Almost all patients with RB-ILD have a smoking history of 30 pack-years or more, either current or past, and the condition typically occurs in individuals between their 30s and 60s [8,9,14-17]. A case report also described RBILD in a nonsmoker exposed to secondhand smoke [7,18]. Studies on the gender prevalence of RB-ILD have shown mixed results; some report a higher prevalence in males [4,6,8], while others report a higher prevalence in females [9], and another study found no gender difference [7,17].
When distinguishing between RB and RB-ILD, the presence of symptoms is key. The most common symptoms in RB-ILD patients are progressively worsening exertional dyspnea and a dry cough, although wheezing and sputum production may also occur [9]. While symptoms typically develop gradually, an acute onset of RB-ILD has been reported in a case study [19]. Asymptomatic cases may be found incidentally during physical examinations, where crackles are heard, or through abnormalities in radiographic imaging or pulmonary function tests. Inspiratory crackles heard bilaterally in the lower lung fields are a common physical finding. A case series reported wheezing in 69% of patients, and digital clubbing was either absent or present in fewer than 25% of cases [2,4,5,7-9].
4. Pulmonary function tests
RB-ILD primarily affects the bronchi but may also involve inflammation of the alveolar septa, leading to obstructive, restrictive, or mixed ventilatory abnormalities on pulmonary function tests [8,9]. Mild to moderate reductions in the diffusing capacity for carbon monoxide (DLCO) are common, although this decrease does not always correlate with disease severity. Due to its association with smoking, RB-ILD is often seen with emphysema, which can cause obstructive ventilatory defects and a decrease in DLCO, even when lung volumes are normal [4,7].
5. Radiologic findings
Radiological findings in RB-ILD are typically not severe [4-6,20]. Chest X-ray abnormalities may include thickening of the central or peripheral bronchial walls or widespread bilateral reticular and nodular opacities; however, 20% to 28% of patients may have normal X-rays [6]. Chest CT may reveal diffuse centrilobular ground-glass nodules or irregular ground-glass opacities along with thickened bronchial walls. Some studies report these imaging findings are mainly in the upper lobes [6,7], while others find no lobar difference [20]. These CT findings can resemble those of subacute hypersensitivity pneumonitis, but the two conditions can be distinguished by bronchoalveolar lavage. Centrilobular emphysema in the upper lobes is present in 50% to 57% of cases but is usually mild [6,7,20]. The frequency of mild interstitial fibrosis, such as linear or reticular opacities within the lobules, varies from 20% to 75% [6,7,9,21], while severe fibrosis, like traction bronchiectasis or honeycombing, is rarely seen [6,20]. In asymptomatic smokers with RB, similar imaging findings may be less extensive [20,22,23].
6. Diagnosis
RB-ILD can be clinically diagnosed in patients with a smoking history who present with respiratory symptoms, impaired pulmonary function, and reduced diffusing capacity, along with characteristic chest CT findings such as centrilobular ground-glass nodules. An increase in pigmented macrophages, without lymphocytosis, in the bronchoalveolar lavage fluid further supports the diagnosis [24]. These pigmented alveolar macrophages, known as ‘smoker’s macrophages,’ contain components of cigarette smoke, particularly kaolinite (aluminum silicate) [25]. In most cases, surgical or bronchoscopic biopsies are not necessary for diagnosis.
1) Bronchoalveolar lavage
Bronchoalveolar lavage fluid typically shows an increased total cell count and pigmented alveolar macrophages, but the overall cellular composition is similar to that of healthy smokers’ bronchoalveolar lavage fluid. The absence of pigmented alveolar macrophages suggests the need to consider other diagnoses. Unlike hypersensitivity pneumonitis, RB-ILD does not show lymphocytosis; however, if lymphocytosis is present in the bronchoalveolar lavage fluid along with the characteristic CT findings, hypersensitivity pneumonitis should be considered [8,17]. Bronchoalveolar lavage and transbronchial lung biopsy can help differentiate hypersensitivity pneumonitis or sarcoidosis, but they are less useful for distinguishing RB-ILD from DIP [15].
2) Pathologic findings
Pathological findings in RB include clusters of pigmented alveolar macrophages containing brownish pigment in the alveoli, lymphocytic infiltration around the mucosa and bronchioles, and perivascular fibrosis [2,4,5,14]. These changes often extend to nearby alveoli, causing mild nonspecific inflammation in the alveolar septa around the bronchioles and more noticeable fibrosis compared to RB alone. This pattern is characteristic of RB-ILD. At low magnification, these features are sparsely distributed around the bronchioles [2,4]. However, many studies suggest that RB and RB-ILD cannot be distinguished pathologically, so differentiation between the two relies primarily on clinical symptoms and radiological evidence of ILD [1,26].
7. Treatment
The treatment indications for RB-ILD are not well-defined, but it is generally considered in cases with functional impairment [4,27]. Some studies have shown that lesions may improve spontaneously after smoking cessation, making smoking cessation the most important aspect of treatment [4,28]. The duration of improvement after smoking cessation varies from 1 to 30 years [2]. However, some clinical case series include patients who received steroids or immunosuppressants in addition to smoking cessation, which complicates the assessment of smoking cessation alone. It is also unclear whether steroids can influence the natural course of the disease [5,7,8,20,28].
One study found that after smoking cessation and steroid treatment, chest high-resolution CT (HRCT) scans showed improvements in bronchial wall thickening, centrilobular nodules, and ground-glass opacities in 43% of patients, while areas of low attenuation, such as emphysema, worsened, indicating an irreversible pattern [20]. In contrast, other studies reported no improvement or even worsening of the condition despite smoking cessation and steroid treatment [7,8], with some patients unable to reduce or stop steroid therapy [8]. There are also case reports of using immunosuppressants like azathioprine and cyclophosphamide in patients who do not respond to steroids [9].
8. Prognosis
The progression of RB-ILD varies, but clinical symptoms and results from pulmonary function typically worsen, regardless of smoking status or treatment [9]. However, most patients are expected to survive long term, with mortality from RB-ILD being rare. Although there is a lack of long-term follow-up studies to accurately determine median survival, a study tracking 32 RB-ILD patients found that only one patient progressed and died from lung disease over an average follow-up period of 7 years. It was estimated that at least 75% of patients would survive for more than 7 years [9].
Desquamative Interstitial Pneumonia
1. Recommendation
Smoking cessation is strongly recommended as a firstline strategy for treatment of DIP. (Level of evidence, Expert consensus; Grade of recommendation, Strong for recommendation)
Voting: Strong for recommendation 6/6
Steroids are recommended for patients with symptoms or reduced lung function. (Level of evidence, Expert consensus; Grade of recommendation, Strong for recommendation)
Voting: Strong for recommendation 5/6, Conditional for recommendation 1/6
2. Summary
DIP is marked by the buildup of pigmented alveolar macrophages in the alveoli. While the exact cause is unclear, it is often linked to current or past smoking. Clinically, the condition typically presents with progressively worsening exertional dyspnea and a dry cough, with pulmonary function tests showing restrictive ventilatory impairment. Chest HRCT typically shows diffuse ground-glass opacities that extend from the upper to lower lungs, usually near the pleura. Bronchoalveolar lavage generally reveals an increase in total cell count and pigmented alveolar macrophages, which are associated with smoking. The main treatments include smoking cessation and steroids to reduce lung inflammation.
DIP is a rare ILD first identified by Liebow et al. [29] in 1965. The disease was initially named based on the belief that the primary histopathological feature was the desquamation of epithelial cells [29]. However, it is now understood to be characterized by the accumulation of alveolar macrophages, sometimes accompanied by giant cells [30]. Despite this clarification, the term DIP is still commonly used [16].
Initially, it was reported that 90% of DIP patients were smokers [31]. Recent studies indicate that the incidence of DIP in smokers ranges from 60% to 87% [5,8,14]. While smoking is a major factor, some cases have also been reported in nonsmokers [5,8,14,30]. DIP has also been linked to exposure to various inorganic dusts and substances, including digestive powder, diesel fumes, beryllium, copper dust, solder smoke, and nylon filaments, particularly in textile workers [7,14,32,33]. In some DIP cases, high concentrations of inorganic particles have been found in lung biopsy samples. Therefore, when occupational exposure to inorganic dust is suspected, mineralogical analysis of tissue samples may be required [34].
Cases of DIP associated with CTD, such as rheumatoid arthritis (RA) and systemic sclerosis (SSc), have also been reported [35,36]. In pediatric cases, genetic defects affecting surfactant function, including mutations in surfactant proteins B and C and ABCA3, have been implicated. ABCA3 mutations are linked to a poor prognosis [37]. Although ABCA3 mutations are very rare in adults, a case series has reported three adult patients with biallelic mutation [38].
3. Clinical features
DIP typically affects individuals in their 40s to 50s with a smoking history of around 30 pack-years, and it is about twice as common in men as in women [5,8,29,30]. The most frequent symptoms are progressively worsening exertional dyspnea and a dry cough. While systemic symptoms like chest pain, weight loss, and fatigue may also occur, hemoptysis is uncommon. [5,8,29,30]. Inspiratory crackles are heard in approximately 50% to 60% of patients in the lower lung fields, and finger clubbing may be present in some cases [5,8,29,30].
4. Pulmonary function tests
DIP usually shows mild restrictive ventilatory impairment and a moderate reduction in diffusing capacity, both of which generally correlate with disease severity [5,8,29,30]. However, since DIP is often linked to smoking, it is frequently accompanied by emphysema, which can cause obstructive ventilatory impairment. In some cases, the diffusing capacity may be significantly reduced even when lung volumes remain normal [30].
5. Radiologic findings
Chest X-rays may sometimes appear normal, with abnormalities often being limited or nonspecific [16,29]. In chest CT, DIP is characterized by diffuse ground-glass opacities that affect both lungs, typically more pronounced in the lower lobes and spreading from the upper to lower regions [16,29]. A study involving 22 patients found bilateral ground-glass opacities in all cases, with 73% primarily affecting the lower lobes and 59% being peripheral (Figure 1) [39]. Unlike RB-ILD, centrilobular nodules were rarely seen [39]. Reticular opacities were present in 60% of patients [11], traction bronchiectasis due to fibrosis around the lung parenchyma was common. Honeycombing, however, is generally rare [39]. Long-term follow-up has shown that 10% to 20% of DIP patients may develop honeycombing over time [39,40]. Although the distribution of interstitial abnormalities in DIP can resemble that of usual interstitial pneumonia (UIP), the extent of ground-glass opacities and the relatively reduced presence of honeycombing help distinguish DIP from UIP [39].
6. Diagnosis
1) Bronchoalveolar lavage
The diagnosis of DIP is based on clinical, functional, radiological, and pathological findings. Bronchoalveolar lavage fluid typically shows an increased total cell count and a higher number of alveolar macrophages containing pigment deposits related to smoking [41]. The distribution of cells in bronchoalveolar lavage is generally similar to that in healthy smokers, and the absence of pigmented alveolar macrophages suggests other potential diagnoses. In nonsmokers with DIP, macrophages may increase without pigment deposits. Additionally, an elevated proportion of eosinophils or neutrophils may be seen in DIP patients, but this is considered a nonspecific finding [40,42,43].
2) Pathologic findings
Transbronchial lung biopsy can help differentiate DIP from hypersensitivity pneumonitis or sarcoidosis, but it is not particularly effective in distinguishing RB-ILD from DIP [40]. To confirm the histopathological pattern of IIP, including DIP, a surgical lung biopsy is recommended [44]. Recently, transbronchial lung cryobiopsy has emerged as a new method for obtaining tissue samples in the diagnosis of ILDs, with experienced centers reporting that it provides sufficient samples to enhance both safety and diagnostic accuracy [41].
The characteristic feature of DIP is the uniform accumulation of numerous alveolar macrophages in the alveolar spaces. These macrophages have eosinophilic cytoplasm and often contain fine, light-brown pigment granules [5,29]. The interstitium shows mild infiltration by chronic inflammatory cells, while the alveolar structure remains relatively intact (Figure 2). Moderate eosinophilic infiltration or lymphoid aggregates may also be seen [34]. Fibrosis in the interstitium is typically minimal, and when present, it resembles changes seen in emphysema. However, architectural distortion or cystic changes are generally rare [45].
7. Treatment
The key aspect of treating DIP is smoking cessation. Studies indicate that 20% to 50% of patients experience clinical improvement after quitting smoking. However, the full effect of smoking cessation on the disease’s progression is not well understood [34]. While some patients show improvement, others continue to experience disease progression despite stopping smoking. The reasons for these differing responses are not yet clear.
The treatment of DIP generally involves long-term corticosteroid therapy [29,37,39]. Prednisone is typically started at 0.5 to 1 mg/kg, with gradual tapering over several weeks to months depending on the clinical response and tolerance [46]. In some treatment-resistant cases, azathioprine and cyclophosphamide have been used, but their role remains unclear [47]. For patients not responding to steroids, macrolide antibiotics, such as clarithromycin, have been suggested, with some cases showing rapid and significant clinical and radiological improvement [48]. In occupational DIP, it is crucial to cease exposure. In one study, two out of five patients who returned to work experienced a relapse [33].
8. Prognosis
The survival rate of DIP has been reported between 68% and 94% [5,8,16,29]. Studies show a 10-year survival rate of about 70%, although data availability limits these findings [1,8]. However, patients with DIP tend to progress to respiratory failure more frequently than those with RB-ILD [8]. A systematic review of 362 adult patients diagnosed through histopathology found that 91% started treatment, most commonly involving smoking cessation counseling and corticosteroid therapy, with treatment durations ranging from 2 weeks to several months, and maintenance therapy in some cases [49]. In a study of 60 cases, 38 (65%) showed positive outcomes, five (8%) remained stable, 15 (25%) died, and two (3%) received lung transplants. Furthermore, at least 18% of patients relapsed after stopping treatment [49]. Lung transplantation may be an option for those with endstage respiratory failure, although recurrence of DIP in the transplanted lung has been reported [50,51].
Lymphoid Interstitial Pneumonia
1. Recommendation
Steroids are recommended for patients with symptoms or impaired lung function. (Level of evidence, Expert consensus; Grade of recommendation, Strong for recommendation)
Voting: Strong for recommendation 4/6, Conditional for recommendation 2/6
2. Summary
LIP is a rare ILD marked by multiclonal lymphocytic proliferation in the lung tissue, diagnosed clinically and pathologically. It can occur as an idiopathic condition or in conjunction with autoimmune or infectious diseases. Common respiratory symptoms include dyspnea, dry cough, and pleuritic chest pain, with systemic symptoms such as fatigue, fever, and weight loss also common. Crackles are often heard on auscultation, and wheezing may be present. Pulmonary function tests typically show restrictive impairment. Chest HRCT typically reveals ground-glass opacities, centrilobular and subpleural nodules, bronchovascular wall thickening, and peribronchial cysts, mainly in the lower lobes. Bronchoalveolar lavage fluid may show lymphocytosis. Histopathologically, LIP is characterized by interstitial infiltration of small lymphocytes and varying numbers of plasma cells. In mild cases, observation without treatment may be appropriate. For symptomatic patients or those with impaired lung function, corticosteroid therapy is the main treatment
LIP is a rare ILD characterized by a benign polyclonal lymphoproliferative disorder, with multiclonal lymphocytic proliferation in the lung tissue, diagnosed clinically and pathologically [52]. First described by Carrington and Liebow in 1966, it was later referred to as diffuse pulmonary lymphoreticular infiltrates associated with dysproteinemia. LIP involves the infiltration of T cells, B cells, plasma cells, and histiocytes into the pulmonary interstitium, triggering an inflammatory response. While LIP can occur without a known cause, it is also associated with CTD and infections [53].
LIP is commonly associated with CTD such as Sjogren’s syndrome, systemic lupus erythematosus, and RA. Other conditions linked to LIP include primary biliary cirrhosis, Crohn’s disease, myasthenia gravis, Hashimoto’s thyroiditis, autoimmune hemolytic anemia, and pernicious anemia, with Sjogren’s syndrome being the most closely associated. Infectious diseases related to LIP include human immunodeficiency virus (HIV)/acquired immune deficiency syndrome (AIDS), Epstein-Barr virus, human herpesvirus 8, chronic active hepatitis, Legionella pneumonia, Pneumocystis jirovecii pneumonia, Castleman’s disease, and tuberculosis. LIP can also occur in patients taking medications like phenytoin or those with common variable immunodeficiency, undergoing allogeneic bone marrow transplantation, or experiencing graft-versus-host disease [54,55].
3. Clinical features
LIP is more common in individuals aged 40 to 70 years, with a higher prevalence in women [54], although idiopathic LIP is more frequently seen in men. LIP associated with CTD typically affects women. The onset of symptoms is gradual, ranging from 2 months to 12 years. Respiratory symptoms commonly include dyspnea, dry cough, and pleuritic chest pain, while systemic symptoms may involve fatigue, fever, weight loss, and night sweats [53,54]. Crackles are often heard on auscultation, and wheezing may occur during expiration. About 60% of patients show dysproteinemia, with hypergammaglobulinemia being more common than hypogammaglobulinemia [53,54].
5. Radiologic findings
Chest X-rays are often normal, though reticular or nodular opacities may be seen in the lower lung fields [55]. Chest HRCT typically reveals ground-glass opacities, centrilobular and subpleural nodules, bronchovascular bundle thickening, and peribronchovascular cysts, mainly in the lower lobes (Figure 3) [55-57]. The cysts are thought to result from ischemic changes due to vascular occlusion from infiltrated lymphoid tissue or from a ball valve mechanism, where the lymphoid tissue obstructs the bronchi partially or completely [54].
Conditions that should be differentiated from LIP due to cyst formation include lymphangioleiomyomatosis, pulmonary Langerhans cell histiocytosis, Birt-Hogg-Dubé syndrome, and amyloidosis. In LIP, cysts typically range from 3 mm and 1 cm in size, are round, and are distributed diffusely and irregularly around blood vessels [58]. Although lymphocytic and plasma cell infiltration of the interlobular septa can lead to septal thickening on HRCT, this is uncommon. Lymphadenopathy can present in various patterns, but pleural effusion and lung consolidation are rare in LIP. When these features occur, malignancies like lymphoma should be considered. Pulmonary nodules larger than 11 mm or those that grow in size may indicate lymphoma. The use of positron emission tomography-CT (to distinguish these lesions is uncertain, as increased activity can also be seen in LIP-associated nodules [55].
6. Diagnosis
In bronchoalveolar lavage fluid, lymphocytosis with a normal CD4/CD8 ratio may be seen, but this is not specific to LIP. Due to the relatively low diagnostic yield of transbronchial lung biopsy, surgical lung biopsy is recommended for diagnosing LIP [53]. Histologically, LIP is marked by interstitial infiltration of small lymphocytes, plasma cells, immunoblasts, macrophages, and histiocytes (Figure 4). Germinal centers and nodular lymphoid aggregates are present in about 50% of cases. The lymphocytic infiltration is composed of both T and B cells, with B cells mainly forming nodular lymphoid follicles and T cells predominantly found in the interstitium. Occasionally, nonnecrotizing granulomas may be present, though they are not always easily detected [59]. Cysts seen on chest CT are not typically found in histological examination. As LIP progresses, interstitial fibrosis and honeycombing can develop.
7. Treatment
There are no randomized controlled trials comparing treatments for LIP with a control group, and most studies are based on case reports. Treatment for LIP depends on the patient’s symptoms, functional status, and any underlying conditions like CTD, HIV infection, or immunodeficiency. For both idiopathic and secondary LIP, mild cases may only require observation. However, if symptoms are present or lung function is affected, oral corticosteroids are used [53,54,60]. About 50% to 60% of patients show improvement, either symptomatically or in radiological findings. The initial treatment typically involves prednisone (or an equivalent dose of prednisolone) at 0.75 to 1.0 mg/kg/day (up to 100 mg/day), given once daily for 8 to 12 weeks. If the patient responds, the dose is gradually reduced to 0.25 mg/kg/day over 6 to 12 weeks [61].
If steroid therapy does not yield a response, alternative treatments such as azathioprine, cyclophosphamide, cyclosporine, rituximab, hydroxychloroquine, mycophenolate, or tumor necrosis factor inhibitors may be considered [53,54,61-63]. Long-term high-dose steroids (>20 mg/day) should be paired with prophylactic antibiotics to prevent P. jirovecii pneumonia. For LIP-associated with HIV, antiviral therapy can be beneficial [64-66]. If LIP occurs in an HIV patient not receiving antiviral therapy, antiviral therapy should be initiated. If there is no response to antiviral therapy or if LIP requires treatment in an HIV patient already on antivirals, corticosteroids may be added [67,68]. No antifibrotic agents have been reported for preventing or delaying fibrosis progression in LIP [61].
8. Prognosis
The natural course and prognosis of LIP are not fully understood, but possible outcomes include [53,54,60,69] (1) spontaneous improvement or stabilization, (2) recovery with corticosteroids alone or combined with immunosuppressive therapy, (3) progression to pulmonary fibrosis and respiratory failure, (4) development of pulmonary or systemic infections, and (5) development of lymphomas. Currently, there are no clinical, laboratory, or pathological markers that can reliably predict these outcomes.
A study of 15 patients with LIP (eight with Sjogren’s syndrome, one with RA, one with systemic lupus erythematosus, one with polymyositis, one with common variable immunodeficiency, and three with idiopathic LIP) found that 13 patients received steroid therapy, with eight out of nine evaluable patients showing clinical improvement or stabilization. The median survival was 11.5 years [53]. Despite treatment, the 5-year mortality rate for LIP ranges from 33% to 55% [61]. Infections are a significant complication, especially in patients with primary immunodeficiencies (e.g., HIV) or those undergoing immunosuppressive therapy [53,60,70]. Progression to intrapulmonary or systemic lymphoma is rare but can occur in about 5% of cases, with a higher risk in patients with Sjogren’s syndrome [54,71-74]. Lymphomas associated with LIP are typically well-differentiated, slowly growing mucosa-associated lymphoid tissue lymphomas [73].
Acute Interstitial Pneumonia
1. Recommendation
Steroids are recommended for treating AIP. (Level of evidence, Expert consensus; Grade of recommendation, Strong for recommendation)
Voting: Strong for recommendation 4/6, Conditional for recommendation 2/6
2. Summary
AIP is a rare, rapidly progressing lung disease that occurs in previously healthy individuals without underlying lung conditions. Clinically, it resembles acute respiratory distress syndrome (ARDS), with the key difference being the absence of a clear cause. AIP typically affects individuals over 40 years of age, regardless of gender or smoking history, and is often preceded by prodromal symptoms 7 to 14 days before the disease onset. Once it begins, the disease progresses quickly within a few days. Diagnosis is confirmed through clinical features similar to ARDS and histological evidence of diffuse alveolar damage (DAD). Current treatment primarily focuses on supportive care, such as oxygen therapy and lung-protective ventilation. Although steroid therapy, other immunosuppressive treatments, and lung transplantation are commonly used, there is insufficient evidence to confirm their effectiveness, highlighting the need for further research and clinical experience.
AIP is a rapidly progressing severe lung disease that occurs in previously healthy individuals without preexisting lung conditions, distinguishing it from other types of IIP [75,76]. Known as ‘Hamman-Rich syndrome,’ AIP was recognized as a separate acute ILD, distinct from idiopathic pulmonary fibrosis (IPF), following a consensus between the American Thoracic Society and the European Respiratory Society in 2000 [77,78].
3. Clinical features
AIP typically affects individuals over 40 years of age, with the average age of onset being 55, and is not associated with gender or smoking status [76,79-81]. The disease begins with prodromal symptoms, including muscle pain, joint pain, and chills, lasting 7 to 14 days. This is followed by symptoms such as fever, cough, shortness of breath, and hypoxemia. On physical examination, widespread crackles are heard in both lungs. The disease progresses rapidly within a few days, often requiring noninvasive or invasive mechanical ventilation [75,76,81].
4. Diagnosis
AIP is diagnosed based on clinical features resembling ARDS, with no identifiable cause, and is confirmed by histological evidence of DAD. Chest X-ray typically shows diffuse airspace consolidation with air bronchogram in both lungs, which can may be mistaken for cardiogenic pulmonary edema, requiring an echocardiogram for differentiation [82].
1) Radiologic findings
Chest HRCT commonly reveals widespread or patchy ground-glass opacities and consolidation, mainly in the subpleural regions of both lungs, without pleural effusion (Figure 5). These findings progress from the exudative phase, showing ground-glass opacities and mild consolidation due to septal edema, to the organizing phase, with fibrosis, traction bronchiectasis, and subpleural honeycombing [81-85]. While these findings resemble ARDS, AIP generally presents more symmetrically and bilaterally, primarily affecting the lower lobes [86].
2) Pathologic findings
Histological diagnosis is typically made through open lung biopsy or video-assisted thoracoscopic surgery biopsy [82,87,88]. The histopathological features of AIP align with those of DAD and depend on the biopsy timing. In the exudative phase, edema, hyaline membrane formation, and acute interstitial inflammation are present, while the organizing phase is marked by loose organizing fibrosis and hyperplasia of type II pneumocytes (Figure 6) [89].
3) Bronchoalveolar lavage
Bronchoscopy and bronchoalveolar lavage can help differentiate AIP from other causes of diffuse lung infiltrates, such as alveolar hemorrhage, eosinophilic lung disease, infection, or malignancy. Although bronchoalveolar lavage fluid findings are nonspecific, they may show increased neutrophils and atypical epithelial cells [90]. Differential diagnosis should focus on distinguishing AIP from other rapidly progressing ILDs, such as acute exacerbations of IPF and DIP. Additional tests are needed to rule out CTD-ILDs linked to RA, SSc, Sjogren’s syndrome, mixed connective tissue disease (MCTD), idiopathic inflammatory myopathies, and systemic lupus erythematosus.
5. Treatment
The only established treatment for AIP is supportive care, including oxygen supplementation and mechanical ventilation. Due to the rapid progression to respiratory failure in most cases, noninvasive or invasive mechanical ventilation is often needed. A lung-protective ventilation strategy, as recommended for ARDS, should be used [91]. Preventive measures are also essential to avoid complications in critically ill patients, such as thromboembolism, gastrointestinal bleeding, and secondary infections.
Steroids have traditionally been used to treat AIP, but data on high-dose steroid therapy are limited to small case reports with varying dosing regimens and outcomes, making their routine use in AIP treatment difficult. More research and clinical experience are needed. If steroids or other conservative treatments are ineffective, alternative immunosuppressive therapies, lung transplantation, or extracorporeal membrane oxygenation may be considered. However, the number of reported cases involving these treatments is still limited, and their practical use remains restricted [80,92-95].
6. Prognosis
Studies show that the mortality rate for AIP is very high, surpassing 50%, with most deaths occurring within 6 months of symptom onset [94]. In some survivors, pulmonary function can return to nearly normal levels without recurrence, unlike other ILD patients. However, there are also reports of cases progressing to recurrent or chronic ILD [80,95].
Idiopathic Pleuroparenchymal Fibroelastosis
1. Recommendation
Based on expert consensus, the use of steroids and antifibrotic agents is neither recommended nor discouraged. (Level of evidence, Expert consensus; Grade of recommendation, Inconclusive)
Voting: Conditional for recommendation 1/6, Inconclusive 4/6, Conditional against 1/6
2. Summary
IPPFE is a rare ILD marked by fibrosis of the pleura and upper lung parenchyma. It primarily affects nonsmokers aged 30 to 60 years. Symptoms, including dyspnea, dry cough, nonspecific chest discomfort, and pleural pain, develop gradually over several years. Pneumothorax may be the initial symptom and recurs in about half of the cases. Chest CT typically shows pleuroparenchymal thickening and subpleural reticular opacities, along with parenchymal fibrosis in the upper lobes. Histopathology reveals intraalveolar fibrosis and elastosis (IAFE) and visceral pleural fibrosis, with Elastica van Gieson staining showing fibrosis and elastosis in the subpleural parenchyma within the pulmonary lobule. Diagnosis is made through clinical, radiological, and histopathological findings, although biopsy may not be necessary if pathology is difficult to obtain. There is no proven treatment that extends survival in IPPFE. Survival prognosis is unclear, but % FVC and GAP (gender, age, and physiology) stage are significant predictors of mortality. Common causes of death include chronic respiratory failure with hypercapnia, acute exacerbations, cachexia, pneumonia, and pulmonary embolism.
IPPFE is a rare ILD characterized by fibrosis of the pleura and adjacent lung parenchyma, primarily in the upper lobes [96]. Initially, case reports described fibrosis in the upper lobes with distinct pathological features, setting it apart from other types of IIP. However, IPPFE was first introduced in 2004 to describe five patients with unique radiological and pathological characteristics [97]. Further research on IPPFE led to its classification in 2013 as a rare form of IIP [1].
3. Epidemiology and etiology
Although research on IPPFE has grown in recent years, there are no standardized international diagnostic criteria, so the exact prevalence and incidence remain unclear. A retrospective study in Japan found that 12 out of 205 patients (5.9%) diagnosed with IIP through biopsy had IPPFE [98]. Other studies using imaging diagnosis reported IPPFE in 7.7% to 10.4% of IIP patients [98,99]. A separate study at a university hospital in Korea found that 28 out of 455 patients (6.3%) with IPF had PPFE [100].
IPPFE is considered a form of IIP, though its cause is largely unknown. Secondary causes of PPFE must be ruled out for an IPPFE diagnosis [101]. Secondary PPFE is often linked to factors such as medications [97,102], radiation therapy [97], organ transplantation [103-106], CTD [107-115], fibrotic ILD [100,116,117], chronic respiratory infections [118-120], environmental exposures [119,121,122], and thoracic surgeries [123] (Table 1). Smoking has not been significantly associated with IPPFE development [124].
4. Clinical features
IPPFE can affect individuals of any age, but it is most common in those aged 30 to 60 years [125-127]. While gender differences are not consistent across reports, it is often seen in nonsmokers [99,125-128]. Clinically, IPPFE progresses slowly over several years. Symptoms include dyspnea, dry cough, nonspecific chest discomfort, and pleuritic chest pain [96,126,127]. In a study by Lee et al. [127], 21 of 26 patients with IPPFE reported dyspnea, and 18 reported a cough. Progressive weight loss is common after diagnosis, with more than 5% weight loss per year being linked to a poor prognosis [101]. About half of IPPFE patients develop platythorax, which is a flattening of the chest due to reduced anteroposterior diameter [129], caused by significant upper lobe volume loss and reduced chest wall volume [130]. Some patients may also have a deeply sunken suprasternal notch. Breath sounds may be normal, but crackles can be heard if the disease extends beyond the upper lobes or if other ILDs are present [96]. Pneumothorax and mediastinal emphysema may be the first signs of IPPFE [131], occurring in 25% to 60% of cases during follow-up, with 56% experiencing recurrence [132]. Pneumothorax is associated with lower survival rates in IPPFE patients [132].
5. Laboratory findings
There are no specific laboratory findings unique to IPPFE, but certain elevated markers can be helpful. Increased desmosine levels in urine, when compared to those in patients with IPF, chronic obstructive pulmonary disease, or healthy individuals, may serve as a potential noninvasive diagnostic indicator for suspected IPPFE cases. Elevated levels of Krebs von den Lungen-6 (KL-6) and surfactance protein D (SP-D) may also be observed, and while their degree of elevation correlates with disease progression, further studies are needed to confirm their diagnostic and clinical value [133-135]. Additionally, autoantibodies such as rheumatoid factor, anti-neutrophil cytoplasmic antibody, and immunoglobulin G against fungi may be elevated, although the levels are inconsistent and can rise when underlying diseases are poorly controlled, reducing their effectiveness in diagnosing IPPFE [97,121,135,136].
6. Pulmonary function tests
IPPFE typically presents with a restrictive pattern, showing reduced FVC, total lung capacity (TLC), and diffusing capacity of the lung divided by alveolar volume (DLCO/VA). The FEV1/FVC ratio is usually normal or elevated. The decrease in FVC can be as rapid, or even faster, than that seen in UIP. Arterial blood gas analysis, like in other ILDs, may indicate hypoxemia, hypercapnia, and respiratory alkalosis [96].
7. Radiologic findings
Chest X-rays may show irregular pleural thickening in the upper lobes, although this may not be visible in the early stages. Other findings like bronchiectasis, ground-glass opacities, reticular patterns, and pneumothorax can also occur. As the disease progresses, platythorax, or flattening of the chest due to decreased anteroposterior diameter, may become noticeable in comparison to the diaphragm [124].
Chest CT scans are particularly helpful in diagnosing PPFE. Typical findings include subpleural reticular opacities, pleuroparenchymal thickening, adjacent parenchymal fibrosis, traction bronchiectasis, bullae, cysts, ground-glass opacities, and patterns resembling UIP or nonspecific interstitial pneumonia, mainly in the upper lobes [1,96,124]. Occasionally, a pleural cap may be seen at the lung apices [137]. Lower lobe pleural thickening and subpleural fibrosis are usually mild or absent in IPPFE (Figure 7). However, PPFE can coexist with other conditions like IPF [138-142], CTD-ILD [110,112,143], or fibrotic hypersensitivity pneumonitis [117,144], in which case lower lobe involvement may also be seen.
8. Diagnosis
A multidisciplinary approach involving clinical, radiological, and pathological findings is essential for diagnosing IPPFE. Histologically, IPPFE is characterized by IAFE and visceral pleural fibrosis, which can be observed with Elastica van Gieson staining. IAFE consist of dense collagen fibrosis filling alveolar spaces, while elastin deposition remains in the alveolar walls [125], primarily in the upper lobes. Visceral pleural fibrosis is often patchy and may be overlooked in biopsy samples (Figure 8).
A surgical lung biopsy from at least two sites is crucial for confirming the diagnosis of IPPFE, as it not only provides a definitive diagnosis but also helps assess histological patterns in other lobes if imaging shows abnormalities beyond the upper lobes. However, surgical biopsies carry risks like pneumothorax, mediastinal emphysema, bronchopleural fistula, and prolonged air leaks, so caution is advised. Nonsurgical biopsy methods, such as transbronchial lung biopsy [145], transbronchial cryobiopsy [146], and transthoracic needle biopsy [136], may also be considered.
Differential diagnoses should exclude other causes of upper lobe fibrosis, including chronic hypersensitivity pneumonitis, sarcoidosis, and UIP with upper lobe involvement. Other conditions to consider include non-tuberculous mycobacterial infection, postinjury lung remodeling, pneumoconiosis, malignancies, and nonspecific findings such as apical caps [147,148].
1) Diagnostic criteria for IPPFE
In 2012, Reddy et al. [126] established the first diagnostic criteria for PPFE, combining chest CT findings and pathological features. They categorized the diagnosis into three subtypes: ‘definite,’ ‘consistent with,’ or ‘inconsistent with’ PPFE (Table 2) [126]. The criteria defined IPPFE based on histopathological and radiological characteristics being either ‘definite’ or ‘consistent.’ While this classification enhanced clinicians’ understanding of IPPFE, there was debate about the need for pathological evaluation. Many patients with IPPFE experience declining lung function and poor prognosis, and due to the lack of effective treatments after diagnosis, concerns arose about the necessity of biopsy given the risks of complications like pneumothorax and acute exacerbation.
In 2017, Enomoto et al. [129] proposed updated diagnostic criteria based on a multicenter analysis of 44 patients. They recommended a diagnostic approach focusing on clinical and radiological features, where a diagnosis could be made if all three radiological criteria were met. In conclusion, while clinical and radiological findings can support a diagnosis when pathology is hard to obtain, the most accurate diagnosis is made by combining histopathological findings.
9. Treatment
1) Pharmacological treatment
Currently, research on pharmacological treatments for IPPFE is very limited, and no medication has been proven to improve survival [96,101,149,150]. Low-dose steroids are sometimes used empirically, although there is minimal evidence this practice. In a study of 29 patients with IPPFE, nine were treated with oral steroids, with two showing improvement on chest HRCT [99]. High-dose steroids or immunosuppressants are rarely used due to the increased risk of infection [96].
In a retrospective study of 259 IPF patients, 64 had coexisting PPFE. Of these, eight (12.5%) were treated with nintedanib and 26 (40.6%) with pirfenidone. Among the typical IPF group, 38 patients (19.4%) received nintedanib and 53 (27.1%) received pirfenidone. Antifibrotic drugs significantly slowed lung function decline in the typical IPF group but had no significant effect in IPF patients with coexisting PPFE. Multivariate analysis showed that the presence of PPFE in IPF patients was a significant predictor of poor response to antifibrotic treatment (odds ratio [OR], 7.096; p=0.002) [140].
No prospective clinical trials have evaluated the efficacy of pirfenidone in IPPFE patients. All published studies are either case reports or retrospective studies involving small patient groups [99,129,151,152]. One study of 44 patients with IPPFE found that eight were treated with pirfenidone, but there was no significant improvement [129]. Another study of 29 patients reported that 10 received pirfenidone, with only one showing stabilization of % FVC [99].
Similarly, no prospective clinical trials have evaluated the efficacy of nintedanib in IPPFE patients. The Nintedanib in Progressive Fibrosing Interstitial Lung Diseases (INBUILD) study, which found that nintedanib significantly slowed lung function decline in patients with progressive pulmonary fibrosis, included a small number of IPPFE patients, though the exact number was not specified. However, no separate analysis of the PPFE subgroup was conducted, providing limited evidence for nintedanib’s effectiveness in IPPFE [153,154]. Two retrospective studies showed conflicting results. One study compared the annual decline in % FVC before and during treatment with various drugs in 21 patients with IPPFE and secondary PPFE. It found that eight out of nine patients treated with nintedanib experienced stabilization or a slower decline in % FVC after treatment, with a change from −13.6%±13.4%/year before treatment to −1.6%±6.02%/year during treatment. In contrast, no significant difference was found in patients treated with other drugs [155]. Another study comparing 15 IPPFE patients and 27 IPF patients treated with nintedanib for more than 6 months found that while nintedanib slowed the annual decline in % FVC in IPF patients, it had no significant effect in IPPFE patients [156].
2) Non-pharmacologic treatment
Non-pharmacologic treatment options for advanced IPPFE and secondary PPFE include lung transplantation [157-163], although data on posttransplant outcomes are limited. A Japanese study of 31 IPPFE and 69 IPF patients who underwent lung transplantation over 20 years found no significant difference in survival between the two groups [164]. Severe pleural thickening, low body mass index (BMI), flattened chest, and significant restrictive lung function impairment may increase risks during transplantation, making careful patient selection essential [164].
A recent study of 89 IPPFE patients found that 53 (59.6%) experienced 120 episodes of pneumothorax, with 76.7% being small and 70.8% asymptomatic. Chest tube insertion was performed in 23 cases (19.2%) and pleurodesis in 13 cases (10.8%), while three cases (2.5%) required surgery or other interventions [132].
One study suggested that pulmonary rehabilitation may be beneficial [129], and noninvasive positive pressure ventilation may help advanced IPPFE patients with daytime hypercapnia, though it can be difficult to tolerate [165]. As with other ILDs, oxygen therapy is necessary for patients with hypoxemia, and vaccinations are recommended to prevent infections [96].
10. Prognosis
1) Overall prognosis
No large-scale prospective studies on IPPFE patients have been conducted so far, and retrospective studies show highly variable clinical outcomes [96,99,101,124,125,149,150,166-169]. A literature review, which combined survival data from 85 patients in studies before PPFE was officially recognized, reported a median survival time of 11 years [124]. A Japanese retrospective study involving 52 IPPFE patients found a mean survival time of 96 months, with a 5-year survival rate of 58% [168]. However, a separate analysis of 44 IPPFE patients indicated a median survival time of only 35 months and a 5-year survival rate of 28.9% [129]. One study noted a median annual decline in FVC of 20.3%, suggesting faster progression than IPF [126]. In a follow-up of six IPPFE patients over roughly 40 months, half had died [170]. Patients with secondary PPFE following transplantation generally experience faster disease progression and poorer prognosis [132].
A study comparing 29 IPPFE patients with 67 IPF patients found that IPPFE patients had significantly worse prognosis than those with IPF [100]. Further analysis by GAP stage showed no difference in prognosis between the groups at stage I. However, at GAP stages II and III, outcomes were notably poorer for IPPFE patients compared to IPF patients [100].
2) Prognostic factors
Factors linked to disease progression in IPPFE patients include reduced FVC, increased residual volume (RV)/TLC, lower BMI, and a decreased flat chest index [169]. Mortality predictors include % FVC and GAP stage [100]. In addition, poorer prognosis has been associated with telomerase-related gene mutations [171], coexisting UIP patterns in the lower lobes [140,172], and exposure to alkylating agents [173]. Common causes of death in IPPFE patients are chronic respiratory failure with hypercapnia, acute exacerbations [172], cachexia, pneumonia, and pulmonary embolism [100,144].
3) Prognostic impact of PPFE in patients with ILD
The presence of PPFE alongside ILD, including conditions like IPF [139-143], CTD-ILD [111,113,144], and fibrotic hypersensitivity pneumonitis, has notable prognostic implications [118,145]. In a study of 110 histologically confirmed IPF patients, 11 showed PPFE patterns on upper lobe HRCT, and nine were confirmed histologically. These patients exhibited higher RV and RV/TLC ratios, elevated PaCO2 levels, and greater complication rates, including pneumothorax and mediastinal emphysema. Although survival rates were not significantly different, they tended to be lower in those with coexisting PPFE [139]. Another study graded PPFE on HRCT in IPF patients and found that in a derivation cohort of 142, 49% had PPFE findings, and in a validation cohort of 145, 72% showed PPFE. Marked PPFE, present in 10.8% of cases, was linked to a significant 1-year FVC decline and increased mortality [143]. A review of 419 IIP patients (primarily IPF and unclassifiable fibrotic ILD) showed 24.1% had PPFE-like HRCT findings, and outcomes were significantly worse in this subgroup [142]. Similarly, in a study of 259 IPF patients, 64 with coexisting PPFE had a median survival of 34 months compared to 62.3 months in those without IPPFE, indicating a significantly poorer prognosis [141].
In a study of 113 patients with CTD-ILD, 21 (19%) displayed PPFE patterns on radiology. Conditions linked to PPFE included SSc (6/14, 43%), Sjogren’s syndrome (4/14, 29%), MCTD (5/18, 28%), inflammatory myopathy (4/36, 11%), and RA (2/31, 6%) [144]. In a study of 539 SSc-ILD patients, 18% showed PPFE patterns, with 11% having extensive IPPFE. IPPFE was independently linked to bronchial abnormalities and shorter survival in SSc-ILD [111]. In a study analyzing 477 RA-ILD patients, 6.5% had PPFE, associated with lower BMI, reduced FVC, UIP patterns, higher pneumothorax risk, and lower DLCO but was not linked to increased mortality [113]. A study involving 233 hypersensitivity pneumonitis patients found PPFE in 23%, and its presence correlated with impaired lung function and higher mortality [118].
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