Restrictive Lung Disease

Etiology

The acronym "PAINT" can be used to memorize the causes of restrictive lung disease into pleural, alveolar, interstitial, neuromuscular, and thoracic cage abnormalities. Nevertheless, a more accurate division takes into account the pathogenetic mechanism.

Restrictive lung syndromes can be caused by:

• Pulmonary parenchyma diseases (intrinsic causes)
• Extrapulmonary diseases (extrinsic causes)

Intrinsic, or pulmonary causes, involve the lung parenchyma itself, while the extrinsic restrictive lung diseases originate from neuromuscular disorders, obesity, and other extra-parenchymal disorders.[1] In both intrinsic or extrinsic pulmonary conditions, lung volumes become reduced due to restrictions in pulmonary mechanics. 

Pulmonary Parenchyma Diseases (Intrinsic Causes)

Intrinsic restriction can be caused by intrapulmonary restriction due to inflammatory processes within the lung tissue by diseases categorized under interstitial lung diseases.

• Idiopathic pulmonary fibrosis (IPF)
• Non-specific interstitial pneumonia (NSIP)
• Cryptogenic organizing pneumonia (COP)
• Sarcoidosis
• Acute interstitial pneumonia (AIP)
• Inorganic dust exposure such as silicosis, asbestosis, talc, pneumoconiosis, berylliosis, hard metal fibrosis, coal worker's pneumoconiosis, chemical worker's lung
• Organic dust exposure such as farmer's lung, bird fancier's lung, bagassosis, and mushroom worker's lung, humidifier lung, hot tub pneumonitis
• Hypersensitivity pneumonitis
• Systemic sclerosis
• Pulmonary vasculitis
• Pulmonary Langerhans cell histiocytosis (formerly referred to as histiocytosis X)
• Medications such as nitrofurantoin, amiodarone, gold, phenytoin, thiazides, hydralazine, bleomycin, carmustine, cyclophosphamide, methotrexate
• Radiation therapy

These conditions can be grouped into diseases that lead to an increased elastic return (e.g., diffuse infiltrative pneumopathies, and interstitial diseases), and diseases provoked by the occupation of alveolar spaces (e.g., pneumonia).

Extrinsic or Extrapulmonary Diseases

They can be a result of diseases of the chest wall, such as:

• Kyphoscoliosis
• Pleural conditions such as effusions, trapped lung, pleural scarring, chronic empyema, asbestosis
• Obesity
• Neuromuscular disorders like muscular dystrophy, amyotrophic lateral sclerosis, polio, and phrenic neuropathies.[4] 
• Ascites

Extrapulmonary diseases can also be schematically grouped into pathologies that produce a decreased muscle tone of the respiratory pump (e.g., myopathies, and neurological deficits), deformations of the rib cage (e.g., kyphoscoliosis), and space occupation (e.g., pleural effusions, pneumothorax).

In brief, the causes of restrictive diseases can, therefore, be manifold. In some conditions, such as IPF, the causes are unknown. In this context, a challenge concerns the genetic factors that contribute to disease risk. Kaur et al.[5], for instance, illustrated the genetics in IPF and correlations with prognosis and treatment. More recently, the role of rare variation in FAM13A, TERT, and RTEL1 gene regions involved in the risk of IPF was demonstrated.[6]

Epidemiology

The overall prevalence of restrictive diseases is difficult to estimate precisely because the groups involve multiple pathological conditions, each of which can occur in numerous clinical stages. It has been determined, however, that up to 3-6 cases per 100,000 persons suffer from intrinsic lung diseases in the United States.[7] Among the other conditions, the prevalence of sarcoidosis in North America has been calculated as 10-40 cases per 100,000 persons[8] with a higher prevalence in Sweden (64 cases per 100,000 individuals).

National and global population studies demonstrated that there are certain classes of individuals reported to be at a higher risk for having a restrictive pattern on spirometry. The populations with higher associations to restrictive lung patterns include:

• Elderly- The prevalence of restrictive conditions increases from 2.7 cases per 100,000 persons in individuals aged 35-44 years to over 175 cases per 100,000 in those older than 75 years.[9] Nevertheless, sarcoidosis, collagen-vascular-associated diseases, and pulmonary Langerhans cell histiocytosis occur in patients aged 20-40 years. 
• African Americans- Compared to Whites (10.9 cases per 100,000), the prevalence in this group is 35.5 cases per 100,000 persons.[4] 
• Females- Sarcoidosis is slightly more common in women. Moreover, the female gender has also been reported an increased risk for a restrictive pattern.[10] Again, IPF is more common in men than in women. 
• Obese individuals- Restrictive patterns are related to an elevated body mass index (BMI) with a decrease in lung volumes attributed to an increased amount of central obesity.[10] 
• Smokers[4]- For instance, IPF individuals are usually current or past smokers.

Those that have specific occupational and environmental exposures are also at increased risk. Frequently encountering substances at workplaces such as asbestos, coal dust, and several other hazardous specks of dust can cause tissue alterations in the lungs leading to inflammation, tissue scarring, and a restrictive pattern on spirometry.[10] Restrictive lung diseases are a rare occurrence during pregnancy, but if it is present, it is likely due to neuromuscular disease or kyphoscoliosis.[11]

An interesting finding concerns not only the epidemiology of the established pathology but functional subclinical alterations as well as the temporal evolution. In an epidemiological study, Kurth et al. showed that restrictive patterns on spirometry were found to fall from 7.2% to 5.4% from 1988-1994 and from 2007-2010, which may be related to increased occupational safety precautions and falling rates of cigarette smoking.[4]

Pathophysiology

The intrinsic pulmonary restriction is most commonly characterized by inflammation of the pulmonary parenchyma with subsequent deposition of collagen in the interstitium, which ultimately leads to pulmonary fibrosis. Over time, this progressive fibrosis thickens the alveolar septae, imposing a physical barrier to gas exchange. This is reflected in pulmonary function testing (PFT), where decreased diffusing capacity for carbon dioxide (DLCO) can be observed.[1][12] Besides decreasing DLCO, lung tissue fibrosis decreases the compliance of the lung tissue, reducing the inspiratory capacity.[13] 

The pathophysiology of extrapulmonary forms provides an altered mechanical function very often induced by deformations of the rib cage, but also linked to neurological or muscular pathologies, or from the occupation of space, as in the case of pleural effusions.

The Compliance

The distensibility of the respiratory system is termed as compliance (C). It a key concept in respiratory physiology and represents the volume change produced by a change in the distending pressure. It is determined by elastic forces formula:

C=ΔV/ΔP

Of note, lung compliance is independent of the thoracic cage, which is a semirigid casing, but lung and thorax are systems arranged in series. Thus, the compliance of an intact respiratory system is the sum of the compliances of both of these structures. Therefore, it is affected by any disease of the lungs, pleura, or chest wall. Lung compliance decreases if the lung is over rigid (restrictive pathologies) and increases in less stiff conditions such as emphysema. Thoracic compliance decreases in conditions of reduced distensibility of the rib cage (obesity, kyphoscoliosis). Combined compliance of thorax and lungs is 110 ml/cmH2O, whereas the compliance of lung alone is approximately 200 ml/cmH2O. Decreased compliance, either from intrapulmonary or extrapulmonary etiology, results in greater pressure generation and energy requirements from the respiratory muscles for any given tidal volume.[13] These changes in respiratory physiology eventually lead to tissue hypoxia and dyspnea.

Hypoxemia

Hypoxemia (PaO2<60 mmHg), whether or not in association with hypercapnia (PaCO2>45 mmHg), can be a consequence of lung damage, and an expression of respiratory failure. In restrictive syndromes, it occurs with different mechanisms depending on the type of the disease. In the intrinsic conditions, it is produced by alterations in the gas diffusion with a mismatch in the ventilation-perfusion ratio. This process leads, in turn, to an increased intrapulmonary shunt that is the portion of the pulmonary blood flow that bypasses the alveoli or perfuses unventilated alveoli and does not participate in the gas exchanges. On the other hand, hypoventilation and pump failure are prominent in the extrinsic conditions.

Functional Characteristics

Functional characteristics of a restrictive pattern in pulmonary function tests (PFTs) include decreased TLC and forced vital capacity (FVC). This latter parameter is the maximum amount of air exhaled after a maximal inhalation and depends on the elasticity of the lung tissue, the anatomy of the thoracic cage, and the function of the respiratory muscles. According to the American Thoracic Society (ATS), the TLC predicted (adjusted for gender, age, height) value can be used for assessing the severity of the restrictive condition:[14][15]

• TLC < 80% = Restrictive disease
• 70-80 % predicted: mild restrictive disease
• 60-70% predicted: moderate restrictive disease
• 50-60% predicted: moderately severe restrictive disease
• < 50% predicted: severe restrictive disease

Of note, in restrictive diseases, the forced expiratory volume over 1 second (FEV1) usually slightly decreases or stays normal, and the ratio of FEV1 to FVC is generally preserved or increased. These alterations in pulmonary dynamics can be compensated by an increased respiratory rate, with hypercapnia developing only at later stages of the disease.[16] 

The functional data are different from those observed in obstructive syndromes in which TLC and FVC are normal (80-120% of predicted) or increased, while the significant figure is the decrease in the FEV1 compared to FCV.

In summary, the patterns in PFTs in the two groups of respiratory disease are:

Restrictive Patterns: 

• Decreased FVC and TLC
• FEV1 is usually slightly decreased or stays normal
• The ratio of FEV1 to FVC is usually preserved or increased.
• Reduced DLCO

Obstructive Patterns:

• TLC and FCV are normal or increased
• Decreased FEV1 compared to FCV
• The ratio of FEV1 to FVC is decreased
• Reduced DLCO in emphysema, normal in chronic bronchitis, normal or increased in asthma

There are also combined obstructive and restrictive patterns, usually featuring low or normal FVC, low FEV1, and a lower FEV1 to FVC ratio and with a decreased, normal, or increased TLC.

Histopathology

Lesions that determine intrinsic interstitial diseases originate from lesions of the alveolar capillaries with protein exudation, hemorrhage, and accumulation of inflammatory elements in the alveolar spaces. Alternatively, edema and interstitial inflammatory infiltration may occur. Interstitial fibrosis represents the consequence of both previous processes. Beyond a didactic schematism, the histopathological findings are manifold; some of those more specific, while others can be found in different conditions.

Usual Interstitial Pneumonia and Idiopathic Pulmonary Fibrosis

The morphological pattern of the usual interstitial pneumonia (UIP) identifies a set of modifications of the pulmonary microstructure characterized by the alternation of areas of a normal lung with fibrotic areas and prevalent subpleural and paraseptal distribution. Although this picture describes IPF, it is not exclusive to IPF alone but can also be detected in other clinical entities. Indeed, although the term UIP is often used interchangeably with IPF, other clinical conditions can show the pathological findings of UIP. In particular, IPF is a specific form of chronic fibrosing interstitial pneumopathy, an unknown etiology (idiopathic UIP) where the alveolitis produces fibroblast proliferation and collagen deposition. Accurate histopathological analysis, however, can identify distinctive elements. One of the main characteristics of the UIP/IPF pattern is the temporal heterogeneity of fibrosis. This peculiar aspect is represented by the coexistence of dense scar areas of mature collagen fibrosis and "honeycomb" areas, and young fibroblastic proliferation called fibroblastic foci. Furthermore, in the IPF, a polypoid proliferation of myofibroblasts, generally protruding into alveolar or bronchiolar cavities, characterized by a stroma with scarce collagen fibers, can be observed. The interstitial septa appear fibrotic and coated with hyperplastic type 2 pneumocytes or with epithelium in bronchiolar metaplasia with a hyperplastic aspect.

Non-Specific Interstitial Pneumonia

It has histological and radiological characteristics different from all the other interstitial diseases of unknown etiology. It is essential to know its morphologic and clinic features as, compared to IPF, this disease manifests a much better prognosis. Morphologically, there are changes in lung architecture that do not fully meet the criteria which underlie the other forms of pulmonary interstitial disease. Three subgroups of the NSIP pattern can be recognized:

• Cellular Pattern: A mild to moderate chronic inflammatory interstitial infiltrate, mainly represented by lymphocytes and plasma cells, occasionally arranged in nodular aggregates
• Fibrous Pattern: Scarce cellular elements with a greater fibrous component
• Mixed Pattern: Coexistence of the two forms

Cryptogenic Organizing Pneumonia

The morphological pattern often shows a bronchiolocentric location with the maintenance of the pulmonary architecture in the areas surrounding the remodeling process. The morphological characteristics are the proliferation of connective tissue (Masson bodies) inside of the small airways and alveolar ducts, with occlusion of the bronchioles (obliterating bronchiolitis) and surrounding alveoli (organized pneumonia).

Sarcoidosis

It is a multisystemic inflammatory disease that begins more frequently between 20 and 40 years of age and represents the most frequent of all interstitial lung diseases. The lungs are almost constantly affected (about 90% of cases) with bilateral pulmonary hilar lymph node involvement and possible simultaneous involvement of the lungs. Histopathology features include noncaseating epithelioid granulomas with tightly packed epithelioid cells, Langhans giant cells, and T lymphocytes. These findings are localized in interstitium adjacent to bronchioles as well as around and within vessel walls, pleura, and connective tissue septa. There are Schaumann bodies (laminated concretions of calcium and protein) and asteroid elements (stellate inclusions within giant cells).

History and Physical

A comprehensive history and thorough physical examination are required to identify and classify these complex disorders appropriately. A careful history-taker must be sure to include inquisition as to the severity of symptoms, time course/origin of symptoms, rate of worsening of symptoms, family history, smoking and drug history, as well as occupational and environmental exposure history.[3] Each condition has its own set of signs and symptoms which are unique to the particular disease and its pathophysiology. However, most are characterized by an insidious progression of dyspnea.[13] Moreover, ILDs classically produce the "3Cs": cough, clubbing of the nails, and coarse crackles on auscultation.[17]

Common additional characteristics in patients with extrinsic restriction will include an increased BMI, spine deviation, or have a history of neuromuscular disease.

Clinical features and prognosis vary among the diseases. For instance, IPF involves a progressive decline in lung function that leads to eventual respiratory failure. As a consequence, the condition has a poor prognosis with a median survival of 3 to 5 years after diagnosis.

Evaluation

The mainstay for evaluation for pulmonary restriction is based on pulmonary function tests (PFTs). Initial results indicative of pulmonary restriction will be a decreased TLC with a preserved FEV1/FVC ratio (greater than 70%). Once restrictive, a restrictive pattern is suggested on spirometry; patients should be referred for full PFTs with DLCO measurement, which will be decreased on patients with intrinsic pulmonary restriction.[18] Patients with extrinsic pulmonary restriction will also present with a restrictive pattern on PFTs; however, DLCO remains normal.[19] Additional testing with high resolution computed tomography (HRCT), inflammatory markers, and specific autoantibodies should be done on an individual basis according to the suspected etiology of the pulmonary restriction.

In the IPF, the high-resolution computerized tomography (HRTC) demonstrates the typical appearance with coarse crosslinking in the basal regions, posterior in the early stages, peripheral/sub-pleural. "Honeycomb" cystic alterations and bronchiectasis that become evident for traction fibrotic.

A special type among the ILDs is idiopathic pulmonary fibrosis. Guidelines from the ATS suggests considering adult patients with newly detected bilateral fibrosis on a chest radiograph or chest CT, bibasilar inspiratory crackles, and an age typically older than 60 years of an unknown cause, to be clinically suspected for having IPF.[15]

Treatment / Management

Management of restrictive lung disease varies depending on the etiology of the restriction. Patients diagnosed with IPF have been traditionally treated with immunosuppression; however, new anti-fibrotic drugs such as pirfenidone and nintedanib are increasingly used as they have shown to slow down disease progression.[20] Patients with autoimmune conditions that can lead to interstitial lung diseases like systemic sclerosis are being treated with immunosuppressant drugs, including steroids, mycophenolate mofetil, and cyclophosphamide depending on the degree of disease.[21] 

Patients with acute exacerbations are usually treated with steroids over several days; however, prolonged steroid therapy is not recommended due to their associated complications.[22] Oxygen therapy, managing comorbid conditions, and pulmonary rehabilitation, in addition to pirfenidone and nintedanib, are prescribed as treatments suggested for idiopathic pulmonary fibrosis.[1][23] For obese patients, management involves losing weight by a combination of diet and physical exercise.[3] Morbidly obese patients who fail to lose weight by traditional methods should be referred for gastric bypass surgery evaluation as it has been shown effective in achieving significant weight loss and improvement on PFTs.[24] Impairment in pulmonary function in patients with severe scoliosis may be controlled with surgical correction.[25] Patients with extensive pulmonary fibrosis and chronic respiratory failure should be evaluated as possible candidates for lung transplantation.[26] (B3)

Differential Diagnosis

The differential diagnosis of pulmonary restriction remains broad even after it has been diagnosed by PFTs as there are several causes of pulmonary restriction. Intrinsic pulmonary restriction can be caused by any of the interstitial lung diseases such as

• Idiopathic pulmonary fibrosis
• Non-specific interstitial pneumonia
• Cryptogenic organizing pneumonia
• Acute interstitial pneumonia
• Pneumoconiosis
• Hypersensitivity pneumonitis
• Systemic sclerosis
• Sarcoidosis

Causes of extrinsic pulmonary restriction include

• Obesity
• Spinal deviation
• Neuromuscular disorders

Prognosis

The prognosis of patients with restrictive lung disease varies greatly depending on the etiology of pulmonary restriction. Patients with pulmonary restriction from a pleural effusion should experience resolution of symptoms upon drainage, and pregnant patients should also recover upon delivery. Intrinsic pulmonary restriction from cryptogenic organizing pneumonia is associated with excellent long term outcomes when treated. Patients diagnosed with IPF have a median survival of 3-5 years after diagnosis.[27][28] Acute interstitial pneumonia has a grave prognosis as it is associated with greater than 70% mortality in 3 months.[29] Due to the diverse nature of restrictive lung disease, all efforts should be made to obtain a specific diagnosis once pulmonary restriction has been confirmed. 

Complications

Advanced restrictive lung disease results in hypoxemia, which can only be compensated by elevations in respiratory rate. Increased energy expenditure in breathing can lead to muscle wasting and weight loss. Once compensatory mechanisms fail, and hypoxia worsens, patients develop chronic respiratory failure. Sleep disorders, including obstructive sleep apnea (OSA), which are common in patients with extrinsic pulmonary restriction due to obesity, have also been noted in a significant amount of patients with intrinsic restrictive lung disease.[30] Chronic respiratory failure and lung architecture distortion lead to pulmonary hypertension and cor-pulmonale.