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Interstitial lung diseases (ILD) are a complex and diverse group of disorders. ILD are more frequently diagnosed and prevalent now. In this article, diagnosis approach, including new bronchoscopy and genetic tools, and some recently added concepts are revisited, as progressive fibrosing interstitial lung diseases and interstitial lung abnormalities.
Recently information relative to idiopathic pulmonary fibrosis is shown, including genetics and pathophysiology. We look over the dynamic world of interstitial lung diseases related to connective tissue diseases, principal characteristics of this group and the principles that define which of the various available therapies should be chosen. Finally new concepts and guidelines published about the diagnosis and management of hypersensitivity pneumonitis are reported. New data and treatments have changed our traditional vision of these lung diseases and we will new options in the next years.
Keywords: Lung Diseases, Interstitial; Idiopathic Interstitial Pneumonias; Idiopathic Pulmonary Fibrosis; Alveolitis, Extrinsic Allergic; Connective Tissue Diseases; hypersensitivity pneumonitis
Interstitial lung diseases (ILD) are a diverse and challenging group of heterogeneous diseases. Idiopathic pulmonary fibrosis (IPF) is the most known but interstitial lung disease related to connective tissue diseases (C TD - ILD) and hypersensitivity pneumonitis (HP) have been more recognized and reported in the past years. There have been considerable advances in the last years, especially with new therapies and trials available.
In this review, we will update dia gnosis and therapies for interstitial lung diseases. Also, we revisited the last advances for more common diseases.
Diagnosis of interstitial lung diseases.
Precise diagnosis of interstitial lung disease is a challenging and probably the most difficult step in the study of these diseases.
The last ATS / ERS consensus classification of idiopathic interstitial pneumonias (IIP) is presented in table 1 1 . High re solution computed tomography (HRCT) is the fundamental tool for diagnosis. Details about HRCT technique, lung images classification and histological findings have been published 2 . For usual interstitial pneumonia (UIP) pattern, usually the diagnosis and t herapeutic decisions will be straightforward.
In the scenery of diagnostic uncertainty after a exhaustive study, lung biopsy usually is proposed. Transbronchial lung cryobiopsy (TLC) as alternative to surgical biopsy is still controverted, with studies showing dissimilar results. The study of Romagnoli et al showed an important discordance between surgical biopsy and TLC 3 ; although, in the study of Troy et al TLC improved the ac curacy of diagnosis combined with other elements 4 . These apparently contradictory results could be merged in one sense; the sample size of TLC is bigger the sample size of surgical biopsy and the diagnosis hardly will be the same; moreover, we should not forget, the correlation between pathologist ILD diagnosis, using only surgical biopsies, is not good 5 . Therefore, is probably TLC add a small piece of information in many cases, but enough to allow the multidisciplinary committee take a therapeutic decision , as other studies have shown 6 . Complications of TLC as bleeding and pneumothorax are not uncommon and must be considered.
Table 1. Idiopathic interstitial pneumonia Classification 1
Recent evidence confirms than multidisciplinary committee improve the diagnosis accuracy of ILD 7 – 9 . Multidisciplinary committees (MDC) should summarize their work including diagnosis or working diagnosis, certainty about this diagno sis and proposed therapy 10 . Follow up is also, an important task for MDC. Initiatives to improve and standardize MDC are in progress and probably we will see new changes.
New genetic testing (Veracyte®, MUC5B promoter risk allele, Telomerase components ) to classify ILD are being reported 11 – 13 . Some of these, can be used in clinical setting today, but are not available in everywhere. The real - world efficacy of this tests is not clear yet, but some studies show promissory results 14 . As TLC, in a clinical context, can add certain at diagnosis. Studies in breath condensate are very promising 15 , especially for the simplicity to get the sample but they are still on development.
Emerging and evolving concepts.
Some new concepts have been added in the last years.
Interstitial pneumonia with autoimmune features (IPAF) concept was proposed in 2015 16 . IPAF is referred to patients with interstitial lung diseases and some findings related to autoimmune diseases, but do not fulfill criteria to a specific autoimmune condition. These findings have been divided in three categories: clinical domain (i.e.: rayna ud), serological domain (i.e.: a nti - cyclic citrullinated peptides) and morphological domain, which could be radiol ogical (i.e.: lymphoid interstitial pneumonia pattern) or histological (i.e.: organizing pneumonia combined with non - specific interstitial pneumonia). The concept of IPAF is not a specific diagnosis and there is still controversy about its usefulness 17,18
Progressive fibrosing interstitial lung diseases (PF - ILD) is another new concept. The use of a phenotype according to behavior of ILD was proposed many years ago 1 . The concept of PF - ILD has consolidated in the last years with trials showing effectiveness of therapy 19 . PF - ILD include non IPF diseases which show a sustained decline of lung function (forced vital capacity), imaging progression (fibrosis score) and/or clinical worsening (dyspnea). Specific criteria has been published 20 . Diseases i ncluded are idiopathic non - specific interstitial pneumonia, hypersensitivity pneumonitis, Sarcoidosis, unclassifiable interstitial pneumonias, CTD - ILD and others. The prevalence of PF - ILD could be a challenge for health system 21 . The INBUILD trial demonstr ated nintedanib use in these patients is effective 19 , with a magnitude of effect similar to that described inIPF patients. The use of pirfenidone shown positive effects in patients with unclassifiable interstitial pneumonia and progressive phenotype in one study, but there was controversial issues about methodology 22 . Other trials ongoing, including this kind of patients, will be available in next years.
Interstitial lung abnormalities (ILA) are referred to HRCT findings that are potentially compatible w ith ILD in asymptomatic patient. The concept of ILA is in evolution and there is not a universal definition. Patients with ILA should not have symptoms, physical exam findings or functional impairment; if these are present, it should be referred as mild di sease. ILA are increasingly recognized and some of these patients will evolve to IPF or other ILD, but there is not yet accuracy prediction tools 23 .
Idiopathic pulmonary fibrosis.
IPF is the most common ILD, at least in the north hemisphere countries, and the prevalence has increased. Is not clear, if this is by higher incidence or because the disease is more recognized 24 .
The IPF physiopathology is not completely understood yet, but has been advances in the last years. The MUC5B promoter risk allele is the most common mutation linked to IPF 25 . The MUC5B gene is related to mucociliary clearance epithelial activity but it is not clear how exactly the overexpression of mucin leads to develop IPF. Telomerase related mutations (TRM) have also been describ ed in patients with IPF, especially in familiar IPF. Different components of this protein complex can be affected for mutation related to impair the reparation function of telomerase. Some studies have found until 30 % of TRM in patients with familiar IPF and 10 % of TRM in patients with non - familiar IPF (sporadic) 26 .
Probably, the most notorious advance in the last year is the approval of drugs antifibrotic: nintedanib and pirfenidone. New evidence has shown both drugs can have an impact on survival 27,2 8 , something not proved in the initial trials. How long is extended this benefit and when to stop the treatment is not clear.
Trials of new promissory drugs and studies with combined drugs are ongoing (i.e., pirfenidone and nintedanib ), so is expected there will be new treatments in the next years. Non pharmacologic treatment components are very important, as rehabilitation, vaccines, and oxygen use. Gastroesophageal reflux disease treatment is controversial, with studies showing contr adictory results 29 – 32 . For patients with advanced diseases lung transplantation is the only option.
Connective tissue diseases associated with interstitial lung diseases.
The connective tissue diseases (CTD) that are often associated with interstitia l lung disease (ILD) include systemic sclerosis (SS), rheumatoid arthritis (RA), primary Sjogren's syndrome (pSS), idiopathic inflammatory myopathies (IIM), mixed connective tissue disease (MCTD) and systemic vasculitis. They may occur in patients with a k nown CTD or ILD may be the debut of the disease.
CTD - ILD are associated with significant morbidity and mortality 33 , however, compared to those with idiopathic interstitial pneumonias (NII), patients with CTD - ILD are more likely to respond to immunosuppressive therapy and have a better prognosis 34 .
All patients with CTD should be evaluated in targeted search for ILD and vice versa since the debut of symptoms and periodically thereafter. The evaluation should include a thorough clinical histo ry, physical exam, autoimmune serology, lung function tests and HRCT. Progressive dyspnea, cough and respiratory functional tests with restrictive pattern are common in CTD - ILD. Spirometry may be normal in mild illnesses. Gas diffusion capacity (DLCO) can be disproportionately reduced due to pulmonary hypertension (PH) or emphysema. For serial monitoring of patients with CTD - ILD, forced life capacity (FVC) and DLCO are frequently used to predict prognosis, progression and response to therapy 35 .
HRCT is more sensitive than chest x - ray and allows to describe the specific patterns that are associated with each CTD; the same patterns described for IIP are used (Table 1). The radiological pattern of NSIP is the most common in all CTD, except in RA where UIP p redominates 36 . In addition to the ILD pattern, HRCT provides information on the airways, pulmonary artery, pleura, pericardium, emphysema, presence of co - existing cancer and extra - pulmonary structures that may be relevant in the management of patient (i.e. : dilated esophagus, distal clavicular erosions).
A few years ago, a bronchioloalveolar lavage (BAL) rich in neutrophils or eosinophils was considered to represent an inflammatory pattern of CTD - ILD. There is currently consensus that BAL information do es not add value to lung function tests and HRCT findings to predict disease progression or response to therapy, except when lung infection is suspected 37 . Histopathology is not usually required in well - established cases of CTD - ILD 38 .
The distinction between IPF and CTD - ILD has important therapeutic implications. Antifibrotic agents such as pirfenidone and nintedanib have shown benefit in IPF and other progressive fibrous lung diseases, but immunomodulators such as azathioprine and prednisone, typically used in CTD - ILD , can be potentially harmful 39 . M ultidisciplinary discussion of these patients, including a trained rheumatologists, is essential to understand the differences in opportunity and aggressiveness of treatment, follow - up, prognosis, and timing for lung transplantatio n 40 .
Smoking cessation, pulmonary rehabilitation, oxygen sup plementation and appropriate vaccination, associated with the management of comorbidities such as gastroesophageal reflux disease (GERD), pulmonary hypertension (PH) and extrapulmonary manifestations of different CTD, make the integrated work of pneumology and rheumatology fundamental 41 .
Discrimination of the predominance of inflammatory versus fibrotic interstitial compromise in CTD - ILD commands therapeutic decisions. SS - ILD is the subgroup of CTD - ILD in which controlled randomized trials have been conducted. These treatments are used in other CTD for which there is not yet strong evidence. In 2016 was demonstrated the benefit in SS - ILD of mofetil mycophenolate (MMF), in a similar magnitude of effect to cyclophosphamide, with better tolerance and fewer adverse events 42 . Azathioprine, in routine clinical practice, is conside red a well - tolerated and commonly used alternative agent for maintenance therapy. In SS, corticosteroids should be avoided at doses higher than the equivalent of 15 mg of prednisone per day as it is associated with renal crisis 43 . Tocilizumab, an antibody against the interleucine - 6 receptor, was recently approved in SS - ILD patients with high skin sclerosis score and a systemic inflammatory profile 44 .
In the group of patients with fibrotic ILD, the utility of nintedanib, a triple tyrosine kinase inhibitor, h as been demonstrated to decrease the CVF rate of fall in patients with SS - ILD and in patients with other non - IPF progressive fibrosing diseases of autoimmune etiology (SS, RA) 19,45 . The effect of pirfenidone, the other antifibrotic agent approved in IPF, is currently being investigated in patients with SS - ILD with or without MMF 46
Autologous hematopoietic progenitor transplantation is another treatment that could be considered in patients with SS - ILD with rapidly progressive disease at risk of organ failure 47 .
Respect to RA disease modifying anti - rheumatic drugs, methotrexate may exceptionally produce acute pneumonitis, but its role in the development of pulmonary fibrosis has been definitively ruled out 48 . In RA - ILD there is active research with biological drugs, such as rituximab 49 , tocilizumab 50 , abatacept 51 and tofacitinib 52 .
Some patients can show a rapidly progressive ILD, particularly in patients with IIM. These potentially fatal ILD must be distinguished from chronic forms. Corticosteroids are the first therapeutic line in IIM - ILD. Rapidly progressive forms are usually treated with high - dose corticosteroids, associated with addition of a second or third immunosuppressant 53,54 . Calcineurin inhibitors (tacrolimus and cyclosporine A) have received special attention in patients with IIM - ILD 55 , although there are non - randomized controlled trials supporting these therapeutic decisions.
HP was not considered an important disease until early century 56 . In 2017, India ILD registry reported HP as the most common cause of ILD 57 . In USA, mortality has increased in the last 30 years 58 .
HP is an immune - mediated disease typically produced by inhalation of antigens. HP diagnosis is a challenge and there was no guidelines or consensus until last year. In 2020, it was published the first ATS Clinical Guideline of diagnosis of HP introducing changes and an algorithm to diagnosis 59 .
HP classically was divided in acute, subacute, and chronic without clear limits between them. The current classification propose two types: Fibrotic and No fibrotic. These types are relatively easy to define according to lung HRCT or lung biopsy. The guideline also defines the radiological signs and elements of HP, some these have not previously defined 59 .
The list of HP causes, and antigens is enormous, and every year are added new probable etiologies. Antigen identification is relevant and fail to identify the antigen is associated with worse prognosis 60 . Use of questionaries to identify potential antigen is suggested. Expert based qu estionaries has been published 61
The diagnosis is hard; HP must be considered in every new patient with ILD. Clinical course can be indolent or rapidly progressive and antigen is identified in about 50 % of patients. Some patients present as Flu - like symptoms. Patients can have digital clubbing and rales, more common in fibrotic form. HRCT can have a mix of ground glass opacities, air trapping areas and varied fibrotic changes 59 . Antigen and serological test are not standardized, and their interpretation can be misleading 62 . Lymphocytosis in BAL can be useful in some cases. Lung biopsy is a useful tool but may have interpretation challenges due to mix of patterns, especially when it is done by non - experienced pathologist 63 . Histopathology criteria has been published 59 .
The approach to diagnosis of HP will depend on the clinical presentation. In some cases, the history and Lung CT will be enough. Other patients will require BAL or lung biopsy. An expert panel report for diagnosis and evaluation has been p ublished 64 . Also an algorithm to classify the diagnosis confidence has been proposed 59 ( figure 1 ).
Therapy for HP is largely based in expert recommendations. Non fibrotic HP usually received treatment with corticosteroids and immunosuppressors, with variable results. There is not randomized controlled trials supporting these therapies and some observational studies suggest that these treatments could worsen the prognosis 65,66 . If an immunosuppressor treatment is started, you should follow up the patient closely to see improves or worsening and stop it.
For fibrotic HP, the study I NBUILD showed benefits on decline of FVC in patients with progressive phenotype 19 . In this trial, 25 % of sample had HP as diagnosis. If pirfenidone have the same effect, is not known.
Lung transplantation is an option in advanced disease.
In this review, we have summarized new information and concepts emerged in the field of ILD. It is not possible review every topic and we selected the more commons ILD with more new information available.
Although there is so much to learn about ILD, the knowledge about pathophysiology, genetics, clinical presentation, new laboratory tests, therapeutics ways and pharmacological alternatives have increased in the last decade. Multidisciplinary committees are consolidated, and they mu st be established as a standard on ILD management. Many trials on going about new drugs will be available in the next years and probably we will have new therapeutics alternatives.
Figure 1. Hypersensitivity pneumonitis diagnosis based on incorporation of imaging, exposure assessment, BAL lymphocytosis, and histopathological findings. All confidence levels are subject to multidisciplinary discussion.
*Confidence may increase to “definite” if the pathologist’s conclusion persists after reevaluation in the context of additional clinical information or an expert second opinion on histopathology. HP = hypersensitivity pneumonitis; HRCT = high - resolution computed tomography.
Reprinted with permission of the American Thoracic Society. Copyright © 2021 American Thoracic Society. All rights reserved.
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The American Journal of Respiratory and Critical Care Medicine is an official journal of the American Thoracic Society.
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
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