|Year : 2020 | Volume
| Issue : 4 | Page : 359-378
Management of interstitial lung diseases: A consensus statement of the Indian Chest Society (ICS) and National College of Chest Physicians (NCCP)
Sheetu Singh1, Bharat Bhushan Sharma2, Mohan Bairwa3, Dipti Gothi4, Unnati Desai5, Jyotsna M Joshi5, Deepak Talwar6, Abhijeet Singh6, Raja Dhar7, Ambika Sharma1, Bineet Ahluwalia1, Daya K Mangal8, Nirmal K Jain9, Khushboo Pilania10, Vijay Hadda11, Parvaiz A Koul12, Shanti Kumar Luhadia13, Rajesh Swarnkar14, Shailender Nath Gaur15, Aloke G Ghoshal16, Amita Nene17, Arpita Jindal18, Bhavin Jankharia19, Chetambath Ravindran20, Dhruv Choudhary21, Digambar Behera22, DJ Christopher23, Gopi C Khilnani24, Jai Kumar Samaria25, Harpreet Singh26, Krishna Bihari Gupta27, Manju Pilania28, Manohar L Gupta29, Narayan Misra30, Nishtha Singh31, Prahlad R Gupta32, Prashant N Chhajed33, Raj Kumar34, Rajesh Chawla35, Rajendra K Jenaw1, Rakesh Chawla36, Randeep Guleria11, Ritesh Agarwal22, R Narsimhan37, Sandeep Katiyar38, Sanjeev Mehta39, Sahajal Dhooria22, Sushmita R Chowdhury40, Surinder K Jindal41, Subodh K Katiyar42, Sudhir Chaudhri43, Neeraj Gupta44, Sunita Singh45, Surya Kant46, Zarir Udwadia47, Virendra Singh31, Ganesh Raghu48
1 Department of Respiratory Medicine, SMS Medical College, Jaipur, Rajasthan, India
2 Department of Medicine, SMS Medical College, Jaipur, Rajasthan, India
3 Centre for Community Medicine, All India Institute of Medical Sciences, New Delhi, India
4 Department of Pulmonary, Sleep and Critical Care Medicine, ESI-PGIMSR, Delhi, India
5 Department of Pulmonary Medicine, TNMC and BYL Nair Hospital, Mumbai, Maharashtra, India
6 Division of Pulmonary and Critical Care Medicine, Metro Centre for Respiratory Diseases, Metro Multi Speciality Hospital, Noida, Uttar Pradesh, India
7 Department of Pulmonology, Fortis Hospital, Kolkata, West Bengal, India
8 Department of Public Health and Epidemiology, IIHMR University, Jaipur, Rajasthan, India
9 Jain Chest Care Center, Jaipur, Rajasthan, India
10 Department of Radio Diagnosis, Max Super Specialty Hospital, Noida, Uttar Pradesh, India
11 Department of Pulmonary, Critical Care and Sleep Medicine, AIIMS, New Delhi, India
12 Department of Internal and Pulmonary Medicine, Sher-I-Kashmir Institute of Medical Sciences, Srinagar, Jammu and Kashmir, India
13 Department of Respiratory Medicine, Geetanjali Medical College and Hospital, Udaipur, Rajasthan, India
14 Department of Respiratory, Critical Care, Sleep and Interventional Pulmonology, Getwell Hospital and Research Institute, Nagpur, Maharashtra, India
15 Department of Respiratory Medicine, School of Medical Science and Research, Sharda University, Greater Noida, Uttar Pradesh, India
16 Department of Respiratory Medicine, National Allergy Asthma Bronchitis Institute, Kolkata, West Bengal, India
17 Department of Respiratory Medicine, Bombay Hospital and Medical Research Center, Mumbai, Maharashtra, India
18 Department of Pathology, SMS Medical College, Jaipur, Rajasthan, India
19 Department of Radiodiagnosis, Jankharia Imaging, Mumbai, Maharashtra, India
20 Department of Pulmonary Medicine, DM Wayanad Institute of Medical Sciences, Wayanad, Kerala, India
21 Department of Pulmonary and Critical Care Medicine, Pt. B.D.S PGIMS, Rohtak, Haryana, India
22 Department of Pulmonary Medicine, PGIMER, Chandigarh, India
23 Department of Pulmonary Medicine, Christian Medical College, Vellore, Tamil Nadu, India
24 Department of Pulmonary Medicine, PSRI, Institute of Pulmonary, Critical Care and Sleep Medicine, New Delhi, India
25 Department of Chest Diseases, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India
26 Department of Medicine, PGIMS, Rohtak, Haryana, India
27 Department of Respiratory Medicine, PGIMS, Rohtak, Haryana, India
28 Department of Community Medicine, RUHS College of Medical Sciences, Jaipur, Rajasthan, India
29 Department of Pulmonary and Sleep Medicine, Santokba Durlabhji Memorial Hospital, Jaipur, Rajasthan, India
30 Department of Pulmonary Medicine, MKCG Medical College and Hospital, Brahmapur, Odisha, India
31 Department of Pulmonary Medicine, Asthma Bhawan, Jaipur, Rajasthan, India
32 Department of Pulmonary Medicine, NIMS University, Jaipur, Rajasthan, India
33 Lung Care and Sleep Center, Institute of Pulmonology Medical Research and Development, Mumbai, Maharashtra, India
34 Department of Respiratory Medicine, Vallabhbhai Patel Chest Institute, University of Delhi, Delhi, India
35 Department of Respiratory Medicine, Critical Care and Sleep Disorders, Indraprastha Apollo Hospitals, New Delhi, India
36 Department of Respiratory Medicine, Critical Care and Sleep disorders, Jaipur Golden Hospital and Saroj Superspeciality Hospital, Delhi, India
37 Department of Respiratory Medicine, Apollo Hospitals, Chennai, Tamil Nadu, India
38 Department of Pulmonary Medicine, Apollo Spectra Hospital, Kanpur, Uttar Pradesh, India
39 Department of Pulmonology, The Chest and Allergy Center, Mumbai, Maharashtra, India
40 Department of Pulmonary Medicine, Apollo Gleneagles Hospital, Kolkata, West Bengal, India
41 Jindal Chest Clinic, Chandigarh, India
42 Chest Care Center, Kanpur, Uttar Pradesh, India
43 Department of Respiratory Medicine, GSVM Medical College and Hospital, Kanpur, Uttar Pradesh, India
44 Department of Respiratory Medicine, JLN Medical College & Hospital, Ajmer, India
45 Department of Pathology, PGIMS, Rohtak, Haryana, India
46 Department of Respiratory Medicine, KGMU, Lucknow, Uttar Pradesh, India
47 Department of Pulmonary Medicine, Hinduja Hospital, Mumbai, Maharashtra, India
48 Department of Medicine, University of Washington, Seattle, USA
|Date of Submission||21-Apr-2020|
|Date of Acceptance||29-Apr-2020|
|Date of Web Publication||01-Jul-2020|
Dr. Virendra Singh
Department of Pulmonary Medicine, Asthma Bhawan, Vidyadhar Nagar, Jaipur - 302 023, Rajasthan
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Background: Interstitial lung disease (ILD) is a complex and heterogeneous group of acute and chronic lung diseases of several known and unknown causes. While clinical practice guidelines (CPG) for idiopathic pulmonary fibrosis (IPF) have been recently updated, CPG for ILD other than IPF are needed. Methods: A working group of multidisciplinary clinicians familiar with clinical management of ILD (pulmonologists, radiologist, pathologist, and rheumatologist) and three epidemiologists selected by the leaderships of Indian Chest Society and National College of Chest Physicians, India, posed questions to address the clinically relevant situation. A systematic search was performed on PubMed, Embase, and Cochrane databases. A modified GRADE approach was used to grade the evidence. The working group discussed the evidence and reached a consensus of opinions for each question following face-to-face discussions. Results: Statements have been made for each specific question and the grade of evidence has been provided after performing a systematic review of literature. For most of the questions addressed, the available evidence was insufficient and of low to very low quality. The consensus of the opinions of the working group has been presented as statements for the questions and not as an evidence-based CPG for the management of ILD. Conclusion: This document provides the guidelines made by consensus of opinions among experts following discussion of systematic review of evidence pertaining to the specific questions for management of ILD other than IPF. It is hoped that this document will help the clinician understand the accumulated evidence and help better management of idiopathic and nonidiopathic interstitial pneumonias.
Keywords: Consensus statement of interstitial lung disease, idiopathic pulmonary fibrosis, interstitial lung disease, management guidelines
|How to cite this article:|
Singh S, Sharma BB, Bairwa M, Gothi D, Desai U, Joshi JM, Talwar D, Singh A, Dhar R, Sharma A, Ahluwalia B, Mangal DK, Jain NK, Pilania K, Hadda V, Koul PA, Luhadia SK, Swarnkar R, Gaur SN, Ghoshal AG, Nene A, Jindal A, Jankharia B, Ravindran C, Choudhary D, Behera D, Christopher D J, Khilnani GC, Samaria JK, Singh H, Gupta KB, Pilania M, Gupta ML, Misra N, Singh N, Gupta PR, Chhajed PN, Kumar R, Chawla R, Jenaw RK, Chawla R, Guleria R, Agarwal R, Narsimhan R, Katiyar S, Mehta S, Dhooria S, Chowdhury SR, Jindal SK, Katiyar SK, Chaudhri S, Gupta N, Singh S, Kant S, Udwadia Z, Singh V, Raghu G. Management of interstitial lung diseases: A consensus statement of the Indian Chest Society (ICS) and National College of Chest Physicians (NCCP). Lung India 2020;37:359-78
|How to cite this URL:|
Singh S, Sharma BB, Bairwa M, Gothi D, Desai U, Joshi JM, Talwar D, Singh A, Dhar R, Sharma A, Ahluwalia B, Mangal DK, Jain NK, Pilania K, Hadda V, Koul PA, Luhadia SK, Swarnkar R, Gaur SN, Ghoshal AG, Nene A, Jindal A, Jankharia B, Ravindran C, Choudhary D, Behera D, Christopher D J, Khilnani GC, Samaria JK, Singh H, Gupta KB, Pilania M, Gupta ML, Misra N, Singh N, Gupta PR, Chhajed PN, Kumar R, Chawla R, Jenaw RK, Chawla R, Guleria R, Agarwal R, Narsimhan R, Katiyar S, Mehta S, Dhooria S, Chowdhury SR, Jindal SK, Katiyar SK, Chaudhri S, Gupta N, Singh S, Kant S, Udwadia Z, Singh V, Raghu G. Management of interstitial lung diseases: A consensus statement of the Indian Chest Society (ICS) and National College of Chest Physicians (NCCP). Lung India [serial online] 2020 [cited 2020 Aug 6];37:359-78. Available from: http://www.lungindia.com/text.asp?2020/37/4/359/288739
Summary of interstitial lung disease consensus statements
Interstitial lung disease (ILD) is a broad and complex heterogeneous group of lung diseases. While clinical practice guidelines (CPG) have been developed for the diagnosis and management of idiopathic pulmonary fibrosis (IPF), CPG for the diagnosis and management of patients with other ILD are lacking. There is an unmet need for the development of evidence based CPGs for all major subtypes of ILDs. These consensus statements were developed by an ILD working group with the collaboration of Indian Chest Society (ICS) and National College of Chest Physicians (NCCP), India, after systematic review of existing evidence. This statement is aimed to provide the physicians working in diverse health-care systems with a better understanding to diagnose and manage patients with non-IPF ILD in India and beyond. It is also hoped that this document will be useful to physicians confronted with patients who are not willing, wanting, and/or able to be subjected to invasive diagnostic interventions.
A working group of multidisciplinary clinicians familiar with clinical management of ILD (pulmonologists, radiologist, pathologist, and rheumatologist) and epidemiologists selected by the leaderships of ICS and NCCP posed 29 search questions to address the clinically relevant situation. A systematic search was performed on the PubMed, Embase databases, and the Cochrane Library. Data related to each question were reviewed in face-to-face discussions among the group members. Statements framed reflect the consensus opinion of the working group. A modified GRADE approach was used to grade the evidence.
Outcome: The following statements were the consensus of the working group for patients diagnosed with ILD:
- Baseline spirometry should be obtained in all patients with suspected interstitial lung disease (ILD)
- Volume scans on multidetector computed tomography (MDCT) (16 slice or higher) are preferable at initial assessment
- BAL may be used to diagnose certain rare ILDs. When performed, infection must be ruled out (especially Mycobacterium tuberculosis) by special stains, molecular techniques, and cultures of the BAL specimen, if suspected by the clinician
- TBLB may be considered in those patients likely to have ILDs, particularly if the disease has a tendency for bronchocentric involvement
- In patients not-at-high risk for surgical complications, the conditional recommendation for the surgical lung biopsy (SLB) made in the 2018 CPG was endorsed
- TBLC may be considered for obtaining biopsy in carefully selected patients with ILD at centers with expertise in the procedure
- Endorsement of the conditional recommendations for the multidisciplinary discussion (MDD) made by the international experts for the diagnosis of ILD
- Most common comorbidities encountered in ILD are gastroesophageal reflux disease (GERD), pulmonary hypertension (PH), lung cancer, obstructive sleep apnea (OSA), and venous thromboembolism (VTE)
- Every effort should be made to identify and treat the comorbid conditions influencing cough in ILD
- Pulmonary rehabilitation is suggested in dyspneic patients with ILD
- Endorsement of the recommendations for the annual influenza vaccination and Pneumococcal vaccination by the Advisory Committee on Immunization Practices (ACIP) to all patients with ILD
- Treatment indicated for underlying lung disease as the mainstay of therapy and supplemental oxygen for patients with hypoxemia
- Consideration of NIV as early as possible in patients who require high-flow supplemental oxygen at rest
- The consideration of MV in patients with AE ILD with respiratory failure should be made only after proper counseling
- Lung transplantation is the only treatment with clearly proven survival benefit in advanced ILD
- Palliative care for all patients with advanced ILDs
- Monitoring of disease with spirometry is advised at 4–6 months intervals
- Oral corticosteroids for 4–12 weeks are an appropriate treatment option for patients with acute/subacute HP
- ANA testing (by indirect immunofluorescence method), rheumatoid factor (RF), and antibody to Cyclic Citrullinated Peptide (anti-CCP) testing at baseline for all patients with ILD
- Corticosteroids may be given to treat RA-ILD
- Low-dose oral corticosteroids may be used for the treatment of systemic sclerosis (SSC-ILD) and high-dose should be avoided in scleroderma as it is associated with risk of renal crisis
- Cyclophosphamide or mycophenolate mofetil treatment in SSC-ILD is appropriate for patients with progressive disease
- Avoidance of continued exposure to silica and direct inhalation of tobacco products is strongly urged
- The updated recommendations published by the ATS for the diagnosis and treatment of IPF are endorsed, including treatment with antifibrotic agents, pirfenidone or nintedanib
| Introduction|| |
Interstitial lung diseases (ILDs) are a broad and heterogeneous group of lung diseases with overlapping clinical, radiological, and histopathological features. While clinical practice guidelines (CPGs) have been developed by international experts for idiopathic pulmonary fibrosis (IPF), the need for CPGs to guide clinicians to diagnose and treat patients with other ILD is evident. The Indian Chest Society (ICS) and the National College of Chest Physicians (NCCP), India, took an initiative for a task force to frame a consensus statement for management of ILD. The target audiences are clinicians who care for adults with ILD. Given the lack of evidence-based CPG for general ILD and specific ILD other than IPF, the objective of this task force was to develop a document to help the clinicians within and beyond India, to have a better understanding of the most appropriate diagnostic and therapeutic interventions available.
We believe that this document will be useful for clinicians in making accurate diagnosis and appropriate therapeutic interventions for patients with ILD other than IPF.
| Methodology|| |
A working group of multidisciplinary expert clinicians familiar with clinical management of ILD (45 pulmonologists, 2 radiologist, 2 pathologist, 1 rheumatologist, and 3 epidemiologists India, with Co-chairs VS and GR posed) selected by the leadership of the ICS and NCCP, India, posed 29 search questions to address the management of ILD. A systematic search was performed on the PubMed and Embase databases and the Cochrane Library. A modified GRADE approach was used to grade the evidence [Table 1]. The working group discussed the evidence and reached a consensus of opinions for each question following face-to-face discussions. A consensus was sought for all questions – it was unanimous in cases with high quality evidence. Greater than 80% agreement was used as threshold to determine consensus for those with a lesser quality of evidence. CPGs developed by international experts for diagnosis and management of IPF were reviewed and endorsed by the group. The specific questions addressed in this document are pertinent to the adult patient suspected to have ILD as defined:
|Table 1: The modified grade system including grades and each statement was graded as per the strengths|
Click here to view
Unexplained respiratory symptoms with chest radiograph or CT evidence of “ILD” – these include bilateral lung involvement with parenchymal densities including bilateral nodules and/or airspace densities and/or fibrotic patterns [Figure 1].
|Figure 1: Classification of interstitial lung disease on the basis of known or unknown etiology|
Click here to view
Q 1: Should spirometry, DLCO, and 6-minute walk test be performed in the initial evaluation?
- The ATS guidelines on lung function testing and 6MWT for the clinical practice were endorsed as a standard of care to ensure quality ,
- Baseline spirometry should be obtained in all patients with suspected interstitial lung disease (ILD) (2A)
- Plethysmographic lung volumes should be done wherever feasible (3A)
- Initial evaluation should include DLCO corrected to hemoglobin (DLCOcorrHb) wherever feasible (3A)
- 6MWT should be assessed at baseline (2A).
| Discussion|| |
Spirometry, DLCO, and 6MWT are routine lung function tests to assess the functional impairment at rest and with activity of the patient in an objective manner at diagnosis as well as to prognosticate the disease rather than a diagnostic tool to characterize the subtype of ILD., They are also useful to assess disease progression and response to treatment., In this regard, the rate of FVC decline has been used as primary endpoint in most if not all clinical trials including IPF and scleroderma.,
During 6MWT, patients appreciate their symptoms of shortness of breath by correlating their symptoms to distance walked and fall in oxygen saturation and thereby appreciate the need to use supplemental oxygen. Baseline lung functions are advisable for all patients, useful for monitoring progress of disease and treatment response [Figure 2].
|Figure 2: The role of lung function tests in the evaluation of patients with interstitial lung disease|
Click here to view
There were no identified harms associated with patients performing the tests other than the requirement of learning the technique of correctly performing the test and out-of-pocket cost involved.
Q 2. Should computed tomography scan chest be performed in diagnosis of interstitial lung disease?
- The 2018 ATS-ERS-JRS-ALAT guidelines were endorsed and stated that high-resolution computed tomography (HRCT) of chest with proper technique is needed to recognize patterns and distribution of the abnormalities that may be diagnostic of some specific ILD on the first instance (1A)
- Volume scans on multidetector computed tomography (MDCT) [16 slice or higher] are preferable at initial assessment (1A)
- Follow-up CT should be obtained for clinical relevant reasons and/or during follow-up when clinically indicated, with the similar acquisition protocol (usual practice point).
| Discussion|| |
'Obtaining HRCT scans of the chest' has become quite essential component of diagnostic evaluation in ILD and is in essence a motherhood statement. The disease specific patterns have diagnostic and prognostic significance [Figure 3].
|Figure 3: The axial image on high resolution computed tomography (HRCT) of chest (a) shows honeycombing with subpleural lower lobe predominance. The sagittal image (b) shows the subpleural distribution better. This is suggestive of the usual interstitial pneumonia pattern and in the absence of an etiology, would be suggestive of idiopathic pulmonary fibrosis. (c) Hypersensitivity pneumonitis. Axial image shows diffuse ill-defined bronchocentric nodules (arrow) that are characteristic of this condition. These nodules coalesce to form areas of ground-glass attenuation. (d) Silicosis. Axial computed tomography scan shows nodules of varying sizes (arrow) with egg-shell subcarinal node calcification and a confluent soft tissue mass of progressive massive fibrosis. (e and f) Scleroderma interstitial lung disease nonspecific interstitial pneumonia pattern. 34-year-old lady with scleroderma. Axial supine (e) and sagittal (f) images show reticular opacities (arrow in e) with subpleural sparing (arrowhead in f) that are typical of an nonspecific interstitial pneumonia pattern. (g) Cryptogenic organising pneumonia. Axial computed tomography scan shows areas of ground glass attenuation in the centre (arrow) with peripheral consolidation (arrowhead) - this is the typical reverse halo or atoll sign. (h) Sarcoidosis. Axial computed tomography scan shows perivascular (arrow), subpleural (arrowhead) and fissures (short arrow on the left) nodules typical of the disease|
Click here to view
The major concern with the volumetric technique is the radiation dose exposure. However, recent technological advances allow significant reduction of the radiation exposure without a compromise in quality.,,,,,
Quality of HRCT would be another concern; [Table 2] provides the recommended protocol for obtaining a good-quality HRCT. Interacting with the radiologist and communicating the requirements would be a step toward multidisciplinary discussion.
|Table 2: Recommended high-resolution computed tomography scanning protocol for patient's being evaluated for interstitial lung disease|
Click here to view
Q 3. Should following procedure/s be performed in diagnosis?
- Bronchoalveolar lavage (BAL)
- Transbronchial lung biopsy (TBLB)
- Transbronchial cryobiopsy (TBLC)
- Video-assisted thoracoscopic (VATS) lung biopsy.
- BAL may be used to diagnose certain rare ILDs such as pulmonary alveolar proteinosis (PAP), PLCH, and eosinophilic pneumonia (3B).
- When performed, infection must be ruled out (especially Mycobacterium tuberculosis) by special stains, molecular techniques, and cultures of the BAL specimen, if suspected by the clinician (usual practice point)
- Noninvasive tests such as sputum for microbiologic and molecular testing should precede a flexible bronchoscopy; a positive result obviates the need of a BAL.
- Conventional TBLB should not be done in patients with UIP pattern on HRCT (2A)
- TBLB may be considered in those patients likely to have ILDs, particularly if the disease has a tendency for bronchocentric involvement such as sarcoidosis and HP (3B).
- The site of biopsy site should be guided by HRCT (usual practice point)
- TBLC may be considered for obtaining biopsy in carefully selected patients with ILD at centers with expertise in the procedure (2A)
- In patients not-at-high risk for surgical complications, the conditional recommendation for the surgical lung biopsy (SLB) made in the 2018 CPG was endorsed by this group and should be considered for diagnosis of ILD based on availability of local surgical expertise if the HRCT does not show a characteristic pattern of a specific ILD subtype (1A)
- VATS lung biopsy should be preferred over open lung biopsy (1A)
- Patients with forced vital capacity (FVC) ≥55% and diffusion capacity (DLCOcorrtoHb) ≥35%, and either absent or only mild PH, are at minimal risk of complications (2B)
- SLB should not be performed in patients with respiratory failure/those on mechanical ventilation as it is associated with risk of high mortality (1A).
| Discussion|| |
A properly performed BAL [Table 3] helps ascertain the cellularity by differential count, rules out infections, especially mycobacterial, fungal, and viral, thereby narrowing the differential diagnoses of ILD. In appropriate clinical settings, BAL specimens are useful to diagnose alveolar proteinosis and alveolar hemorrhage. In resource-limited setting, a properly performed and analyzed BAL may be of particular benefit in non-IPF ILDs. BAL and lung biopsy of any kind are not indicated in patients with known CTD manifesting ILD for the purpose of the specific histopathology diagnosis.
|Table 3: Procedure, handling of specimen and cellular analysis to be done on Bronchoalveolar lavage fluid as per the American Thoracic Society guidelines 2012|
Click here to view
Although BAL is a relatively safe procedure, the risks associated with the procedure and conscious sedation are relative. Rarely, BAL may precipitate an episode of acute exacerbation of underlying ILD. Patients may experience discomfort and/or cough during the procedure. Appropriate standardization of the process and interpretation of BAL results needs to be ensured to minimize variability.
Transbronchial lung biopsy
The diagnostic yield of a TBLB specimen is high in ILD with a peribronchovascular or centrilobular pattern of distribution such as sarcoidosis, HP, PAP, lymphangitis carcinomatosis, and alveolar microlithiasis. Recent reports suggest the utility of TBLB for molecular diagnosis of UIP.,
With the exception of sarcoidosis, TBLB has limitations with diagnostic yield because of the small size of the biopsy specimen, high probability of crush artifacts, sampling errors, inability to penetrate beyond the peribronchial region, and disintegration of the friable tissue. Further, patients with IPF may have NSIP pattern in some areas of their lungs and thus small sized TBLBs may misclassify UIP as NSIP. Bleeding (1%–4%), pneumothorax (1%–6%), and mortality (<0.05%) constitute the main complications.,,
Transbronchial lung cryobiopsy
TBLC has advantages over TBLB by providing larger lung specimens with little crush artefact. The larger size of the specimen increases the probability of sampling the tissue of interest. Previous data has shown that a relatively lower proportion of patients with ILD undergo lung biopsies reflecting the reluctance on part of physician or patient or due to lack of facilities for SLB., Performing a cryobiopsy would bridge the gap of providing larger tissue with good yield without the cost, risk and surgical expertise required for SLB.
The technique is relatively new with varying levels of expertise and lack of standardized and/or validated technique. The rate of complications are variable; pneumothorax (3%–33%), moderate-to-severe bleeding (0%–78%), acute exacerbation, and death (0.04%–4.3%).,,,,,,,,,,,,,,, Due to the risk of complications, the technique should be performed by experts trained and familiar with the technique in carefully selected patients (FVC ≥1.5 L and 50% of predicted, FEV1 ≥0.8 L, DLCO ≥30% of predicted, PaO2 ≥60 mm Hg, absence of extensive fibrotic changes on CT scan, no or mild pulmonary hypertension, no coagulopathy) in only specialized centers.,,,,, It is further suggested that the procedure be performed safely under general anesthesia with an artificial airway (rigid bronchoscope, endotracheal tube, and laryngeal mask airway) in place along with the use of fluoroscopy and prophylactic occlusion balloon/Fogarty balloon catheter/bronchial blocker and with stand by surgeon.,,
Video-assisted thoracic surgery lung biopsy
VATS-associated lung biopsy provides specimen with large size, from multiple lobes and with preserved architecture. This is currently considered as the gold standard for sample collection for histopathological diagnosis by obtaining adequate samples from 2 to 3 lobes increasing the diagnostic yield.
This requires general anesthesia and has associated risks. Postoperative pneumonia, pleural effusion, chronic chest pain, prolonged air leak, acute exacerbation of ILD, requirement of mechanical ventilation, delayed wound healing, neuropathic pain, prolonged hospital stay, readmission to hospital within 1 month of discharge, and death are the complications of SLB.,,,,, Acute exacerbation requires special mention as it is associated with high mortality rates. Complications are more frequently encountered in patients with IPF (compared to other ILDs), FVC <55% or DLCO <35% and those undergoing nonelective SLB.,
Q 4. Should integrated multidisciplinary team-guided discussion be performed?
- The conditional recommendations for the multidisciplinary discussion (MDD) made by the international experts for the diagnosis of ILD were endorsed and the need for the MDD was emphasized whenever there are inconsistencies between clinical, radiological or pathological features (1A)
- MDD should include clinician or pulmonary physician, radiologist, and pathologist (2A)
- Pathologist is not needed for MDD if diagnosis of ILD is established without surgical biopsy and rheumatologist may be part of MDD on case-to-case basis (usual practice point).
| Discussion|| |
Multidisciplinary interaction is vital for improving the initial diagnosis and reducing the number of patients with undifferentiated ILD [Figure 4]. The usefulness of MDD, especially in cases with atypical findings, and its clinical utility or better management has been well documented.,,,,, Telephone, conference calling, communication by texting via smartphones, other current and/or evolving digital/electronic means and E-mails are appropriate means of communication among experts, provided they allow a thorough two-way interaction.
|Figure 4: Advantages of multidisciplinary discussion in diagnosis of interstitial lung disease|
Click here to view
While there are no undesirable effects from the patients perspective, face-to-face MDD may not be feasible for all patients with ILD. It is unclear if all patients with ILD need a MDD by experienced experts for accurate diagnosis. The need for MDD in difficult cases, especially for the ones that are atypical, unclassifiable, or newly diagnosed, is evident.,, Largely, the decision will depend on the experience of the MDD team.
Q 5. What are the essential diagnostic “evaluation” needed for patients with severe interstitial lung disease presenting with respiratory failure at the initial visit (and are not in acute exacerbation)?
- The panel endorsed the following standard of care for all patients with interstitial lung disease with respiratory failure at initial evaluation
- Detailed history
- Complete blood count
- A comprehensive metabolic panel including, liver and kidney function tests and serum electrolytes
- Chest radiograph and HRCT chest
- Pulse oximetry
- Arterial blood gases (if SpO2 < 90%)
- Additional tests to be considered at the initial visit include connective tissue disease markers (rheumatoid factor, antinuclear antibody (ANA), myositis panel, anticyclic citrullinated peptide).
Following tests may be considered in selected patients with severe ILD
- Transthoracic echocardiogram, cardiac enzymes (clinical suggestion, acute worsening)
- CT pulmonary angiography (only if acute worsening)
- BAL cellular analysis or any biopsy procedure should be avoided
- BAL can be considered to rule out infection only if clinically indicated and indispensable for decision-making.
| Discussion|| |
There was no evidence pertaining to this question. A typical scenario was presented to the working group. The panel advocated detailed history and tests for diagnosis of ILD and also tests to rule out concomitant cardiac or pulmonary vascular disorders.
The investigations of the clinical scenario would provide clues to the specific subtype of ILD; in addition, they may help in identifying diagnosing comorbid conditions that might possibly leading to deterioration of the patient.
Other than the costs involved in conducting the investigations, the working group did not find any untoward side effect of the investigations.
Q 6. Should the following tests be done to monitor progress of interstitial lung disease?
- Forced vital capacity (FVC)
- Diffusion capacity
- Disease monitoring in IPF is advised at 4–6-month interval with FVC (2A), DLCOcorrtoHb (3A), 6-min walk test: For distance and SpO2 measurements (2A) and Medical Research Council Dyspnea Score (MRCDS)
- HRCT chest determined/guided by clinical needs/indicated (usual practice point)
- In other ILDs, the panel suggested FVC at 6 months interval till clinical stability is achieved, thereafter every 12 months (3A). DLCOcorrtoHb may be repeated yearly. The role of 6MWT in CTD associated ILDs is limited due to presence of various confounding factors (usual practice point).
| Discussion|| |
The working group endorses the use of pulmonary function tests in prognosticating ILD. A marginal decline of 5%–10% in FVC has also been proposed as indicator of significant disease progression and mortality in some studies. Patients who are too sick to perform the tests may be evaluated with MRCDS [Figure 5].,
|Figure 5: Investigations conducted during follow-up of patient with interstitial lung disease|
Click here to view
Lung function tests and 6-min walk test provide objective tools to judge treatment response and disease progression. Deterioration of patient can be assessed by these tests to diagnose whether deterioration is due to worsening disease or comorbid illness.
Other than the cost and the effort to perform the tests which some patient may find uncomfortable, there are no untoward effects of the investigations. The standard 6 MWT that utilizes finger oximetry for assessing oxygenation may give false reading in some patients with Raynaud's phenomenon, sclerodactyly, dysrhythmia, and methemogobinemia.
Q 7. What are the common comorbidities in interstitial lung disease and how to screen for them?
- Most common comorbidities encountered in ILD are gastroesophageal reflux disease (GERD), pulmonary hypertension (PH), lung cancer, obstructive sleep apnea (OSA), and venous thromboembolism (VTE)
- Screening tools for monitoring comorbidities in ILD patients are:
- GERD: A validated GERD questionnaire (3A)
- PH: Echocardiography as a screening tool for PH/PAH in ILD patients (3A). ILD patients though right heart catheterization remains the gold standard for documenting the diagnosis. [3A]
- CT for Lung cancer: A significant smoking history (2A), chest pain (3A), hemoptysis (3A), and areas of emphysema on HRCT (2A) act as warning signs for lung cancer and should trigger a search for the same.
- OSA: ILD patients with high body mass index (BMI) (3A) and a positive sleep apnea screening questionnaire (3A) may be evaluated by polysomnography
- VTE: Sudden onset and/or rapid worsening of dyspnea, palpitations, lower extremity edema with positive wells or revised Geneva score may act as trigger to search for VTE (3A).
| Discussion|| |
Diagnosis and treatment of comorbid conditions associated with ILD would likely improve outcome and the quality of life of patients.,,,,,,,,,
Other than the associated costs, there are no untoward effects of the investigations.
The cost-effectiveness of CT screening for lung cancer is unknown in low-resource and tuberculosis-endemic settings.
Q 8. Should following therapies be used for management of cough in interstitial lung disease?
- A short trial of oral prednisolone in distressing cough associated with IPF is an appropriate consideration (3B)
- Gabapentin may be tried for intractable cough (3B)
- Thalidomide may be tried for intractable/distressing cough associated with IPF (2B)
- Every effort should be made to identify and treat the comorbid conditions influencing cough in ILD (usual practice point).
| Discussion|| |
Evaluation and treatment for comorbid conditions that might explain other reasons of cough may lead to targeted treatment and reduction in cough frequency in some patients. Empirical trial of a short course of prednisolone, gabapentin, or thalidomide may be worthwhile for the potential desirable effect of suppressing intractable cough [Figure 6].
|Figure 6: Flow chart describing the steps of nonspecific and specific therapies in the treatment of cough associated with interstitial lung disease|
Click here to view
Drug adverse effects are the undesirable consequences of the use of such agents for cough control. Weighing the risk benefit ratio, a short course may be attempted in cases of debilitating cough.
Q 9. Should following therapies be used for management of dyspnea in progressive interstitial lung disease?
- Pulmonary rehabilitation
- Supplemental oxygen
- Nebulized opioid therapy.
The workinggroup suggests:
- Pulmonary rehabilitation in dyspneic patients with ILD (2A)
- Supplemental oxygen in patients with documented resting hypoxemia and/or exercise-induced hypoxemia, and desaturation while sleeping (2B)
- Long-term oxygen therapy (LTOT) for patients with ILD who have persistent resting hypoxemia (3A)
- Nebulized opioid therapy is not beneficial to relieve dyspnea in all ILD patients and may be used only for patients receiving comfort and palliative care (2A).
| Discussion|| |
Pulmonary rehabilitation is useful for patients to cope with dyspnea, inactivity, and reduced quality of life. The beneficial effects in symptoms, physical activity, 6 min walk distance, and quality of life have been documented.,
Oxygen therapy alleviates symptoms of dyspnea, improves activity, dyspnea scores, and walk distance. Opioid therapy does not relieve dyspnea in all ILD patients  and may be helpful in small group with end stage lung disease, primarily for palliative care.
Pulmonary rehabilitation has no beneficial effects on survival. The effects last as long as program is continued. The lack of facilities in reasonable proximity to patients' home and cost of travelling to such facilities pose additional logistic challenges.
Cost of oxygen therapy, emotional willingness, and behavioral changes to accept the dependency upon supplemental oxygen for daily activities either continuously or as needed at home and in public places and fire hazards associated with inadvertent oxygen use are some of the undesirable consequences that patients will need to be aware of.
Concomitant respiratory depression, addiction, altered mental status, lethargy, excessive sleep, and side effects such as constipation are undesirable consequences of the therapy.
Q 10. Should patients with interstitial lung disease receive vaccination against influenza and pneumococci?
- The working group endorsed the recommendation by ACIP (Advisory Committee on Immunization Practices) for vaccinations (influenza and Pneumococci) for all patients with ILD (usual practice point).
| Discussion|| |
Influenza and pneumococcal vaccinations have been associated with decreased infection and fewer exacerbations, hospital visits, admissions, and death in patients with chronic lung disease.,,,
Minimal chances of allergic reactions and cost are the undesirable consequences.
Q 11. Should pulmonary hypertension associated with interstitial lung disease be treated with medications indicated for pulmonary hypertension?
- The group endorses the guidelines for management of chronic PH-specific therapy for patients with PH (1A) and the treatment of underlying lung disease as the mainstay of therapy and supplemental oxygen in cases of hypoxemia.,
- Ambrisentan is contraindicated in patients with PH related to IPF. The therapeutic benefits of other PH-specific therapy in ILD-related PH remains unknown (2A).
| Discussion|| |
The group acknowledged the ambiguous results of studies evaluating role of various drugs in PH associated with ILD.,,, Potential therapeutic benefits with use of sildenafil in patients with severe lung function impairment in improving gas exchange status and quality of life might be considered for the well informed patient particularly with right ventricular dysfunction.,
Ambrisentan has been associated with disease progression and increased hospitalization in IPF, and is thus contraindicated in the same. Side effects associated with other medications use for the management of PH include systemic hypotension, liver toxicity, and require monitoring for known side effects.
Q 12. Should noninvasive ventilation (NIV) and mechanical ventilation (MV) be used in patients with interstitial lung disease?
- Consideration of NIV as early as possible in patients who require high-flow supplemental oxygen at rest, especially in patients manifesting acute exacerbation (AE)-ILD with respiratory failure as it has been associated with better short term outcomes (2A).
- The consideration of MV in patients with AE ILD with respiratory failure should be made only after proper counseling (2A)
| Discussion|| |
NIV has been shown to improve dyspnea and respiratory failure in a subset of patients., MV may help tide over short term respiratory failure due to reversible causes.
Apart from the cost of NIV, asynchrony with ventilator, the inability to communicate, eat, and drink are hindrances to its use.
MV is associated with increased mortality and worse outcomes in patients with acute exacerbation of ILD. Thus, it should be applied after weighing risk benefit ratio on case to case basis.
Q 13. Should lung transplantation be advised to patients with interstitial lung disease?
- Lung transplantation is the only treatment with clearly proven survival benefit in advanced ILD, especially IPF, and should be considered in carefully selected patients (2A).
| Discussion|| |
Lung transplant is a viable option with proven survival benefits in selected patients with end stage fibrotic lung disease.
Posttransplant survival is variable in lung transplant programs. While the 5-year survival in most experienced lung transplant programs is about 70%, less experienced programs have lesser survival rates. Patients and their care givers may need to relocate to places away from their homes to be close to lung transplant programs. Psychosocialstress, financial restrains/burden, side effects of the procedure, and medications are all significant limitations.
Q 14. Should palliative care be advised to patients with interstitial lung disease?
- The working group suggests that all patients with advanced ILDs receive palliative care to improve quality of life (1A)
- Multidisciplinary collaborative care for the potential of reduced rates of respiratory related hospitalizations and death (2A).
| Discussion|| |
The most prominent symptoms in a terminally ill ILD patient are dyspnea, cough, depression, and heart burn. Palliative care aims at addressing these symptoms with the aim to provide a better quality of life through pulmonary rehabilitation,, morphine, oxygen therapy, NIV, and antireflux therapy for gastroesophageal reflux  [Figure 7].
|Figure 7: Components of palliative care to be administered to patients with interstitial lung disease|
Click here to view
The side effects of the medications used to alleviate the symptoms to comfort the patient may limit the optimum benefits for the patient; there are no survival benefits.
Questions, statements, and remarks summarized for a few specific interstitial lung disease
Q 15. Should serum precipitins be done to evaluate for HP?
- Based on lack of standardization and lack of validated testing antigens, the working group opined against obtaining serum for precipitins routinely for patients with ILD (2A).
A raised serum precipitin in conjugation with appropriate clinical presentation, radiology, and biopsy may prompt further diagnostic evaluation that might lead toward a diagnosis of HP.
However, they have variable diagnostic accuracies with positive results in exposed healthy individuals and negative results in patients with HP., While the positive test merely indicates the exposure, the test is insensitive and thus the awareness of the presence or absence of the specific IgG may not be helpful for all patients.
Q 16. Should following drugs be used in the treatment of HP?
- Oral corticosteroids
- Mycophenolate (MMF).
- Oral corticosteroids for 4–12 weeks are an appropriate treatment option for patients with acute/subacute HP with monitoring of lung function parameters and side effects (1A)
- Prolonged use of oral steroids (2A), azathioprine, and MMF (3A) should be based on clinical response and tolerance.
| Discussion|| |
In patients with acute HP, there is improvement in symptoms and lung functions with oral corticosteroid. However, this benefit is not sustained over long term. Limited retrospective data is available on role of immunosuppressants in chronic HP with studies claiming improvement in lung functions, diffusion, and steroid sparing effects.
Side effects of specific therapy [Table 4] in addition to the costs incurred are the undesirable side effects. Continued immunosuppression may have impact on survival. In countries with high prevalence of tuberculosis, monitoring for new or recurrent tubercular infection should be done. Short-term use of oral corticosteroids in HP has been advised by the group based on a RCT conducted over 25 years ago. There is a lack of evidence pertaining to duration and dose of corticosteroids for long-term therapy in HP. Prolonged use of corticosteroids and other immunosuppressants should be prescribed after weighing benefit of individual response and side effects associated with the drugs [Table 4].
|Table 4: Doses, side effects and management of side effects of commonly used drugs in the treatment of interstitial lung disease|
Click here to view
Inability to identify the inciting antigen is associated with worse survival. Thereby, every effort should be made to identify the inciting antigen. The antigen may be unique to the area of residence depending on occupation, environment, and local customs; thus, enquiry should be directed to determining the exposure in a detailed manner.
Q 17. Should pirfenidone and nintedanib be used in the treatment of idiopathic pulmonary fibrosis?
- All symptomatic IPF patients with FVC of >50% predicted should be initiated on pirfenidone (1B)
- The patients on pirfenidone developing ≥10% subsequent decline in FVC in any 6–12 months period should be given a choice of continuation of therapy or switch to an alternative therapy depending on case to case basis (UPP)
- All symptomatic IPF patients with FVC of >50% predicted should be initiated on nintedanib (1B)
- The patients on nintedanib developing ≥10% subsequent decline in FVC in any 6–12 months period should be given a choice of continuation of therapy or switch to an alternative therapy on case to case basis (UPP)
- Either Pirfenidone or Nintedanib may be chosen for patients with IPF based on patient preference and tolerability (UPP).
| Discussion|| |
Pirfenidone has been associated with slowing of the absolute decline in FVC, increases progression-free survival, and reduces mortality. Nintedanib has been associated with reduction in decline in predicted FVC, acute exacerbation and risk of all cause, and respiratory related and on treatment mortality.,
Side effects of the drugs [Table 4] in addition to their cost are the undesirable effects. Duration of treatment is life-long.
Q 18. Should N-acetylcysteine be used in the treatment of IPF?
- NAC is currently not recommended for routine treatment of IPF and may be considered in certain subgroups on a case to case basis (UPP).
| Discussion|| |
NAC has not shown any beneficial effects on lung functions, adverse outcomes and death. A genotype analysis of single nucleotide polymorphism(SNPs) of patients with IPF found that TOLLIP polymorph rs3750920 TT was associated with favourable response to NAC while CC polymorph was associated with increased mortality.
Side effects such as nausea and vomiting and cost are other issues.
Q 19. Should combination therapy be used for IPF?
- More evidence is needed to recommend use of pirfenidone in combination with nintedanib or NAC and the dose of individual drugs to be used in such therapy in patients with IPF.
Large randomized controlled trials are needed to compare combination therapy with placebo before advocating the same.
The side effects and cost of therapy are more in case of combination therapy.
Q 20. Should antiacid therapy be used in the treatment of IPF?
- The committee suggests that antiacid treatment may be initiated in patients with IPF at the time of diagnosis (3B).
There have been conflicting studies on the efficacy of antiacid treatment in patients with IPF with some reporting lesser mortality whereas others have not found significant improvement.,, Antireflux surgery has shown to have nonsignificant improvement in FVC, acute exacerbations and mortality.
Side effects are minimal for medical management of reflux disease. Surgical complications are associated with laparoscopic reflux surgery.
Q 21. Should ANA testing be performed in patients with interstitial lung disease?
- All patients with ILD should undergo ANA testing (by indirect immunofluorescence method), rheumatoid factor (RF) and anti-CCP testing at baseline (3A)
- Additional serologic testing should be advised in patients with a high pre-test probability for connective tissue disease (CTD)-ILD (3A)
- Repeat serological testing is indicated in presence of signs and symptoms of CTD (if previously negative) (3A)
- Repeat serological testing is not indicated in previously screened serology positive CTD ILD patients (3B).
| Discussion|| |
ANA testing is vital to rule out CTD-ILD, since many a times ILD may be the only manifestation of autoimmune disease.
Not all autoimmune ILDs have a positive ANA panel. Cost effectiveness has not been ascertained despite it being recommended as a screening test in 2011 and 2018 guidelines. The group endorsed and reinstated the recommendation made in the 2018 guideline even in context of resource-limited settings. The diagnosis of ILD requires meticulous evaluation for an underlying CTD, with major implications for prognosis and management.
Q 22. Rheumatoid arthritis associated interstitial lung disease
- Should steroids be used to treat patients of RA-ILD?
- Should following drugs such as cyclophosphamide, mycophenolate mofetil, and rituximab be used in the treatment of RA-ILD?
- Should drugs such as methotrexate, leflunomide, and antitumor necrosis factor (TNF) be continued for the treatment of RA who develops ILD?
- Corticosteroids may be used in the treatment of RA-ILD (3B)
- Cyclophosphamide (2B), mycophenolate mofetil (2B), and rituximab (3B) may be used in the treatment of RA-ILD in case of no response to corticosteroids
- Role of other drugs in RA patients who develop ILD:
- Methotrexate should be discontinued in patients of RA diagnosed with ILD (2B)
- Leflunomide can be continued in patients diagnosed with RA-ILD (1B)
- Other antitumor necrosis factor (TNF) agents may be used cautiously (3B).
| Discussion|| |
The treatment of RA-ILD with anti-inflammatory agents is complex as the evidence is very low. Considerable debate and discussion amongst the working group was held. Many of drugs used in the treatment of RA are associated with causing ILD; thereby, there were no consensus reached-section is divided into the drugs used in the treatment of RA-ILD and whether some of the drugs should be continued in RA patients who develop ILD.
Corticosteroids are anti-inflammatory drugs which help suppress disease activity leading to improvement insymptoms and lung functions.,, Additional immunosuppressants such cyclophosphamide, MMF, and rituximab have steroid sparing effects.,,
Immunosuppression and potential side effects associated with individual agents and infection is of significant concern and patients will need frequent monitoring through blood counts during visits. In addition, there is propensity to cause ILD by some of the immunosuppressants such as methotrexate., While these risks are relative, the patient will need appropriate monitoring to detect adverse effects that may require prompt intervention.
Q 23. Scleroderma associated interstitial lung disease
- Should steroids be used to treat patients of scleroderma associated ILD (SSC-ILD)?
- Should drugs such as cyclophosphamide, mycophenolate mofetil, and azathioprine be used to treat patients of SSC-ILD?
- Should Rituximab be used to treat patients of SSC-ILD?
- Low-dose steroids may be continued in the treatment of SSC-ILD. High-dose steroids should be avoided in scleroderma as it is associated with risk of renal crisis (2B)
- Treatment in SSC-ILD may be initiated in cases with progressive disease with either cyclophosphamide or mycophenolate mofetil (1A)
- Mycophenolate mofetil has better tolerability and lesser side effects, though more expensive (1A)
- Azathioprine is an alternate drug for maintenance therapy in SSC-ILD (1A)
- Rituximab could be considered in patients with refractory scleroderma. It should be administered at tertiary care level after evaluating for the pros and cons of treatment (2B).
| Discussion|| |
Corticosteroids and other drugs have been associated with improvement in dyspnea, lung functions, and quality of life.
High-dose corticosteroids may precipitate renal crisis in patients with SSC-ILD. Immunosuppression and secondary infection are a dreaded complication of these drugs. Effect lasts till the drugs are taken and there is no long lasting benefits. Based on scleroderma lung study I and II, the working group endorsed the use of either cyclophosphamide, MMF, or azathioprine for the treatment of SSC-ILD., MMF is equivalent to cyclophosphamide though with better safety profile.
The group acknowledged the awareness of ongoing clinical trials with antifibrotic agents – pirfenidone and nintedanib and were not aware of the data published since. Nintedanib, an anti-fibrotic drug has been shown to reduce the annual decline in lung functions associated with SSC-ILD. However, there was no advantage on the other manifestations of the SSC.
Q 24. Should serum ACE be done to evaluate for sarcoidosis?
- The group did not consider the utility of measuring serum ACE routinely for the diagnosis of sarcoidosis (2A).
| Discussion|| |
Poor sensitivity and specificity along with unwarranted cost have precluded ACE as test of choice for sarcoidosis.,
Q 25. Should endobronchial biopsy, transbronchial lung biopsy, and transbronchial needle aspiration be performed in diagnosis of sarcoidosis?
- Combined EBB, TBLB, and TBNA has the maximum yield for the diagnosis of pulmonary sarcoidosis (1A)
- The choice of technique used for TBNA (conventional or endobronchial ultrasound, EBUS) is deferred to the operator when performed in conjunction with EBB and TBLB (1A).
| Discussion|| |
The working group reviewed the available literature and unanimously agreed that combination of procedures such as TBNA, TBLB, and endobronchial biopsies lead to higher yield in diagnosing sarcoidosis rather than either procedure alone.,,,
Combining the three procedures increases the duration and cost. Combining TBLB to TBNA and EBB would increase risk of bleeding and pneumothorax, which were minimal with only former two procedures.
Q 26. Should following drugs be used in the treatment of pulmonary sarcoidosis?
- Observe patients without pharmacological interventions in patients who are asymptomatic stage 0/1 pulmonary sarcoidosis (1A)
- Treat patients with symptomatic stage 1 and all stage 2,3 and 4 pulmonary sarcoidosis with oral corticosteroids (1A)
- Additional immunosuppressant – methotrexate (2A), azathioprine (3A/B), leflunomide (3A), and hydroxychloroquine – may be tried in patients not responding to oral steroids or with associated steroid toxicity
- Infliximab may be tried after carefully weighing the risk benefit ratio in patients with refractory pulmonary sarcoidosis (1A).
| Discussion|| |
Corticosteroids improve dyspnea score, lung functions and radiology in sarcoidosis.,, Other immunosuppressants may be given in resistant cases or those on high-dose corticosteroids.,,, They have steroid sparing and therapeutic effects [Figure 8].
Corticosteroids have no significant benefits for asymptomatic stage 0/1 sarcoidosis. Moreover, the effects last as long as they are used. There is no long-term benefits in term of lung functions. Immunosuppression is another concerning feature not only for corticosteroids but for other immunosuppressants as well.
Q 27. Should steroids and cyclophosphamide be used in the treatment of idiopathic nonspecific interstitial pneumonia?
- Oral corticosteroids are suggested for the treatment of iNSIP (3B)
- Immunosuppressants such as cyclophosphamide may be used as add-on therapy in patients not responsive to steroids (3B).
| Discussion|| |
Corticosteroids improves symptom score and lung function with response more pronounced in cellular NSIP, concomitant consolidation, seronegative ANA and shorter disease duration.,,
Risk of immunosuppression including bacterial and mycobacterial infections is the dreaded complication and may impact survival. The current approach relies on retrospective studies; RCT's are lacking, probably due to the ambiguity with regards to the diagnosis of iNSIP. In asymptomatic or mildly symptomatic cases close observation is often done, as the risk of treatment outweighs the benefits. In symptomatic patients, oral corticosteroids are the mainstay of therapy.
Q 28. Should silica exposure and tobacco smoke inhalation be avoided in patients with silicosis?
- Avoidance of continued exposure to silica and direct inhalation of tobacco products is advisable (usual practice point).
| Discussion|| |
Avoidance of exposure is vital to avoid harmful effects of silica on the lungs. Tobacco products need to be avoided to prevent concomitant illnesses such as chronic obstructive lung disease and lung cancer.
Other than logistic issues of finding an alternate occupation, there are no undesirable effects. Preventive, remedial, rehabilitative measures should be implemented as silicosis is an incurable disease. Legislations and bills to promote a safe working environment are essential throughout the world.
Q 29. Should the following therapies be offered to patient with silicosis?
- Oral corticosteroid
- Aluminum inhalation
- Whole lung lavage
- Rehabilitation and exercise training.
- No Corticosteroids for routine treatment of acute or chronic silicosis as the risk benefit balance seems to disfavor their use (3A)
- Aluminum inhalation for the treatment of silicosis is not advised (3A)
- Whole lung lavage as potential benefits in the treatment of alveolar proteinosis due to acute silicosis/silicoproteinosis may be suggested in carefully selected patient population at specialized centers (3B)
- Rehabilitation and exercise training of at least 4–8 weeks is advised for potential beneficial effects in terms of improvement in exercise capacity and quality of life in patients with chronic silicosis (1B).
| Discussion|| |
Corticosteroids and aluminum may have improvement in symptoms of dyspnea. However, risk outweighs harm. In cases of acute silicosis, whole lung lavage may be attempted, which may lead to improvement in lung functions., Exercise training has the benefit of improving quality of life and exercise capacity.,
The risk associated with immunosuppression caused due to corticosteroids far outweighs the benefits which are minimal. Similarly, aluminum is associated with impaired cognition and dementia. Experimental therapies such whole lung lavage is associated with risk of it being an invasive procedure with complications such as respiratory failure and side effects of sedatives. Exercise training done under supervision has minimal side effects other than cost and logistics. Various modalities have been tried in past for the treatment of silicosis but most lack efficacy or have potential for serious side effects. Currently pulmonary rehabilitation is the only modality that improves quality of life for patients with chronic silicosis.
Approach to a patient suspected to have interstitial lung disease
A careful history of symptoms, including symptoms suggestive of CTD, environmental exposures, occupational, and family history should be taken. A thorough clinical examination for signs of extrapulmonary involvement in CTD-ILD should be taken [Figure 9]. An algorithm is provided in [Figure 10].
|Figure 9: Physical examination findings in various connective tissue diseases. (a) Vasospasm induced blanching of finger tips in patient suggestive of Raynaud's phenomenon in scleroderma; (b) Resorption of peripheries suggestive of sclerodactyly in scleroderma; (c) Raised papules on dorsum of proximal inter-pharyngeal joints suggestive of gottron's papules in dermatomyositis; (d) Scaly lesions in the hands suggestive of mechanic's hands seen in dermatomyositis; (e) swan neck deformity due to hyperextension of the proximal interphalangeal joint and flexion of the distal interphalangeal joint in a case with rheumatoid arthritis. (f) Raised papules on eyelid suggestive of heliotrope rash in dermatomyositis; (g and h) Increased skin folds around mouth and restricted mouth opening in patient of scleroderma|
Click here to view
|Figure 10: Algorithm providing approach to patient suspected to have interstitial lung disease|
Click here to view
The intent of providing this document was to guide the clinicians in the community with consensus of the opinion of experts based on their experience and systematic review of the evidence. We acknowledge the limitations of the methodology used to develop this document. First, the document reflects the opinions of the selected participants including only one rheumatologist. Second, meta-analysis was not done and there was no methodologist involved in the project. Acknowledging that the task force committee reached the consensus of the evidence discussed in 2018, pertinent new reports published since have not been discussed by the committee and incorporated in this document. These include the results of the INBUILD trial published in Oct 2019 and of subgroup analyses of the trial as well as the just published guideline on diagnosis and detection of sarcoidosis.
Evidence-based CPG for individual ILD are needed and for this to materialize, well designed, prospective studies are warranted. These include studies to determine the diagnostic accuracy and yield of lung biopsy techniques. Molecular signatures, genomic classifiers, machine learning tools, and circulating biomarkers in non-IPF fibrotic lung diseases are needed to make a diagnosis with MDD and without the requirement of surgical lung biopsy for the conventional histopathology features to differentiate the UIP patterns associated with ILD other than IPF. It is hoped that ongoing and future clinical trials will determine the safety and efficacy of currently available and new pharmacological as well as nonpharmacological interventions for non-IPF fibrotic ILD's.
| Conclusion|| |
For the very first time, extensive literature search, review, and discussion of available evidence was done by a working group to formulate the consensus statement for management of ILD in general and for a few specific ILD, other than IPF. The consensus statements provide an understanding of the current clinical practices and a suggested framework for the practicing physicians when confronted with patient presenting with ILD. The clinicians should apply the statements made in the clinical context of individual patient, considering the patient's values and preferences, and should not consider these statements as CPG or mandates.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Indian Chest Society and National College of Chest Physicians.
Conflicts of interest
GR 47 has received grant from NIH for IPF studies, personal fees from Roche, Boerhinger Ingelheim and Respivant for consultancy for IPF studies. He is consultant for IPF studies for BMS, Bellerophan, Fibrogen, Gilead, Nitto, Promedior, Sanofi, Veracyte, Biogen, Genentech and Avalyn.
| References|| |
ATS Committee on Proficiency Standards for Clinical Pulmonary Function Laboratories. ATS statement: Guidelines for the six-minute walk test. Am J Respir Crit Care Med 2002;166:111-7.
Culver BH, Graham BL, Coates AL, Wanger J, Berry CE, Clarke PK, et al
. Recommendations for a standardized pulmonary function report. An Official American Thoracic Society Technical Statement. Am J Respir Crit Care Med 2017;196:1463-72.
Collard HR, King TE Jr., Bartelson BB, Vourlekis JS, Schwarz MI, Brown KK. Changes in clinical and physiologic variables predict survival in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2003;168:538-42.
Hamada K, Nagai S, Tanaka S, Handa T, Shigematsu M, Nagao T, et al
. Significance of pulmonary arterial pressure and diffusion capacity of the lung as prognosticator in patients with idiopathic pulmonary fibrosis. Chest 2007;131:650-6.
The diagnosis, assessment and treatment of diffuse parenchymal lung disease in adults. Introduction. Thorax 1999;54 Suppl 1:S1-14.
Pietinalho A, Tukiainen P, Haahtela T, Persson T, Selroos O. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: A double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Study Group. Chest 1999;116:424-31.
Distler O, Highland KB, Gahlemann M, Azuma A, Fischer A, Mayes MD, et al
. Nintedanib for systemic sclerosis-associated interstitial lung disease. N Engl J Med 2019;380:2518-28.
Karimi-Shah BA, Chowdhury BA. Forced vital capacity in idiopathic pulmonary fibrosis–FDA review of pirfenidone and nintedanib. N Engl J Med 2015;372:1189-91.
Sverzellati N. Highlights of HRCT imaging in IPF. Respir Res 2013;14 Suppl 1:S3.
Bankier AA, Tack D. Dose reduction strategies for thoracic multidetector computed tomography: Background, current issues, and recommendations. J Thorac Imaging 2010;25:278-88.
Naidich DP, Marshall CH, Gribbin C, Arams RS, McCauley DI. Low-dose CT of the lungs: Preliminary observations. Radiology 1990;175:729-31.
Zwirewich CV, Mayo JR, Müller NL. Low-dose high-resolution CT of lung parenchyma. Radiology 1991;180:413-7.
Sverzellati N, Zompatori M, De Luca G, Chetta A, Bnà C, Ormitti F, et al
. Evaluation of quantitative CT indexes in idiopathic interstitial pneumonitis using a low-dose technique. Eur J Radiol 2005;56:370-5.
Sverzellati N, Guerci L, Randi G, Calabrò E, La Vecchia C, Marchianò A, et al
. Interstitial lung diseases in a lung cancer screening trial. Eur Respir J 2011;38:392-400.
Baumueller S, Winklehner A, Karlo C, Goetti R, Flohr T, Russi EW, et al
. Low-dose CT of the lung: Potential value of iterative reconstructions. Eur Radiol 2012;22:2597-606.
Raghu G, Remy-Jardin M, Myers JL, Richeldi L, Ryerson CJ, Lederer DJ, et al
. Diagnosis of idiopathic pulmonary fibrosis. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline. Am J Respir Crit Care Med 2018;198:e44–e68.
Meyer KC, Raghu G, Baughman RP, Brown KK, Costabel U, du Bois RM, et al
. An official American Thoracic Society clinical practice guideline: the clinical utility of bronchoalveolar lavage cellular analysis in interstitial lung disease. Am J Respir Crit Care Med 2012;185:1004–14.
Chockalingam A, Duraiswamy R, Jagadeesan M. Bronchoalveolar lavage cellular analyses in conjunction with high-resolution computed tomography imaging as a diagnostic intervention for patients with suspected interstitial lung disease. Lung India 2016;33:287–91.
] [Full text]
Sindhwani G, Shirazi N, Sodhi R, Raghuvanshi S, Rawat J. Transbronchial lung biopsy in patients with diffuse parenchymal lung disease without 'idiopathic pulmonary fibrosis pattern' on HRCT scan: experience from a tertiary care center of North India. Lung India 2015;32:453–6.
] [Full text]
Kim SY, Diggans J, Pankratz D, Huang J, Pagan M, Sindy N,et al
. Classification of usual interstitial pneumonia in patients with interstitial lung disease: assessment of a machine learning approach using high-dimensional transcriptional data. Lancet Respir Med 2015;3:473–82.
Pankratz DG, Choi Y, Imtiaz U, Fedorowicz GM, Anderson JD, Colby TV, et al
. Usual interstitial pneumonia can be detected in transbronchial biopsies using machine learning. Ann Am Thorac Soc 2017;14:1646–54.
Flaherty KR, Travis WD, Colby TV, Toews GB, Kazerooni EA, Gross BH, et al
. Histopathologic variability in usual and nonspecific interstitial pneumonias. Am J Respir Crit Care Med 2001;164:1722–7.
Sehgal IS, Bal A, Dhooria S, Agrawal P, Gupta N, Ram B, et al
. A prospective randomized controlled trial comparing the efficacy and safety of cup vs. alligator forceps for performing transbronchial lung biopsy in patients with sarcoidosis. Chest 2016;149:1584-6.
Ganganah O, Guo SL, Chiniah M, Li YS. Efficacy and safety of cryobiopsy versus forceps biopsy for interstitial lung diseases and lung tumours: A systematic review and meta-analysis. Respirology 2016;21:834-41.
Singh S, Collins BF, Sharma BB, Joshi JM, Talwar D, Katiyar S, et al
. Interstitial lung disease in India. Results of a prospective registry. Am J Respir Crit Care Med 2017;195:801-13.
Dhooria S, Agarwal R, Sehgal IS, Prasad KT, Garg M, Bal A, et al
. Spectrum of interstitial lung diseases at a tertiary center in a developing country: A study of 803 subjects. PLoS One 2018;13:e0191938.
Iftikhar IH, Alghothani L, Sardi A, Berkowitz D, Musani AI. Transbronchial lung cryobiopsy and video-assisted thoracoscopic lung biopsy in the diagnosis of diffuse parenchymal lung disease. A meta-analysis of diagnostic test accuracy. Ann Am Thorac Soc 2017;14:1197-211.
Kropski JA, Pritchett JM, Mason WR, Sivarajan L, Gleaves LA, Johnson JE, et al
. Bronchoscopic cryobiopsy for the diagnosis of diffuse parenchymal lung disease. PLoS One 2013;8:e78674.
Hernández-González F, Lucena CM, Ramírez J, Sánchez M, Jimenez MJ, Xaubet A, et al
. Cryobiopsy in the diagnosis of diffuse interstitial lung disease: Yield and cost-effectiveness analysis. Arch Bronconeumol 2015;51:261-7.
Pajares V, Puzo C, Castillo D, Lerma E, Montero MA, Ramos-Barbón D, et al
. Diagnostic yield of transbronchial cryobiopsy in interstitial lung disease: A randomized trial. Respirology 2014;19:900-6.
Griff S, Schönfeld N, Ammenwerth W, Blum TG, Grah C, Bauer TT, et al
. Diagnostic yield of transbronchial cryobiopsy in non-neoplastic lung disease: A retrospective case series. BMC Pulm Med 2014;14:171.
Fruchter O, Fridel L, El Raouf BA, Abdel-Rahman N, Rosengarten D, Kramer MR. Histological diagnosis of interstitial lung diseases by cryo-transbronchial biopsy. Respirology 2014;19:683-8.
Hagmeyer L, Theegarten D, Wohlschläger J, Treml M, Matthes S, Priegnitz C, et al
. The role of transbronchial cryobiopsy and surgical lung biopsy in the diagnostic algorithm of interstitial lung disease. Clin Respir J 2016;10:589-95.
Tomassetti S, Wells AU, Costabel U, Cavazza A, Colby TV, Rossi G, et al
. Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2016;193:745-52.
Ravaglia C, Bonifazi M, Wells AU, Tomassetti S, Gurioli C, Piciucchi S, et al
. Safety and diagnostic yield of transbronchial lung cryobiopsy in diffuse parenchymal lung diseases: A comparative study versus video-assisted thoracoscopic lung biopsy and a systematic review of the literature. Respiration 2016;91:215-27.
Dhooria S, Sehgal IS, Aggarwal AN, Behera D, Agarwal R. Diagnostic yield and safety of cryoprobe transbronchial lung biopsy in diffuse parenchymal lung diseases: Systematic review and meta-analysis. Respir Care 2016;61:700-12.
Casoni GL, Tomassetti S, Cavazza A, Colby TV, Dubini A, Ryu JH, et al
. Transbronchial lung cryobiopsy in the diagnosis of fibrotic interstitial lung diseases. PLoS One 2014;9:e86716.
Johannson KA, Marcoux VS, Ronksley PE, Ryerson CJ. Diagnostic yield and complications of transbronchial lung cryobiopsy for interstitial lung disease. A systematic review and metaanalysis. Ann Am Thorac Soc 2016;13:1828-38.
Ussavarungsi K, Kern RM, Roden AC, Ryu JH, Edell ES. Transbronchial cryobiopsy in diffuse parenchymal lung disease: Retrospective analysis of 74 cases. Chest 2017;151:400-8.
Lentz RJ, Taylor TM, Kropski JA, Sandler KL, Johnson JE, Blackwell TS, et al
. Utility of flexible bronchoscopic cryobiopsy for diagnosis of diffuse parenchymal lung diseases. J Bronchology Interv Pulmonol 2018;25:88-96.
Ramaswamy A, Homer R, Killam J, Pisani MA, Murphy TE, Araujo K, et al
. Comparison of transbronchial and cryobiopsies in evaluation of diffuse parenchymal lung disease. J Bronchology Interv Pulmonol 2016;23:14-21.
Ravaglia C, Wells AU, Tomassetti S, Dubini A, Cavazza A, Piciucchi S, et al
. Transbronchial lung cryobiopsy in diffuse parenchymal lung disease: Comparison between biopsy from 1 segment and biopsy from 2 segments – Diagnostic yield and complications. Respiration 2017;93:285-92.
Sriprasart T, Aragaki A, Baughman R, Wikenheiser-Brokamp K, Khanna G, Tanase D, et al
. A single US center experience of transbronchial lung cryobiopsy for diagnosing interstitial lung disease with a 2-Scope technique. J Bronchology Interv Pulmonol 2017;24:131-5.
Dhooria S, Mehta RM, Srinivasan A, Madan K, Sehgal IS, Pattabhiraman V, et al
. The safety and efficacy of different methods for obtaining transbronchial lung cryobiopsy in diffuse lung diseases. Clin Respir J 2018;12:1711-20.
Dhooria S, Sehgal IS, Bal A, Aggarwal AN, Behera D, Agarwal R. Transbronchial lung biopsy with a flexible cryoprobe during rigid bronchoscopy: Standardizing the procedure. Lung India 2016;33:248-9.
] [Full text]
Dhooria S, Agarwal R, Sehgal IS, Aggarwal AN, Goyal R, Guleria R, et al
. Bronchoscopic lung cryobiopsy: An Indian association for bronchology position statement. Lung India 2019;36:48-59.
] [Full text]
Han Q, Luo Q, Xie JX, Wu LL, Liao LY, Zhang XX, et al
. Diagnostic yield and postoperative mortality associated with surgical lung biopsy for evaluation of interstitial lung diseases: A systematic review and meta-analysis. J Thorac Cardiovasc Surg 2015;149:1394-4010.
Kreider ME, Hansen-Flaschen J, Ahmad NN, Rossman MD, Kaiser LR, Kucharczuk JC, et al
. Complications of video-assisted thoracoscopic lung biopsy in patients with interstitial lung disease. Ann Thorac Surg 2007;83:1140-4.
Bando M, Ohno S, Hosono T, Yanase K, Sato Y, Sohara Y, et al
. Risk of acute exacerbation after video-assisted thoracoscopic lung biopsy for interstitial lung disease. J Bronchology Interv Pulmonol 2009;16:229-35.
Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States. 2000 to 2011. Am J Respir Crit Care Med 2016;193:1161-7.
Raj R, Brown KK. Mortality related to surgical lung biopsy in patients with interstitial lung disease. The devil is in the denominator. Am J Respir Crit Care Med 2016;193:1082-4.
Flaherty KR, King TE Jr., Raghu G, Lynch JP 3rd
, Colby TV, Travis WD, et al
. Idiopathic interstitial pneumonia: What is the effect of a multidisciplinary approach to diagnosis? Am J Respir Crit Care Med 2004;170:904-10.
Thomeer M, Demedts M, Behr J, Buhl R, Costabel U, Flower CD, et al
. Multidisciplinary interobserver agreement in the diagnosis of idiopathic pulmonary fibrosis. Eur Respir J 2008;31:585-91.
Walsh SLF, Wells AU, Desai SR, Poletti V, Piciucchi S, Dubini A, et al
. Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease: A case-cohort study. Lancet Respir Med 2016;4:557-65.
Raghu G, Collard HR, Egan JJ, Martinez FJ, Behr J, Brown KK, et al
. An official ATS/ERS/JRS/ALAT statement: Idiopathic pulmonary fibrosis: Evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011;183:788-824.
Travis WD, Costabel U, Hansell DM, King TE Jr., Lynch DA, Nicholson AG, et al
. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733-48.
Oral presentation. Respirology 2016;21:20-79.
Israeli-Shani L, Epstein Shochet G, Levi Y, Kutchuk M, Koslow M, Shitrit D. The Significance of adding rheumatological assessment to the multidisciplinary team in the diagnosis of interstitial lung disease (ILD). A24 IPF: Clinical Studies, Therapeutics, and More I. American Thoracic Society International Conference Abstracts: American Thoracic Society; 2017. p. A1118-A.
Rivera Ortega P, Luburich P, Llatjos R, Vicens Zygmunt V, Martinez F, Planas L, et al
. Relevance of the expert ILD clinical-radiological evaluation of referred cases to the MDT. Eur Respir J 2016;48:PA811.
Zappala CJ, Latsi PI, Nicholson AG, Colby TV, Cramer D, Renzoni EA, et al
. Marginal decline in forced vital capacity is associated with a poor outcome in idiopathic pulmonary fibrosis. Eur Respir J 2010;35:830-6.
Mura M, Ferretti A, Ferro O, Zompatori M, Cavalli A, Schiavina M, et al
. Functional predictors of exertional dyspnea, 6-min walking distance and HRCT fibrosis score in idiopathic pulmonary fibrosis. Respiration 2006;73:495-502.
Khadawardi H, Mura M. A simple dyspnoea scale as part of the assessment to predict outcome across chronic interstitial lung disease. Respirology 2017;22:501-7.
Raghu G, Freudenberger TD, Yang S, Curtis JR, Spada C, Hayes J, et al
. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006;27:136-42.
Sweet MP, Patti MG, Leard LE, Golden JA, Hays SR, Hoopes C, et al
. Gastroesophageal reflux in patients with idiopathic pulmonary fibrosis referred for lung transplantation. J Thorac Cardiovasc Surg 2007;133:1078-84.
Gao F, Hobson AR, Shang ZM, Pei YX, Gao Y, Wang JX, et al
. The prevalence of gastro-esophageal reflux disease and esophageal dysmotility in Chinese patients with idiopathic pulmonary fibrosis. BMC Gastroenterol 2015;15:26.
Savarino E, Carbone R, Marabotto E, Furnari M, Sconfienza L, Ghio M, et al
. Gastro-oesophageal reflux and gastric aspiration in idiopathic pulmonary fibrosis patients. Eur Respir J 2013;42:1322-31.
Soares RV, Forsythe A, Hogarth K, Sweiss NJ, Noth I, Patti MG. Interstitial lung disease and gastroesophageal reflux disease: Key role of esophageal function tests in the diagnosis and treatment. Arq Gastroenterol 2011;48:91-7.
Galiè N, Humbert M, Vachiery JL, Gibbs S, Lang I, Torbicki A, et al
. 2015 ESC/ERS Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension: The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed By: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016;37:67-119.
Archontogeorgis K, Steiropoulos P, Tzouvelekis A, Nena E, Bouros D. Lung cancer and interstitial lung diseases: A systematic review. Pulm Med 2012;2012:315918.
Li C, Wu W, Chen N, Song H, Lu T, Yang Z, et al
. Clinical characteristics and outcomes of lung cancer patients with combined pulmonary fibrosis and emphysema: A systematic review and meta-analysis of 13 studies. J Thorac Dis 2017;9:5322-34.
Kuramochi J, Inase N, Miyazaki Y, Kawachi H, Takemura T, Yoshizawa Y. Lung cancer in chronic hypersensitivity pneumonitis. Respiration 2011;82:263-7.
Jastrzebski D, Gumola A, Gawlik R, Kozielski J. Dyspnea and quality of life in patients with pulmonary fibrosis after six weeks of respiratory rehabilitation. J Physiol Pharmacol 2006;57 Suppl 4:139-48.
Naji NA, Connor MC, Donnelly SC, McDonnell TJ. Effectiveness of pulmonary rehabilitation in restrictive lung disease. J Cardiopulm Rehabil 2006;26:237-43.
Polosa R, Simidchiev A, Walters EH. Nebulised morphine for severe interstitial lung disease. Cochrane Database Syst Rev 2002;(3):CD002872.
Huie TJ, Olson AL, Cosgrove GP, Janssen WJ, Lara AR, Lynch DA, et al
. A detailed evaluation of acute respiratory decline in patients with fibrotic lung disease: Aetiology and outcomes. Respirology 2010;15:909-17.
Tomczyk S, Bennett NM, Stoecker C, Gierke R, Moore MR, Whitney CG, et al
. Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged≥65 years: Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Morb Mortal Wkly Rep 2014;63:822-5.
Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and control of seasonal influenza with vaccines: Recommendations of the advisory committee on immunization practices-United States, 2018-19 influenza Season. MMWR Morb Mortal Wkly Rep 2018;67:1-20.
Chadha MS, Potdar VA, Saha S, Koul PA, Broor S, Dar L, et al
. Dynamics of influenza seasonality at sub-regional levels in India and implications for vaccination timing. PLoS One 2015;10:e0124122.
Taichman DB, Ornelas J, Chung L, Klinger JR, Lewis S, Mandel J, et al
. Pharmacologic therapy for pulmonary arterial hypertension in adults: CHEST guideline and expert panel report. Chest 2014;146:449-75.
Klinger JR, Elliott CG, Levine DJ, Bossone E, Duvall L, Fagan K, et al
. Therapy for pulmonary arterial hypertension in adults: Update of the CHEST guideline and expert panel report. Chest 2019;155:565-86.
Corte TJ, Keir GJ, Dimopoulos K, Howard L, Corris PA, Parfitt L, et al
. Bosentan in pulmonary hypertension associated with fibrotic idiopathic interstitial pneumonia. Am J Respir Crit Care Med 2014;190:208-17.
Idiopathic Pulmonary Fibrosis Clinical Research Network, Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, et al
. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010;363:620-8.
Saggar R, Khanna D, Vaidya A, Derhovanessian A, Maranian P, Duffy E, et al
. Changes in right heart haemodynamics and echocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis. Thorax 2014;69:123-9.
Hoeper MM, Halank M, Wilkens H, Günther A, Weimann G, Gebert I, et al
. Riociguat for interstitial lung disease and pulmonary hypertension: A pilot trial. Eur Respir J 2013;41:853-60.
Han MK, Bach DS, Hagan PG, Yow E, Flaherty KR, Toews GB, et al
. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and right-sided ventricular dysfunction. Chest 2013;143:1699-708.
Raghu G, Behr J, Brown KK, Egan JJ, Kawut SM, Flaherty KR, et al
. Treatment of idiopathic pulmonary fibrosis with ambrisentan: A parallel, randomized trial. Ann Intern Med 2013;158:641-9.
Dreher M, Ekkernkamp E, Schmoor C, Schoenheit-Kenn U, Winterkamp S, Kenn K. Pulmonary rehabilitation and noninvasive ventilation in patients with hypercapnic interstitial lung disease. Respiration 2015;89:208-13.
Faverio P, De Giacomi F, Sardella L, Fiorentino G, Carone M, Salerno F, et al
. Management of acute respiratory failure in interstitial lung diseases: Overview and clinical insights. BMC Pulm Med 2018;18:70.
Rush B, Wiskar K, Berger L, Griesdale D. The use of mechanical ventilation in patients with idiopathic pulmonary fibrosis in the United States: A nationwide retrospective cohort analysis. Respir Med 2016;111:72-6.
Kistler KD, Nalysnyk L, Rotella P, Esser D. Lung transplantation in idiopathic pulmonary fibrosis: A systematic review of the literature. BMC Pulm Med 2014;14:139.
Takeyasu M, Miyamoto A, Kato D, Takahashi Y, Ogawa K, Murase K, et al
. Continuous intravenous morphine infusion for severe dyspnea in terminally ill interstitial pneumonia patients. Intern Med 2016;55:725-9.
Gilbert CR, Smith CM. Advanced lung disease: Quality of life and role of palliative care. Mt Sinai J Med 2009;76:63-70.
Ryerson CJ, Camp PG, Eves ND, Schaeffer M, Syed N, Dhillon S, et al
. High oxygen delivery to preserve exercise capacity in patients with idiopathic pulmonary fibrosis treated with nintedanib. Methodology of the HOPE-IPF Study. Ann Am Thorac Soc 2016;13:1640-7.
Kreuter M, Bendstrup E, Russell AM, Bajwah S, Lindell K, Adir Y, et al
. Palliative care in interstitial lung disease: Living well. Lancet Respir Med 2017;5:968-80.
Cormier Y, Létourneau L, Racine G. Significance of precipitins and asymptomatic lymphocytic alveolitis: A 20-yr follow-up. Eur Respir J 2004;23:523-5.
Girard M, Lacasse Y, Cormier Y. Hypersensitivity pneumonitis. Allergy 2009;64:322-34.
Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid treatment on the recovery of pulmonary function in farmer's lung. Am Rev Respir Dis 1992;145:3-5.
Fernández Pérez ER, Swigris JJ, Forssén AV, Tourin O, Solomon JJ, Huie TJ, et al
. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest 2013;144:1644-51.
Sharma BB, Singh S, Singh V. Hypersensitivity pneumonitis: The dug-well lung. Allergy Asthma Proc 2013;34:e59-64.
King TE Jr., Bradford WZ, Castro-Bernardini S, Fagan EA, Glaspole I, Glassberg MK, et al
. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2083-92.
Richeldi L, du Bois RM, Raghu G, Azuma A, Brown KK, Costabel U, et al
. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014;370:2071-82.
Richeldi L, Cottin V, du Bois RM, Selman M, Kimura T, Bailes Z, et al
. Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med 2016;113:74-9.
Jeldres Pulgar A, Labarca G. Is N-acetylcysteine effective in the treatment of pulmonary fibrosis? Medwave 2016;16:e6555.
Oldham JM, Ma SF, Martinez FJ, Anstrom KJ, Raghu G, Schwartz DA, et al
. TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med. 2015;192:1475-82.
Vancheri C, Kreuter M, Richeldi L, Ryerson CJ, Valeyre D, Grutters JC, et al
. Nintedanib with add-on pirfenidone in idiopathic pulmonary fibrosis. Results of the injourney trial. Am J Respir Crit Care Med 2018;197:356-63.
Lee CM, Lee DH, Ahn BK, Hwang JJ, Yoon H, Shin CM, et al
. Protective effect of proton pump inhibitor for survival in patients with gastroesophageal reflux disease and idiopathic pulmonary fibrosis. J Neurogastroenterol Motil 2016;22:444-51.
Kreuter M, Spagnolo P, Wuyts W, Renzoni E, Koschel D, Bonella F, et al
. Antacid therapy and disease progression in patients with idiopathic pulmonary fibrosis who received pirfenidone. Respiration 2017;93:415-23.
Fidler L, Sitzer N, Shapera S, Shah PS. Treatment of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Chest 2018;153:1405-15.
Raghu G, Pellegrini CA, Yow E, Flaherty KR, Meyer K, Noth I, et al
. Laparoscopic anti-reflux surgery for the treatment of idiopathic pulmonary fibrosis (WRAP-IPF): A multicentre, randomised, controlled phase 2 trial. Lancet Respir Med 2018;6:707-14.
Shaw M, Collins BF, Ho LA, Raghu G. Rheumatoid arthritis-associated lung disease. Eur Respir Rev 2015;24:1-6.
Lake F, Proudman S. Rheumatoid arthritis and lung disease: From mechanisms to a practical approach. Semin Respir Crit Care Med 2014;35:222-38.
Rojas-Serrano J, González-Velásquez E, Mejía M, Sánchez-Rodríguez A, Carrillo G. Interstitial lung disease related to rheumatoid arthritis: Evolution after treatment. Reumatol Clin 2012;8:68-71.
Fischer A, Brown KK, Du Bois RM, Frankel SK, Cosgrove GP, Fernandez-Perez ER, et al
. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol 2013;40:640-6.
Zhang G, Xu T, Zhang H, Ye S, Wang Q, Zhang L, et al
. Randomized control multi-center clinical study of mycophenolate mofetil and cyclophosphamide in the treatment of connective tissue disease related interstitial lung disease. Zhonghua Yi Xue Za Zhi 2015;95:3641-5.
Md Yusof MY, Kabia A, Darby M, Lettieri G, Beirne P, Vital EM, et al
. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years' experience at a single centre. Rheumatology (Oxford) 2017;56:1348-57.
Bongartz T, Nannini C, Medina-Velasquez YF, Achenbach SJ, Crowson CS, Ryu JH, et al
. Incidence and mortality of interstitial lung disease in rheumatoid arthritis: A population-based study. Arthritis Rheum 2010;62:1583-91.
Conway R, Low C, Coughlan RJ, O'Donnell MJ, Carey JJ. Methotrexate and lung disease in rheumatoid arthritis: A meta-analysis of randomized controlled trials. Arthritis Rheumatol 2014;66:803-12.
Steen VD, Medsger TA Jr. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum 1998;41:1613-9.
Tashkin DP, Elashoff R, Clements PJ, Goldin J, Roth MD, Furst DE, et al
. Cyclophosphamide versus placebo in scleroderma lung disease. N Engl JMed 2006;354:2655-66.
Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, et al
. Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): A randomised controlled, double-blind, parallel group trial. Lancet Respir Med 2016;4:708-19.
Ungprasert P, Carmona EM, Crowson CS, Matteson EL. Diagnostic utility of angiotensin-converting enzyme in sarcoidosis: A population-based study. Lung 2016;194:91-5.
Podwysocki B, Skowron-Szlósarczyk S, Zwoliński J, Szklarz E, Jankowska E, Masiak M. The usefulness of serum angiotensin-converting enzyme test in the diagnosis of sarcoidosis. Mater Med Pol 1991;23:121-4.
Navani N, Booth HL, Kocjan G, Falzon M, Capitanio A, Brown JM, et al
. Combination of endobronchial ultrasound-guided transbronchial needle aspiration with standard bronchoscopic techniques for the diagnosis of stage I and stage II pulmonary sarcoidosis. Respirology 2011;16:467-72.
Gupta D, Dadhwal DS, Agarwal R, Gupta N, Bal A, Aggarwal AN. Endobronchial ultrasound-guided transbronchial needle aspiration vs. conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. Chest 2014;146:547-56.
Goyal A, Gupta D, Agarwal R, Bal A, Nijhawan R, Aggarwal AN. Value of different bronchoscopic sampling techniques in diagnosis of sarcoidosis: A prospective study of 151 patients. J Bronchology Interv Pulmonol 2014;21:220-6.
Gibson GJ, Prescott RJ, Muers MF, Middleton WG, Mitchell DN, Connolly CK, et al
. British Thoracic Society sarcoidosis study: Effects of long term corticosteroid treatment. Thorax 1996;51:238-47.
Israel HL, Fouts DW, Beggs RA. A controlled trial of prednisone treatment of sarcoidosis. Am Rev Respir Dis 1973;107:609-14.
Selroos O, Sellergren TL. Corticosteroid therapy of pulmonary sarcoidosis. A prospective evaluation of alternate day and daily dosage in stage II disease. Scand J Respir Dis 1979;60:215-21.
Baughman RP, Winget DB, Lower EE. Methotrexate is steroid sparing in acute sarcoidosis: Results of a double blind, randomized trial. Sarcoidosis Vasc Diffuse Lung Dis 2000;17:60-6.
Müller-Quernheim J, Kienast K, Held M, Pfeifer S, Costabel U. Treatment of chronic sarcoidosis with an azathioprine/prednisolone regimen. Eur Respir J 1999;14:1117-22.
Kremer J, Genovese M, Cannon GW, Caldwell J, Cush J, Furst DE, et al
. Combination leflunomide and methotrexate (MTX) therapy for patients with active rheumatoid arthritis failing MTX monotherapy: Open-label extension of a randomized, double-blind, placebo controlled trial. J Rheumatol 2004;31:1521-31.
Baltzan M, Mehta S, Kirkham TH, Cosio MG. Randomized trial of prolonged chloroquine therapy in advanced pulmonary sarcoidosis. Am J Respir Crit Care Med. 1999;160:192-7.
Cottin V, Donsbeck AV, Revel D, Loire R, Cordier JF. Nonspecific interstitial pneumonia. Individualization of a clinicopathologic entity in a series of 12 patients. Am J Respir Crit Care Med 1998;158:1286-93.
Akira M, Inoue Y, Arai T, Okuma T, Kawata Y. Long-term follow-up high-resolution CT findings in non-specific interstitial pneumonia. Thorax 2011;66:61-5.
Furihata T, Ishii Y, Fukuda T. Predictive factors for response to steroid therapy in patients with nonspecific interstitial pneumonia. Dokkyo J Med Sci 2012;39:201-7.
Sharma SK, Pande JN, Verma K. Effect of prednisolone treatment in chronic silicosis. Am Rev Respir Dis 1991;143:814-21.
Thomas H. Aluminium therapy in the prevention and treatment of silicosis: Used for over 30 years in Canada but generally rejected elsewhere. In: Bridging the gaps. Abstracts of the 12th
Cochrane Colloquium; 2004 2-6 Oct. Ottawa, Canada; 2004.
Mason GR, Abraham JL, Hoffman L, Cole S, Lippmann M, Wasserman K. Treatment of mixed-dust pneumoconiosis with whole lung lavage. Am Rev Respir Dis 1982;126:1102-7.
Stafford M, Cappa A, Weyant M, Lara A, Ellis J Jr., Weitzel NS, et al
. Treatment of acute silicoproteinosis by whole-lung lavage. Semin Cardiothorac Vasc Anesth 2013;17:152-9.
Dale MT, McKeough ZJ, Troosters T, Bye P, Alison JA. Exercise training to improve exercise capacity and quality of life in people with non-malignant dust-related respiratory diseases. Cochrane Database Syst Rev 2015;11:CD009385.
Ochmann U, Kotschy-Lang N, Raab W, Kellberger J, Nowak D, Jörres RA. Long-term efficacy of pulmonary rehabilitation in patients with occupational respiratory diseases. Respiration 2012;84:396-405.
Graham R, Mancher M, Miller Wolman D, Greenfield S, Steinberg E, editors. Institute of Medicine Committee on Standards for Developing Trustworthy Clinical Practice G. In: Clinical Practice Guidelines We Can Trust. Washington (DC): National Academies Press (US) Copyright 2011 by the National Academy of Sciences; 2011.
Flaherty KR, Wells AU, Cottin V, Devaraj A, Walsh SLF, Inoue Y, et al. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med 2019;381:1718-27.
Wells AU, Flaherty KR, Brown KK, Inoue Y, Devaraj A, Richeldi L, et al. Nintedanib in patients with progressive fibrosing interstitial lung diseases-subgroup analyses by interstitial lung disease diagnosis in the INBUILD trial: a randomised, double-blind, placebo-controlled, parallel-group trial. Lancet Respir Med 2020;8:453-60.
Crouser ED, Maier LA, Wilson KC, Bonham CA, Morgenthau AS, Patterson KC, et al. Diagnosis and Detection of Sarcoidosis. Am J Respir Crit Care Med 2020; 201:e26-e51.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10]
[Table 1], [Table 2], [Table 3], [Table 4]