Restrictive Lung Disease

Author: Sat Sharma, MD, FRCPC, Professor and Head, Division of Pulmonary
Medicine, Department of Internal Medicine, University of Manitoba; Site Director,
Respiratory Medicine, St. Boniface General Hospital
Contributor Information and Disclosures

Updated: Jun 5, 2006

• Print This
• Email This

• Overview
• Differential Diagnoses & Workup
• Treatment & Medication
• Follow-up
• Multimedia

• References
• Keywords

Introduction
Background

Restrictive lung diseases are characterized by reduced lung volume, either because of an
alteration in lung parenchyma or because of a disease of the pleura, chest wall, or
neuromuscular apparatus. In physiological terms, restrictive lung diseases are
characterized by reduced total lung capacity (TLC), vital capacity, or resting lung
volume. Accompanying characteristics are preserved airflow and normal airway
resistance, which are measured as the functional residual capacity (FRC). If caused by
parenchymal lung disease, restrictive lung disorders are accompanied by reduced gas
transfer, which may be marked clinically by desaturation after exercise.

The many disorders that cause reduction or restriction of lung volumes may be divided
into 2 groups based on anatomical structures.

The first is intrinsic lung diseases or diseases of the lung parenchyma. The diseases
cause inflammation or scarring of the lung tissue (interstitial lung disease) or result in
filling of the air spaces with exudate and debris (pneumonitis). These diseases can be
characterized according to etiological factors. They include idiopathic fibrotic diseases,
connective tissue diseases, drug-induced lung disease, and primary diseases of the lungs
(including sarcoidosis).

The second is extrinsic disorders or extraparenchymal diseases. The chest wall, pleura,
and respiratory muscles are the components of the respiratory pump, and they need to
function normally for effective ventilation. Diseases of these structures result in lung
restriction, impaired ventilatory function, and respiratory failure (eg, nonmuscular
diseases of the chest wall, neuromuscular disorders).

Pathophysiology

Air flows to and from the alveoli as lungs inflate and deflate during each respiratory
cycle. Lung inflation is accomplished by a contraction of respiratory, diaphragmatic,
and external intercostal muscles, whereas deflation is passive. FRC is the volume of air
in the lungs when the respiratory muscles are fully relaxed and no airflow is present.
The volume of FRC is determined by the balance of the inward elastic recoil of the
lungs and the outward elastic recoil of the chest wall. Restrictive lung diseases are
characterized by a reduction in FRC and other lung volumes because of pathology in
lungs, pleura, or the structures of the thoracic cage.

The distensibility of the respiratory system is called compliance, the volume change
produced by a change in the distending pressure. Lung compliance is independent of the
thoracic cage, which is a semirigid container. The compliance of an intact respiratory
system is an algebraic sum of the compliances of both of these structures; therefore, it is
influenced by any disease of the lungs, pleura, or chest wall.

In cases of intrinsic lung disease, the physiological effects of diffuse parenchymal

disorders reduce all lung volumes by the excessive elastic recoil of the lungs, in
comparison to the outward recoil forces of the chest wall. Expiratory airflow is reduced
in proportion to lung volume.

Arterial hypoxemia in these disorders is primarily caused by ventilation-perfusion

mismatching, with further contribution from an intrapulmonary shunt. The diffusion of
oxygen is impaired, which contributes a little towards hypoxemia at rest but is primarily
the mechanism of exercise-induced desaturation.

Hyperventilation at rest and exercise is caused by the reflexes arising from the lungs and
the need to maintain minute ventilation by reducing tidal volume and increasing
respiratory frequency.

In cases of extrinsic disorders of the pleura and thoracic cage, the total compliance by
the respiratory system is reduced, and, hence, lung volumes are reduced. As a result of
atelectasis, gas distribution becomes nonuniform, resulting in ventilation-perfusion
mismatch and hypoxemia. In kyphoscoliosis, lateral curvature, anteroposterior
angulation, kyphosis, or several of these conditions are present. The Cobb angle, an
angle formed by 2 limbs of a convex prime curvature of the spine, is an indication of the
severity of disease. An angle greater than 100° is usually associated with respiratory
failure.

Neuromuscular disorders affect an integral part of the respiratory system, a vital pump.
The respiratory pump can be impaired at the level of the central nervous system, spinal
cord, peripheral nervous system, neuromuscular junction, or respiratory muscle. The
pattern of ventilatory impairment is highly dependent on the specific neuromuscular
disease.

Frequency
United States

For intrinsic lung diseases, studies cite an overall prevalence of 3-6 cases per 100,000
persons, with a prevalence of idiopathic pulmonary fibrosis (IPF) of 27-29 cases per
100,000 persons. The prevalence for adults aged 35-44 years is 2.7 cases per 100,000
persons. Prevalence exceeded 175 cases per 100,000 persons among patients older than
75 years. Exposure to dust, metals, organic solvents, and agricultural employment is
associated with increased risk.

• In North America, the prevalence of sarcoidosis is 10-40 cases per 100,000

persons.
• The incidence of chronic interstitial lung diseases in persons with collagen
vascular diseases is variable, but it is increasing for most diseases.
• Kyphoscoliosis is a common extrinsic disorder. It is associated with an
incidence of mild deformities amounting to 1 case per 1000 persons, with severe
deformity occurring in 1 case per 10,000 persons.
• Other nonmuscular and neuromuscular disorders are rare, but their incidence and
prevalence are not well known.

International

In Sweden, the prevalence rate for sarcoidosis is 64 cases per 100,000 persons. In Japan,
the prevalence rate of sarcoidosis is 10-40 cases per 100,000 persons. The prevalence of
sarcoidosis is difficult to determine, and tuberculosis is common.

• The worldwide prevalence of fibrotic lung diseases is difficult to determine

because studies have not been performed.

Mortality/Morbidity

The mortality and morbidity from various causes of restrictive lung disease is dependent
on the underlying case of the disease process.

The median survival time for patients with IPF is less than 3 years. Factors that predict
poor outcome include older age, male gender, severe dyspnea, history of cigarette
smoking, severe loss of lung function, appearance and severity of fibrosis on radiologic
studies, lack of response to therapy, and prominent fibroblastic foci on histopathologic
evaluation.

Race

Although a familial variant of IPF exists, a genetic predisposition is not documented.

US prevalence of sarcoidosis is estimated to be 10-17 times higher among African
Americans compared to white Americans.

Sex

Lymphangioleiomyomatosis (LAM) and lung involvement in tuberous sclerosis occur

exclusively in premenopausal women. Men are more likely to have pneumoconiosis
because of occupational exposure, IPF, and collagen vascular diseases (eg, rheumatoid
lung). Worldwide, sarcoidosis is slightly more common in women.

Age

IPF is rare in children. Some intrinsic lung diseases present in patients aged 20-40
years. These include sarcoidosis, collagen vascular–associated diseases, and
histiocytosis X. Most patients with IPF are older than 50 years.

Clinical
History

• The initial evaluation of patients should consist of a complete history, including

a total review of past systemic conditions. A careful history of occupation,
travel, habits, hobbies, exposures, and HIV risk factors is critical to help identify
any etiologic agent.
• Duration of illness
o Acute disorders last days to weeks and include acute interstitial
pneumonitis, eosinophilic pneumonia, and diffuse alveolar hemorrhage.
o Hypersensitivity pneumonitis and bronchiolitis obliterans-organizing
pneumonia (BOOP) may manifest as acute, subacute, or chronic disease.
o Subacute disorders lasting weeks to months include sarcoidosis, drug-
induced interstitial lung disease, alveolar hemorrhage syndrome, BOOP,
and connective tissue diseases.
o Chronic cases lasting months to years include IPF, sarcoidosis, and
pulmonary histiocytosis X.
• Smoking history: Pulmonary histiocytosis X, desquamative interstitial
pneumonitis, IPF, and respiratory bronchiolitis occur with increased frequency
among persons who smoke or those who previously smoked.
• Prior medication use
o A detailed history of previously used medications is needed to exclude
the possibility of drug-induced lung disease. These commonly used
drugs are nitrofurantoin, amiodarone, gold, chemotherapeutic agents,
procainamide, and hydralazine.
o Radiation may also cause pneumonitis and fibrosis.
• Family history: Familial associations include IPF, sarcoidosis, and LAM.
• Occupational history
o Seek a strict chronological listing of the patient's lifelong employment,
including specific duties and known exposures.
o Inhaled inorganic dust from substances (eg, silica, asbestos, beryllium,
hard metals, cobalt) can cause pneumoconiosis.
o Inhaled organic dust may cause hypersensitivity and pneumonitis.
• Environmental exposure: A review of the domestic and work environment of the
patient and spouse is invaluable.
• Symptoms of intrinsic diseases
o Progressive exertional dyspnea is the predominant symptom. Grading the
level of dyspnea is useful as a method to gauge the severity of the
disease and to follow its course.
 oA dry cough is common and may be a disturbing sign. A productive
cough is an unusual sign in most patients with diffuse parenchymal lung
disorders.
o Hemoptysis or grossly bloody sputum occurs in patients with diffuse
alveolar hemorrhage syndromes and vasculitis.
o Wheezing is an uncommon manifestation but can occur in patients with
lymphangitic carcinomatosis, chronic eosinophilic pneumonia, and
respiratory bronchiolitis.
o Chest pain is uncommon in most instances of the disease, but pleuritic
chest pain can occur in patients with rheumatoid arthritis, systemic lupus
erythematosus, and some drug-induced disorders.
• Symptoms of extrinsic disorders
o Nonmuscular diseases of the chest wall affect patients with
kyphoscoliosis. Patients younger than 35 years tend to be asymptomatic,
whereas middle-aged patients develop dyspnea, decreased exercise
tolerance, and respiratory infections.
o The cause of respiratory failure is often multifactorial and is secondary to
spinal deformity, muscle weakness, disordered ventilatory control, sleep
disordered breathing, and airway disease.
o Neuromuscular disorders occur as the respiratory muscle weakness
progresses. Patients develop dyspnea upon exertion, followed by
dyspnea at rest, and their condition ultimately advances to respiratory
failure.
o Patients with neuromuscular diseases develop significant respiratory
muscle weakness and may demonstrate fatigue, dyspnea, impaired
control of secretions, and recurrent lower respiratory tract infections.
Acute and chronic respiratory failure, pulmonary hypertension, and cor
pulmonale eventually ensue.

Physical

• Intrinsic disorders
o The physical examination in patients with intrinsic lung disorders may
yield distinguishing physical findings.
o Those with chest wall disorders show obvious massive obesity and an
abnormal configuration of the thoracic cage (eg, kyphoscoliosis,
ankylosing spondylitis).
o Velcro crackles are common in most patients with interstitial lung
disorders.
o Inspiratory squeaks or scattered, late, inspiratory high-pitched rhonchi
are frequently heard in patients with bronchiolitis.
o Cyanosis at rest is uncommon in persons with interstitial lung diseases,
and this is usually a late manifestation of advanced disease.
o Digital clubbing is common in those with IPF and is rare in others (eg,
those with sarcoidosis or hypersensitivity pneumonitis).
o Extrapulmonary findings, including erythema nodosum, suggest
sarcoidosis. A maculopapular rash can occur in those with connective
tissue diseases, or it may be drug-induced. Raynaud phenomenon may be
present in patients with connective tissue diseases, and telangiectasia is
present in those with scleroderma. Peripheral lymphadenopathy, salivary
 gland enlargement, and hepatosplenomegaly are signs of systemic
sarcoidosis. Uveitis may be observed in those with sarcoidosis and
ankylosing spondylitis.
o Cor pulmonale occurs in the late stages of pulmonary fibrosis or
advanced kyphoscoliosis. Pulmonary hypertension and cor pulmonale
become evident when signs include a loud P2, right-sided precordial lift,
and right-sided gallop.
• Extrinsic disorders
o By their very nature, severe kyphoscoliosis and massive obesity are
easily recognizable. The pleural disorders are associated with decreased
tactile fremitus, dullness upon percussion, and decreased intensity of
breath sounds.
o In cases of neuromuscular diseases, the physical examination findings
may indicate accessory muscles usage, rapid shallow breathing,
paradoxical breathing, and other features of systemic involvement.

Causes

• Intrinsic lung diseases

o Collagen vascular diseases, including scleroderma, polymyositis,
dermatomyositis, systemic lupus erythematosus, rheumatoid arthritis,
and ankylosing spondylitis, are a cause of restrictive lung disease.
o Other causes may include drugs and other treatments (eg, nitrofurantoin,
amiodarone, gold, dilantin, bleomycin, bischloroethylnitrosourea [BCNU
or carmustine], cyclophosphamide, methotrexate, radiation).
o Causes related to primary or unclassified diseases may include
sarcoidosis, pulmonary histiocytosis X, LAM, pulmonary vasculitis,
alveolar proteinosis, eosinophilic pneumonia, and BOOP.
o Inorganic dust exposure (eg, silicosis, asbestosis, talc, pneumoconiosis,
berylliosis, hard metal fibrosis, coal worker's pneumoconiosis) may
cause restrictive lung disease.
o Organic dust exposure (eg, farmer's lung, bird fancier's lung, bagassosis,
and mushroom worker lung, which all cause hypersensitivity
pneumonitis) is another cause.
• Idiopathic fibrotic disorders: These may include acute interstitial pneumonia,
IPF (usually interstitial pneumonitis), lymphocytic interstitial pneumonitis,
desquamative interstitial pneumonitis, and nonspecific interstitial pneumonitis.
• Extrinsic disorders
o Nonmuscular diseases of the chest wall, in which kyphosis can be
idiopathic or secondary, may cause restrictive lung disease. The most
common cause of secondary kyphoscoliosis is neuromuscular disease
(eg, polio, muscular dystrophy). Fibrothorax, massive pleural effusion,
morbid obesity, ankylosing spondylitis, and thoracoplasty are other
causes.
o Neuromuscular diseases manifest as respiratory muscle weakness and are
due to myopathy or myositis, quadriplegia, or phrenic neuropathy from
infectious or metabolic causes.

Workup
Laboratory Studies

• Intrinsic lung diseases

o Routine laboratory evaluations often fail to reveal positive findings. However,
anemia can indicate vasculitis, polycythemia can indicate hypoxemia in
advanced disease, and leukocytosis can suggest acute hypersensitivity
pneumonitis.
o The decision to perform additional tests should be directed by the findings of
the clinical assessment. Antinuclear antibodies and rheumatoid factor should
be measured to screen for collagen vascular disorders, creatine kinase for
polymyositis, antineutrophilic cytoplasmic antibodies for vasculitis, and
antiglomerular basement membrane antibody for Goodpasture syndrome.
o The presence of precipitating antibodies to an antigen may help in diagnosing
hypersensitivity pneumonitis. Serum angiotensin-converting enzyme levels are
often elevated in patients with sarcoidosis, but this finding has poor specificity.
• Extrinsic disorders: An elevated creatine kinase level may indicate myositis, which may
cause muscle weakness and restrictive lung disease.

Imaging Studies

• Chest radiography for intrinsic lung disorders

o The diagnosis of an interstitial lung disorder is often initially based on
abnormal chest radiograph findings, which can be normal in as many as 10% of
patients. All previous chest films should be reviewed.
o The most common radiographic abnormality is a reticular pattern. Nodular,
reticulonodular, or mixed patterns, such as alveolar filling (ie, ground-glass
appearance), and increased interstitial markings are not unusual; however,
these are not predictive of a specific pathological picture.
o Air-space opacities suggest pulmonary hemorrhage, eosinophilic pneumonia,
and BOOP.
o Upper-zone predominance on chest radiographs is observed in patients with
sarcoidosis, histiocytosis X, chronic hypersensitivity pneumonitis,
pneumoconiosis, or ankylosing spondylitis. Lower-zone predominance is seen
in patients with IPF, asbestosis, or collagen vascular diseases.
o The finding of honeycombing correlates with advanced fibrosis and indicates a
poor prognosis. Bilateral hilar lymphadenopathy, with or without mediastinal
adenopathy, suggests sarcoidosis.
• Computed tomography of the chest
o High-resolution computed tomography of the chest can be helpful, but the
accuracy of the findings for helping determine a specific etiology is
inconsistent. Bibasilar peripheral lung zone involvement is seen in patients
with IPF, asbestosis, connective tissue disease, or eosinophilic pneumonia.
o Central disease along bronchovascular bundles is indicative of sarcoidosis or
lymphangitic carcinoma.
o Upper-zone predominance is observed in patients with sarcoidosis,
eosinophilic granuloma, or chronic hypersensitivity pneumonitis. Lower-zone
predominance is seen in patients with IPF, asbestosis, or rheumatoid arthritis.
o Lower-zone and peripheral infiltration is ordinarily seen in patients with IPF or
asbestosis.
o The presence of bilateral cysts and nodules, with preservation of lung volumes,
may suggest a diagnosis of LAM or histiocytosis X.
 o Bibasilar reticular fibrosis with coexisting retraction bronchiectasis indicates
end-stage irreversible disease, and ground-glass attenuation may indicate the
presence of an active inflammatory process with potential to respond to
medical therapy.
• Tests for extrinsic disorders
o Evidence of nonmuscular diseases of the chest wall and associated deformities
of the spinal column and ribs are readily appreciated on chest radiographs.
The severity of kyphoscoliosis is determined by the Cobb angle, which, when
greater than 100°, indicates severe deformity. Neuromuscular diseases are
also diagnosed based on chest radiograph findings showing low volumes and
basal atelectasis.
o Fluoroscopy is used to assess for diaphragm paralysis.
o A positive result from a sniff test may demonstrate paradoxical upward
movement of the affected diaphragm.

Other Tests

• Pulmonary function testing

o Complete lung function testing includes spirometry, lung volume, diffusing
capacity, and arterial blood gas measurements. Pulmonary function test
findings do not indicate a specific diagnosis or help distinguish alveolitis from
fibrosis. Findings from sequential tests are invaluable for monitoring the
course of the disease and assessing the response to therapy.
o All disorders are associated with a restrictive defect with a reduction in TLC,
FRC, and residual volume (RV).
o While a reduction in the forced expiratory volume in one second (FEV1) and
the forced vital capacity (FVC) with a normal or increased FEV1 -to-FVC ratio
suggests a restrictive pattern, the diagnosis of restriction is based on a
decreased TLC. The assessment of the severity of restriction is also based on
TLC.
o An obstructive airflow limitation may be observed in patients with sarcoidosis,
LAM, hypersensitivity pneumonitis, and pulmonary fibrosis with concomitant
chronic obstructive pulmonary disease.
• Tests for extrinsic lung disorders
o In nonmuscular diseases of the chest wall, severe kyphoscoliosis produces a
restrictive pattern. The TLC is markedly reduced, with relative preservation of
the RV. The vital capacity is reduced, and the RV-to-TLC ratio is elevated. Chest
wall components are reduced, and inspiratory muscle weakness may also
contribute to the restrictive process. Maximal inspiratory and expiratory
pressures are modestly decreased in patients with mild disease but are
severely reduced in patients with advanced disease.
o Hypoxemia is due to a ventilation-perfusion mismatch caused by the
underlying atelectasis and shunt.
o In neuromuscular diseases, the maximal inspiratory and expiratory mouth
pressures vary from normal to severely reduced. When maximal inspiratory
pressure falls below 30 cm of water, ventilatory failure commonly ensues.
o Patients with chronic muscular diseases have a decreased vital capacity and
FRC, but the RV is preserved. TLC is also moderately reduced. Breathing during
sleep is often abnormal in these patients. They have nocturnal desaturation
during rapid eye movement sleep, secondary to hypoventilation.
 o The diffusing capacity of lung for carbon monoxide (DLCO) is reduced in all
patients with intrinsic lung disorders, and the severity of the reduction does
not correlate well with the stage of the disease. The DLCO is the most sensitive
parameter, and findings may be abnormal even when the lung volumes are
preserved. A normal DLCO value excludes intrinsic lung disease and indicates a
chest wall, pleural, or neuromuscular cause of restrictive lung disease.
o Arterial blood gas values at rest may reveal hypoxemia. Arterial oxygen
desaturation occurs with exercise, along with an excessive increase in the
respiratory rate and a high ratio of dead-space gas volume to tidal gas volume.
o Cardiopulmonary exercise testing with measurements of gas exchange and
oxygenation is more sensitive, and findings correlate better with lung biopsy
but do not help predict the prognosis. A 6-minute walk test with oximetry
provides a measure of oxygen requirement and a quantifiable measure of
disease progression.

Procedures

• Bronchoalveolar lavage
o In selected cases, bronchoalveolar lavage (BAL) cellular analysis may be helpful
to narrow the differential diagnosis. However, the utility of BAL in the clinical
assessment and management of interstitial lung diseases remains to be
established.
o Performing BAL lymphocytosis in patients with IPF may help predict steroid
responsiveness. A predominance of T lymphocytes with an elevated CD4-to-
CD8 ratio is characteristic but not diagnostic of sarcoidosis.
o BAL fluid may contain malignant cells, asbestos bodies, eosinophils, and
hemosiderin macrophages, which assist in making a diagnosis.
• Lung biopsy
o A lung biopsy is not always required to make a diagnosis in patients suggested
to have interstitial lung diseases. A lung biopsy can provide information that
may help lead to a specific diagnosis, assess for disease activity, exclude
neoplastic and infectious processes, establish a definitive diagnosis, and
predict the prognosis.
o Fiberoptic bronchoscopy with transbronchial lung biopsy is often the initial
procedure of choice, especially when sarcoidosis, lymphangitic carcinomatosis,
eosinophilic pneumonia, Goodpasture syndrome, histiocytosis X,
hypersensitivity pneumonitis, or infection is suggested based on clinical
evidence.
• Surgical lung biopsy
o Video-assisted thoracoscopic lung biopsy is the preferred method for
obtaining lung tissue samples for analysis.
o Histologic patterns may be helpful in narrowing the differential diagnosis.
Honeycombing is seen in end-stage disease, in which the original disease
process often cannot be differentiated.

The common histologic patterns include interstitial pneumonitis (ie,
IPF). 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 is the hallmark of this disease. Also, the lung
architecture is completely destroyed.

Desquamative interstitial pneumonitis is characterized by diffuse and
temporally uniform involvement of the lung parenchyma. The alveoli
are filled with macrophages and hyperplastic type II pneumocytes.

BOOP (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.

Diffuse alveolar damage is marked by a nonspecific reaction with
diffuse temporally uniform involvement and marked thickening of the
alveolar septa; inflammatory cell infiltration and type II cell
hyperplasia and fibroblast proliferation are present.

For acute interstitial pneumonia, the pathological appearance is
identical to that of diffuse alveolar damage.

In eosinophilic pneumonia, the eosinophils and macrophages are the
predominant alveolar inflammatory cells, and they also extend into
the interstitium.

Lymphocytic interstitial pneumonitis marked by a lymphoid infiltrate
that involves both the interstitium and alveolar spaces is the
prominent finding.

In nonspecific interstitial pneumonia, the lesions are characterized by
a relatively uniform appearance consisting of mononuclear interstitial
infiltrates associated with varying degrees of interstitial fibrosis.

Granulomatous lung diseases are marked by granulomas characterized
by the accumulation of T lymphocytes, macrophages, and epithelioid
cells. These may progress to pulmonary fibrosis.

Histologic Findings

The histological findings of various interstitial pneumonias include an interstitial

cellular infiltrate and interstitial fibrosis, eventually leading to an end-stage honeycomb
lung. These findings are described in detail in Procedures.

Contrasting Clinical, Radiologic, and Histologic Features of Acute Interstitial

Pneumonia (AIP), Usual Interstitial Pneumonia (UIP), Nonspecific Interstitial
Pneumonia (NSIP), and BOOP

Open table in new window

[ CLOSE WINDOW ]

Table
Features AIP UIP NSIP BOOP

Pathologic

Temporal appearance Uniform Heterogeneous Uniform Uniform

Interstitial Usually
Scant Scant Variable
inflammation prominent
 Collagen fibrosis No Patchy Variable, diffuse No

Fibroblast Diffuse, Patchy (fibroblast Patchy,

Occasional
proliferation interstitial foci) airspace

BOOP areas Rare No Rare --

Honeycomb changes Rare Yes Rare No

Hyaline membranes Yes, often focal No No No

Features AIP UIP NSIP BOOP

Pathologic

Temporal appearance Uniform Heterogeneous Uniform Uniform

Interstitial Usually
Scant Scant Variable
inflammation prominent

Collagen fibrosis No Patchy Variable, diffuse No

Fibroblast Diffuse, Patchy (fibroblast Patchy,

Occasional
proliferation interstitial foci) airspace

BOOP areas Rare No Rare --

Honeycomb changes Rare Yes Rare No

Hyaline membranes Yes, often focal No No No

Treatment
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

 o The rate of progression of 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.
o 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.
o Conventional therapies (corticosteroids, azathioprine, cyclophosphamide)
provide only marginal benefit to patients with IPF.
o Lung transplantation should be considered for patients with IPF refractory to
medical therapy.
o Because of a lack of response to available anti-inflammatory therapy,
alternative approaches to therapy are being pursued. 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.
• Corticosteroids
o 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.
o Questions about which patients should be treated, when therapy should be
started, and what constitutes the best therapy receive uncertain answers at
present.
o 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 FVC, TLC, and
DLCO. The optimal duration of therapy is not known, but treatment for 1-2
years is suggested.
• Cytotoxic therapy
o 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.
o 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.
o Because of potentially serious toxicities, cyclophosphamide is reserved for
fulminant or severe inflammatory disorders refractory to alternate therapy.
• Antifibrotic therapies
o These therapies, including colchicine, are suggested for a variety of fibrotic
disorders, including IPF.
o Recent studies demonstrate no difference in the decline of pulmonary
function with either colchicine or prednisone; therefore, a trial of therapy with
colchicine is reasonable in less symptomatic patients or those who are
experiencing adverse effects with steroid therapy.
o A recent study showed that in patients with idiopathic pulmonary fibrosis,
interferon gamma-1b did not affect progression-free survival, pulmonary
 function, or the quality of life. No survival benefit was demonstrated in this
trial.
• Collagen vascular disease
o 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.
o Patients with severe disease or those who have a deteriorating course must be
treated with corticosteroids, cytotoxic therapy, or both.
• Sarcoidosis
o 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.
o 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
o 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.
o Treatment of neuromuscular diseases includes preventive therapies to
minimize the impact of impaired secretion clearance and the prevention and
prompt treatment of respiratory infections.
o The 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.
o 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.
o 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.
o 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.

Consultations
 • Consultation with a pulmonologist is helpful for diagnosis and management.

Medication
Medications are best employed for the specific diagnosis. Corticosteroids, cytotoxic
agents, and immunosuppressive agents have been used with varying success.

Corticosteroids

Have anti-inflammatory properties and can modify the body's immune response.

Prednisone (Deltasone, Orasone, Meticorten)

Used as an immunosuppressant in the treatment of autoimmune disorders. By reversing

increased capillary permeability and suppressing PMN activity, may decrease
inflammation. Oral corticosteroid with relatively less mineralocorticoid activity.
Therapy is best prescribed in consultation with a pulmonary disease specialist.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

1 mg/kg/d PO, up to 100 mg/d initially, followed by a taper after 8 wk to a maintenance

dose of 0.25-0.5 mg/kg/d

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Coadministration with estrogens may decrease clearance; concurrent use with digoxin
may cause digitalis toxicity secondary to hypokalemia; phenobarbital, phenytoin, and
rifampin may increase metabolism (consider increasing maintenance dose); monitor for
hypokalemia with coadministration of diuretics

• Dosing
• Interactions
• Contraindications
• Precautions
Documented hypersensitivity; viral infection, peptic ulcer disease, hepatic dysfunction,
connective tissue infections, and fungal or tubercular skin infections; GI disease

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

B - Usually safe but benefits must outweigh the risks.

Precautions

Abrupt discontinuation of glucocorticoids may cause adrenal crisis; hyperglycemia,

edema, osteonecrosis, myopathy, peptic ulcer disease, hypokalemia, osteoporosis,
euphoria, psychosis, myasthenia gravis, growth suppression, and infections may occur

Cytotoxic agents

These agents inhibit cell growth and proliferation.

Cyclophosphamide (Cytoxan, Neosar)

Chemically related to nitrogen mustards. As an alkylating agent, mechanism of action

of active metabolites may involve cross-linking of DNA, which may interfere with
growth of normal and neoplastic cells of immune system. Possible steroid-sparing
medication.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

2 mg/kg/d IV; adjust dose according to leukocyte count

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions
Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive
effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum
levels and antimicrobial effects of quinolones
Chloramphenicol may increase half-life while decreasing metabolite concentrations;
may increase effect of anticoagulants; coadministration with high doses of
phenobarbital may increase rate of metabolism and leukopenic activity; thiazide
diuretics may prolong cyclophosphamide-induced leukopenia and neuromuscular
blockade by inhibiting cholinesterase activity

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; severely depressed bone marrow function

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to

monitor for hematopoietic suppression; regularly examine urine for RBCs, which may
precede hemorrhagic cystitis

Azathioprine (Imuran)

Inhibits mitosis and cellular metabolism by antagonizing purine metabolism and

inhibiting synthesis of DNA, RNA, and proteins. These effects may decrease
proliferation of immune cells and result in lower autoimmune activity. Possible steroid-
sparing medication.

• Dosing
• Interactions
• Contraindications
• Precautions

Adult

3 mg/kg/d PO/IV; not to exceed 200 mg/d

Pediatric

Not established

• Dosing
• Interactions
• Contraindications
• Precautions

Toxicity increases with allopurinol; concurrent use with ACE inhibitors may induce
severe leukopenia; may increase levels of methotrexate metabolites and decrease effects
of anticoagulants, neuromuscular blockers, and cyclosporine

• Dosing
• Interactions
• Contraindications
• Precautions

Documented hypersensitivity; low levels of serum thiopurine methyl transferase

(TPMT)

• Dosing
• Interactions
• Contraindications
• Precautions

Pregnancy

D - Unsafe in pregnancy

Precautions

Increases risk of neoplasia; caution with liver disease and renal impairment;
hematologic toxicities may occur; check TPMT level prior to therapy and follow liver,
renal, and hematologic function; pancreatitis rarely associated

Anti-inflammatory agents

Reduce inflammation by inhibiting key steps of the immune system.

Colchicine

Decreases leukocyte motility and phagocytosis observed in inflammatory responses.

• Dosing
• Interactions
• Contraindications
• Precautions
Adult

0.6 mg/d PO

Pediatric

Not established

Follow-up
Deterrence/Prevention

Acute exacerbation in patients with 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.

Complications

Acute exacerbation in patients with 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.

Prognosis

• The natural history of interstitial lung diseases is variable. It depends on the

specific diagnosis and the extent and severity of lung involvement. IPF is
typically a relentless progressive disorder, and patients have a mean survival of
4-6 years after diagnosis.
• Pulmonary sarcoidosis has a relatively benign self-limiting course, with
spontaneous recovery or stabilization in most cases. Approximately 15% of
patients develop pulmonary fibrosis and disability.
• Prognosis for collagen vascular diseases, eosinophilic pneumonia, BOOP, and
drug-induced lung disease is generally favorable with treatment.
• Patients with chest wall diseases and neuromuscular disorders develop
progressive respiratory failure and succumb during an intercurrent pulmonary
infection.

Miscellaneous
Medicolegal Pitfalls
 • Irrespective of lung biopsy findings, if patients are symptomatic, they should
receive a trial period of therapy. For many years, the absolute standard for
diagnosis of IPF was purported to be surgical lung biopsy. This theory (and
subsequent biopsy findings) helped differentiate patients with cellular, as
opposed to fibrotic, disease. In practice, the same histologic patterns are seen in
both types of patients.
• Therapeutic options for IPF are limited. Drugs with antifibrotic properties or
anti-inflammatory agents that work against growth factors and suppress
inflammation are needed.
• An absolute requirement is that all patients with restrictive lung disease must be
differentiated as having either intrinsic or extrinsic disorders, the determination
of which is based on pulmonary function test findings.

Special Concerns

• The clinical course of IPF is variable. In most cases, the course involves a
progressive deterioration culminating in death from respiratory failure. The
secular survival interval expectation among newly diagnosed patients is
typically 3-5 years.
• A low FVC, low DLCO, low arterial oxygen at presentation, male sex, and older
age are markers of a poor prognosis.
• Improvement after a trial corticosteroid therapy is associated with a favorable
prognosis and is more probable in patients with cellular changes, which may be
noted on lung biopsy findings, or ground-glass attenuation, which may be noted
on a high-resolution CT scan image.

References

References
1. Baughman RP, Lower EE. Use of intermittent, intravenous cyclophosphamide
for idiopathic pulmonary fibrosis. Chest. Oct 1992;102(4):1090-4. [Medline].
2. Baydur A. Respiratory muscle strength and control of ventilation in patients
with neuromuscular disease. Chest. Feb 1991;99(2):330-8. [Medline].
3. Bjoraker JA, Ryu JH, Edwin MK, et al. Prognostic significance of
histopathologic subsets in idiopathic pulmonary fibrosis. Am J Respir Crit Care
Med. Jan 1998;157(1):199-203. [Medline].
4. Douglas WW, Ryu JH, Swensen SJ, et al. Colchicine versus prednisone in the
treatment of idiopathic pulmonary fibrosis. A randomized prospective study.
Members of the Lung Study Group. Am J Respir Crit Care
Med. Jul 1998;158(1):220-5. [Medline].
5. Fishbein MC. Diagnosis: to biopsy or not to biopsy: assessing the role of
surgical lung biopsy in the diagnosis of idiopathic pulmonary
fibrosis. Chest. Nov 2005;128(5 Suppl 1):520S-525S.
6. Flaherty KR, Martinez FJ, Travis W, Lynch JP 3rd. Nonspecific interstitial
pneumonia (NSIP). Semin Respir Crit Care Med. Aug 2001;22(4):423-34.
7. Flaherty KR, Toews GB, Travis WD, et al. Clinical significance of histological
classification of idiopathic interstitial pneumonia. Eur Respir
J. Feb 2002;19(2):275-83. [Medline].
8. Gay SE, Kazerooni EA, Toews GB, et al. Idiopathic pulmonary fibrosis:
predicting response to therapy and survival. Am J Respir Crit Care
Med. Apr 1998;157(4 Pt 1):1063-72. [Medline].
9. Goldstein RH, Fine A. Potential therapeutic initiatives for fibrogenic lung
diseases. Chest. Sep 1995;108(3):848-55. [Medline].
10. Hunninghake GW, Kalica AR. Approaches to the treatment of pulmonary
fibrosis. Am J Respir Crit Care Med. Mar 1995;151(3 Pt 1):915-8. [Medline].
11. Katzenstein AL, Myers JL. Idiopathic pulmonary fibrosis: clinical relevance of
pathologic classification. Am J Respir Crit Care Med. Apr 1998;157(4 Pt
1):1301-15. [Medline].
12. Martinez FJ, Safrin S, Weycker D, et al. The clinical course of patients with
idiopathic pulmonary fibrosis. Ann Intern Med. Jun 21 2005;142(12 Pt 1):963-7.
13. Mathieson JR, Mayo JR, Staples CA, Muller NL. Chronic diffuse infiltrative
lung disease: comparison of diagnostic accuracy of CT and chest
radiography. Radiology. Apr 1989;171(1):111-6. [Medline].
14. Muller NL. Clinical value of high-resolution CT in chronic diffuse lung
disease. AJR Am J Roentgenol. Dec 1991;157(6):1163-70. [Medline].
15. Parambil JG, Myers JL, Ryu JH. Histopathologic features and outcome of
patients with acute exacerbation of idiopathic pulmonary fibrosis undergoing
surgical lung biopsy. Chest. Nov 2005;128(5):3310-5.
16. Peckham RM, Shorr AF, Helman DL. Potential limitations of clinical criteria for
the diagnosis of idiopathic pulmonary fibrosis/cryptogenic fibrosing
alveolitis. Respiration. Mar-Apr 2004;71(2):165-9.
17. Raghu G, Brown KK, Bradford WZ, et al. A placebo-controlled trial of
interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J
Med. Jan 8 2004;350(2):125-33. [Medline].
18. Remy-Jardin M, Remy J, Giraud F, et al. Computed tomography assessment of
ground-glass opacity: semiology and significance. J Thorac
Imaging. Fall 1993;8(4):249-64. [Medline].
19. Shah NR, Noble P, Jackson RM, et al. A critical assessment of treatment options
for idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung
Dis. Oct 2005;22(3):167-74. [Medline].
20. Turner-Warwick M, Burrows B, Johnson A. Cryptogenic fibrosing alveolitis:
response to corticosteroid treatment and its effect on
survival. Thorax. Aug 1980;35(8):593-9. [Medline].
21. Vianello A, Bevilacqua M, Salvador V, et al. Long-term nasal intermittent
positive pressure ventilation in advanced Duchenne''s muscular
dystrophy. Chest. Feb 1994;105(2):445-8. [Medline].
22. Wagner JD, Stahler C, Knox S, et al. Clinical utility of open lung biopsy for
undiagnosed pulmonary infiltrates. Am J Surg. Aug 1992;164(2):104-7;
discussion 108. [Medline].
23. Wells A. Clinical usefulness of high resolution computed tomography in
cryptogenic fibrosing alveolitis. Thorax. Dec 1998;53(12):1080-7. [Medline].
24. Winterbauer RH, Hammar SP, Hallman KO, et al. Diffuse interstitial
pneumonitis. Clinicopathologic correlations in 20 patients treated with
prednisone/azathioprine. Am J Med. Oct 1978;65(4):661-72. [Medline].
25. du Bois RM. Evolving concepts in the early and accurate diagnosis of idiopathic
pulmonary fibrosis. Clin Chest Med. Mar 2006;27(1 Suppl 1):S17-25, v-vi.