Author(s): Rajashree Srinivasan, MD, MBBS, Saylee Dhamdhere, MD, Nikhil Gopal, MBBS
Originally published: September 20, 2014 Last updated: May 25, 2023
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Disease/Disorder

Definition

Restrictive lung diseases (RLDs) are a heterogeneous group of disorders characterized by reduced lung volume, primarily caused by an alteration in lung parenchyma or secondary to a disease of the pleura, chest wall, or neuromuscular apparatus. It presents with various levels of respiratory insufficiency.

RLDs are characterized by reduced total lung capacity (TLC), vital capacity, or resting lung volume. TLC below 80% of the predicted volume is indicative of interstitial lung disease (ILD); however, clinical correlation is mandatory. Diffuse capacity is typically reduced and represents the most sensitive test of respiration.

Although the etiologies of RLD are diverse, the final functional deficits are similar.1

Etiology

Idiopathic interstitial pneumonia (IIP)

  • Idiopathic pulmonary fibrosis (IPF) most common
  • Acute interstitial pneumonia
  • Lymphocytic interstitial pneumonitis
  • Desquamative interstitial pneumonitis
  • Nonspecific interstitial pneumonitis

Chronic interstitial disease associated with collagen-vascular disorder (CTD)

  • Rheumatoid arthritis (RA-ILD)
  • Progressive systemic sclerosis (SSc-ILD)
  • Systemic lupus erythematosus
  • Polymyositis/dermatomyositis
  • Sjogren syndrome
  • Overlap syndrome
    • Diffuse amyloidosis of lung
    • Chronic eosinophilic pneumonia
    • Lymphangioleiomyomatosis
    • Whipple’s disease
    • Weber-Christian disease
    • Hermansky-Pudlak syndrome
    • Unclassified
    • Drugs and toxins
    • Hypersensitive pneumonitis

Vasculitides

  • Churg-Strauss syndrome
  • Hypersensitivity angiitis

Inherited disorders

  • Tuberous sclerosis
  • Neurofibromatosis
  • Familial pulmonary fibrosis
  • Sarcoidosis
  • Histiocytosis X
  • Goodpasture syndrome
  • Idiopathic pulmonary hemosiderosis
  • Wegener granulomatosis
  • Lymphocytic infiltrative disorders
  • Lymphomatoid granulomatosis
  • lmmunoblastic lymphadenopathy
  • Pulmonary veno-occlusive disease
  • Ankylosing spondylitis

Epidemiology including risk factors and primary prevention

In seventeen methodologically diverse investigations examining the incidence, prevalence, and relative frequencies of ILD subtypes, the incidence of ILD ranged from 1 to 31.5 per 100,000 person-years and the prevalence ranged from 6.3 to 71 per 100,000 individuals.2

Rates are higher in men than in women, and the epidemiology is markedly affected by age and occupational exposures.

Although the etiology of IPF, the most common subtype of ILD, is unknown, several potential risk factors (e.g., cigarette smoking, chronic viral infections, environmental factors) have been described. Gastroesophageal reflux disease (GERD) has been implicated as a risk factor through its microaspiration.3 Familial forms of IPF account for less than 5% of the total population.3

Patho-anatomy/physiology

Some ILDs are considered fibro-proliferative disorders, in which alveolar epithelial injury and fibroblastic proliferation result in fibrosis, whereas others are largely inflammatory disorders in which the pathogenic process changes to a fibro-proliferative pathway under certain conditions. Regardless of the trigger, the mechanisms involved in the etiology and evolution of fibrosing ILDs are similar.4

External factors such as smoking, environmental chemicals, infections, and GERD cause epithelial cell injury and aberrant repair, alveolar macrophage activation, neutrophil recruitment, and oxidative stress in genetically susceptible individuals. Increased extracellular matrix (ECM) turnover leads to the development of fibrosis over time.5 In a feed-forward loop, the increased lung tissue stiffness further activates and stimulates fibroblasts to drive a self-sustaining process of fibrosis. As a greater proportion of lung tissue is lost to fibrosis, the lung’s volume is diminished and gas exchange is hindered, resulting in worsening breathlessness and capacity for exertion.4

Pulmonary fibrosis has been linked to rare pathogenic mutations in telomere maintenance genes and chromosome-protected terminal telomere shortening. Patients with rare telomere-related variants TERT, TERC, PARN,or RTEL1 have varying degrees of pulmonary fibrosis, ranging from IPF to CTD-ILD.5

ILDs involve the parenchyma and alveolar interstitium of the lung that share common clinical, radiologic, and physiologic features. They are characterized by reduced distensibility of the lung parenchyma and present different grades of pulmonary disruption.6

These diseases are not confined to the interstitium, as the name erroneously indicates, but also include the alveolar epithelial and endothelial cells. Although these diseases primarily attack the alveolar structure, airways, arteries, and veins can also be involved.7 Although a higher profusion of fibroblast foci is associated with a decline in the diffuse capacity and increased mortality in some studies,3 a histopathology system to aid in the clinical management has not been evaluated.

Alveolar interstitial fibrosis is a common denominator of ILD. However, they are also distinguished by the presence of a chronic alveolitis causing a derangement of alveolar structures and leading to loss of functional gas exchange units (end-stage lung).

IIP is a subgroup of ILD of unknown etiology. IPF is one of the most common forms of IIP and is associated with substantial morbidity and mortality.8

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Most patients present with dry cough and exertion-induced dyspnea. Over time, the cough becomes paroxysmal and debilitating, and dyspnea at rest ensues.

Typical features include a restrictive ventilatory defect at rest and variably reduced exercise tolerance and alveolar arterial oxygen gradients based on the ILD.

Untreated ILDs are progressive fibrotic diseases with an overall poor prognosis. Most patients’ condition deteriorates as they irreversibly lose alveolar-capillary units with increasing severity of their symptoms. As the right heart attempts to deal with the progressive loss of vascular bed, it hypertrophies to maintain cardiac output and eventually fails with resultant Cor pulmonale.

The prognosis of IPF is poor, with a 30% to 50% 5-year survival. IPF is not very responsive to medical therapy, and patients are subject to episodes of acute exacerbation and rapid clinical deterioration. However, some patients remain stable, whereas others have an accelerated course.

In advanced stages, progressive pulmonary fibrosis leads to pulmonary hypertension and Cor pulmonale. Criteria for referral for lung transplant are symptomatic disease, refractory medical therapy, TVC less than 60% to 70%, diffuse capacity less than 40% of predicted, and evidence of resting or exercise-induced hypoxia.

Lung transplantation is the best therapy for patients who are proper candidates and can tolerate the procedure.9

Specific secondary or associated conditions and complications

Acute deterioration is cryptogenic or may occur secondary to infections, pneumonia, pulmonary embolism, pneumothorax, or heart failure and is characterized by worsening pulmonary function.

Acute exacerbation is diagnosed as clinical deterioration in the absence of infection and heart failure. The finding of diffuse alveolar damage suggests acute injury. The cause remains cryptogenic. Presence of fever, flu-like symptoms, and neutrophilia on bronchoalveolar lavage is suggestive of infection; however, despite a suggested role, no relationship has been made with viruses, such as Epstein-Barr, cytomegalovirus, and others. Bacterial infections are more common; in one study, torque teno virus was found in 28% of the patients with ILD exacerbations.10

Essentials of Assessment

History

A careful history of occupation, travel, habits, medications, and exposures should be assessed. Diagnosis of IPF requires the exclusion of known causes of ILDs (e.g., domestic and occupational exposures, connective tissue disease, drug toxicity).

Medications (e.g., amiodarone, propranolol, methotrexate, cyclophosphamide) can cause ILD.

Physical examination

Distinguishing features include crackles on auscultation of the lungs. Digital clubbing is common in IPF. Cyanosis is uncommon and when present can signify an advanced stage.

Loud P2 sound on auscultation of the heart is indicative of Cor Pulmonale.

Rapid shallow breathing, use of accessory respiratory muscles, and tachypnea may denote a respiratory insufficiency.

Laboratory studies

Routine laboratory assessments often fail to reveal positive findings. Although there is no specific role of serology in diagnosing IPF, serologic testing should be performed to diagnose CTD.

Serum markers, such as serum amyloid A, soluble interleukin-2 receptor, lysozyme, angiotensin-converting enzyme (ACE), and glycoprotein KL-6, have been reported to be markers of sarcoidosis. Serum ACE levels may correlate with total body granuloma.

Imaging

The diagnosis of ILD is often initially based on abnormal chest radiologic findings. Though the most common finding is a reticular pattern, it is not predictive of an accurate diagnosis.

The presence of usual interstitial pneumonia pattern on high-resolution computed tomography (HRCT) scanning is diagnostic of IPF. The extent of fibrosis and honeycombing on HRCT has been shown to predict mortality and to correlate with FVC and DLco % predicted.11

Supplemental assessment tools

In the absence of the typical findings on HRCT, a surgical lung biopsy is recommended. Transbronchial biopsy is not recommended for the diagnosis because of its high morbidity.3

Diffusion capacity is typically reduced and is the most sensitive test of respiratory function.6 A threshold of less than 40% of the predictive is associated with reduced mortality. Ventilatory and gas exchange abnormalities are the main factors that limit exercise capacity. Cardiac dysfunction contributes to the deficits as well.

There are data that suggest that the accuracy of diagnosis of IPF is improved by a formal multidisciplinary discussion between pulmonologists, radiologists, and pathologists.3

Sequential pulmonary functional test (PFT) findings are essential to monitor the course and determine the efficacy of treatment in ILD. Reduced vital capacity and diffuse capacity are predictive parameters of low survival rate. However, the value of PFTs in sarcoidosis is debatable.6

Another assessment tool is the 6-minute walk distance; less than 300 m ambulated is considered very impaired.

Early predictions of outcomes

PFTs and exercise-induced hypoxemia can aid in defining the prognosis of the disease. A reduced survival was reported with vital capacity less than 60% of the predicted or with a decrease in vital capacity greater than 10% in 1 year.12 Patients with exercise desaturation, defined as a fall in oxygen saturation to 88% or less during a 6-minute walk test, had significantly higher mortality than patients who did not desaturate.13

Composite scoring systems have been developed to predict mortality in patients with progressive fibrosing ILDs. One of the most widely used is the GAP (gender, age, physiology) model, which was developed to predict mortality in patients with IPF based on gender, age, FVC % predicted and DLco % predicted. Since then, it has been demonstrated that this model can also predict mortality in patients with RA-ILD, SSc-ILD, unclassifiable ILD, and a mixed cohort.4

Blood biomarkers have also been investigated as predictors of disease progression in patients with fibrosing ILDs. These include KL-6, which has been associated with a higher rate of disease progression in patients with IPF and CTD-ILDs, and surfactant protein-D (SP-D).4

In individuals with fibrosing ILDs, genetic alterations and telomere length have also been examined as predictors of disease development. In IPF patients, rs35705950, a minor allele of a single nucleotide polymorphism (SNP) in MUC5B, a gene encoding a component of mucus secretions, has been linked to improved survival, whereas rs5743890, a minor allele of an SNP in TOLLIP (toll interacting protein), has been linked to worse survival.4

Environmental

A significant increase in risk is noted with exposure to metal dusts (brass, lead, steel), wood dust (pine), farming, raising birds, hairdressing, stone cutting/polishing, and exposure to livestock/vegetable dust.

Medical Management

Management generally includes a combination of supportive care, use of selected medications (pirfenidone, nintedanib), consideration of participation in clinical trials, referral for lung transplantation evaluation when appropriate, and identification and treatment of comorbidities. Supportive case (supplemental oxygen, pulmonary rehabilitation, vaccination, palliative care).

Professional Issues

End of life issues and care are important discussion points that need to be addressed by the clinician.

Rehabilitation Management and Treatments

Functional assessment and necessity of rehabilitation in ILD

Interstitial Lung Diseases comprise a heterogeneous group of disorders characterized by inflammation and/or fibrosis of the lung parenchyma and vasculature which leads to structural and mechanical pulmonary system alterations. This mainly causes pathological reduction of pulmonary and cardiovascular functions.14 Patients gradually develop exertional dyspnoea which limits their exercise tolerance and endurance deteriorates to the extent that performing activities of daily living becomes difficult.15 Patients experience secondary deficits including cardiac, peripheral muscle and psychologic impairments, which along with the declining respiratory function, further limit exercise capacity and greatly reduce their health-related quality of life (HRQL). Current medical management for ILD is limited. Pharmacotherapies able to slow disease progression but are unable to provide a cure. In this setting, interventions that improve functional capacity have an important role.

Mechanism of reduced exercise capacity in ILD

The mechanism for reduced exercise capacity in ILD is multifactorial. It is closely associated with impaired circulatory function due to pulmonary hypertension and cardiac dysfunction with resultant exercise induced hypoxemia. Impaired gas exchange, due to destruction of the pulmonary capillary bed, is also involved leading to a ventilation-perfusion mismatch and oxygen diffusion limitations. Peripheral muscle dysfunction from chronic physical deconditioning can further play a role. Treatments for ILD such as corticosteroids and immunosuppressive therapy may also lead to drug-induced myopathy.

Available or current treatment guidelines

Pulmonary rehabilitation is an evidence-based, multidisciplinary, comprehensive intervention involving a program of structured exercise, self-management education and psychosocial support. Pulmonary rehabilitation (PR) for patients diagnosed with ILD are delivered in different settings and models. It is principally completed as an outpatient program though may be inpatient or home/community based. Traditionally, PR programs are center-based and shown positive outcomes in sarcoidosis16 and pneumoconiosis patients.

It has been shown to enhance exercise tolerance, improve symptoms and health-related quality of life, and reduce exacerbations in patients with recurrent exacerbations.17

Most pulmonary rehabilitation programs for ILD patients have a duration of 8 to 12 weeks and promote significant effects on functional capacity, quality of life and sensation of dyspnea. Frequency of the program can be variable, but they generally meet two to three times weekly.

A typical pulmonary rehabilitation team consists of nurses, respiratory therapists, physical therapists, social workers, dieticians. Coordination with the treating physician team, consisting of pulmonologists, physiatrists, radiologists, and pathologists is recommended. Rehabilitation focuses on a combination of endurance and strength training. Participants generally engage in walking training and stationary cycling. Upper limb endurance training and functional strength training for the lower limbs is also performed.1 Endurance training targeted at 60% of the maximal workload for 20 to 30 minutes 5 times a week is recommended. Interval training with intensity for 2 to 3 minutes at 60% to 80% of maximum workload followed by equal periods of rest are also acceptable.

Recently, in the face of the COVID-19 pandemic, telerehabilitation has been gaining prominence, as this strategy is safe and presents results similar to the rehabilitation programs traditionally performed in chronic respiratory disease, mainly in relation to the improvement of functional capacity.18

Patients with ILD can safely participate in pulmonary rehabilitation. Those on home oxygen at baseline have been able to complete a 24-week program without serious side effects. Severity of disease should not disqualify patients with ILD from participating in pulmonary rehabilitation.

The primary goal of pulmonary rehabilitation is to restore the patient’s ability to function without extreme breathlessness. The mechanism of improved outcomes has not yet been established though may be attributed to increased aerobic capacity and increased peripheral muscle performance.

Limitations of pulmonary rehabilitation

While pulmonary rehabilitation has been shown to improve overall wellbeing in ILD, there is currently no evidence to suggest it improves long-term survival and further research is needed.  Additionally, benefits of pulmonary rehabilitation may be less in those with severe ILD and are generally less than those seen in COPD. In the post-COVID-19 world, a ‘hybrid’ model of pulmonary rehabilitation may be more desirable, with some components held in person and others via telehealth technology. This would be determined by the infrastructure and expertise of individual centers, and the needs of their patients. In order to achieve a truly patient-centered pulmonary rehabilitation program, high-quality studies addressing these outstanding questions, as well as multidisciplinary collaboration, are required.19

Patient & family education

Along with exercise, education is a core component of pulmonary rehabilitation. The goal of patient education is to help patients take more responsibility for their self-care and to help them cope with changes that have taken place in their physical and functional status.31 A comprehensive PR program will cover the following core educational topics: (1) managing breathlessness and cough; (2) overcoming fatigue; (3) managing anxiety, depression and panic; (4) basics of oxygen therapy; (5) health maintenance in ILD (vaccinations, importance of exercise and good nutrition, management of flares); and  (6) maintenance of physical activity after PR. The patient and family need to be educated on the overall prognosis of the ILD and its prognostic factors.

Optional educational topics may include managing medications and their side effects, management of co-existing medical conditions, end of life care and advance directive, and accessing home care/support for patient and caregivers.

Decisions about life support combining personal choices and prognosis as directed by the physician are important educational needs of the patient.

Emerging/unique interventions

HQRL and St George’s Respiratory Questionnaire are widely used instruments to assess health status in patients with chronic obstructive pulmonary disease and have been established in ILD as well. In one study, ILD patients had worse HQRL scores with similar ventilator impairment compared with chronic obstructive pulmonary disease.20 In monitoring the response to therapy, vital capacity and diffuse capacity are the most parameters. A change in vital capacity greater than 10% to 15% and greater than 20% in diffuse capacity is significant.

The 6-min walk test (6MWT) is more commonly used to monitor progress of ILDs over time and during rehabilitation programs. changes in the 6MWT may help to assess the costs and benefits of new therapies to individual patients of the test and individual patient characteristics.21

Cardiopulmonary exercise testing (CPET) provides important information concerning exertional dyspnea and mechanisms of exercise limitation as a comprehensive assessment of the physiological changes in the respiratory, cardiovascular and musculoskeletal systems during exercise, which may be also useful for exercise prescription.22

Peripheral muscle dysfunction is also a critical factor in determining exercise intolerance in patients with chronic lung diseases, including ILD. In one study by Zamboti etal, reliability and validity results, TUGu (timed-up-and-go with usual), TUGf (timed-up-and-go-fast) and 5rep-STS (sit to stand) seem to be the most appropriate tests to evaluate functional performance in ILD.23

Translation into practice: Practice “pearls”/performance improvement in practice (PIPs)/changes in clinical practice behaviors and skills

Main challenges in pulmonary rehabilitation are 1) insufficient number of programs, and 2) underuse of available programs. There are undoubtedly multiple factors underlying underuse of pulmonary rehabilitation, but two major categories are 1) inadequate awareness and knowledge of pulmonary rehabilitation (among professionals, payers, and patients), leading to insufficient referrals; and 2) lack of access to pulmonary rehabilitation for many eligible respiratory patients. Patient factors include fear of the intervention, transportation barriers (including distance and mobility issues), timing of the program, insufficient knowledge of pulmonary rehabilitation (including outcome expectations), and social barriers.24

Exercise training improves exercise capacity and symptoms in patients with ILD, but these benefits are not sustained 6 months following intervention.15

Reduced activity levels because of dyspnea and misconceptions about the safety of exercise can lead to cardiovascular and peripheral muscle deconditioning. Studies have shown that patients with worse disease benefit the most from pulmonary rehabilitation.1

Although the American Thoracic Society (ATS)/European Respiratory Society (ERS) supports pulmonary rehabilitation in ILD patients, most of the supporting data come from evidence for chronic obstructive pulmonary disease. Several studies have effectively demonstrated the efficacy of pulmonary rehabilitation in patients with ILD.25

Cutting Edge/ Emerging and Unique Concepts and Practice

Treatment of IPF continues to pose a challenge in terms of improving mortality and morbidity. Controlled therapeutic trials are needed to establish the least toxic and most effective long-term treatment.

Advancements in the treatment of CTD-ILD have included a re-evaluation of methotrexate-induced lung injury as well as emerging insights on anti-IL-6 therapy and anti-fibrotic treatment for this condition.26

Methotrexate use is likely not a significant cause of chronic fibrotic lung disease in rheumatoid arthritis, and this medication may even delay the onset of ILD.27

The efficacy of the anti-fibrotic agent nintedanib in the treatment of progressive fibrosing ILDs extends to the treatment of progressive connective tissue disease-associated ILD.28 Also, anti-IL-6 therapy is emerging as a potential new treatment option for systemic-sclerosis associated ILD.29

Further research is needed to identify noninvasive prognostic markers of disease progression so that treatment can be started before irreversible damage to the lungs occurs.

Gaps in the Evidence-Based Knowledge

As noted earlier, patient participation in pulmonary rehab programs is low, on the basis of these findings, policy, funding, service delivery, and other interventions to improve participation in PR can be developed and evaluated.32

The pharmacologic treatment for IPF is without definitive, proven benefit. The use of a combination of prednisone, azathioprine, and glucocorticoids has been the conventional approach to treatment. Recommendations made by the ATS/ERS guidelines though the evidence is weak. The efficacy and safety of the treatment is unknown.

In the case of CTD, the pathogenesis is critical to the development of immune system dysfunction and immune-mediated pulmonary inflammation. Therefore, immunosuppression is the frequent strategy. Efficacy and safety of the treatment has not been supported.30

References

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  13. Lama VN, Flaherty KR, Toews GB, et al. Prognostic Value of Desaturation during a 6-Minute Walk Test in Idiopathic Interstitial Pneumonia. https://doi.org/101164/rccm200302-219OC. 2012;168(9):1084-1090. doi:10.1164/RCCM.200302-219OC
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  31. Gilmartin ME. Pulmonary rehabilitation. Patient and family education. Clin Chest Med. 1986 Dec;7(4):619-27. PMID: 3791907.
  32. Pulmonary Rehabilitation: Overwhelming Evidence but Lost in Translation? Kylie Johnston, Karen Grimmer-Somers https://doi.org/10.3138/physio.62.4.368

Original Version of the Topic

Farha S. Ikramuddin, MD MBBS. Pulmonary rehabilitation in intrinsic restrictive lung diseases. 9/20/2014

Previous Revision(s) of the Topic

Rajashree Srinivasan, MD, MBBS, Veronica Reyor, DO. Pulmonary rehabilitation in intrinsic restrictive lung diseases. 9/27/2020

Author Disclosures

Rajashree Srinivasan, MD, MBBS
Nothing to Disclose

Saylee Dhamdhere, MD
Nothing to Disclose

Nikhil Gopal, MBBS
Nothing to Disclose