Medical Care
Treatment depends on the specific diagnosis, which is based on findings from the clinical evaluation, imaging studies, and lung biopsy.
Corticosteroids, immunosuppressive agents, and cytotoxic agents are the mainstay of therapy for many of the interstitial lung diseases. Objective data assessing the risks and benefits of immunosuppressive and cytotoxic agents to treat diverse interstitial lung disorders are sparse. Direct comparisons among these agents are lacking.
Ancillary therapies include supplemental oxygen therapy, which alleviates exercise-induced hypoxemia and improves performance.
Idiopathic pulmonary fibrosis
The rate of progression of idiopathic pulmonary fibrosis (IPF) is highly variable, and controversy exists regarding the timing of treatment. The disease may be responsive to treatment in the early, so-called inflammatory stage. IPF always progresses insidiously, and documenting the changes over short periods is difficult. Initiate a trial of therapy for 6-12 weeks, starting as early as possible, with the hope of slowing disease progression. Discontinue therapy if no benefit is observed or if adverse effects develop.
The prognosis for patients with IPF who do not respond to medical therapy is poor. They usually die within 2-3 years. These and other patients with severe functional impairment, oxygen dependency, and a deteriorating course should be listed for lung transplantation.
Conventional therapies (corticosteroids, azathioprine, [45] cyclophosphamide) provide only marginal benefit to patients with IPF. Corticosteroids have never been studied against placebo. Retrospective studies have not demonstrated any benefit from steroid monotherapy. [46] Acute exacerbations may not respond to high-dose corticosteroid therapy. [47]
Intermittent intravenous cyclophosphamide given to IPF patients surviving 6 months improved pulmonary function and reduced prednisone dosage in one study. [48] However, current guidelines recommend against the use of combination immunosuppressant therapy, owing to limited efficacy data. [49]
Thalidomide has been shown to attenuate pulmonary fibrosis after a bleomycin challenge in animal models. [50] A randomized crossover design study has demonstrated a significant reduction in cough and improved quality of life in patients with IPF. [51]
Pulmonary rehabilitation has been demonstrated to improve overall quality of life and can provide education and psychosocial support for patients with IPF. [52]
A retrospective cohort study found that treatment of gastroesophageal reflux disease was associated with an increased length of survival and reduced radiographic evidence of fibrosis. [53]
Supplemental oxygen can be provided for patients with hypoxemia (PaO2< 55 mm Hg or oxygen saturation [SaO2] < 88%) at rest or during exertion. However, rigorous studies of benefit or improvement in quality of life have not been demonstrated, as it has been in the COPD population.
Lung transplantation should be considered for patients with IPF refractory to medical therapy. [54] Transplantation has been reserved for patients at advanced stages of IPF. The 5-year mortality rate remains around 50%. However, bronchiolitis obliterans syndrome (BOS), a process of progressive fibrosis of the bronchioles, can occur post transplantation and has high mortality.
Because of a lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued. [55] Emerging strategies to treat patients with IPF include agents that inhibit epithelial injury or enhance repair, anticytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches. [56]
Corticosteroids
Corticosteroids are a first-line therapy but are associated with myriad adverse effects. Corticosteroids, the most commonly used drugs, halt or slow the progression of pulmonary parenchymal fibrosis with variable success.
Questions about which patients should be treated, when therapy should be started, [57] and what constitutes the best therapy receive uncertain answers at present.
Although subjectively most patients with IPF feel better, an objective improvement occurs in 20-30% patients. A favorable response is a reduction in symptoms; the clearing of radiographs; and improvements in forced vital capacity (FVC), total lung capacity (TLC), and diffusion capacity of the lungs for carbon monoxide (DLCO). The optimal duration of therapy is not known, but treatment for 1-2 years is suggested.
Cytotoxic therapy
Immunosuppressive cytotoxic agents may be considered for patients who do not respond to steroids, experience adverse effects, or have contraindications to high-dose corticosteroid therapy. The failure of steroid therapy is defined as a fall in FVC or TLC by 10%, a worsened radiographic appearance, and a decreased gas exchange at rest or with exercise.
Azathioprine is less toxic than methotrexate or cyclophosphamide and may be preferred as a corticosteroid-sparing agent for disorders that are not life threatening. A response to therapy may not occur for 3-6 months.
Because of potentially serious toxicities, cyclophosphamide is reserved for fulminant or severe inflammatory disorders refractory to alternate therapy.
Antifibrotic therapies
These therapies, including colchicine, are suggested for a variety of fibrotic disorders, including IPF.
IPF subjects given high-dose prednisone had an increased incidence of serious adverse effects and shortened survival compared with those given colchicine in a prospective randomized study [58] ; therefore, a trial of therapy with colchicine is reasonable in less symptomatic patients or those who are experiencing adverse effects with steroid therapy.
One study showed that in patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or quality of life. No survival benefit was demonstrated in this trial. [59]
Nintedanib, a triple tyrosine kinase inhibitor of fibroblast growth factor (FGF), vascular endothelial growth factor (VEGF), and platelet-derived growth factor (PDGF), has been demonstrated to lead to a reduction in the decline of FVC, led to improved quality of life, and yielded a reduction in acute exacerbations of IPF. [60] In 2014, the INPULSIS studies, two randomized, double-blind, phase 3 trials, were able to demonstrate that nintedanib led to a reduced rate of progression of disease in patients with IPF. [61]
Pirfenidone an oral medication that reduces fibroblast proliferation and collagen deposition, via down-regulation of transforming growth factor (TGF)–β and tumor necrosis factor (TNF)–α, was investigated in 2010 in two phase 3 trials. [62, 63] Results suggested that pirfenidone may reduce the FVC decline associated with IPF. Some conflicting data necessitated an additional phase 3 study. In 2014, the ASCEND trial, a multicenter, randomized control trial, demonstrated a reduction in the composite outcome of FVC decline and all-cause mortality. [61] Additional secondary outcomes demonstrated no significant decrease in all-cause mortality decline in the treatment arm. However, there was a significant improvement in progression-free survival.
Collagen-vascular disease
Therapy for pulmonary fibrosis associated with collagen-vascular disease is controversial because the course may be indolent. Because these diseases begin as an alveolitis, an aggressive approach may be warranted.
Patients with severe disease or those who have a deteriorating course must be treated with corticosteroids, cytotoxic therapy, or both.
Sarcoidosis
Because the disease remits spontaneously, patients with respiratory symptoms and radiographic or pulmonary function evidence of extensive disease may benefit from corticosteroids. Patients with hypercalcemia or extrapulmonary involvement generally require treatment. Therapy should be continued for 6 months or longer; however, even after prolonged treatment, up to 50% of patients relapse after therapy is discontinued.
For patients who do not respond to corticosteroids, alternate therapies (eg, chloroquine, methotrexate, azathioprine) may be used; however, data are limited.
Treatment of extrinsic lung disorders
Patients with nonmuscular chest wall disorders and neuromuscular disease may develop problems with ventilation and gas exchange during sleep. The effect of decreased chest wall and lung compliance or decreased muscle strength is hypercapnia and hypoxemia, which occurs initially during sleep. Identify and treat the cause of muscle weakness.
Treatment of neuromuscular diseases includes preventive therapies to minimize the impact of impaired secretion clearance and the prevention and prompt treatment of respiratory infections.
Patients who develop respiratory failure or have severe gas exchange abnormalities during sleep may be treated with noninvasive positive-pressure ventilation via a nasal or oronasal mask. Patients in whom these devices fail may require a permanent tracheotomy and ventilator assistance with a portable ventilator. [64]
Noninvasive ventilation with body-wrap ventilators or positive-pressure ventilation has been proven beneficial because it helps relieve dyspnea and pulmonary hypertension and helps improve RV and gas exchange. Also, hospitalization rates are markedly reduced and the activities of daily living are enhanced. [65]
Treatment for massive obesity consists of weight loss, which causes dramatic improvement in pulmonary function test findings but is harder to achieve. These patients require polysomnographic study because of the high incidence of nocturnal hypoventilation or upper airway obstructions. Either continuous positive airway pressure or noninvasive pressure ventilation helps correct hypoventilation and upper airway obstruction.
In advanced disease, when respiratory failure develops, these patients are treated with mechanical ventilation. If they have copious secretions, cannot control their upper airway, or are not cooperative, then invasive ventilation with a tracheotomy tube is indicated. In other patients, eg, those who have good airway control and minimal secretions, use noninvasive ventilation, initially nocturnal, and then intermittently.
Surgical Care
If a pleural disorder is the cause of the restriction, surgery can occasionally be curative. Trapped lung and chronic empyema may be cured with decortication. FVC and FEV1 improve after decortication for chronic empyema, and chest wall deformity may improve after surgery as well. [66]
Consultations
Consultation with a pulmonologist is helpful for diagnosis and management.
Prevention
Acute exacerbation in patients with idiopathic pulmonary fibrosis (IPF) is a recently recognized complication that occurs unpredictably and presents as worsening dyspnea. Chest radiography demonstrates bilateral mixed alveolar-interstitial infiltrates and CT scan reveals ground-glass opacities and consolidation. The treatment includes high-dose systemic corticosteroids, although these are likely not effective, and the disease portends extremely poor prognosis.
-
Approximately half of the patients with idiopathic pulmonary fibrosis develop clubbing. Clubbing is commonly seen in patients with asbestosis.
-
Lung volume is plotted against transpulmonary pressure. Compliance is the change in volume for a given change in pressure. A patient with emphysema has a higher lung compliance compared with a patient with no lung disease, while a patient with restrictive lung disease has a reduction in compliance.
-
Idealized flow volume curves for normal, obstructive, and restrictive lungs.
-
The expiratory flow volume curves of 2 patients are depicted graphically. A is a patient with restrictive lung disease (idiopathic pulmonary fibrosis), low forced vital capacity (FVC), but an increased ratio of forced expiratory volume in 1 second (FEV1) to FVC because of increased elastic recoil. B is a patient with chronic obstructive lung disease whose FEV1/FVC ratio is low but whose lung volumes are increased.
-
Pulmonary function test results from a patient with restrictive lung disease.
-
Gross pathology of small and firm lungs due to restrictive lung disease from advanced pulmonary fibrosis.
-
Intrinsic lung disease may progress to extensive fibrosis, regardless of etiology. This is described as honeycomb lung.
-
End-stage sarcoidosis.
-
Usual interstitial pneumonitis (left).
-
Usual interstitial pneumonitis (right).
-
Histopathology of a case of idiopathic pulmonary fibrosis. Alveolitis with fibroblast proliferation and collagen deposition is present.
-
In usual interstitial pneumonitis or idiopathic pulmonary fibrosis, subpleural and paraseptal inflammation is present, with an appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal, or nearly normal, alveoli interspersed between fibrotic areas are the hallmarks of this disease. Additionally, the lung architecture is completely destroyed.
-
Characteristic features of usual interstitial pneumonitis as described in the image below.
-
Cryptogenic organizing pneumonia (also called proliferative bronchiolitis) is often patchy and peribronchiolar. The proliferation of granulation tissue within small airways and alveolar ducts is excessive and is associated with chronic inflammation of surrounding alveoli.
-
Cryptogenic organizing pneumonia, as described in the image below, showing a close-up view of fibrogranulation tissue in terminal airspaces.
-
Granulomatous lung diseases are marked by granulomas characterized by the accumulation of T lymphocytes, macrophages, and epithelioid cells. These may progress to pulmonary fibrosis. This low-power image shows well-formed granuloma along the airway.
-
Multiple well-formed noncaseating granulomas secondary to sarcoidosis.
-
Sarcoid granulomas.
-
High-power view of sarcoid granuloma shows giant cells.
-
A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen.
-
A patient who developed restrictive lung disease had findings of cryptogenic organizing pneumonia on an open lung biopsy specimen. The biopsy sample shows intraluminal buds of granulation tissue.
-
Lymphocytic interstitial pneumonitis, for which the prominent finding is a lymphoid infiltrate that involves both the interstitium and alveolar spaces.
-
Usual interstitial pneumonitis honeycombing.
-
Chest radiograph of a 67-year-old man diagnosed with idiopathic pulmonary fibrosis, based on open lung biopsy findings. Extensive bilateral reticulonodular opacities are seen in both lower lobes.
-
High-resolution CT scan of the same patient in the image below demonstrates peripheral honeycombing and several areas of ground-glass attenuation. Ground-glass opacification may correlate with active alveolitis and a favorable response to therapy.
-
A CT scan image from a 59-year-old woman shows advanced pulmonary fibrosis. Extensive honeycombing and traction bronchiectasis are present.
-
Restrictive lung disease may occur in stage II and stage III sarcoidosis. In this image, mediastinal lymphadenopathy is shown secondary to stage II disease.
-
Sarcoidosis on CT scan shows nodules in midlung zones. These nodules are predominantly along the bronchovascular bundles and in a subpleural location.
-
Restrictive lung disease secondary to sarcoidosis.
-
A chest radiograph of stage III sarcoidosis. This stage refers to pulmonary infiltrates without evidence of mediastinal lymphadenopathy.
-
Chest radiograph from a 39-year-old woman with severe kyphoscoliosis who developed hypercapnic respiratory failure. Spirometry findings showed a severe restrictive lung disease, with a forced expiratory volume in one second of 0.4 L/s and a forced vital capacity of 0.5 L.
-
The flow volume curve of a patient with lung fibrosis.
-
Likely case of idiopathic pulmonary fibrosis, which should be treated with prednisone.
-
Pressure volume curve comparing lungs with emphysema, lungs with restrictive disease, and normal lungs.
Tables
Causes |
Examples |
Diagnosis |
PFT Findings |
Pleural |
Trapped lung, pleural scarring, large pleural effusions, chronic empyema, asbestosis |
Radiography, CT scanning, pleural manometry, pleural biopsy |
Low RVa, low TLC, low FVC |
Alveolar |
Edema, hemorrhage |
Radiography, CT scanning, physical examination |
Increased DLCOb in hemorrhage (Intrapulmonary hemoglobin absorbs the carbon monoxide, thus increasing the DLCO reading.) |
Interstitial |
Interstitial lung disease including IPFc, NSIPd, COPe |
Radiography, CT scanning, physical examination, echo often shows pulmonary hypertension |
Low RV, low FVC, low TLC, decreased DLCO, poor lung compliance |
Neuromuscular |
Myasthenia gravis, ALSf, myopathy |
Physical examination, EMGsg, serology |
Low RV, low TLC, low NIFh, low MMVi |
Thoracic/extrathoracic |
Obesity, kyphoscoliosis, ascites |
Physical examination |
Low ERVj and FRC in obesity, low VCk, TLC, FRCl in kyphoscoliosis |
aResidual volume. bDiffusion capacity of the lungs for carbon monoxide. cIdiopathic pulmonary fibrosis. dNonspecific interstitial pneumonitis. eCryptogenic organizing pneumonia. fAmyotrophic lateral sclerosis. gElectromyography. hNegative inspiratory force. iMaximal voluntary ventilation. jExpiratory reserve volume. kVital capacity. lFunctional residual capacity. |
|||
Features |
AIP |
UIP |
NSIP |
COP |
Pathologic |
||||
Temporal appearance |
Uniform |
Heterogeneous |
Uniform |
Uniform |
Interstitial inflammation |
Scant |
Scant |
Usually prominent |
Variable |
Collagen fibrosis |
No |
Patchy |
Variable, diffuse |
No |
Fibroblast proliferation |
Diffuse, interstitial |
Patchy (fibroblast foci) |
Occasional |
Patchy, airspace |
COP areas |
Rare |
No |
Rare |
-- |
Honeycomb changes |
Rare |
Yes |
Rare |
No |
Hyaline membranes |
Yes, often focal |
No |
No |
No |
