Fibrotic lung diseases

Diffuse parenchymal lung diseases encompass a large number of conditions, with a wide range of causes, clinical manifestations, imaging and pathological characteristics, as well as variable outcomes.

Despite the intrinsic heterogeneity of this group of diseases, in most of them, the walls of the lung alveoli are infiltrated by various combinations of inflammatory cells, fibrosis and proliferation of certain cells that form the normal alveolar wall.

Since these pathological abnormalities predominate in the pulmonary interstitium, the disorders are called interstitial lung diseases (ILDs). Idiopathic pulmonary fibrosis (IPF) is the archetype of fibrosis and the most common of the ILDs.

Characterized by an imaging and pathological pattern of usual interstitial pneumonia (UIP), without an identifiable cause, or associated with a disease known for its association with pulmonary fibrosis, it occurs more commonly in men (male:female ratio 7:3) and It is more common in people >60 years old.

IPF is a chronic and irreversible disease, which progresses to respiratory failure and death (mean interval between diagnosis and death, 3 years). Unlike IPF, other PIDs are generally characterized by a younger mean age at presentation (20-60 years) and a more balanced sex ratio.

The variable underlying pathological characteristics of other PIDs with fibrosis are usually less prominent than the inflammatory infiltration, resulting in greater heterogeneity and often. less severe outcomes, compared to IPF. However, a number of these other PIDs are also characterized by progressive fibrosis.

As in any other organ, pulmonary fibrosis can be the manifestation of other clinical entities, and if progressive, will ultimately result in organ failure, causing respiratory symptoms, exercise intolerance, reduced quality of life, and increased risk of death. .

For the purposes of classification and management, ILDs are generally assigned to many disease categories, based on a known underlying disease (e.g., pulmonary fibrosis associated with rheumatoid arthritis) (RA-ILD), a triggering agent (e.g., pneumoconiosis) or, unknown cause (e.g., IPF).

Although each isolated fibrosing ILD is rare, collectively, ILDs affect a considerable number of patients, representing a substantial disease burden.

The overall prevalence of PID is estimated to reach 76.0 cases/100,000 people in Europe and 74.3 cases per 100,000 in the USA.

Sarcoidosis , CTE-associated ILD (CTE-ILD), and IPF are the most common fibrotic ILD, with an estimated prevalence of 30.2, 12.1, and 8.2 cases/100,000, respectively .

In patients with fibrotic ILD other than IPF, 13-40% have a progressive fibrotic phenotype, which represents between 20-28 patients/100,000 people, in Europe and the USA.

Pulmonary fibrosis is distributed worldwide, with geographical variants. The estimated prevalence of IPF is 8 cases/100,000 inhabitants; It is higher in North America and Europe than in the rest of the world, while the prevalence of sarcoidosis is higher in northern Europe and Japan, and among black people.

Fibrosis formation is an essential body response against pathogens and, under normal conditions, in wound healing. Pulmonary fibrosis has several specific triggers . Exaggerated cascades of inflammatory and fibrotic responses are triggered, leading to the formation of fibrotic tissue, remodeling, and deposition of extracellular matrix, which, in turn, perpetuates the formation of fibrosis.

Very little is still known about the pathophysiology of specific pathological entities, and the factors that differentiate normal wound repair from progression to fibrosis. Although the susceptibility and initial inflammatory responses, different depending on each disease, are considered important, it is currently believed that common mechanisms intervene in later phases.

Various genetic studies have identified common and rare variants, which are associated with increased susceptibility to fibrotic lung diseases, with notable similarities to familial IPF and other fibrotic ILDs. For example, a common polymorphism in the promoter of MUC5B, which is involved in airway clearance and host defense against bacteria, is associated with increased risks of IPF, RA with ILD (A[R-ILD), and pneumonitis. due to chronic hypersensitivity (NHC), but not systemic sclerosis (SS) with EPI (ES-ILD), sarcoidosis or antisynthetase syndrome.

Telomere shortening and telomere-related gene mutations are found in IPF and other fibrotic diseases. Some rare genetic variants, such as those related to telomere mutations, are clearly associated with progressive disease.

In addition to different shared genetic risk factors, PIDs have heterogeneous and overlapping baseline values. In IPF, it has not yet been established whether aggression to the integrity of alveolar epithelial cells can initiate the disease, due to the interaction between epithelial cells and myofibroblasts.

Among patients with sarcoidosis, only a small percentage with granulomatous inflammation in response to a persistent, unknown, presumed trigger progresses to fibrosis. In SS-ILD, a combination of inflammatory dysfunction with endothelial dysfunction is observed, while, in most patients, vasculopathy leads to pulmonary fibrosis, which allows establishing the prognosis.

Investigation of specific conditions suggests that various inflammatory responses can lead to a profibrotic environment and a milieu of cytokines (including, especially, growth factors, such as β-transformation, connective tissue, platelet-derived, WNT signaling, and Hedgehog .

The shared descending pathways activate and maintain a complex interaction that causes the activation and differentiation of fibroblasts into myofibroblasts, which further orchestrate fibrogenesis. Once established, changes in the structural tissue and profibrotic milieu form a progression, leading to self-perpetuating fibrosis.

PIDs can be divided into 5 broad clinical categories:

1. PID related to different primary diseases (e.g., sarcoidosis, Langerhans cell granulomatosis, eosinophilic pneumonia, lymphangioleiomyomatosis, and pulmonary alveolar proteinosis).
    
2. PPE related to environmental exposures, including inorganic inhalation pneumonitis and hypersensitivity pneumonitis, primarily related to inhalation of organic particles (e.g., household or occupational exposure to mold or birds or other exposures).
    
3. PID induced by drugs, illicit drugs or irradiation.
    
4. PID associated with connective tissue disease.
    
5. RA-ILD and ES-ILD, idiopathic inflammatory myopathy, primary Sjögren’s disease, and nonspecific idiopathic interstitial pneumonia and other less common entities.

Pulmonary fibrosis can occur in the context of many of these ILDs and a separation can be made between pulmonary fibrosis in the context of underlying systemic diseases, such as CTE and sarcoidosis, and conditions that are restricted to the lung, such as NHC, drug-induced IPF, non-specific IPF and IPF. There is also overlap between groups (e.g., drug-induced pulmonary fibrosis in CTE and a genetic predisposition in several ILDs).

Due to the epidemiology and burden of fibrosis within each diagnostic category, clinicians most frequently see patients with CTE-ILD, IPF, NHC, sarcoidosis, or unclassifiable fibrotic ILD.

Currently, there is specific interest in the potential development of fibrosis after COVID-19.

Although infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes varied symptoms of lung diseases, male sex, advanced age, obesity, and coexisting conditions appear to be risk factors for the development of SARS.

Pulmonary fibrosis is a known complication of acute respiratory diseases, ARDS, while there are similarities in the fibroproliferative response and risk factors, in pulmonary fibrosis in the context of ARDS, and pulmonary fibrosis in the context of other diseases.

However, analysis of long-term follow-up data after ARDS or infection with another strain of SARS-CoV2, in 2003 showed fibrotic changes that mostly remained stable over time, with little clinical relevance. Current prospective studies are investigating the effect and long-term course of pulmonary fibrosis caused by Covid-19.

Apart from the specific symptoms of the disease, the main presenting symptoms are: cough, progressive dyspnea on exertion and exercise intolerance. Diagnosis is often delayed by several months or even years.

A thorough medical history is necessary , including environmental exposures, medication use, and extrapulmonary signs. Lung auscultation reveals crackles (also called velcro or crepitations), indicating fibrosis, although crackling sounds may be heard in patients with hypersensitivity pneumonitis.

Premature hair graying and hematologic abnormalities may be a sign of telomeropathy-related fibrosis.

In CTE, pulmonary fibrosis may develop after the underlying condition has been diagnosed or before extrapulmonary manifestations appear. Hands, joints and skin should be well examined. Serological testing is recommended, including for antinuclear antibodies and anti-citrullinated peptide.

If there is clinical suspicion of an autoimmune disease , it is recommended to consult a rheumatologist to continue with more advanced studies.

High-resolution computed tomography ( CTl) establishes the diagnosis of pulmonary fibrosis by revealing reticulation, architectural distortion, and loss of lung volume. Patterns suggestive of specific causes can also be identified.

The UIP pattern is the hallmark of pulmonary fibrosis, frequently observed in IPF, RA-ILD, and advanced disease, regardless of the underlying condition. On the contrary, the most common pattern in SS-ILD is that of non-specific interstitial pneumonia , with mixed reticulation and ground-glass attenuation, to different extents, often with traction bronchiectasis, central axial distribution and preservation of the subpleural area.

Expiratory imaging can be helpful, especially in NHC. Pulmonary function tests assess the level of deterioration of the disease and are the most widely used measure to monitor the course of the disease and response to therapy.

In patients with pulmonary fibrosis, testing typically shows a restrictive lung function pattern (decreased functional vital capacity [FVC]; normal or decreased forced expiratory volume in 1 second/FVC ratio; decreased total lung capacity; residual volume low) along with the decrease in the diffusing capacity of carbon monoxide.

However, normal lung function does not rule out pulmonary fibrosis.

If the combination of clinical findings and images are not diagnostic, more invasive procedures should be resorted to. Bronchoalveolar lavage helps in the diagnosis of hypersensitivity pneumonitis and sarcoidosis. Biopsies of the bronchial mucosa and lymph nodes are indicated when sarcoidosis is suspected.

It is recommended that all the information collected be synthesized by a multidisciplinary team with experience in PID, who can establish a diagnosis or discuss the indication of additional diagnostic procedures, such as thoracoscopic lung biopsy or transbronchial cryobiopsy.

It is very important to evaluate the weight of the diagnosis and the therapeutic consequences against the potential risks associated with each procedure, to address the discussion among the members of the multidisciplinary team, with the participation of the patient.

Consideration of the disease course is important to guide diagnosis and treatment as it may reduce the need for invasive diagnostic procedures. Although in most cases, the first diagnosis of choice can be made with sufficient confidence, a subgroup of patients with PID remains unclassifiable, even after extensive evaluation.

In virtually all patients with a certain diagnosis, the natural course of untreated IPF is its progression to respiratory failure. In contrast, more than half of patients diagnosed with pulmonary fibrosis other than IPF have a chronic disease that is stable or improves with immunomodulatory therapy.

Despite treatment considered appropriate, a proportion of patients will have progressive pulmonary fibrosis associated with worsening respiratory symptoms, decreased lung function, worsening quality of life, with risk of death, regardless of the ILD classification.

Outcomes may be similar to IPF, especially in patients with a UIP pattern, such as those with RA-ILD and some with NHC. Progression and prognosis depend on the underlying entity. However, the longitudinal course of the disease varies and must be identified on an individual basis, as it has implications for decisions and treatment. Sometimes it may lead to reconsideration of the diagnosis.

No serum biomarker has been validated to monitor disease progression or assess the respective components of inflammation and fibrosis. To establish prognosis, scores have been developed, especially based on sex, age, FVC, and lung diffusing capacity for carbon monoxide.

In case series, predictors of disease progression despite immunomodulatory therapy include demographic characteristics (e.g., African ancestry in patients with SS-ILD or sarcoidosis); more extensive disease on CT images; further deterioration of lung function; presence of honeycombing and a UIP pattern on CT, with persistence of the disease-causing agent.

There is no standard definition of disease progression in patients with pulmonary fibrosis. Because a decrease in FVC predicts death in patients with IPF, it is a measure that has been used as a pivotal point in studies of antifibrotic drugs.

In a clinical trial that evaluated the effectiveness of an antifibrotic treatment in patients with progressive fibrotic PID, 41 patients were required to meet at least 1 of the following disease progression criteria, within 24 months prior to detection: relative 10% or more of predicted FVC; relative decrease of 5-10% of the predicted value of FVC and worsening of symptoms, or an increase in the extent of disease on chest CT. Other criteria have also been used.

A threshold or rate of decline has not been formally accepted in clinical practice; Assessment of fibrosis progression is generally based on serial lung function tests performed at 3-6 month intervals.

Because small variations in FVC can be confused with measurement errors, multimodal assessment of progression also includes: worsening of symptoms and exercise capacity, increased fibrosis on imaging, decreased lung capacity diffusion of carbon monoxide, need for oxygen therapy and, clinical events predictive of early death (acute exacerbation of fibrosis or non-selective hospitalization)

For most patients, the diagnosis of pulmonary fibrosis is a life-changing verdict. Uncertainty about the prognosis, together with an increase in the burden of symptoms, has a significant effect on the quality of life of both the patient and her family. Depending on the underlying condition, treatment may aim to improve the disease or slow its progression, and improve or maintain quality of life.

In patients with NHC, it is a priority to avoid the offending antigen and encourage smoking cessation.

Vaccination against pneumococcus and influenza is recommended. Based on expert opinion, in patients with hypoxemia at rest (arterial O2 partial pressure [PaO2] <55 mm Hg, O2 saturation measured by pulse oximetry <89%, or PaO2 <60 mm Hg and cor pulmonale or polycythemia) supplemental O2 is indicated.

Pulmonary rehabilitation and outpatient oxygen therapy in patients with isolated exertional hypoxemia improves quality of life, reduces dyspnea, and increases walking ability. Accurate identification and treatment of coexisting conditions are essential.

Lung transplantation is an option for selected patients, although extrapulmonary disease or severe coexisting disease may disqualify them as recipients, especially those with CTE. For many, the focus is on palliative care.

Decisions about drug treatment are based on the underlying diagnosis and course of the disease. For patients with IPF, treatment with antifibrotic medications (pirfenidone or nintedanib) is recommended.

In most cases of fibrotic PID other than IPF, immunomodulators are indicated, alone or with glucocorticoids, which. They are generally used as first-line therapy if inflammation is suspected.

However, except for SS–ILD and sarcoidosis, the evidence supporting this approach is very weak. In patients with a UIP pattern, there is theoretical concern that immunosuppression may not be beneficial or even be harmful, as previously demonstrated in IPF.

Nintedanib has been approved in the US and Europe for patients with SSc-ILD and chronic fibrotic ILD with a progressive phenotype . This agent is not associated with improvement in function, but buffers the decrease in FVC by approximately half, supporting the notion that progressive pulmonary fibrosis may be amenable to treatment with antifibrotics, regardless of the specific underlying disease.

Pirfenidone reduces disease progression in patients with unclassifiable progressive fibrotic PID. When considering drug treatment, there must be a balance between the benefit of long-term preservation of lung function with the risk of side effects. But, many questions still remain about the timing and sequence of these treatments.

Pulmonary fibrosis is a pathological process arising from multiple underlying causes.

Monitoring disease progression has become a priority in therapeutic decision guidelines.

It is also expected that in the coming years there will be different biomarkers and novel techniques, such as molecular classifiers, that can provide more information on the evaluation and monitoring of fibrosis, compared to the inflammatory progressive disease, which results in more targeted, individualized treatments, as it is clear that a “one size fits all” approach does not apply to the broad spectrum of fibrosing diseases.

Current research may lead to diagnoses and interventions to prevent, halt, and potentially reverse the development of life limitations caused by pulmonary fibrosis.