Pathophysiological Insights and Clinical Management Strategies for Interstitial Lung Diseases

Abstract

Interstitial lung disease (ILD) represents a heterogeneous group of diseases in which inflammation and/or fibrosis in the pulmonary interstitium results in an impaired gas exchange, difficulties in breathing, and reduced quality of daily life, and contributes to elevated global morbidity and mortality rates. ILD is an umbrella term, with idiopathic pulmonary fibrosis (IPF) being a prime focus because of its progressive and severe form. Out of 300 underlying etiologies, ILD is one of the major reasons for global morbidity and mortality. This review offers a comprehensive overview of six main categories of ILD covering autoimmune, idiopathic interstitial pneumonia, hypersensitivity pneumonitis, drug-induced, infection-related, and unclassified ILD that underscore the complexity of diagnosis and treatment challenges. This review also provides an evidence-based overview of recent advancements in the diagnosis and management of ILD, with precision pharmacotherapy, multidisciplinary care, and emerging therapeutic strategies. From clinical trial data, it also recommends the disease-specific use of pharmacological agents—such as pirfenidone and nintedanib for IPF, and mycophenolate mofetil for connective tissue disease-associated ILD. The manuscript also emphasizes the evolving role of non-pharmacological interventions, including the 6-minute walk test and pulmonary rehabilitation, in enhancing functional capacity and quality of life. To address the current global health concerns, topics of post-COVID-19 ILD and immune checkpoint inhibitor-associated lung disease are integrated. Additionally, future directions are explored, including the role of lung transplantation and novel antifibrotic therapies like anti-Transforming Growth Factor (TGF)-β antibody cocktails. Together, these insights aim to refine diagnostic precision, personalize treatment, and improve clinical outcomes across the heterogeneous ILD spectrum.

INTRODUCTION

Interstitial lung disease (ILD) represents a heterogeneous group of diseases associated with anatomical changes in the pulmonary interstitium (Wijsenbeek et al., 2022; Maher, 2024). It is generally characterized by inflammation and/or fibrosis within the alveolar interstitium of the lung, resulting in impaired gas exchange, breathing difficulties and reduced quality of daily life (Oldham et al., 2022). It is one of the major causes of mortality and morbidity on a worldwide scale. The term ILD is used as an umbrella term for a variety of separate diseases. Pulmonologists define ILD mainly as a lung inflammation of the interstitium that can have multiple causes. It is described as a progressive, severe lung disease with a poor prognosis, in which healthy lung tissue becomes scarred. With this definition, idiopathic pulmonary fibrosis (IPF) is often the main focus (Maher et al., 2021a). At a basic level, ILDs affect the tissue and space around the alveoli. ILD is the most common term used in reference to IPF. As the lungs become increasingly damaged, patients may develop changes in lung capacity and hypertension, which usually will result in elevated blood pressure between the heart and the lung. Around 30% to 40% of ILD cases advance to pulmonary fibrosis, leading to breathlessness and respiratory failure (Oldham et al., 2022). The typical survival duration for these individuals is roughly 2.5 to 3.5 years. In the United States, ILD affects over 650,000 individuals, while idiopathic pulmonary fibrosis (IPF) affects roughly 200,000 people, leading to 26,000 deaths annually (Jeganathan and Sathananthan, 2021). In comparison with existing international guidelines, this review provides updated information on the pathological and diagnostic perspectives of ILD, along with some novel therapeutic mechanisms. Basic concepts will be reviewed and discussed critically to assist clinicians with the multidisciplinary approach suggested for diagnosis and stratification of the severity of ILD.

CLASSIFICATION AND NOMENCLATURE OF ILD

ILD consists of a wide range of pathologic, radiologic and clinical entities, each representing an important public and individual health concern. Individuals diagnosed with ILD demonstrate significant variability in disease progression and prognosis. Therefore, clinicians and those involved in clinical research must distinguish ILDs among etiologic entities, as more than 300 underlying causes can result in ILD (Exarchos et al., 2023). Discriminating ILDs based on pathologic characteristics, such as inflammation, fibrosis, or both, is also critical to employ appropriate treatment strategies. ILDs are classified according to their root causes and can be divided into 6 broad categories, including 1) autoimmune ILD, 2) idiopathic interstitial pneumonia, 3) hypersensitivity pneumonitis, 4) drug-induced ILD, 5) infection-related ILD, and 6) unclassified ILD (O’Callaghan et al., 2021; Maher, 2024). While these conditions present comparable clinical symptoms, they are defined by distinct histopathological characteristics and differing prognoses. The prevalent forms of ILD involve IPF, representing more than 30% of cases, connective tissue disease (CTD), comprising around 25% of cases and hypersensitivity pneumonitis, which constitutes roughly 15% of cases (Oldham et al., 2022). Other varieties of ILD consist of drug-related ILD and post-infectious ILD, including that which arises after COVID-19 (Stewart et al., 2023).

Although different types of ILDs display distinct pathophysiological features, clinical symptoms, and prognostic results, they all possess the capacity to result in irreversible pulmonary fibrosis. Once pulmonary fibrosis develops, it can keep progressing even if the root cause of the ILD has been treated or removed (Wong et al., 2020; Molina-Molina et al., 2022). The phrase progressive pulmonary fibrosis (PPF) refers to the advancement of disease noted in a particular subset of patients with ILD, which can be better defined and treated according to the extent of fibrosis rather than the initial cause (Raghu et al., 2022). People with ILD related to connective tissue disease (CTD-ILD) who qualify for PPF typically have a life expectancy of around four years, whereas the overall survival period for the wider group of CTD-ILD patients is between eight and ten years (Pugashetti et al., 2023).

EPIDEMIOLOGICAL STUDIES ON ILD

The epidemiological studies on ILD have begun to comprehend the global patterns in the incidence and prevalence of ILD. From 2010 to 2013 in the United States, ILD, including etiology, formed 3.6% of ambulatory care and emergency department visits, whereas idiopathic pulmonary fibrosis (IPF) was responsible for 0.9% of all ambulatory care and emergency department physician visits in the United States. Kaul and his co-workers estimated the ILD prevalence and incidence ranges in heterogeneous studies and they found the incidence of ILD ranged from 1.0 to 31.5 per 100,000 population and prevalence ranged from 6.3 to 71 per 100,000 population, annually (Kaul et al., 2021). In 2019, the Global Burden of Disease study estimated that approximately 654,841 people in the United States were impacted by ILD, indicating a prevalence rate of 179.7 per 100,000 in men and 218.9 per 100,000 in women. This indicated a roughly 19% rise since 2010 (Jeganathan and Sathananthan, 2021). The occurrence of ILD generally increases with age, reaching its highest point in individuals between 80 and 84 years old. The typical age when people are diagnosed ranges from 67 to 72 years (Zaman et al., 2020). Generally, IPF predominantly affects males, with a sex ratio of about 3:1 and former smokers, while chronic hypersensitivity pneumonitis (CHP) incidence is weakly related to smoking, and there is a marginal male predominance in sarcoidosis and chronic eosinophilic pneumonia (EAA). IPF is seen in adults with an incidence estimated between 3 to 9 cases per million (Maher et al., 2021b). Veterans Affairs database in the United States demonstrated an increase in the rate of IPF from 73 per 100,000 person-years in 2010 to 210 per 100,000 person-years in 2019 (Kaul et al., 2022). This condition has been observed to be on the rise in various populations; however, the cause of this rise is not well understood (Hutchinson et al., 2015). A number of case-control studies have demonstrated that woodworking with bare skin exposure to wood dust and metal dust (Hubbard et al., 1996; Pauchet et al., 2022), smoking (Abramson et al., 2020), and living in areas with high levels of urban air pollution are risk factors for IPF (Conti et al., 2018).

Hypersensitivity pneumonitis is one of the interstitial lung diseases that originate from antigenic particles such as avian proteins and spores originating from molds or fungi (Furusawa et al., 2022). Hypersensitivity pneumonitis incidence rates differ across the United States, ranging from 1.67 to 2.71 cases per 100,000 population and increasing with age (Perez et al., 2018). In contrast to IPF, the rates of hypersensitivity pneumonitis are nearly equal for both sexes and generally, its prognosis is favorable if the antigenic particles are avoided (Barnes et al., 2022).

CTD-ILD is not constant in all connective tissue diseases and can significantly differ in prevalence according to the specific underlying condition (Steele et al., 2012). It is reported that approximately 65% of patients with systemic sclerosis (SSc) and 80% with diffuse cutaneous systemic sclerosis (DCSSc) may develop ILD. Among patients with IIM, which include polymyositis, dermatomyositis, and antisynthetase syndrome, the prevalence of ILD varies from 36-45%, however, the rates can reach 80% in patients with specific antisynthetase antibodies (Hallowell and Paik, 2021; Laporte et al., 2022; Hallowell and Danoff, 2023). Furthermore, about 52-67% of patients with mixed connective tissue disease, 11-27% of individuals with Sjogren’s syndrome, 1.5-5% of those with rheumatoid arthritis, and approximately 1-2% of patients with systemic lupus erythematosus (SLE) develop ILD (Mageau et al., 2022).

Forced Vital Capacity (FVC), and the diffusion capacity of the lungs for carbon monoxide (DLCO) were combined with age and sex to define the GAP index (gender, age, and physiology) to predict survival in fibrotic interstitial lung disease (ILD) in three groups of disease severity (Ley et al., 2012). GAP stage 1, which affects nearly half the cases of IPF patients has an adjusted one-year mortality rate of 5.6% and a three-year mortality rate of 16.3%. On the other hand, 10% of new patients present GAP stage 3, this is having a 1-year survival rate of 60.8% and a 3-year survival rate of 23.2% (Ley et al., 2012).

IPF and other idiopathic lung diseases associated with pulmonary fibrosis are associated with several disease-related comorbidities including pulmonary hypertension, and lung cancer. Polysomnography has confirmed obstructive sleep apnoea in one-third of patients who present with newly diagnosed fibrotic interstitial lung disease (Furusawa et al., 2022; Peljto et al., 2023). At present, no data are available which support the hypothesis that the management of obstructive sleep apnoea has a bearing on the prognosis. In general, studies have reported that the prevalence of pulmonary hypertension in IPF patients has variable ranges from 3 to 86 percent, while in patients with pulmonary fibrosis waiting for a lung transplant, the number is as high as 86 percent (Raghu et al., 2015a, 2024, 2015b).

The incidence of developing lung cancer has been assumed to be 25.2 per 1000 person-years among patients with ILD, which is at least three-fold higher than among individuals without ILD whose age and smoking history were comparable to those of the patients with ILD (Karampitsakos et al., 2017; Kato et al., 2018; Tzouvelekis et al., 2019). Pulmonary fibrosis is characterized by significant sensitivity to acute exacerbation – an event that is accompanied by a progressive worsening of dyspnoea over several days to weeks (Song et al., 2011; Collard et al., 2016; Cooper et al., 2017). In such cases, CT scans of the lung’s demonstrative of areas of ground-glass opacities, which points to acute lung injury and diffuse alveolar damage. In patients with IPF, the estimated one-year incidence of AEs is 14.2% while 3-years incidence rises to 20.7% (Song et al., 2011). Acute exacerbations in IPF are associated with significantly poor outcomes, with an estimated life expectancy of just 2.2 months (Song et al., 2011; Salonen et al., 2020).

PATHOPHYSIOLOGY

Chronic progressive interstitial lung disease results from an impaired wound-healing response in genetically susceptible patients (Pardo and Selman, 2021). Further assessment indicates that up to 5% of patients in this type of ILD may have other family members with the same condition (Hunninghake et al., 2020) Several gene variations linked to familial and sporadic IPF have been identified through genome-wide association studies. These are genes involved in the effects on host immunity, telomerase, epithelial barrier, and cell replication (Fingerlin et al., 2013; Allen et al., 2020). Symptomatic hypersensitivity pneumonitis is observed in people who have been exposed to a particular antigen and is marked by immune-mediated granulomatous inflammation (Barnes et al., 2022; Furusawa et al., 2022). In fibrotic hypersensitivity pneumonitis, the biological pathways of fibrosis seem to be similar to those found in IPF, and the concern genetic factors involved in the development of fibrotic hypersensitivity appear to be similar to those of IPF (Furusawa et al., 2022). Nevertheless, many questions have been raised about the biological mechanisms behind connective tissue diseases, like scleroderma or rheumatoid arthritis, and the reason why this group of patients experiences ILD. In the case of scleroderma and idiopathic inflammatory myopathy, the development of ILD is associated with certain autoantibodies (Kuwana et al., 2021). In rheumatoid arthritis, ILD occurs in patients with a genetic profile that appears to be associated with IPF (Juge et al., 2018).

ILD may also be exacerbated by drugs and infections (Molyneaux and Maher, 2013; Skeoch et al., 2018; Baker et al., 2023). The drugs most associated with ILD include bleomycin, amiodarone, nitrofurantoin, and immune checkpoint inhibitors, which are used in cancer immunotherapy (Delaunay et al., 2017; Okada et al., 2020). Even up to 11% of patients discharged after severe COVID-19 infection were found to have residual interstitial lung abnormalities (Batah and Fabro, 2021; Stewart et al., 2023). The mechanisms underlying post-COVID-19 ILD in these patients are still poorly characterized. Interstitial infiltrates in the periphery of the lungs infected with COVID-19 typically improve spontaneously. However, some patients with COVID-19 have developed restrictive-type pulmonary fibrosis (Roach et al., 2022). Diseases caused by other coronaviruses—MERS (Middle East Respiratory Syndrome) and SARS (severe acute respiratory syndrome)—have also been linked to the development of ILD (Ngai et al., 2010; Zhang et al., 2020).

CLINICAL PRESENTATION

Dyspnea is the primary and most apparent symptom in patients with ILD, especially during vigorous physical activity (Swigris et al., 2010; Bonini and Fiorenzano, 2017). The onset of dyspnea is often preceded by a noticeable decline in the individual’s physical capacity. Patients with chronic ILD frequently exhibit a resting dependency on oxygen. There is considerable variability and latency in the development of dyspnea among ILD patients. Those with chronic bronchiolitis or diffuse alveolar damage typically experience acute or subacute dyspnea evolution over a few days to weeks. In contrast, patients with IPF or rheumatoid ILD of ischemic origin often report symptom onset over several weeks, whereas scleroderma-associated ILD and chronic hypersensitivity pneumonitis may develop over months (Schoenfeld and Castelino, 2015).

Approximately 30% to 50% of patients with IPF are getting a cough that significantly affects their quality of life (Saunders et al., 2023). As ILD progresses, patients frequently experience fatigue and unintended weight loss. Weight loss in ILD patients is associated with a poor prognosis, with a reduction of more than 5% at any point during the disease course linked to a 2.5-fold increase in risk of mortality (Hallowell and Paik, 2021; Kreuter et al., 2023).

Most patients with ILD caused by CTD are diagnosed with the underlying CTD before developing respiratory symptoms associated with ILD. However, ILD can be the primary manifestation of systemic autoimmune disease in a small percentage of patients. This occurs most commonly in idiopathic inflammatory myopathy, where ILD precedes myopathy symptoms and signs in 7.2% to 37.5% of patients (Hallowell and Paik, 2021).

Clinicians should routinely inquire about systemic symptoms in patients with ILD (Gaubitz, 2006). A thorough history should include an evaluation of potential exposures to causative factors such as allergens linked to hypersensitivity pneumonitis, drugs known to induce ILD, or occupational exposures associated with pneumoconioses, including silicosis or asbestosis (Raghu et al., 2022).

ASSESSMENT AND DIAGNOSIS OF ILDS

At present, approximately 7% to 42% of individuals with pulmonary fibrosis exhibit digital clubbing (van Manen et al., 2017). On chest auscultation, 93% of patients with IPF and 73% with non-IPF ILD have distinct Velcro-like crepitations at the lung bases (Moran-Mendoza et al., 2021). Patients with hypersensitivity pneumonitis may also have high-pitched end-inspiratory squawks on lung auscultation. Signs of CTD, such as active arthritis, skin thickening (mechanic’s hands), and Gottron papules, may be noted during physical examination. Patients with end-stage fibrotic ILD may present with cyanosis or clinical findings of pulmonary hypertension, including a loud second pulmonary heart sound (S2), S3 or S4 gallop rhythm, elevated blood pressure and peripheral edema.

Compared with CT scans, the sensitivity of chest radiography for detecting ILD is 63%, and the specificity is 93% (Ghodrati et al., 2022). Serologic testing for autoantibodies (e.g., antinuclear antibody, extended myositis panel, antineutrophil cytoplasmic antibodies, rheumatoid factor, or anti-cyclic citrullinated peptide antibodies) and serum-specific IgG antibodies (precipitins) may suggest CTD or hypersensitivity pneumonitis as potential diagnoses. However, the sensitivity of precipitins for hypersensitivity pneumonitis is only 57% to 64% (Szturmowicz et al., 2019).

Thoracic CT is the primary diagnostic tool for identifying and diagnosing ILD, with approximately 91% sensitivity and 71% specificity for distinguishing ILD subtypes. Different ILD patterns often exhibit characteristic appearances on CT scans (Table 1), which correspond to the various histopathologic patterns associated with ILD classification (Fig. 1, Table 1). However, neither CT imaging nor histopathology alone is definitive for diagnosing specific ILDs. Histopathologic characteristics are not exclusive to any particular class of ILD diagnosis, and overlaps exist among histopathologic and radiologic findings. There are many common patterns such as usual interstitial pneumonia, nonspecific interstitial pneumonia, organizing pneumonia, and diffuse alveolar damage. Specific histopathological patterns and CT imaging for different patterns are vital to discuss for differential diagnosis among different classes of ILD.

Table 1.

Histopathological and Radiographic Patterns in Different Conditions of ILD

Condition	Histopathological Patterns		Radiographic Patterns		Seen in	Prognosis
Usual Interstitial Pneumonia (UIP)		- Interstitial patchy fibrosis. - Fibrosis with architectural distortion (scarring, short arrows). - Normal lung (arrowheads). - Extensive fibrosis around airways (long arrow) (Mukhopadhyay, 2022).		- Honeycomb change in the left upper lobe (arrow) (Mukhopadhyay, 2022).	- IPF - Rheumatoid-ILD - Asbestosis - Scleroderma-ILD - HP - Sarcoidosis	- Very poor prognosis. - The average survival time is uniformly poor (3-4 years) after the diagnosis.
Nonspecific Interstitial Pneumonia (NSIP)		- Inflammation and/or fibrosis within the alveolar wall. - Relative preservation of the lung architecture - Homogeneous distribution of change across the lung (Distler et al., 2019).		- Widespread ground-glass opacities mainly in basal and peripheral spaces (Distler et al., 2019).	- iNSIP - Scleroderma-ILD - Rheumatoid-ILD - Drug-induced ILD - Smoking-induced ILD	- Intermediate prognosis. - In untreated cases, the average survival time is about 8-10 years from diagnosis.
Organizing Pneumonia (OP)		- Patchy consolidations of alveolar ducts and ground-glass opacities in the peribronchial and subpleural areas. - Alveoli with loosely formed fibrous connective tissue (Masson bodies). - Mild associated inflammatory cell infiltrate (Maher, 2024).		- Patchy consolidation. - Cryptogenic disease is often unifocal while autoimmune disease tends to be multifocal. - Central ground glass opacity with surrounding ring of consolidation (Atoll sign) (Maher, 2024).	- COP - IIM associated ILD - Drug-induced ild - Rheumatoid-ild - Vasculitis	- Good prognosis, often responds well to immunomodulatory therapy. - Some individuals with secondary OP progress to pulmonary fibrosis.
Diffuse Alveolar Damage (DAD)		- Exudative diffuse alveolar damage with areas of congestion, haemorrhage, thick alveolar septa and loose collagen deposition (Erjefält et al., 2022)		- Widespread patchy, dependent ground glass opacities. - Interlobular septal thickening (possibly reflecting edema). - Traction bronchiecstasis and often cystic destruction of the lung (Huang et al., 2022)	- ARDS - AIP - IIM (especially MDA5+) associated ILD - Acute exacerbations of existing ILD - Post COVID-ILD	- Very poor prognosis. - The average survival time is about 2.2 months.
Hypersensitivity Pneumonitis (HP)		- Aggregation of histiocytes and giant cells with cholesterol crystals within the cytoplasm. - Poorly formed non-necrotizing airway-centred granulomata. - In fibrotic/ chronic, the fibrosis tends to be airway centred. - In some cases, fibrosis may show features consistent with UIP or NSIP (Barnes et al., 2022)		- In non-fibrotic/ acute cases, there are centrilobular nodules, patchy ground glass and mosaic attenuation. - In fibrotic/ chronic cases, there are peribroncho-vascular fibrosis in an upper or mid-zone distribution. It will be associated with mosaic attenuation and traction bronchiectasis (Cardinal-Fernández et al., 2016; Barnes et al., 2022).	- Non-fibrotic HP - Fibrotic HP	- Prognosis is good in nonfibrotic HP and it frequently resolves without significant sequelae. - In fibrotic HP, the prognosis is intermediate.
Unclassified ILD (uILD)		- The lung is showing a mixed cellular and fibrotic nonspecific interstitial pneumonia pattern. - Inflammatory cells consisted of lymphocytes, numerous plasma cells with few eosinophils are observed. - A small granuloma is present (arrow) (Leung et al., 2015; Travis et al., 2002)		- The lung architecture is distorted, ground glass, and traction bronchiectasis. - Importantly, there is no lobar predilection and absence of honeycombing (Leung et al., 2015; Skolnik and Ryerson, 2016).	In uILD, there are inconsistent, overlaping or insufficient histopathological finding with other ILDs such as IPF, NSIP & CTD-associated ILD. - Chronic Eosinophilic Pneumonia (CEP) - Acute Eosinophilic Pneumonia (AEP)	Disease progression is unpredictable, with some patients experiencing significant declines in lung function, while others remain stable.

AIP, Acute Interstitial Pneumonia; ARDS, Acute Respiratory Distress Syndrome; COP, cryptogenic organizing pneumonia; HP, Hypersensitivity Pneumonitis; IIM, Idiopathic Inflammatory Myopathy; iNSIP, Idiopathic Nonspecific Interstitial Pneumonia; IPF, Idiopathic Pulmonary Fibrosis; MDA5+, Anti-melanoma Differentiation–Associated gene 5.

Fig. 1.

Broad classification of interstitial lung disease (ILD).

Usual interstitial pneumonia (UIP) is defined by the presence of patchy interstitial fibrosis, indicating that the lung tissue displays regions of scarring and thickening (Lucà et al., 2024; Mukhopadhyay, 2022). This fibrosis exhibits varying intensity and is characteristic of the condition. Another notable characteristic of UIP is honeycombing, manifested as clusters of cystic air pockets usually found in the subpleural areas of the lungs. Honeycombing signifies advanced UIP disease and correlates with a poor prognosis. Fibrosis is generally patchy and exhibits temporal heterogeneity, a crucial trait for diagnosing IPF and differentiating it from other ILDs. UIP typically exhibits a relative deficiency of inflammatory cells. Moreover, the existence of fibroblast foci, which are specific regions of active fibrosis, constitutes another distinguishing aspect of UIP (Rabeyrin et al., 2015). These foci signify persistent fibrotic activity and are crucial for comprehending disease progression.

CT reveals UIP characterized by a reticular pattern, which manifests as a network of fine lines, and honeycombing, identified as clustered cystic air spaces, especially in the subpleural areas of the lung (Rabeyrin et al., 2015; Mukhopadhyay, 2022). The changes are more pronounced at the lung peripheries. The distribution pattern of UIP distinguishes it from other ILDs. Honeycombing is associated with advanced disease and a poor prognosis, making it a critical diagnostic marker. Ground-glass opacities often indicate inflammation or early-stage fibrosis. Unlike certain other interstitial lung diseases, UIP typically does not display significant nodular opacities on CT scans. This absence of nodularity is a key distinguishing feature when evaluating lung conditions (Wu et al., 2020). Imaging findings play a crucial role for radiologists in identifying UIP and guiding subsequent management.

Non-specific interstitial pneumonia (NSIP) is defined by a uniform pattern of interstitial inflammation and fibrosis (Myers, 2018). NSIP generally presents a more uniform appearance, lacking the temporal heterogeneity seen in UIP. The fibrosis associated with NSIP is typically less severe and correlates with a more favorable prognosis compared to UIP. The inflammatory infiltrate in NSIP is mainly lymphocytic and varies in fibrosis levels. This consistency in inflammation sets NSIP apart from other interstitial lung diseases, including UIP, which exhibits significant temporal heterogeneity. The fibrosis in NSIP generally presents as a patchy distribution, rather than the dense and irregular fibrosis observed in UIP. This less severe fibrotic change contributes to the better prognosis of NSIP. A key histological feature of NSIP is the absence of honeycombing, a hallmark of UIP indicative of advanced disease (Lucà et al., 2024). The lack of honeycombing in NSIP suggests a more favorable disease course and a better response to treatment. NSIP may also demonstrate thickening of the alveolar septa due to the inflammatory process, contributing to the ground-glass opacities often observed in imaging studies. Unlike UIP, NSIP typically has minimal or no fibroblast foci, which are clusters of activated fibroblasts indicating ongoing fibrosis. This absence underscores NSIP’s distinct pathological process and further differentiates it from UIP.

High-resolution computed tomography (HRCT) of NSIP characteristically reveals ground-glass opacities and reticular patterns, while honeycombing is typically absent. A key finding in NSIP is the presence of ground-glass opacities. The observed areas of increased attenuation in the lung parenchyma indicate inflammation or the initial phases of fibrosis. Ground-glass opacities frequently exhibit a patchy distribution within the lungs, commonly associated with reticular patterns. Reticular patterns, characterized by fine linear opacities, suggest interstitial thickening and are commonly observed alongside ground-glass opacities. NSIP often demonstrates a lower lobe predominance, meaning the lower lobes of the lungs are more frequently affected than the upper lobes. Additionally, the ground-glass opacities and reticular patterns in NSIP often show a subpleural distribution, with changes more pronounced near the pleural surfaces of the lungs (Johkoh, 2014). This subpleural predominance further aids in distinguishing NSIP from other interstitial lung diseases that may exhibit different distribution patterns. The lack of honeycombing serves as a distinguishing characteristic that differentiates NSIP from UIP, in which honeycombing indicates advanced fibrosis and a more severe stage of lung disease (Salvatore and Smith, 2018).

OP is marked by the presence of loose organizing fibrous tissue within the alveolar spaces (Lucà et al., 2024). This tissue is composed of fibroblasts, myofibroblasts, and inflammatory cells, which collectively contribute to the organization process. The granulation tissue typically fills the alveolar ducts and alveoli, leading to obstruction of these airspaces. The histological changes in organizing pneumonia are often patchy, meaning that the fibrous connective tissue (Masson bodies) may not be uniformly distributed throughout the lung (Zare Mehrjardi et al., 2017; Arenas-Jiménez et al., 2022). This patchy nature can complicate the diagnosis, as it may resemble other ILDs, if not carefully evaluated. In addition to granulation tissue, there is often a mixed inflammatory cell infiltrate, which may include lymphocytes, plasma cells, and eosinophils. This inflammatory response is part of the body’s attempt to heal the lung tissue. Organizing pneumonia typically does not show significant fibrosis in the early stages. Instead, the focus is on the organization of the airspaces rather than the development of fibrotic changes.

The CT of OP characteristically presents bilateral patchy ground-glass opacities and consolidations. These findings can be diffuse or localized and may mimic other interstitial lung diseases, making accurate diagnosis challenging. The opacities can be bilateral and often have a peripheral distribution, which is a distinguishing feature of OP. In some cases, there may be associated bronchial wall thickening or bronchiectasis (Zare Mehrjardi et al., 2017). This can help differentiate organizing pneumonia from other types of lung diseases that may present similarly. Unlike some other interstitial lung diseases, organizing pneumonia typically does not present with significant nodular opacities. This absence can be a helpful diagnostic clue when interpreting CT images (Zhao et al., 2014). A notable aspect of organizing pneumonia is its favourable response to corticosteroid therapy. If a patient shows significant improvement in symptoms and imaging findings after starting corticosteroids, it supports the diagnosis of organizing pneumonia. It is essential to consider other conditions that may mimic organizing pneumonia on CT, such as infections, other forms of interstitial lung disease, or malignancies. A thorough clinical correlation and sometimes a lung biopsy may be necessary for a definitive diagnosis.

Diffuse alveolar damage (DAD) is characterized by the following histological features as an indication of its pathophysiological mechanisms. Alveolar areas are generally covered by hyaline membranes, which are typical for DAD (Thompson and Matthay, 2013). The fluid in the lungs is rich in proteins, fibrin, and cellular debris that settle down due to damage to the alveolar epithelium. Massive damage to alveolar epithelium often leads to necrosis of epithelial cells with disruption of the normal architecture of the alveolus and impaired gas exchange. Histologically, most cases exhibit a polymorphic inflammatory infiltrate comprising neutrophils, lymphocytes, and macrophages, which suggests that the inflammation is the reaction to tissue injury in the lungs (Cardinal-Fernández et al., 2016). In the later stages of DAD, fibrosis develops, which includes the deposit of collagen and other components of the extracellular matrix, leading to scarring and further decline in lung function. DAD commonly progresses through an exudative phase characterized by flooding of the alveolus with fluid and inflammatory cells, then progresses into a proliferative phase where the repair mechanism, such as granulation tissue formation, starts (Batah and Fabro, 2021).

The most prevalent observation in DAD is the existence of bilateral ground-glass opacities. The opacities signify regions of heightened attenuation in the lungs resulting from fluid collection and inflammation within the alveolar spaces. The regions of consolidation may be discerned. This consolidation indicates the accumulation of fluid, inflammatory cells, and debris within the alveoli, typical of the exudative phase of DAD (Huang et al., 2022). As the illness advances, reticular patterns may emerge, signifying the existence of interstitial fibrosis. This can be interpreted as a network of linear opacities on the CT scans. The opacities in DAD typically exhibit a subpleural distribution, indicating they are more prominent at the lung peripheries, which aids in distinguishing DAD from other pulmonary disorders. Air bronchograms may be discernible in regions of consolidation. This transpires when air-filled bronchi are encircled by fluid-filled alveoli, creating a unique imaging characteristic. In contrast to several other pulmonary disorders, DAD generally does not exhibit substantial nodular opacities.

Nonfibrotic HP is characterized by bronchiolocentric chronic inflammation, typically with lymphocytes and occasional plasma cells. The pathology may include poorly defined granulomas or giant cells. Schaumann bodies, indicative of granuloma resolution, are frequently observed (Barnes et al., 2022). While granulomas are helpful markers of ongoing antigen exposure, their absence does not rule out HP. Occasionally, the pattern mimics NSIP. In fibrotic HP, the pathologically is diverse. The fibrotic HP features various forms of interstitial fibrosis, often bronchiolocentric or resembling NSIP or UIP. Granulomas or Schaumann bodies, though present in a minority of cases, aid in diagnosis. Peribronchiolar metaplasia, when affecting over 50% of bronchioles, strongly suggests fibrotic HP. Distinguishing fibrotic HP from UIP/IPF is critical due to differing treatments, but this differentiation can be complex due to overlapping histopathological features.

Radiologically, nonfibrotic HP typically exhibits ground-glass opacities, centrilobular nodules, and air-trapping. Fibrotic HP, on the other hand, shows reticulation, traction bronchiectasis, honeycombing, and bronchiolar obstruction, often presenting a “headcheese” or “triple density” pattern (Salisbury et al., 2019). These radiologic distinctions help differentiate fibrotic HP from UIP/IPF, which tends to show uniform lower-lobe involvement (Barnes et al., 2022; Maher, 2024).

The standard diagnostic method for ILD is a multimodal assessment consisting of pulmonologists, radiologists, and, when necessary, pathologists and rheumatologists. This collaborative strategy (Fig. 2) emphasizes the need to balance clinical data (Maher, 2024).

Fig. 2.

Schematic Diagram for Diagnosis of ILDs.

LUNG BIOPSY AND CRYOBIOPSY IN ILDS

While lung biopsy was previously considered critical for accurate ILD diagnosis, however, advancements in CT imaging have largely replaced it (Raghu et al., 2022). Lung biopsy, especially surgical lung biopsy, is associated with a mortality rate of 1% to 2% (Hutchinson et al., 2016). Currently, fewer than 10% of patients with ILD undergo lung biopsy (Cottin, 2016). In many centres, bronchoscopic transbronchial cryobiopsy, an endoscopic technique that involves rapid freezing of lung tissue before biopsy, has replaced video-assisted thoracic surgery (VATS) for obtaining lung tissue samples. Cryobiopsy is a minimally invasive procedure with a lower complication rate compared to VATS and has a comparable level of diagnostic accuracy (Troy et al., 2020).

In a systematic review of published studies, cryobiopsy was associated with adverse outcomes such as bleeding in 30% of patients and pneumothorax in 8% of patients. Serious complications, including mortality, were rare (Kheir et al., 2022). In 69 patients with ILD, multidisciplinary team evaluation based on cryobiopsy provided a diagnosis with high confidence in 60% of cases, compared with 73% for surgical VATS biopsy (Troy et al., 2020)

Even after a comprehensive clinical evaluation, including lung biopsy, as many as 15% of patients are diagnosed with unclassifiable ILD (Ryerson et al., 2013). The most common reasons for an unclassifiable diagnosis are clinical features that are not specific to a single diagnosis or inconsistent results from other diagnostic tests (Travis et al., 2002; Leung et al., 2015; O’Callaghan et al., 2021). In some patients with unclassifiable ILD, the diagnosis becomes clearer when new clinical signs and symptoms emerge over time (Travis et al., 2002).

When ILD is suspected or diagnosed, pulmonary function testing (including forced vital capacity [FVC] and DLCO) should be performed to assess disease severity. Patients with ILD typically present with a restrictive pattern on spirometry. At baseline, the degree of FVC and DLCO impairment is associated with both short-term and medium-term prognoses (Maher et al., 2023a). A 5% or greater loss of FVC over 3, 6, or 12 months is linked to a poorer prognosis compared with an FVC loss of less than 5% in patients with IPF, systemic sclerosis-related ILD, and other fibrotic ILDs (Zappala et al., 2010; Russell et al., 2016; Goh et al., 2017; Maher et al., 2023b).

PHARMACOLOGIC AND NON-PHARMACOLOGIC MANAGEMENT OF ILD

ILD is a potentially life-threatening condition when it is associated with autoimmune disorders such as systemic sclerosis or rheumatoid arthritis, and with connective tissue disorders such as mixed connective tissue disease. There were no effective treatments for ILD in the past. The treatment of ILD has evolved significantly over the past decade, with the discovery and US Food and Drug Administration (FDA) approval of anti-fibrotic drugs for IPF and other types of PPF, targeted therapies for scleroderma-related ILD, and treatments for ILD-associated pulmonary hypertension. While, multidisciplinary team-based management, lung transplantation, and immunosuppressant drugs such as corticosteroids or disease-modifying anti-rheumatic drugs have been the other treatments for patients with ILD (Fig. 3, 4).

Fig. 3.

Pathophysiology and molecular mechanisms of ILDs. IL - Interleukin (e.g., IL-1, IL-2, IL-6, IL-13); IFN-γ - Interferon gamma; ECM - Extracellular matrix; NrF1 - Nuclear respiratory factor 1; GSH - Glutathione; SOD - Superoxide dismutase; IκB - Inhibitor of kappa B; iNOS - Inducible nitric oxide synthase; CAT - Catalase; NF-κB - Nuclear factor kappa-light-chain-enhancer of activated B cells.

Fig. 4.

Approved Drugs to Treat ILDs. b.i.d - 2 times a day; IV - Intravenous; IPF - Idiopathic Pulmonary Fibrosis; PPF - Progressive Pulmonary Fibrosis; SC - Subcutaneous; t.i.d - 3 times a day.

ILD can be classified in terms of different histopathological patterns, acute exacerbations and the presence or absence of systemic diseases such as autoimmune diseases and there is no general agreement on the use of these treatments for all ILDs. The evidence base of these treatments remains inadequate (Althobiani et al., 2024). Systemic interventions for the treatment of SSc-ILD, such as cyclophosphamide or rituximab, may slow the progression of ILD, but the resolution of the fibrotic process has never been observed. One research study elicited that a high dose of cyclophosphamide via IV followed by a long course of azathioprine and low oral doses of prednisone for the treatment of early SSc-ILD (Liakouli et al., 2024). It could stabilize lung function and make patients comfortable. However, many patients are unable to tolerate the long-term use of these drugs. Furthermore, stem cell transplantation has been reported in several studies to be a potential treatment for ILD, however, it can be life-threatening. Additionally, there is no effective treatment for non-SSc-ILD (Althobiani et al., 2024).

In IPF, antifibrotic agents have been shown to reduce the functional decline associated with the disease. Pirfenidone, a small-molecule pyridine derivative, is an orally administered agent with anti-inflammatory, antioxidant and anti-fibrotic properties (Maher, 2010).

A clinical trial of pirfenidone in rheumatoid arthritis ILD was stopped early due to slow recruitment after enrolling 123 patients (Solomon et al., 2023). In the pirfenidone group, 7 of 63 patients (11%) met the composite primary endpoint of more than a 10% FVC decline or death at 52 weeks compared with 9 of 60 patients (15%) in the placebo group. The rate of FVC decline in the pirfenidone group was 66 mL compared with 146 mL in the placebo group (p=0.01). In the ASCEND clinical trial of 555 patients with IPF randomized to pirfenidone or placebo, pirfenidone reduced FVC decline at the 52-week follow-up (King et al., 2014). The most common adverse effects associated with pirfenidone compared with placebo were photodermatosis (29.2% vs. 9.0%), nausea (35.5% vs. 15.1%), and anorexia (12.4% vs. 4.3%) (Noble et al., 2015). In a pooled analysis that included 1,247 patients, 22 patients (3.5%) receiving pirfenidone had died by week 72 compared with 42 patients (6.7%) receiving placebo (Behr et al., 2021a). In the RELIEF clinical trial, 127 patients with progressive pulmonary fibrosis were treated with pirfenidone. It was observed that pirfenidone slowed FVC decline compared with placebo by 3.53% (Behr et al., 2021b). In a clinical trial of 253 patients with unclassifiable ILD randomized to pirfenidone or placebo for six months, pirfenidone reduced FVC decline compared with placebo (Maher et al., 2020; O’Callaghan et al., 2021).

Another oral agent, nintedanib, is an oral tyrosine kinase inhibitor and is approved worldwide for the treatment of IPF (Richeldi et al., 2014). In a prespecified analysis of combined data from two parallel randomized clinical trials (RCTs), INPULSIS-1 and INPULSIS-2, 1,066 patients were randomized to receive nintedanib or placebo. At the 52-week follow-up, FVC decline was significantly lower in the nintedanib group. In INPULSIS-1, diarrhea occurred in 61.5% of patients randomized to nintedanib and 18.6% of patients randomized to placebo. Corresponding rates of diarrhea in INPULSIS-2 were 63.2% in the nintedanib group and 18.3% in the placebo group. In the SENSCIS RCT, which included 579 patients with systemic sclerosis-related ILD (48.5% of whom were receiving mycophenolate mofetil), nintedanib reduced FVC decline compared with placebo (Distler et al., 2019). In a post hoc analysis, patients who showed the greatest reduction in annual FVC decline were those receiving a combination of nintedanib and mycophenolate mofetil (Highland et al., 2021).

In the INBUILD RCT of 663 patients with progressive pulmonary fibrosis (PPF) due to causes other than IPF, nintedanib significantly reduced FVC decline compared with placebo. A prespecified subgroup analysis demonstrated a consistent effect of nintedanib in patients with PPF, regardless of specific ILD diagnosis (Wells et al., 2020). In a pooled analysis of patients from RCTs of nintedanib, a Weibull distribution analysis estimated a life expectancy of 11.6 years for patients treated with nintedanib compared with 3.7 years for those on placebo (Lancaster et al., 2019).

ILDs are potentially life-threatening conditions that are often associated with autoimmune disorders such as systemic sclerosis or rheumatoid arthritis, and with connective tissue disorders such as mixed connective tissue disease (Gaubitz, 2006; Perelas et al., 2020; Baker et al., 2023). Currently, mortality associated with ILD has been increasing over the last three decades. Multidisciplinary team-based management, lung transplantation, and immunosuppressant drugs such as corticosteroids or disease-modifying anti-rheumatic drugs have been the major treatments for patients with ILD (Lucà et al., 2024). Although many of these treatments may help patients in some way, none can completely cure ILD. Tocilizumab is an anti-interleukin-6 receptor monoclonal antibody that binds to the IL-6 receptor with high affinity. In phase-2 and phase-3 RCT studies, tocilizumab was used to cure systemic sclerosis and acute inflammation (which was described as arthritis, raised platelets or raised C-reactive protein) (Khanna et al., 2016, 2020). The results revealed that tocilizumab did not provide a significant difference in the improvement of the primary endpoint of the 48-week change in the modified Rodnan Skin Score (Khanna et al., 2020). However, in both of these studies, the secondary endpoint of 48-week changes in FVC revealed the significance of tocilizumab treatment which led the FDA to approve this drug as a remedy for scleroderma-ILD in the USA. In the FaSScinate trial of 87 patients, tocilizumab decreased the FVC when compared with placebo at 48-week follow-up. In the FocuSSced trial of 210 patients, tocilizumab decreased percentage of anticipated FVC decline at a 48-week follow-up (Khanna et al., 2020).

The scleroderma lung examines one randomized patient with systemic sclerosis-related ILD to both oral cyclophosphamide or placebo (Tashkin et al., 2006). At 12 months, cyclophosphamide notably improved % anticipated FVC in comparison with placebo (distinction: 2.53%; 95% CI, 0.28%-5.79%). The scleroderma lung examines 2 RCT in comparison oral mycophenolate mofetil 1.5 g twice daily to oral cyclophosphamide in patients with systemic sclerosis-related ILD and determined no distinction in % anticipated FVC among groups; the 24-month baseline-adjusted % anticipated FVC progressed by 2.19% withinside the oral mycophenolate mofetil organization in comparison with 2.88% withinside the cyclophosphamide organization (a distinction among groups of 0.7; 95% CI, −31 to 1.7) (Tashkin et al., 2016). Fewer patients inside the oral mycophenolate mofetil organization discontinued remedy at 12 months (29. 0 vs 43.8%). In the DESIRES multicenter RCT, fifty-six patients in Japan with scleroderma and a changed Rodnan Skin Score extra than 10 have been randomized to rituximab (375 mg/m2) or placebo for 24 weeks (Ebata et al., 2021). At the 24-week follow-up, rituximab notably decreased the changed Rodnan Skin Score (number one outcome) in comparison with placebo by 6.3 in comparison with 2.14, a distinction of −8.44 (95% CI, −11.0 to −5.88). Among individuals with an FVC much less than 80% at baseline, rituximab progressed % anticipated FVC at 24 weeks in comparison with placebo (0.09% vs −2.87%; a distinction of 2.96%; 95%, 0.08-5.84).

In contrast, the PANTHER clinical trial randomized patients to receive the antioxidant N-acetyl cysteine alone, a combination of N-acetyl cysteine, prednisone, and azathioprine, or placebo (Raghu et al., 2012). The study initially planned to recruit 390 patients but was stopped after approximately 50% of data were collected due to an excess of adverse events associated with the combination therapy. Mortality was 10.4% in the combination therapy group (n=77) compared with 1.3% in the placebo group (n=78). There were 23 hospitalizations in the combination therapy group compared with 7 in the placebo group (Raghu et al., 2012). These results highlight the potential risks of immunosuppressive therapy for individuals with fibrotic lung disease. Other drugs tested in RCTs for patients with IPF that failed to show improved outcomes compared with placebo include warfarin, imatinib, γ-interferon, anti-IL13 antibodies, endothelin antagonists, prophylactic antibiotics, and autotaxin inhibitors (Daniels et al., 2010; Noth et al., 2012; Wilson et al., 2020; Maher et al., 2021a; Martinez et al., 2021; Maher et al., 2023b; Raghu et al., 2024)

Few clinical trials have been conducted for patients with ILD due to conditions other than IPF and systemic sclerosis-related ILD. In the RECITAL randomized, double-blind, double-dummy clinical trial, rituximab was compared with cyclophosphamide in 101 patients with ILD caused by systemic sclerosis, mixed connective tissue disease, or idiopathic inflammatory myositis (Maher et al., 2023c). Rituximab was not significantly better than cyclophosphamide for the primary outcome of change in FVC at 24 weeks. However, both drugs increased FVC (cyclophosphamide by a mean [SD] of 99 [329] mL and rituximab by a mean [SD] of 97 [234] mL) and improved quality of life, as assessed by the King’s Brief ILD Questionnaire (K-BILD) at 24 and 48 weeks (Raghu et al., 2020).

Corticosteroids are the first line of treatment for most of the ILDs, especially in that inflammation can be decreased significantly to alleviate the symptoms (Jang et al., 2021). However, for ILD associated with autoimmune diseases, an adequate response cannot always be achieved through corticosteroid therapy alone. These drugs act on the immune response, dampening lung inflammation (Homma et al., 2018). Although corticosteroids and immunosuppressive therapies such as azathioprine and mycophenolate mofetil are frequently prescribed to treat hypersensitivity pneumonitis and rheumatoid arthritis ILD, none have been evaluated in RCTs for these conditions. While evidence-based pharmacotherapies are lacking for hypersensitivity pneumonitis, avoiding an identified inciting cause (such as exposure to birds or molds) may improve the condition. For rheumatoid arthritis ILD, observational data suggest that rituximab, abatacept, and tofacitinib are associated with better pulmonary outcomes, including a lower incidence of ILD and fewer respiratory hospitalizations (Huang et al., 2020; Baker et al., 2023; Pugashetti and Lee, 2024).

Lung transplant is the final therapeutic option for patients with end-stage lung diseases including ILD (Hartert et al., 2014). However, this process is limited due to lung availability. Furthermore, older age and other health-related issues such as cardiovascular disease, diabetes and right-sided heart failure are some of the other factors that often limit the transplant eligibility for patients with ILD. Moreover, recurrent fibrosis has been pointed out, and its management is a critical issue. However, in the United States, the percentage of ILD-associated lung transplants has elevated during the last decade. According to reports, ILD-associated lung transplants accounted for 60 % of all lung transplants in 2018 as compared with 20.4% in 2006 (Bos et al., 2020; Valapour et al., 2020). According to the published data of the International Society for Heart and Lung Transplantation, published in 2019, life expectancy following lung transplant for idiopathic interstitial pneumonias (including IPF) was 5.2 years as compared with 6.7 years for all different ILDs (Chambers et al., 2019). The life expectancy was 6.2 years for all lung transplant recipients (Bos et al., 2020).

It is important to maintain the best lung function after lung transplantation. Postoperative acute rejection is a significant risk factor for the onset of fibrosis; hence, early detection of rejection and proper immunosuppression control are mandatory (Parulekar and Kao, 2019). Recently, a cocktail therapy of anti-tumor growth factor beta antibodies and hypoxia-inducible factor-2 alpha inhibitors has been reported to suppress the onset of fibrosis in a mouse lung transplantation model using bleomycin-induced fibrotic lungs, which may open a way for suppressing recurrent fibrosis in clinical lung transplantation (Dorababu and Maraswami, 2023; Zheng et al., 2024).

Few treatments improve the outcome in patients with ILD and pulmonary hypertension (Zisman et al., 2010; Corte et al., 2014; Behr et al., 2019; Nathan et al., 2019; Behr et al., 2021a). Treprostinil (a prostacyclin analog) is approved for pulmonary hypertension. It promotes vasodilation, inhibits platelet aggregation, and improves exercise capacity and quality of life (Kuwana et al., 2023). In the INCREASE RCT involving 326 patients with ILD and pulmonary hypertension, the inhaled Treprostinil improved the 6-minute walk test distance when compared with placebo. The common adverse symptoms were transient cough (43.6%), headache (27.6%), throat irritation (12.3%) and oropharyngeal pain (11.0%) (Waxman et al., 2021).

Pulmonary rehabilitation (PR) is a strategic program to educate and train patients to enhance their workout capability and reduce signs of chronic lung disease. It is for 8-12 weeks. The current evidence-based guidelines for PR mainly emphasize its critical role in improving symptoms, exercise capacity and quality of life. PR is recognized as a vital component of comprehensive care for ILD, particularly for fibrotic interstitial lung disease and IPF patients, despite being underutilized (Zamparelli et al., 2024). According to a 2021 Cochrane meta-analysis, PR has improved in a 6-minute walk test distance in symptomatic breathlessness patients, in comparison with control (Dowman et al., 2021). PR is also associated with improved dyspnea symptoms and an enhanced quality of life.

Patients with chronic lung disease should be vaccinated for pneumococcus, COVID-19, respiration syncytial virus and influenza virus (Maher, 2024). However, no RCTs have been evaluated to date to confirm the protective effects of these vaccines against acute exacerbations or mortality in such patients (Garibaldi and Danoff, 2016; Lindell, 2018). Patients with smoking cigarettes should be guided to quit smoking. Ambulatory and continuous oxygen treatments are vital for patients with advanced ILD. In 84 patients with fibrotic ILD, it was proved that oxygen therapy was associated with clinically significant improvements in quality of life as measured by the K-BILD score (Visca et al., 2018). The impact of oxygen treatment on the improvement of pulmonary hypertension or mortality has not been assessed in RCTs. However, 24-hour oxygen therapy is necessary for those ILD patients who have resting oxygen saturations below 90%.

Cough and dyspnea are frequently found in fibrotic ILD patients, and both can significantly impair quality of life (Garibaldi and Danoff, 2016; Lindell, 2018). However, RCTs have demonstrated that pirfenidone and nintedanib are not effective against cough or breathlessness. Short-acting opiates can be useful in breathlessness cases in end-stage lung disease patients (Morice et al., 2007). In the crossover trial of IPF, it was observed that nalbuphine can decrease the objective cough frequency in comparison with placebo in 41 patients (Maher et al., 2023d). Morphine decreased wakeful cough frequency (39.4%) in comparison with placebo in a 2-week crossover study (Wu et al., 2024). Constipation (21%) was reported as a side effect of this therapy (Morice et al., 2007; Wu et al., 2024). Benzodiazepines can be useful in acute dyspnea and panic episodes in the last stage patients, however, RCT proofs are not very clear regarding the advantages of this class of drugs (Luckett et al., 2017). A qualitative trial regarding handheld fans demonstrated that these gadgets might offer relief from dyspnea.

For patients with ILD and respiration failure, end-of-life care and access to palliative care services are critical (Gersten et al., 2022; Palmer et al., 2023). Advanced directives provide patients with control over their treatments and outcomes as their disease advances. Intubation and mechanical ventilation must be denied to patients who have reached their terminal stage of disease, and a lung transplant would not be possible. It can produce an adverse effect in these patients.

Several clinical treatment guidelines for patients with idiopathic interstitial pneumonias (IIPs) have been released in the USA, Europe, Japan and India (Montesi, 2020; Okuda et al., 2023). These guidelines cover various aspects of the disease, such as the definition, diagnostic criteria, treatment strategies, and management of complications. Patients with advanced IIPs should be managed by an interstitial pneumonia specialist in a multidisciplinary institution. Guidelines have focused on pharmacologic treatment and anti-fibrotic therapy. Moreover, the latest guidelines for the management of IPF and IIPs have been developed by international experts and organizations in collaboration with patient groups. In addition, various expert and organizational statements on IPF and non-IPF IIPs have been issued. These statements discuss the latest topics in the field of interstitial pneumonia, such as the use of HRCT, future directions in the diagnosis and use of inflammation in the management of IPF, and various therapeutic approaches and considerations for the early-phase diagnosis of various IIPs from the perspective of expert pulmonologists. The information from these guidelines and expert statements for IIPs will provide a comprehensive view of the principles of anti-fibrotic therapy in the clinical setting beyond the patients’ clinical status. The ILD patients should be referred to ILD-dedicated centers that can carry out their diagnosis and manage the complications. Nintedanib and /or pirfenidone are the drug of choice for IPF as suggested by different guidelines such as the American Thoracic Society, European Respiratory Society, Japanese Respiratory Society and Asociacion Latinoamericana de Torax (Kaul et al., 2022). These guidelines are strongly in opposition to the use of azathioprine and increased doses of corticosteroids in IPF patients (Raghu et al., 2022). It strongly suggests the use of nintedanib and conditionally recommends the use of pirfenidone in PPF patients. Mycophenolate mofetil is strongly recommended by American Thoracic Society guidelines for patients of scleroderma and ILD. Tocilizumab, nintedanib, cyclophosphamide, rituximab, and the mixture of mycophenolate and nintedanib are related to conditional positive recommendations (Raghu et al., 2024). The European Society of Cardiology and the European Respiratory Society suggested inhaling treprostinil for patients with pulmonary hypertension (PH) associated with ILD (Weatherald et al., 2024). For patients with IP, the International Society for Heart and Lung Transplantation suggested lung transplant consideration at diagnosis (Leard et al., 2021). For patients with other types of ILD should be assessed for a lung transplant when FVC is less than 80% expected or DLCO is than 40% predicted or if there is proof of PPF within the previous 2 years.

PROGNOSIS

The prognosis of IPF is very poor and life expectancy for patients with IPF is only 3-3.5 years. The FDA performed an analysis of RCTs for pirfenidone and nintedanib and it found that a decline in FVC was related to higher chances of mortality (Paterniti et al., 2017). The data from different clinical trials revealed that 355 (31.4%) patients had an absolute FVC decline of between 5-10% with 24 (6.8%) patients found dead. Additionally, 157 (13.9%) patients had an FVC decline of more than 15% resulting in 26 deaths (16.6%). Compared with patients with less than 5% FVC decline, the risk ratio for death became 1.34 (95% CI, 0.75-2.4) for an FVC change of 5-10%, 2.20 (95% CI, 1.1-4.37) for an FVC decline of 10-15%, and 6.09 (95% CI, 31.4-11.80) for an FVC decline of more than 15%. Slowing FVC decline with pirfenidone or nintedanib resulted in an average number of years of about 1-2.5 years (Cooper et al., 2017). The results of other drugs on the survival of patients are still uncertain. The prognosis and treatment of mixed connective tissue-ILD vary according to histopathological and /or radiological observations (Hutchinson et al., 2015). It also depends on the underlying connective tissue disease.

EMERGING DRUGS AND THEIR TARGETS FOR ILD

The treatment landscape for ILDs is evolving, with several promising new therapies and experimental options on the horizon (Table 2). BI 1015550 (NCT05321069) functions as a selective inhibitor of phosphodiesterase-4B (PDE4B), an enzyme that significantly modulates inflammatory and fibrotic pathways. Through the inhibition of PDE4B, BI 1015550 effectively mitigates TGF-β1-induced fibroblast transformation and extracellular matrix (ECM) deposition. Currently Phase III trial (FIBRONEER) is on the way. Sufenidone (NCT06125327), deupirfenidone (NCT05321420) and yifenidone (NCT05060822) are the pirfenidone analogs that have been chemically modified to improve pharmacokinetics and reduce side effects. They share pirfenidone’s antifibrotic activity, particularly in suppressing TGF-β1 signalling. Sufenidone is in Phase II/III, while deupirfenidone and yifenidone are in Phase II. Bexotegrast (PLN-74809) inhibits αvβ6 and αvβ1 integrins, which activate TGF-β in the ECM. It is being evaluated in a Phase II trial (NCT06097260) for efficacy and safety in IPF. Amphiregulin (AREG-NCT05984992), a small interfering RNA (siRNA), is a TGF-β downstream effector that promotes fibroblast proliferation and ECM synthesis. It is in the early clinical evaluation, the Phase I stage. Similarly, artesunate (NCT05988463), an artemisinin derivative sourced from natural origins, is evidence of TGF-β1 downregulation and antifibrotic characteristics in preclinical studies. Anlotinib (NCT05828953) inhibits various tyrosine kinases, including vascular endothelial growth factor receptor, fibroblast growth factor receptor, and platelet-derived growth factor receptor. Preclinical investigations reveal that it suppresses epithelial-mesenchymal transition and glycolysis in fibroblasts. A Phase II/III trial is currently assessing the efficacy of this agent in patients with IPF and pulmonary fibrosis associated with interstitial lung diseases. The signalling pathways of lysophosphatidic acid (LPA) are significantly implicated in the promotion of fibroblast activation and ECM production. BMS-986278 (NCT06003426), a selective antagonist of the LPA1 receptor, disrupts this signalling pathway. A Phase II trial is ongoing to substantiate its antifibrotic efficacy. XFB-19 (NCT05361733) inhibits C/EBPβ acetylation, reducing myofibroblast transformation and collagen production.

Table 2.

Pharmacologic Agents in Clinical Trials for ILD – Target, Mechanism of Action and Trial Status

Agent	Indication/ Trial Status	Type/ Target/ Mechanism of Action	ClinicalTrial.gov Identifier
Azathioprine	Used selectively in autoimmune ILD, RA-ILD	Purine analog → Immunosuppressant → inhibits DNA synthesis, affecting immune cells	NCT03770663
Tofacitinib	Phase IV Ongoing - targeted for SSc-ILD	JAK inhibitor → reduces fibrogenesis	NCT04311567
Pamrevlumab	Phase III Ongoing (ZEPHYRUS trials), targeted for IPF	Anti-CTGF monoclonal antibody → Inhibits CTGF → reduces fibrogenesis	NCT03955146 & NCT04419558
BI 1015550	Phase III Ongoing, targeted for IPF	Fibroblasts → PDE-4B inhibitor → antifibrotics	NCT05321069
TD139	Phase II (Inhaled) Ongoing, targeted for IPF	Galectin-3 inhibitor → Modulates fibrotic response	NCT04419506
Danazol	Phase II Ongoing (TELO-SCOPE), targeted for IPF	Synthetic androgen → For telomere-associated fibrosis	NCT04638517
BMS-986278	Phase III Ongoing, targeted for IPF	LPAR1 inhibitor → Blocks LPA signalling pathway on fibroblasts	NCT06003426
Saracatinib	Phase Ib/IIa Ongoing, targeted for IPF	Src kinase inhibitor → reduces fibrogenesis	NCT04598919
Dasatinib + Quercetin	Phase I Ongoing, targeted for IPF	Senolytics → Targets senescent cells	NCT02874989
tRNA synthetase inhibitor	Phase I Ongoing, targeted for IPF	Autoimmune modulation	NCT04262167 & NCT02745184
TRK-250	Phase I Ongoing, targeted for IPF	TGF-β1 suppression (inhaled) → Fibrosis suppression	NCT03727802
Anlotinib	Phase II/III Ongoing, targeted for IPF	EMT/Fibroblasts → Inhibiting kinases → blocks fibrogenesis	NCT05828953
Treprostinil	Phase III Ongoing, targeted for IPF	Vasodilation and antifibrotic → Prostacyclin receptor agonist	NCT04708782, NCT05255991
LTI-03	Phase I Ongoing, targeted for IPF	MAPK/ERK/Fibroblasts → ECM suppression	NCT05954988
HZN-825	Phase II Ongoing, targeted for IPF	Anti-inflammatory → Fibroblasts → LPAR1 antagonist	NCT05032066
XFB-19	Phase I Ongoing, targeted for IPF	Myofibroblast modulation → Myofibroblasts → Inhibiting C/EBPβ	NCT05361733
ARO-MMP7	Phase I/IIa Ongoing, targeted for IPF	ECM production	NCT05537025
Venetoclax	Phase I Ongoing, targeted for IPF	Apoptosis regulator → Macrophages → Inhibiting Bcl-2	NCT05976217
Vixarelimab	Phase II, targeted for IPF	Antiinflamatory → IL-31/OSM → Anti-OSMR mAb	NCT05785624
Axatilimab	Phase II, targeted for IPF	Macrophages → Anti-CSF-1R mAb	NCT06132256
Atezolizumab	Phase I Ongoing, targeted for IPF	Smad3/β-catenin → Anti-PD-L1 mAb	NCT05515627
Umbilical cord derived MSCs	Phase I Ongoing, targeted for IPF	Cell therapy → Immunomodulation, anti-fibrosis, and tissue regeneration	NCT05016817
Lung Spheroid Stem Cells	Phase I, targeted for IPF	Regenerative Med → Immunomodulation, anti-fibrosis, and tissue regeneration	NCT04262167
Placental MSCs	Phase I, targeted for IPF	Stem Cell Approach → Immunomodulation, anti-fibrosis, and tissue regeneration	NCT01385644
Saracatinib	Phase Ib/IIa,targeted for IPF	Myofibroblast → Inhibiting Src kinase → Anti-fibrotic	NCT04598919
TTI-101	Phase II, targeted for IPF	JAK/STAT pathway → Inhibiting STAT3	NCT05671835
Jaktinib Hydrochloride	Phase II, targeted for IPF	JAK/STAT pathway → inhibiting JAK1/2	NCT04312594

In RNA therapeutics, ARO-MMP7 (NCT05537025) inhibits Matrix Metalloproteinase 7 (MMP7) using RNA interference to lower ECM remodeling and inflammation. SRN-001 (NCT05984992), another RNAi drug, silences amphiregulin, one of the TGF-β-inducible growth factors involved in the fibroblast-to-myofibroblast transition. Macrophage-directed therapies are also promising. Venetoclax (NCT05976217), a Bcl-2 inhibitor, can reverse macrophage apoptosis, thus breaking chronic inflammation that drives fibrosis. HuL001 (NCT04540770) is an enolase-1 monoclonal antibody, a metabolic enzyme that plays a role in ECM regulation and immune activation. These investigational drugs are at multiple stages of clinical testing, ranging from initial Phase I to advanced Phase III trials. Their mechanisms reflect an emerging enthusiasm for multi-targeted, personalized approaches to stop or reverse fibrosis. If successful, they promise greatly to improve upon the present state of therapy, based as it is largely upon pirfenidone and nintedanib.

CONCLUSIONS

ILD represents a complex, multifaceted category of disorders that require multidisciplinary strategies in diagnosis and treatment, based on the disease conditions. This review highlights the need to incorporate precision pharmacotherapy, functional assessment tools, and multidisciplinary support for improving the outcomes in ILD patients. The review has been updated with novel clinical scenarios, such as post-COVID-19 and drug-induced ILD. Furthermore, investigation into future therapies, including lung transplantation and contemporary antifibrotic drugs, illustrates the changing nature of ILD treatment. Moving forward, continued research in prompt diagnosis and patient-centred care will be crucial in addressing the challenges posed by ILD.