Interstitial lung disease (ILD)/ diffuse interstitial lung disease/ fibrotic interstitial lung

disease/ pulmonary fibrosis

-refers to a broad group of inflammatory lung disorders.
-More than 180 disease entities are characterized by acute,subacute, or chronic
inflammatory infiltration of alveolar walls by cells, fluid, and connective tissue.
-If left untreated, the inflammatory process can progress to irreversible pulmonary
fibrosis.
-The ILD group consists of a wide range of illnesses with varied causes, treatments, and
prognoses. However, because the ILDs all reflect similar anatomic alterations of the lungs

Anatomic Alterations of the Lungs

-involve the bronchi, alveolar walls, and adjacent alveolar spaces.
-In severe cases the extensive inflammation leads to pulmonary fibrosis, granulomas,
honeycombing, and cavitation.

ACUTE STAGE OF ILD

-the general inflammatory condition is characterized by edema and the infiltration of a
variety of white blood cells (e.g., neutrophils, eosinophils, basophils, monocytes, macrophages,
and lymphocytes) in the alveolar walls and interstitial spaces.
-Bronchial inflammation and thickening and increasing airway secretions may also be
present.

CHRONIC STAGE
-the general inflammatory response is also characterized by the infiltration of numerous
white blood cells (especially monocytes, macrophages, and lymphocytes), and some fibroblasts
may also be present in the alveolar walls and interstitial spaces.
-This stage may be followed by further interstitial thickening, fibrosis, granulomas, and, in
some cases, honeycombing and cavity formation.
-Pleural effusion may also be present.
In the chronic stages the basic pathologic features of interstitial fibrosis are identical in
any interstitial lung disorder (so-called end-stage pulmonary fibrosis).

Interstitial lung disorders produce restrictive lung disorders. However, because

bronchial inflammation and excessive airway secretions can also develop in the small airways,
the clinical manifestations associated with an obstructive lung disorder may also be seen.

Therefore, the patient with ILD may demonstrate a restrictive disorder, an obstructive
disorder, or a combination of both.

The major pathologic or structural changes associated with chronic ILDs are as
follows:
•Destruction of the alveoli and adjacent pulmonary capillaries
•Fibrotic thickening of the respiratory bronchioles, alveolar ducts, and alveoli
 •Granulomas
•Honeycombing and cavity formation
•Fibrocalcific pleural plaques (particularly in asbestosis)
•Bronchospasm
•Excessive bronchial secretions (caused by inflammation of airways)

Occupational, Systemic diseases Idiopathic Specific Miscellaneous

environmental, and Interstitial Pathology ILDs
therapeutic exposures Pneumonia

Occupation/Environmental Connective Tissue •Idiopathic •Lymphangioleio •Goodpasture’s

Disease pulmonary myomatosis syndrome
Inorganic Exposure -Scleroderma fibrosis (LAM) •Idiopathic
-Asbestosis -Rheumatoid •Nonspecific •Pulmonary pulmonary
-Coal dust arthritis Cryptogenic Langerhans’ cell hemosiderosis
-Silica -Sjögren’s syndrome Organizing histiocytosis •Chronic
-Beryllium -Polymyositis or Pneumonia •Pulmonary eosinophilic
-Aluminum dermatomyositis (BOOP) alveolar pneumonia
-Barium -Systemic Lupus •Lymphocytic proteinosis
-Clay erythematosus interstitial •The pulmonary
-Iron pneumonia (LIP) vasculitides
-Certain tals Sarcoidosis •Wegener’s
granulomatosis
Organic Exposure •Churg-Strauss
•Hypersensitivity Syndrome
Pneumonitis •Lymphomatoid
•Moldy hay Granulomatosis
•Silage
•Moldy sugar cane
•Mushroom compost
•Barley
•Cheese
•Wood pulp, bark, dust
•Cork dust
•Bird droppings
•Paints

Medications and Ilicit

Drugs
-Antibiotics
-Anti-inflammatory agents
-Chemotherapeutic agents
-Drug-induced systemic
lupus erythematosus
-Ilicit Drugs
-Miscellaneous agents

Radiation Therapy
Irritant Gases

Occupational Disease The three most common types of occupational interstitial lung
disease are asbestosis, chronic silicosis, and coal workers’ pneumoconiosis.

Interstitial Lung Diseases of Known Causes or Associations (also known as

Pneumoconiosis) Occupational, Environmental, and Therapeutic Exposures

INORGANIC PARTICULATE (DUST) EXPOSURE

Asbestos. 
Exposure to asbestos may cause asbestosis—a common form of ILD. Asbestos fibers
are a mixture of fibrous minerals composed of hydrous silicates of magnesium, sodium, and iron
in various proportions.
There are two primary types: the amphiboles (crocidolite, amosite, and anthophyllite)
and chrysotile (most commonly used in industry).
Asbestos fibers typically range from 50 to 100 µm in length and are about 0.5 µm in
diameter.
The chrysotiles have the longest and strongest fibers.
Asbestos fibers can be seen by microscope within the thickened septa as brown or
orange batonlike structures. The fibers characteristically stain for iron with Perls’ stain. The
pathologic process may affect only one lung, a lobe, or a segment of a lobe.
The lower lobes are most commonly affected.
Pleural calcification is common and diagnostic in patients with an asbestos exposure
history.
-abnormalities include pleural changes (plaques, fibrosis, effusions, atelectasis, and
mesothelioma) and parenchhymal scarring and lung cancer.
Asbestos exposure alone increases the risk for lung cancer only minimally (1.5 to 3.0
times).
-asbestos exposure and cigarette smoking act synergistically to increase greatly the risk
for cancer.
-Asbestos exposure also may result in benign asbestos pleural effusions or an entity
known as rounded atelectasis.
Benign asbestos pleural effusions may be asymptomatic or may be associated with
acute chest pain, fever, and dyspnea. -usually resolve on their own, but may recur. Treatment is
drainage to reduce symptoms.
Rounded atelectasis typically manifests as a pleuralbased parenchymal mass that may
be mistaken for carcinoma. The characteristic CT features, such as local volume loss, pleural
thickening, and the “comet tail” appearance of bronchi and vessels curving into the lesion, help
distinguish rounded atelectasis from carcinoma.
The term asbestos-related pulmonary disease encompasses all of these entities,
whereas asbestosis is reserved for patients who have evidence of parenchymal fibrosis. Most
patients with asbestosis have had considerable airborne asbestos exposure many years before
the lung disease becomes apparent.
Exposure frequently is associated with occupations such as shipbuilding or insulation
work. Patients report very slowly progressive dyspnea on exertion and have crackles on lung
examination. Physiologic testing shows restrictive impairment with a reduced DLCO. The chest
radiograph reveals bilateral lower zone reticulonodular infiltrates similar to infiltrates seen in IPF.
With an appropriate exposure history, the presence of radiographic pleural plaques or rounded
atelectasis indicates asbestos as the likely cause of ILD, although neither history nor
radiographic findings is required for establishing the diagnosis. Surgical lung biopsy with
asbestos body determination can establish a definitive diagnosis, but this is infrequently
performed owing to the age and debility of these patients. No medical therapy has been shown
to improve or decrease progression of asbestosis. Severe impairment typically occurs 30 to 40
years after exposure, making almost all patients ineligible for lung transplantation because of
advanced age. Management of asbestosis is supportive.
Common Sources
Associates With Asbestos
Fibers
•Acoustic products
•Automobile undercoating
•Brake lining
•Cements
•Clutch casings
•Floor tiles
•Fire-fighting suits
•Fireproof paints
•Insulation
•Roofing materials
•Ropes
•Steam pipe material

Coal Dust. 
The pulmonary deposition and accumulation of large amounts of coal dust causes what
is known as coal worker’s pneumoconiosis (CWP)
CWP is also known as coal miner’s lung and black lung.
Miners who use cutting machines at the coal face have the greatest exposure, but even
relatively minor exposures may result in the disease.
Indeed, cases have been reported in which coal miners’ wives developed the disease,
presumably from shaking the dust from their husbands’ work clothes.
Simple CWP is characterized by the presence of pinpoint nodules called coal macules
(black spots) throughout the lungs.
The coal macules often develop around the first- and second-generation respiratory
bronchioles and cause the adjacent alveoli to retract. This condition is called focal emphysema.
Complicated CWP or progressive massive fibrosis (PMF) is characterized by areas
of fibrotic nodules greater than 1 cm in diameter.
 The fibrotic nodules generally appear in the peripheral regions of upper lobes and
extend toward the hilum with growth.
The nodules are composed of dense collagenous tissue with black pigmentation. Coal
dust by itself is chemically inert. The fibrotic changes in CWP are usually caused by silica.
Coal workers’ pneumoconiosis develops as the result of chronic inhalation of coal
dust. In the past, it was assumed that silica dust was responsible for the pulmonary disease
seen among coal miners because the clinical and radiographic features are quite similar to
those of chronic silicosis. However, it is now recognized that coal workers’ pneumoconiosis and
silicosis are the result of different exposures.
Simple coal workers’ pneumoconiosis, characterized by multiple small nodular
opacities on the chest radiograph, is asymptomatic. Cough and shortness of breath do not
develop unless the disease progresses to progressive massive fibrosis similar to that seen in
silicosis. There are no proved therapies for either silicosis or coal workers’ pneumoconiosis
other than eliminating future exposure. In patients with significant obstructive impairment or
mucus production, inhaled bronchodilators and corticosteroids may relieve some symptoms.
Exacerbations can be frequent and are treated with antibiotics and systemic corticosteroids.

Silica. 
-Silicosis (also called grinder’s disease or quartz silicosis) is caused by the chronic
inhalation of crystalline, free silica, or silicon dioxide particles.
Silica is the main component of more than 95% of the rocks of the earth. It is found in
sandstone, quartz (beach sand is mostly quartz), flint, granite, many hard rocks, and some
clays.
Simple silicosis is characterized by small rounded nodules scattered throughout the
lungs. No single nodule is greater than 9 mm in diameter. Patients with simple silicosis are
usually symptom-free.
Complicated silicosis is characterized by nodules that coalesce and form large masses
of fibrous tissue, usually in the upper lobes and perihilar regions.
In severe cases the fibrotic regions may undergo tissue necrosis and cavitate.

Chronic silicosis results from chronic exposure to inhaled silica particles. Occupations
that commonly involve exposure to silica include mining, tunneling, sandblasting, and foundry
work. The chest radiograph commonly shows upper lung zone– predominant abnormalities
characterized by multiple small nodular opacities in the central lung tissue. These nodules
(simple silicosis) are asymptomatic and may never progress or cause symptoms. However, in
susceptible individuals, the nodules coalesce into large midlung zone masses known as
progressive massive fibrosis. Some patients with abnormal chest radiographs report few, if
any, symptoms and may have normal lung examination and pulmonary function testing. Many
patients are impaired and have mixed restrictive and obstructive impairment with reduced
diffusion capacity. The physiologic impairment may remain stable or, if progressive, massive
fibrosis occurs, may progress even without continued exposure. Symptoms are typically
exertional dyspnea and variable mucus production.
It is important to recognize the association of silicosis with lung cancer and active
tuberculosis. Patients with silicosis are at increased risk for lung cancer, and the risk is
increased when combined with exposure to tobacco smoke, diesel exhaust, or radon gas.
Patients with silicosis develop active tuberculosis 2 to 30 times more frequently than
co-workers without silicosis. This association is especially important in societies with a high
incidence of human immunodeficiency virus infection, which markedly increases the risk for
silicosis-associated active tuberculosis.
Common Occupations • Abrasives work
Associated With Silica • Brick making
Exposure • Paint making
• Tunneling • Polishing
• Hard-rock mining • Stone drilling
• Sandblasting • Well drilling
• Quarrying • Ceramics work
• Stone Cutting • Foundry work

Beryllium. 
Beryllium is a steel-gray, lightweight metal found in certain plastics and ceramics, rocket
fuels, and x-ray tubes.
As a raw ore, beryllium is not hazardous.
When it is processed into the pure metal or one of its salts, however, it may cause a
tissue reaction when inhaled or implanted into the skin.
The acute inhalation of beryllium fumes or particles may cause a toxic or allergic
pneumonitis sometimes accompanied by rhinitis, pharyngitis, and tracheobronchitis. The
more complex form of berylliosis is characterized by the development of granulomas and a
diffuse interstitial inflammatory reaction

Additional Inorganic Causes of

Interstitial Lung Disease
Aluminium
• Ammunition workers
Baritosis (barium)
• Barite millers and miners
• Ceramic workers
Kalonosis (clay)
• Brick makers and potters
• Ceramics workers
Siderosis (iron)
• Welders Talcosis (certain talcs)
• Ceramics workers
• Papermakers
• Plastics and rubber workers

ORGANIC MATERIALS EXPOSURE

Hypersensitivity Pneumonitis. 
-also called allergic alveolitis or extrinsic allergic alveolitis)
 -is a cell-mediated immune response of the lungs caused by the inhalation of a variety of
offending agents or antigens.
Such antigens include grains, silage, bird droppings or feathers, wood dust (especially
redwood and maple), cork dust, animal pelts, coffee beans, fish meal, mushroom compost, and
molds that grow on sugar cane, barley, and straw.
The immune response to these allergens causes production of antibodies and an
inflammatory response.
The lung inflammation, or pneumonitis, develops after repeated and prolonged
exposure to the allergen.
The term hypersensitivity pneumonitis (or allergic alveolitis) is often renamed according
to the type of exposure that caused the lung disorder.
For example, the hypersensitivity pneumonitis caused by the inhalation of moldy hay is
called farmer’s lung. Table 26-2 provides common causes, exposure sources, and disease
syndromes associated with hypersensitivity pneumonitis.
is a cell-mediated immune reaction to inhaled antigens in susceptible persons. Patients
must be sensitized by an initial exposure, with subsequent reexposure leading to either an acute
or chronic development of HP. Patients with acute HP present to medical attention with a history
of a few days of shortness of breath, chest pain, fever, chills, malaise, and a cough that may be
productive of purulent sputum. Patients who are chronically exposed to low levels of inhaled
antigens may develop subtle interstitial inflammatory reactions in the lung that do not result in
noticeable symptoms for months to years and can present with severe, impairing disease, which
can be very difficult to distinguish from IPF. Common organic antigens known to cause HP
include bacteria and fungi, which may be found in moldy hay (farmer’s lung) or in the home
environment, in particular, in association with central humidification systems (humidifier lung),
indoor hot tubs, and animal proteins (e.g., bird breeder’s lung). Inorganic antigens from
vaporized paints and plastics also can lead to HP.
Because the causal relationship between exposure and lung disease may not be
obvious, a careful systematic occupational, environmental, and avocational history is crucial in
evaluating patients with ILD. Elements that strongly suggest a diagnosis of HP are exposure to
an appropriate antigen and the correct timing of symptom onset to the exposure. Blood samples
may be obtained to determine whether there has been an antibody response to certain antigens
associated with HP (serum precipitins). However, the presence of such antibodies is insufficient
to establish the diagnosis of HP because many individuals develop antibodies in the absence of
disease. Likewise, the absence of detectable antibodies does not rule out the diagnosis of HP
because the culprit may be an antigen that is not included in the blood test panel that is
analyzed.
Specific therapies for HP are strict antigen avoidance and immunosuppression with
corticosteroids in patients with symptomatic or physiologically impairing disease. In acute HP
corticosteroids seem to hasten recovery but do not improve ultimate lung function. In chronic
HP, patients with fibrosis on CT scan have a shorter survival and the benefits of long-term
immunosuppression is unknown.
Causes of Hypersensitivity Pneumonitis
HP
Antigen Exposure Source Disease Syndrome

Bacteria, Thermophilic
Saccharopolyspora rectivirgula Moldy hay, silage Farmer’s lung
Thermoactinomyces vulgaris Moldy sugarcane Bagassosis
Thermoactinomyces sacchari Mushroom compost Mushroom worker’s lung
Thermoactinomyces candidus Heated water reservoirs Air conditioner lung

Bacteria, Nonthermophilic
Baccillus subtilis, Water, detergent Humidifier lung,
Bacillus cereus Washing powder lung

Fungi
Aspergillus sp. Moldy hay Farmer’s lung
Water

Aspergillus clavatus Barley Malt worker’s lung

Penicillium casiei, P. roqueforti Cheese Cheese washer’s lung
Alternaria sp. Wood pulp Woodworker’s lung
Cryptostroma corticale Wood bark Maple bark strripper’s lung
Graphium, Aureobasidium pullulans Wood dust Sequoiosis
Merulius lacrymans Rotten wood Dry rot lung
Penicillium frequentans Cork dust
Aureobasidium pullalans Water Suberosis
Clasdosporium sp/ Hot tub mist Humidifier lung
Trichosporon cutaneum Damp wood and mats Hot tub HP
Japanese summer types HP

Amoebae
Naegleria gruberi
Acanthamoeba polyphaga “Contaminated water” “Humidifier lung”
Acanthamoeba castellani

Animal Protein
Avian proteins Bird droppings, feathers Bird-breeder’s lung

Urine, surem, pelts Rats, gerbils Animal handler’s lung

Chemicals
Isocyanates, trimellitic anhydride Paints, resins, plastics Chemical worker’s lung
Copper sulfate Bordeaux mixture Vineyard sprayer’s lung
Phthakic anhydride Heated epoxy resin Epoxy resin lung
Sodium diazobenzene sulfate Chromatography reagent Pauli’s reagent alveolitis
Pyrethrum Pesticide Pyrethrum HP

Medications and Illicit Drugs.

-lungs are a major target organ affected by these side effects.
 -chemotherapeutic (anticancer agents) are by far the largest group of agents
associated with ILD. Bleomycin, mitomycin, busulfan, cyclophosphamide, methotrexate, and
carmustine (BCNU) are the major offenders. Nitrofurantoin (an antibacterial drug used in the
treatment of urinary tract infections) is also associated with ILD.
-Gold and penicillamine for the treatment of rheumatoid arthritis have also been shown
to cause ILD. The excessive long-term administration of oxygen (oxygen toxicity) is also known
to cause diffuse pulmonary injury and fibrosis. As a general rule, the risk of these drugs causing
an interstitial lung disorder is directly related to the cumulative dosage. However, drug-induced
interstitial disease may be seen as early as 1 month to as late as several years after exposure
to these agents.
-The precise cause of drug-induced ILD is not known. Diagnosis is confirmed by an open
lung biopsy. When interstitial fibrosis is found with no infectious organisms or known industrial
exposure, a drug-induced interstitial process must be suspected.

Drug-Related and Radiation-Related

Disease Many drugs have been associated with pulmonary complications of various
types, including interstitial inflammation and fibrosis, bronchospasm, pulmonary edema, and
pleural effusions. Drugs from many different therapeutic classes can cause ILD, most commonly
chemotherapeutic agents, antibiotics, antiarrhythmic drugs, and immunosuppressive agents.
There are no distinct physiologic, radiographic, or pathologic patterns of drug-induced ILD, and
the diagnosis is usually made when a patient is exposed to a medication known to result in lung
disease, the timing of the exposure is appropriate for the development of the disease, and other
causes of ILD have been excluded.
Treatment is avoidance of further exposure and systemic corticosteroids in markedly
impaired or declining patients. In the specific instance of ILD related to exposure to the
chemotherapeutic agent bleomycin, bleomycin injury is accentuated by exposure to increased
fractional inspired oxygen (FiO2), even months after last drug exposure. Thus, supplemental
oxygen (O2) should be used only if absolutely necessary patients with bleomycin-induced ILD.
Drugs Associated With the Development of Interstitial Lung Disease
Antibiotics
• Nitrofurantoin
• Sulfasalazine
Anti-inflammatory agents
• Aspirin
• Gold
• Penicillamine
• Methotrexate
• Etanercept
• Infliximab
-Leflunomide
Cardiovascular agents
• Amiodarone
• Tocainide
Chemotherapeutic agents
• Bleomycin
 • Mitomycin-C
• Busulfan
• Cyclophosphamide
• Chlorambucil
• Melphalan
• Azathioprine
• Cytosine arabinoside
• Methotrexate
• Procarbazine
• Zinostatin
• Etoposide
• Vinblastine
• Imatinib
• Flutamide
Drug-induced systemic lupus erythematosus
• Procainamide
• Isoniazid
• Hydralazine
• Hydantoins
• Penicillamine
Illicit drugs
• Heroin
• Methadone
• Propoxphene
• Talc as an IV contaminant
Miscellaneous agents
• Oxygen
• Drugs inducing pulmonary infiltrates and eosinophilia: L-tryptophan
• Hydrochlorothiazide
• Radiation

Radiation Therapy. 
Radiation therapy in the management of cancer may cause ILD.
Radiation-induced lung disease is commonly divided into the following two major
phases: the acute pneumonitic phase and the late fibrotic phase.
Acute pneumonitis is rarely seen in patients who receive a total radiation dose of less
than 3500 rad.
By contrast, doses in excess of 6000 rad over 6 weeks almost always cause ILD in and
near the radiated areas.
The acute pneumonitic phase develops about 2 to 3 months after exposure.
Chronic radiation fibrosis is seen in all patients who develop acute pneumonitis.
The late phase of fibrosis may develop (1) immediately after the development of acute
pneumonitis, (2) without an acute pneumonitic period, or (3) after a symptom-free latent period.
When fibrosis does develop, it generally does so 6 to 12 months after radiation exposure.
Pleural effusion is often associated with the late fibrotic phase.
 The precise cause of radiation-induced lung disease is not known. The establishment of
a diagnosis is similar to that for drug-induced interstitial disease (i.e., by obtaining a history of
recent radiation therapy and confirming the diagnosis with an open lung biopsy).
Exposure to therapeutic radiation used to treat cancer may result in ILD. Patients
presenting within 6 months of radiation therapy generally have ground-glass abnormalities
thought to represent acute inflammation. The ground-glass abnormalities can occur in both
radiation-exposed tissue and unexposed tissue. Short-term systemic corticosteroid treatment
can improve lung function. In contrast, radiographic abnormalities that develop more than 6
months after therapy typically appear as densely fibrotic tissue within the radiation port. On CT
scan, a straight line indicating the margin of radiation is frequently evident.These patients do not
improve with corticosteroid therapy, and treatment is supportive.

Irritant Gases.  The inhalation of irritant gases may cause an acute chemical
pneumonitis and, in severe cases, ILD. Most exposures occur in an industrial setting. Table 26-3
lists some of the more common irritant gases and the industrial settings where they may be
found.
Common Irritant Gases Associated with ILD
Gas Industrial Setting

Chlorine Chemical and plastic industries; Nitrogen dioxide

water disinfection May be liberated after exposure of nitric acid
Ammonia to air
Commercial refrigeration; smelting of sulfide Phosgene Used in the production of aniline
ores dyes
Ozone
Welding

Associated Systemic Disease: Connective Tissue Disease

ILD is a well-known complication of various connective tissue diseases. The most
commonly implicated disorders are scleroderma, rheumatoid arthritis, Sjögren syndrome,
polymyositis/ dermatomyositis, and systemic lupus erythematosus. In any of these disorders,
pulmonary involvement may remain undetected until significant impairment is present, because
these patients may be inactive owing to the underlying connective tissue disease. In addition,
there is generally poor correlation between the severity of the pulmonary and nonpulmonary
manifestations of these diseases. In some instances, the lung disease may overshadow or may
occur earlier than the other symptoms of the underlying disease. When symptoms develop,
dyspnea and cough are common. On chest examination, crackles, wheezing, or a pleural rub
may be heard because of the varied patterns of lung involvement in these disorders. The
physiologic features are usually restrictive with decreased DLCO but may be obstructive
depending on the anatomic location of the disease, especially with Sjögren syndrome (because
the collections of lymphocytes that define this disease are most frequent in the bronchioles).
High-resolution CT findings are variable and range from normal lung architecture to
ground-glass abnormalities to reticular and fibrotic changes. The pathologic pattern of injury with
these diseases is equally diverse and correlates with the high-resolution CT findings.
Inflammatory injury patterns are most commonly seen, such as Nonspecific Interstitial
Pneumonitis (NSIP) and organizing pneumonia.
The NSIP inflammatory injury pattern appears as ground-glass abnormalities on
high-resolution CT scan, whereas organizing pneumonia is shown by patchy consolidated
lung with air bronchograms. Both of these pathologic patterns can improve with aggressive
immunosuppression. At the other end of the pathologic response spectrum is fibrotic injury,
which manifests as UIP and shows reticular fibrotic opacities and honeycomb cystic changes on
high-resolution CT scan. These abnormalities typically do not improve with immunosuppression,
although long-term controlled studies are lacking. Specific treatment of connective tissue
disease–associated ILD must be individualized. Patients with evidence of extrapulmonary
inflammation, an inflammatory pathologic pattern such as NSIP or organizing pneumonia on
high-resolution CT or biopsy, or rapidly progressive symptoms, are usually treated with
prolonged immunosuppressive agents such as cyclophosphamide, azathioprine,
mycophenolate, or tacrolimus. More recent studies have begun to provide evidence-based
therapy for these diverse patients.
The Scleroderma Lung Study showed that 1 year of oral cyclophosphamide modestly
improved lung function compared with modest decline in the control group. However, after 1
year off immunosuppressive therapy, the patients treated with cyclophosphamide worsened and
were indistinguishable from the untreated patients in the control group. Many clinicians
hypothesize that to preserve any lung function gained by cyclophosphamide, continued
immunosuppression may be necessary, and mycophenolate is most often used.
Polymyositis-associated ILD is being increasingly recognized as a common disease
entity. Patients usually present with “mechanic’s hands” consisting of thickened skin and painful
fingertip fissures, and 50% have Jo-1 antibodies on antinuclear antibody testing. Lung
pathologic results typically show fibrotic NSIP or organizing pneumonia. As would be expected
with these inflammatory patterns of injury, patients usually benefit from immunosuppression.
Classic treatment is with cyclophosphamide, but tacrolimus and rituximab are emerging as
salvage agents.

Systemic Diseases
Connective Tissue (Collagen Vascular) Diseases

Scleroderma.
Scleroderma is characterized by chronic hardening and thickening of the skin caused
by new collagen formation.
It may occur in a localized form or as a systemic disorder (called systemic sclerosis).
Progressive systemic sclerosis (PSS) is a relatively rare autoimmune disorder that
affects the blood vessels and connective tissue. It causes fibrous degeneration of the
connective tissue of the skin, lungs, and internal organs, especially the esophagus, digestive
tract, and kidney.
Scleroderma of the lung appears in the form of ILD and fibrosis. Of all the collagen
vascular disorders, scleroderma is the one in which pulmonary involvement is most severe and
most likely to cause significant scarring of the lung parenchyma.
The pulmonary complications include diffuse interstitial fibrosis,severe pulmonary
hypertension, pleural disease, and aspiration pneumonitis (secondary to esophageal
involvement).
Scleroderma may also involve the small pulmonary blood vessels and appears to be
independent of the fibrotic process involving the alveolar walls.T
The disease is most commonly seen in women 30 to 50 years of age.

Rheumatoid Arthritis.
Rheumatoid arthritis is primarily an inflammatory joint disease.It may, however, involve
the lungs in the form of (1) pleurisy, with or without effusion; (2) interstitial pneumonitis; (3)
necrobiotic nodules, with or without cavities; (4) Caplan’s syndrome; and (5) pulmonary
hypertension secondary to pulmonary vasculitis.
Pleurisy with or without effusion is the most common pulmonary complication associated
with rheumatoid arthritis. When present, the effusion is generally unilateral (often on the right
side).
Men appear to develop rheumatoid pleural complications more often than women.
Rheumatoid interstitial pneumonitis is characterized by alveolar wall fibrosis, interstitial
and intraalveolar mononuclear cell infiltration, and lymphoid nodules. In severe cases, extensive
fibrosing alveolitis and honeycombing may develop. Rheumatoid interstitial pneumonitisis also
more common in male patients.
Necrobiotic nodules are characterized by the gradual degeneration and swelling of lung
tissue. The pulmonary nodules generally appear as wellcircumscribed masses that often
progress to cavitation. The nodules usually develop in the periphery of the lungs and are more
common in men. Histologically, the pulmonary nodules are identical to the subcutaneous
nodules that develop in rheumatoid arthritis.
Caplan’s syndrome (also called rheumatoid pneumoconiosis) is a progressive pulmonary
fibrosis of the lung commonly seen in coal miners. Caplan’s syndrome is characterized by
rounded densities in the lung periphery that often undergo cavity formation and, in some cases,
calcification.
Pulmonary hypertension is a common secondary complication caused by the
progression of fibrosing alveolitis and pulmonary vasculitis.

Sjögren’s Syndrome.
Sjögren’s syndrome is a lymphocytic infiltration that primarily involves the salivary and
lacrimal glands and is manifested by dry mucous membranes, usually of the mouth and eyes.
Pulmonary involvement also frequently occurs in Sjögren’s syndrome and includes (1)
pleurisy with or without effusion, (2) interstitial fibrosis that is indistinguishable from that of other
collagen vascular disorders, and (3) infiltration of lymphocytes of the tracheobronchial mucous
glands, which in turn causes atrophy of the mucous glands, mucous plugging, atelectasis, and
secondaryinfections.
Sjögren’s syndrome occurs most often in women (90%) and is commonly associated
with rheumatoid arthritis (50% of patients with Sjögren’s syndrome).

Polymyositis-Dermatomyositis.
Polymyositis is a diffuse inflammatory disorder of the striated muscles that primarily
weakens the limbs, neck, and pharynx.
Dermatomyositis is the term used when an erythematous skin rash accompanies the
muscle weakness.
Pulmonary involvement develops in response to (1) recurrent episodes of aspiration
pneumonia caused by esophageal weakness and atrophy, (2) hypostatic pneumonia secondary
to a weakened diaphragm, and (3) drug-induced interstitial pneumonitis.
Polymyositis-dermatomyositis is seen more often in women than men, at about a 2:1
ratio. The disease occurs primarily in two age groups: before the age of 10 years and from 40 to
50 years of age.
In about 40% of the patients, the pulmonary manifestations are seen 1 to 24 months
before the striated muscle or skin shows signs or symptoms.

Systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a multisystem disorder that mainly involves the
joints and skin. It may also cause serious problems in numerous other organs, including the
kidneys, lungs, nervous system, and heart.
Involvement of the lungs appears in about 50% to 70% of cases. Pulmonary
manifestations are characterized by (1) pleurisy with or without effusion, (2) atelectasis, (3)
diffuse infiltrates and pneumonitis, (4) diffuse ILD, (5) uremic pulmonary edema, (6)
diaphragmatic dysfunction, and (7) infections.
Pleurisy with or without effusion is the most common pulmonary complication of SLE.
The effusions are usually exudates with high protein concentration and are frequently bilateral.
Atelectasis commonly develops in response to the pleurisy, effusion, and diaphragmatic
elevation associated with SLE.
Diffuse noninfectious pulmonary infiltrates and pneumonitis are common.
In severe cases, chronic interstitial pneumonitis may develop.
Because SLE frequently impairs the renal system, uremic pulmonary edema may occur.
SLE has also been found to be associated with diaphragmatic dysfunction and reduced
lung volumes.
Some research suggests that a diffuse myopathy affecting the diaphragm is the source
of this problem. About 50% of cases have a complicating pulmonary infection.

Sarcoidosis.
Sarcoidosis is a chronic disorder of unknown origin characterized by the formation of
tubercles of non necrotizing epithelioid tissue (noncaseating granulomas).
Common sites are the eyes, lungs, spleen, liver, skin, mucous membranes, and lacrimal
and salivary glands, usually with the involvement of the lymph glands.
 The lung is the most frequently affected organ, with manifestations generally including
ILD, enlargement of the mediastinal lymph nodes, or a combination of both.
One of the clinical hallmarks of sarcoidosis is an increase in all three major
immunoglobulins (IgM, IgG, and IgA).
The disease is more common among African-Americans and appears most frequently in
patients 10 to 40 years of age, with the highest incidence at 20 to 30 years of age. Women are
affected more often than men, especially among African-Americans.
Sarcoidosis is an idiopathic multisystem inflammatory disorder that commonly involves
the lung.
It is the most common ILD in the United States. The tissue inflammation that occurs in
sarcoidosis has a characteristic pattern in which the inflammatory cells collect in microscopic
nodules called granulomas.
In contrast to IPF, sarcoidosis is more common among young adults than among older
adults. Sarcoidosis often follows a benign course of inflammation without symptoms or longterm
consequences that spontaneously remits.
The most common manifestation of sarcoidosis is asymptomatic hilar adenopathy. Less
frequently, the chest radiograph shows parenchymal opacities in the midlung zone that may be
nodular, reticulonodular, or alveolar. When symptoms occur, cough, chest pain, dyspnea, and
wheezing are most common. Pulmonary physiology may be normal, restrictive, obstructive, or
mixed, all with reduced DLCO.
Obstructive impairment may be related to endobronchial granulomatous inflammation or
scarring.
Corticosteroids are commonly used in the management of sarcoidosis, but treatment
usually is reserved for patients with marked symptoms or physiologic impairment attributable to
the disease.
Although corticosteroids almost always reduce active sarcoid inflammation, long-term
side effects should limit the duration of steroid treatment. For patients requiring long-term
immunosuppression, alternative immunosuppressive agents such as methotrexate,
azathioprine, leflunomide, or tumor necrosis factor-alpha inhibitors such as infliximab should be
used.
Involvement of other organs that may require corticosteroid therapy include cardiac
involvement, uveitis, and peripheral or central nervous system involvement with cranial nerve
abnormalities. Disease activity is difficult to detect in many patients. Serum
angiotensin-converting enzyme levels and gallium scans are not well correlated with disease
activity, and their routine use is discouraged.

Interstitial Lung Disease of Unknown Cause

Idiopathic Interstitial Pneumonias Despite a careful history, physical examination, and
highresolution CT scan, most patients are not found to have an exposure or systemic illness as
a cause of ILD. These patients have a disorder isolated to the lung termed idiopathic interstitial
pneumonia (IIP). Prognosis and potential therapies are completely dependent on the type of
pathologic pattern of IIP.

Idiopathic Interstitial Pneumonias

 Some patients with ILD do not have a readily identified specific exposure, a systemic
disorder, or an underlying genetic cause.
Such instances of ILD are commonly placed in the idiopathic interstitial pneumonia group
or the group with specific pathology.

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory disease with
varying degrees of fibrosis and, in severe cases, honeycombing. The precise cause is
unknown. Although idiopathic pulmonary fibrosis is the term most frequently used for this
disorder, numerous other names appear in the literature, such as acute interstitial
fibrosis of the lung, cryptogenic fibrosing alveolitis, Hamman-Rich syndrome, honeycomb
lung, interstitial fibrosis, and interstitial pneumonitis.
IPF is commonly separated into the following two major disease entities
according to the predominant histologic appearance: desquamative interstitial
pneumonia (DIP) and usual interstitial pneumonia (UIP).
In DIP the most prominent features are hyperplasia and desquamation of the
alveolar type II cells. The alveolar spaces are packed with macrophages, and there is an
even distribution of the interstitial mononuclear infiltrate.
In UIP the most prominent features are interstitial and alveolar wall thickening
caused by chronic inflammatory cells and fibrosis.In severe cases, fibrotic connective
tissue replaces the alveolar walls, the alveolar architecture becomes distorted, and
eventually honeycombing develops.
When honeycombing is present, the inflammatory infiltrate is significantly
reduced. The prognosis for patients with DIP is significantly better than that for patients
with UIP. Some experts believe that DIP and UIP are two distinct ILD entities. Others,
however, believe that DIP and UIP are different stages of the same disease process.
IPF is most commonly seen in men 40 to 70 years of age. Diagnosis is generally
confirmed by an open lung biopsy. Most patients diagnosed with IPF have a more
chronic progressive course, and death usually occurs in 4 to 10 years. Death usually is
the result of progressive acute ventilatory failure, complicated by pulmonary infection.

Idiopathic pulmonary fibrosis (IPF) is the most common IIP and is a

progressive fibrotic disease isolated to the lung.
Although the precise cause of IPF is unknown, studies have demonstrated that
susceptible individuals have lung injury from diverse causes, such as metal dust, farming
dust, tobacco smoke, subclinical gastric aspiration, and mechanical stress from
abnormal surfactant proteins that lead to abnormal lung healing and progressive
fibrosis.31 Most patients are older than 60 years, and IPF is extremely unusual in
persons younger than 40 years. Patients present with chronic cough and exertional
dyspnea, and high-resolution CT suggests a fibrotic process. The diagnosis of IPF is
made by noting a lack of exposure or systemic disease known to cause ILD and
determining UIP as the pathologic pattern of injury. The diagnosis of UIP is made when
high-resolution CT shows bilateral and basilarpredominant peripheral reticular fibrosis
and honeycomb cystic change with absence of significant ground-glass abnormalities,
micronodules, and air trapping. Without these classic findings, a surgical lung biopsy is
needed for diagnosis.32,33 Patients who do not have IPF can have UIP on surgical lung
biopsy (e.g., connective tissue disease), so this pattern of injury and repair is not unique
to IPF. Most patients die as a result of progressive fibrotic lung disease within 4 years of
diagnosis. Data show that approximately half of patients die with gradually progressive
disease over several years.34 The other half experience stable lung function or minimal
decline for months to years and then have sudden worsening over a few weeks or
months, leading to death.35 Baseline parameters that predict an increased risk for death
include severity of dyspnea, severity of restrictive physiologic defect, reduced DLCO,
presence of pulmonary arterial hypertension, degree of fibrosis on high-resolution CT,
and SaO2 desaturation on exertion.36 Serial parameters that predict poor survival
include worsening dyspnea, FVC, and DLCO. Specific treatment for IPF is emerging
after decades of IPF trials showing no benefit with aggressive immunosuppression,37-39
interferon gamma,40 etanercept,41 bosentan, macitentan, ambrisentan, sildenafil,42
imatinib,43 warfarin, N-acetylcysteine,44 and azathioprine in combination with both oral
corticosteroids and N-acetylcysteine.45 Pirfenidone and nintedanib, both molecules with
multiple antifibrotic properties, have recently been shown to slow disease progression in
selected patients with IPF. Perfenidone has been approved for use in Japan, Canada,
and in several European countries at this writing,46,47 and both perfenidone and
nintendanib were approved for use in the United States by the U.S. Food and Drug
Administration on October 15, 2014. Studies have demonstrated concomitant pulmonary
arterial hypertension in IPF leading to worse exercise intolerance and increased
mortality.48,49 Significant pulmonary arterial hyper-tension is suggested in patients with
markedly impaired diffusion capacity but relatively preserved FVC. Medications that
benefit pulmonary arterial hypertension such as bosentan and sildenafil generally have
not proved beneficial for IPF either with or without pulmonary arterial hypertension.

Nonspecific Interstitial Pneumonia. NSIP is an IIP with diffuse inflammation seen

on surgical lung biopsy.52 Patients are on average 7 to 10 years younger than patients
with IPF, but considerable overlap exists. The degree of accompanying interstitial fibrosis
is variable among patients. The most common presentation of NSIP is fibrotic NSIP. This
type involves fibrosis and inflammation. Cellular NSIP is less common. Patients present
with chronic or subacute cough and dyspnea. Highresolution CT shows predominant
ground-glass abnormalities in cellular NSIP and both ground-glass abnormalities and
fibrotic changes in fibrotic NSIP. Given that there is significant clinical and radiographic
overlap between fibrotic NSIP and IPF, surgical lung biopsy is frequently required to
distinguish these two entities, such as when elements of classic UIP are not present on
high-resolution CT images. The prognosis is much better for NSIP than IPF, with most
patients surviving 7 to 10 years. Immunosuppression with oral corticosteroids and
cytotoxic immunosuppressive agents is the primary therapy. Type and duration of
therapy are guided by disease activity and degree of inflammation on biopsy and
ground-glass abnormalities on high-resolution CT. Pathologic NSIP is found frequently
as an IIP and is the most common pattern of injury seen in connective tissue
disease–associated ILD. Owing to this frequent association, many authors consider
 NSIP a connective tissue disease isolated to the lung.53,54 Organizing Pneumonia.
Organizing pneumonia (OP) is the revised term for bronchiolitis obliterans organizing
pneumonia. The term cryptogenic organizing pneumonia is used when this pattern of
injury occurs as an IIP, and it is termed organizing pneumonia when found in the setting
of connective tissue disease. Patients with organizing pneumonia are typically younger
than patients with IPF and present with acute or subacute dyspnea and cough.
Approximately one-third describe a preceding viral illness. However, no other risk factors
are known. High-resolution CT shows alveolar filling with air bronchograms mimicking
acute pneumonia, and the patient with classic organizing pneumonia presents after
having failed to improve despite several courses of antibiotics. Diagnosis usually
requires surgical lung biopsy, especially if the clinical and radiographic features are
uncertain because small areas of organizing pneumonia can be seen in various
inflammatory and fibrotic disorders on transbronchial lung biopsy. Surgical lung biopsy
specimens show young fibroblasts within the alveoli that are presumably recovering from
an injury. The alveolar basement membrane is intact, allowing for significant recovery if
the inflammation or injury can be suppressed. Most patients improve with oral
corticosteroids (0.5 to 1 mg/kg for 6 to 12 weeks). However, many patients have
recurrence after corticosteroid withdrawal and require longterm immunosuppression with
cytotoxic immunosuppressive agents. A few patients develop progressive fibrosis
despite aggressive immunosuppression and may be candidates for lung transplantation.

Cryptogenic Organizing Pneumonia

Cryptogenic organizing pneumonia (COP) (also known as bronchiolitis obliterans
organizing pneumonia [BOOP]) is characterized by connective tissue plugs in the small airways
(hence the term bronchiolitis obliterans) and mononuclear cell infiltration of the surrounding
parenchyma (hence the term organizing pneumonia).
Although most cases have no identifiable cause and therefore are considered idiopathic,
COP has been associated with connective tissue disease, toxic gas inhalation, and infection.
The chest radiograph commonly shows patchy infiltrates of alveolar rather than interstitial
involvement. Diagnosis may require a surgical biopsy when the clinical and radiographic data
are uncertain.
COP is one of the ILDs in which both restrictive and obstructive pathologic lesions are
present.

Lymphocytic Interstitial Pneumonia

Lymphocytic interstitial pneumonia (LIP) is a diffuse pulmonary disorder characterized by
fibrosis and accumulation of lymphocytes in the lungs. It is commonly associated with
lymphoma. The diagnosis usually requires a surgical lung biopsy.
Lymphocytic Interstitial Pneumonia Lymphocytic interstitial pneumonia is a rare disorder
of polyclonal lymphocyte aggregates that accumulate diffusely in the interstitium.55 The
diagnosis almost always requires surgical lung biopsy. Patients are typically younger than
patients with IPF and present with subacute dyspnea and cough. Pulmonary function testing
may show a mixed picture, and high-resolution CT typically shows diffuse ground-glass
attenuation with variable amounts of fibrosis. Most patients respond well to oral corticosteroids,
with a few requiring long-term immunosuppression. Lymphocytic interstitial pneumonia is
frequently associated with connective tissue diseases, especially Sjögren syndrome, and with
immunodeficiency, and these possibilities should be investigated in all patients with lymphocytic
interstitial pneumonia.

The following possibilities must be considered and separated from progression of the
disease:
1. Superimposed infection: Immunosuppressive agents used in the management of
some ILDs increase the risk for infection in the lung and elsewhere. Common bacteria or
uncommon opportunistic infections may be responsible. Pneumonia may be difficult to detect
radiographically because of preexisting radiographic abnormalities, and bronchoscopy with
bronchoalveolar lavage and transbronchial lung biopsy may be needed.
2. Drug reaction: Almost all medications used to treat ILD have been reported to be
capable of causing an adverse pulmonary reaction. Some medications, such as methotrexate,
have been described to result in pulmonary reactions in 5% to 10% of users. An adverse drug
reaction should be considered in all patients with ILD who are being actively treated, particularly
if there is a clear temporal relationship between starting the medication and the new or
progressive respiratory symptoms.
3. Steroid-related muscle weakness. This is a less common complication of
corticosteroid therapy and can cause exercise intolerance indistinguishable from progression of
the underlying lung disease. Steroid-related muscle weakness (steroid myopathy) is difficult to
diagnose because the weakness can result in worsening of the underlying restrictive physiologic
defect. When proximal muscle weakness occurs in combination with progressive respiratory
symptoms, the possibility of steroid myopathy should be considered. A greater than 20% drop in
the FVC in the supine position compared with the sitting position suggests neuromuscular
dysfunction.
4. Pulmonary embolism: Inactivity as a result of disease-related physiologic impairment
and right ventricular dysfunction may be a risk factor for thromboembolic disease. A sudden
decline in respiratory status, sometimes associated with pleuritic chest pain, should raise the
possibility of acute pulmonary embolism.
5. Lung carcinoma: Patients with pulmonary fibrosis have an increased risk for lung
cancer, and the development of lung cancer can contribute to clinical decline. 6. Atherosclerotic
vascular disease: Many patients with ILD have independent risk factors for atherosclerotic
vascular disease. They may have unrelated cardiac disease, such as coronary artery disease,
left ventricular dysfunction, or valvular disease, which can be mistaken for a worsening of the
pulmonary process.
Each of the possible explanations for the patient’s breathlessness should be considered
before ascribing it to progression of the ILD.

Specific Pathology
Lymphangioleiomyomatosis
Lymphangioleiomyomatosis (LAM) is a rare lung disease involving the smooth muscles
of the airways and affects women of childbearing age. It is characterized by the proliferation of
disorderly smooth muscle proliferation throughout the bronchioles, alveolar septa, perivascular
spaces, and lymphatics.
LAM causes the obstruction of small airways and lymphatics. Common clinical features
associated with LAM are recurrent pneumothorax and chylothorax. The diagnosis of LAM is
confirmed with an open lung biopsy. The prognosis is poor; the disease slowly progresses over
2 to 10 years, ending in death resulting from ventilatory failure.
Lymphangioleiomyomatosis (LAM) is a rare disorder of abnormal smooth muscle
tissue proliferating around small airways and leading to severe obstruction and destruction of
alveoli with resultant thin-walled cyst formation.
All patients are women, although both men and women with tuberous sclerosis complex
can develop lung pathologic findings identical to those of LAM that is called tuberous sclerosis
complex LAM.
This peculiar pathologic process is caused by abnormalities in the TSC-2 gene.
Dyspnea on exertion and an obstructive ventilatory impairment with reduced DLCO is
almost always present, except in very early disease. Disease progression is quite variable;
some women having steadily worsening lung function during midlife, whereas some elderly
women experience extremely slow decline over many years.
Risk factors for worsening lung function include a significant bronchodilator response
and possibly pregnancy. Other important disease manifestations include pneumothorax from a
ruptured subpleural cyst.
Unilateral or, less commonly, bilateral chylothorax is seen in about one-third of patients.
This results from lymphatic obstruction by abnormal smooth muscle tissue.
Treatment with a low-fat diet or blocking gut fat absorption is usually ineffective, and
pleurodesis is required. Pleurodesis does not preclude subsequent lung transplantation.
Treatment is with inhaled bronchodilators and inhaled corticosteroids. Younger patients may
ultimately require lung transplantation. Ongoing studies with rapamycin, which blocks the
abnormal TSC-2 gene and inhibits LAM cell proliferation, show promise for the first
disease-specific therapy for an ILD

Exposure-Related Disease Tobacco-Associated Lung Disease

Although the association of first-hand tobacco smoke and obstructive lung disease is
common and well known, tobacco smoke is also an avoidable cause of ILD. Although the
association is rarer than with obstructive lung disease, first-hand tobacco smoke inhalation can
lead to three types of ILD in susceptible individuals: RB-ILD, DIP, and PLCH. The first two
disorders are related. Each disease consists of increased numbers of polyclonal activated
macrophages. The diseases differ by the location of these overly abundant cells.
Respiratory bronchiolitis– associated interstitial lung disease [RB-ILD], desquamative
interstitial pneumonitis [DIP],
In RB-ILD, macrophages accumulate in the respiratory bronchioles leading to
bronchiolar remodeling and fibrosis of adjacent alveoli. As expected for a disease with
combined airway and alveolar injury, pulmonary function testing reveals mixed restriction and
obstruction with frequent air trapping. High-resolution CT images show this mixed pathologic
location with indistinct centrilobular nodules.
 In DIP, the increased macrophages fill the alveoli, manifesting as restrictive impairment
on pulmonary function testing and diffuse ground-glass attenuation on high-resolution CT
imaging.

Pulmonary Langerhans cell histiocytosis (PLCH) is the third interstitial manifestation of

tobacco smoke. Increased numbers of polyclonal macrophages play a prominent role. However,
in PLCH, they are accompanied by fibroblasts and eosinophils in nodules concentrated around
small airways. These nodules are star-shaped (or stellate) and destroy adjacent lung tissue,
leading to the classic high-resolution CT image of stellate nodules associated with cysts, as
seen in Figure 26-7. Although adult smoking-associated PLCH is pathologically similar to
childhood Langerhans cell histiocytosis, the adult form does not involve bone and has not
proved to respond to chemotherapy as the childhood form does. The relationship of these two
disorders has yet to be defined.
In each of these three diseases, the primary treatment is stopping smoking completely.
With abstinence from smoking, most patients either minimally improve or remain stable,8 but a
few progressively worsen, sometimes to the point of needing lung transplantation. Active
treatment with prednisone or other immunosuppressive medications is discouraged because
few, if any, patients improve and the medications have significant side effects.
Pulmonary Langerhans Cell Histiocytosis
Pulmonary Langerhans cell histiocytosis (PLCH) is a smoking-related ILD characterized
by mid-lung zone starshaped nodules with adjacent thin-walled cysts. It was once considered a
benign condition in adults, but long-term complications such as pulmonary hypertension are
becoming increasingly recognized.
Diagnosis is confirmed histologically by tissue biopsy.

Pulmonary Alveolar Proteinosis

Pulmonary alveolar proteinosis is a condition of unknown cause in which the alveoli
become filled with protein and lipids. The lipoprotein material is similar to the pulmonary
surfactant produced by type II cells. In addition, the alveolar macrophages are generally
dysfunctional in this disorder. The disease is most commonly seen in adults 20 to 50 years of
age. Men are affected twice as often as women. The chest radiograph typically reveals bilateral
infiltrates that are most prominent in the perihilar regions (butterfly pattern). It is often
indistinguishable from pulmonary edema. Air bronchograms are commonly seen. The diagnosis
is confirmed by transbronchial or open lung biopsy, or by analysis of fluid removed during
bronchial lavage.

Pulmonary Vasculitides
The pulmonary vasculitides (also called granulomatous vasculitides) consist of a
heterogeneous group of pulmonary disorders characterized by inflammation and destruction of
the pulmonary vessels. The major disorders in this category include Wegener’s granulomatosis,
Churg-Strauss syndrome, and lymphomatoid granulomatosis.
Wegener’s Granulomatosis. Wegener’s granulomatosis is a multisystem
disorder characterized by (1) a necrotizing, granulomatous vasculitis; (2) focal and
segmental glomerulonephritis; and (3) variable degrees of systemic vasculitis of thesmall
 veins and arteries. In the lungs, numerous 1- to 9-cm diameter nodules are commonly
seen in the upper lobes, and cavity formation is often associated with larger lesions.
Wegener’s granulomatosis is considered an aggressive and fatal disorder, although the
prognosis has significantly improved with the use of cytotoxic agents (e.g.,
cyclophosphamide).This disorder is most commonly seen in men older than 50 years of
age. Diagnosis is confirmed by an open lung biopsy. Histologic examination reveals
lesions with marked central necrosis. The area surrounding the necrotizing lesion
consists of inflammatory white blood cells with some fibroblasts. Inflammatory cell
infiltrate and necrotizing vasculitis are seen in the adjacent blood vessels.
Churg-Strauss Syndrome. Churg-Strauss syndrome is a necrotizing vasculitis
that predominantly involves the small vessels of the lungs.The granulomatous lesions
are characterized by a heavy infiltrate of eosinophils, central necrosis, and peripheral
eosinophilia. Cavity formation is rare in this disorder. Clinically, symptoms of asthma
usually precede the onset of vasculitis. In recent years, rapid tapering of oral steroids
with substitution of leukotriene inhibitors such as montelukast (Singulair) and zafirlukast
(Accolate) has been associated with deaths from fulminant Churg-Strauss syndrome
reactions. Neurologic disorders such as mononeuritis multiplex, a simultaneous disease
of several peripheral nerves, are frequently associated with this disorder. Diagnosis is
usually confirmed with an open lung biopsy, and the disease is often rapidly fatal.
Lymphomatoid Granulomatosis. Lymphomatoid granulomatosis is a rare
necrotizing vasculitis that primarily involves the lungs, although neurologic and
cutaneous lesions are sometimes seen. The lesions are usually in the lower lobes, and
cavities develop in more than one third of cases. Pleural effusion is common. Although
the clinical presentation is similar to that of Wegener’s granulomatosis, there are some
distinct differences. For example, more mature lymphoreticular cells are involved in the
formation of the granulomatous lesions and no glomerulonephritis is seen. Histologically,
the lesions simulate malignant lymphoma. This disorder is most commonly seen in men
50 to 70 years of age. Diagnosis is confirmed by open lung biopsy.

Miscellaneous Diffuse Interstitial Lung Diseases

Goodpasture’s Syndrome
Goodpasture’s syndrome is a disease of unknown cause that involves two organ
systems—the lungs and the kidneys. In the lungs there are recurrent episodes of pulmonary
hemorrhage and in some cases pulmonary fibrosis, presumably consequence of the bleeding
episodes. In the kidneys there is a glomerulonephritis characterized by the infiltration of
antibodies within the glomerular basement membrane (GBM). These circulating antibodies
function against the patient’s own GBM. They are commonly abbreviated as anti-GBM
antibodies. It is believed that the anti-GBM antibodies crossreact with the basement membrane
of the alveolar wall and that their deposition in the kidneys and lungs is responsible for
producing the pathophysiologic processes of the disease. Goodpasture’s syndrome is usually
seen in young adults. The average survival period after diagnosis is about 15 weeks. About
50% of patients die from massive pulmonary hemorrhage, and about 50% die from chronic renal
failure.
 An interesting feature of Goodpasture’s syndrome is that the patient frequently
demonstrates an increased pulmonary diffusion capacity (Dlco), which is in direct contrast to
most interstitial lung disorders. The increased carbon monoxide uptake commonly seen in this
disorder is thought to be caused by the increased amount of retained hemoglobin in the
pulmonary tissue.

Idiopathic Pulmonary Hemosiderosis

Idiopathic pulmonary hemosiderosis is a disease entity of unknown cause that is
characterized by recurrent episodes of pulmonary hemorrhage similar to that seen in
Goodpasture’s syndrome. Histologic examination reveals an alveolar hemorrhage with
hemosiderin-laden macrophages and hyperplasia of the alveolar epithelium. Unlike
Goodpasture’s syndrome, however, there is no evidence of circulating antiGBM antibodies
attacking the alveoli or GBMs, and this disorder is not associated with renal disease. Idiopathic
pulmonary hemosiderosis is most often seen in children. As in Goodpasture’s syndrome,
patients commonly demonstrate an increased Dlco, which is in direct contrast to most
interstitial lung disorders. Again, the increased uptake of carbon monoxide is thought to be
caused by the increased amount of hemoglobin retained in the lungs.

Chronic Eosinophilic Pneumonia

Chronic eosinophilic pneumonia is characterized by infiltration of eosinophils and, to a
lesser extent, macrophages into the alveolar and interstitial spaces. Clinically, a unique feature
of this disorder is often seen on the chest radiograph, consisting of a peripheral distribution of
pulmonary infiltrates. This radiographic pattern is commonly referred to as a photographic
negative of pulmonary edema. This is because of the dense peripheral infiltration, with the
sparing of the perihilar areas, seen in chronic eosinophilic pneumonia, compared with the
central pulmonary infiltration with the sparing of the lung periphery seen in pulmonary edema.
An increased number of eosinophils is also commonly seen in the peripheral blood. Histologic
diagnosis is made by means of an open lung biopsy.

CLINICAL DATA OBTAINED AT THE PATIENT’S BEDSIDE

The Physical Examination
Vital Signs
Increased Respiratory Rate (Tachypnea)
Several pathophysiologic mechanisms operating simultaneously may lead to an
increased ventilatory rate:
• Stimulation of peripheral chemoreceptors (hypoxemia)
• Decreased lung compliance–increased ventilatory rate relationship
• Stimulation of the J receptors
• Pain, anxiety
Increased Heart Rate (Pulse) and Blood Pressure
Cyanosis
Digital Clubbing
Peripheral Edema and Venous Distention
 Because polycythemia and cor pulmonale are associated with chronic interstitial lung
disease, the following may be seen:
• Distended neck veins
• Pitting edema
• Enlarged and tender liver

Nonproductive Cough Chest Assessment Findings

• Increased tactile and vocal fremitus
• Dull percussion note
• Bronchial breath sounds
• Crackles
• Pleural friction rub
• Whispered pectoriloquy

CLINICAL DATA OBTAINED FROM LABORATORY

TESTS AND SPECIAL PROCEDURES

Pulmonary Function Test Findings Moderate to Severe Interstitial Lung Disease

(Restrictive Lung Pathology)
FORCED EXPIRATORY VOLUME AND FLOW RATE FINDINGS
FVC FEVT FEV1/FVC ratio FEF25%–75%
↓ N or ↓ N or ↑ N or ↓
FEF50% FEF200–1200 PEFR MVV
N or ↓ N or ↓ N or ↓ N or ↓

LUNG VOLUME AND CAPACITY FINDINGS

VT IRV ERV RV
N or ↓ ↓ ↓ ↓
VC IC FRC TLC RV/TLC ratio
↓ ↓ ↓ ↓ N
DECREASED DIFFUSION CAPACITY

There is an exception to the expected decreased diffusion capacity in the following two
interstitial lung diseases: Goodpasture’s syndrome and idiopathic pulmonary
hemosiderosis. The DLCO is often elevated in response to the increased amount of
hemoglobin retained in the alveolar spaces that is associated with these two disorders.

Arterial Blood Gases

MILD TO MODERATE INTERSTITIAL LUNG DISEASE
Acute Alveolar Hyperventilation with Hypoxemia* (Acute Respiratory Alkalosis)
pH PaCO2 HCO3− PaO2 SaO2 or SpO2
↑ ↓ ↓ (but normal) ↓ ↓
 SEVERE CHRONIC INTERSTITIAL LUNG DISEASE
Chronic Ventilatory Failure with Hypoxemia†
(Compensated Respiratory Acidosis)
pH PaCO2 HCO3− PaO2 SaO2 or SpO2 N
N ↑ ↑ (significantly) ↓b ↓

ACUTE VENTILATORY CHANGES SUPERIMPOSED ON CHRONIC VENTILATORY

FAILURE
Because acute ventilatory changes are frequently seen in patients with chronic
ventilatory failure, the respiratory therapist must be familiar with—and alert for—the following
two dangerous arterial blood gas (ABG) findings:
•Acute alveolar hyperventilation superimposed on chronic ventilatory failure—which
should further alert the respiratory therapist to record the following important ABG assessment:
possible impending acute ventilatory failure
•Acute ventilatory failure (acute hypoventilation) superimposed on chronic ventilatory
failure
Oxygenation Indices* Moderate to Severe Stage Interstitial Lung Disease

Qs/Qt DO2 VO2 C(a-v)O2 O2ER SvO2

↑ ↓ N N ↑ ↓

Hemodynamic Indices: Severe Interstitial Lung Disease

CVP RAP PA PCWP CO SV
↑ ↑ ↑ N N N
SVI CI RVSWI LVSWI PVR SVR
N N ↑ N ↑ N
LABORATORY FINDINGS
• Increased hematocrit and hemoglobin (polycythemia)

RADIOLOGIC FINDINGS
Radiologic findings vary according to the cause.
Chest Radiograph
• Bilateral reticulonodular pattern
• Irregularly shaped opacities
• Granulomas
• Cavity formation
• Honeycombing
• Pleural effusion
As shown in Figure 26-3, in a patient with severe scleroderma, a bilateral reticulonodular
pattern is commonly seen on the radiographs. In patients with asbestosis the opacity is often
described as cloudy in appearance or as having a “groundglass” appearance and is especially
apparent in the lower lobes (Figure 26-4). Calcified pleural plaques may be seen on the superior
border of the diaphragm or along the chest wall (Figure 26-5). The inflammatory response
elicited by the asbestos fibers may also produce a fuzziness and irregularity of the cardiac and
diaphragmatic borders.

General Management of Interstitial Lung Disease

Medications and Procedures Commonly Prescribed by the Physician The management
of interstitial lung disorders is directed at the inflammation associated with the various disorders.

Corticosteroids
-commonly administered with reasonably good results, but the benefit varies remarkably
from one patient and condition (cause) to another (see Appendix II).

Respiratory Care Treatment Protocols

Oxygen therapy is used to treat hypoxemia, decrease the work of breathing, and
decrease myocardial work. Because of the hypoxemia associated with ILDs, supplemental
oxygen is often required. The hypoxemia that develops in an interstitial lung disorder is most
commonly caused by alveolar thickening, fibrosis, and capillary shunting associated with the
disorder (see Oxygen Therapy Protocol, Protocol 9-1).

Mechanical ventilation may be needed to provide and support alveolar gas exchange
and eventually return the patient to spontaneous breathing. Because acute ventilatory failure
superimposed on chronic ventilatory failure is often seen in patients with severe ILD, continuous
mechanical ventilation may be required. Continuous mechanical ventilation is justified when the
acute ventilatory failure is thought to be reversible.

Other Treatments
Plasmapheresis Treatment for Goodpasture’s syndrome is directed at reducing the
circulating anti-GBM antibodies that attack the patient’s GBM. Plasmapheresis, which directly
removes the anti-GBM antibodies from the circulation, has been of some benefit.