2191 Interstitial Lung Disease CHAPTER 293

sarcoidosis (Chap. 367), and ILDs related to CTDs (Chap. 413) as a

group are among the most common forms of ILD.

DIAGNOSTIC APPROACH

The initial diagnostic approach to diffuse parenchymal lung disease is

often broader than a focus on ILD and should include an evaluation

for alternate causes including cardiovascular disease (e.g., heart failure,

Chap. 258), diffuse infections (e.g., pneumocystis pneumonia, Chap.

220), and malignancy (e.g., bronchoalveolar cell carcinoma, Chap. 315

in HPIM 19e). This chapter will focus on the diagnostic evaluation that

helps to distinguish among the various forms of ILD.

■ HISTORY

Age Age at presentation has a strong influence on the pretest probability that IPF, in particular, is present. For example, IPF occurs most

commonly in patients aged >60 and is quite rare among patients aged

<50. In fact, in patients aged >65 without strong evidence for an alternate diagnosis, atypical chest CT findings are still more likely to result

in a histopathologic diagnosis of UIP (a pathologic hallmark of IPF)

than they are to result in an alternate IIP diagnosis. Other common

ILDs, such as sarcoidosis and CTD-associated ILD, and less common

ILDs, such as LAM and pulmonary Langerhans cell histiocytosis

(PLCH), tend to present between the ages of 20 and 40.

Sex Although less influential than age, sex has some influence on

likelihood of various ILDs. LAM (and the related disorder tuberous

sclerosis) (see Chap. 315 in HPIM 19e) is a disorder that is frequently diagnosed in young women. Many CTD-associated ILDs are

more common among women, with the exception of RA-associated

ILD, which is more common among men. IPF and occupational/

exposure-related ILDs (likely due to work-related exposures that tend

to differ between men and women) are more common among men.

Duration of Symptoms Acute presentations (days to weeks) of

ILD are unusual and are commonly misdiagnosed as more common

diseases such as pneumonia, a chronic obstructive pulmonary disease

(COPD) exacerbation, or heart failure. ILDs that can present acutely

include eosinophilic pneumonia, acute interstitial pneumonia (AIP),

HP, and granulomatosis with polyangiitis (GPA). An acute exacerbation of IPF as the initial presentation of this disease should also

be a consideration given its prevalence. ILDs most commonly have

a chronic indolent presentation (months to years) typified by IPF.

However, subacute presentations (weeks to months) can occur in most

of the ILDs, but in the right context could suggest sarcoidosis, CTDassociated ILD, drug-induced ILD, or COP.

Respiratory Symptoms Progressive dyspnea, most frequently

noted with exertion, is the most common complaint in patients presenting with an ILD. Despite this fact, both research studies of general

population samples and clinical experiences of asymptomatic patient

referrals with abnormal chest CT imaging patterns have also demonstrated that some patients, even those with more extensive disease, may

not report dyspnea. Cough, particularly a dry cough, is also common

and can be the most prominent symptom in patients with IPF. Cough

is often reported in other ILDs, particularly those that have prominent

airway involvement including sarcoidosis and HP. Cough with hemoptysis is rare and could suggest an ILD associated with diffuse alveolar

hemorrhage (DAH) (e.g., Goodpasture’s syndrome), GPA, or LAM.

Cough with hemoptysis could also suggest a secondary pulmonary

infection that can be seen in patients with traction bronchiectasis and

in those receiving immunosuppressive therapy. Chest pain is rare in

most of the ILDs with the exception of sarcoidosis where chest discomfort is not uncommon. Fatigue is common to all of the ILDs.

Past Medical History The most pertinent history includes a

personal history of a CTD or a history of symptoms commonly associated with a CTD (e.g., Raynaud’s phenomena). It is also important to

remember that ILD associated with a CTD can be the initial presenting

symptom of the disease and can precede the development of additional

symptomatology by many years. A history of malignancy is important

because some malignancies can be associated with dermatomyositisassociated COP and sarcoid-like reactions. A history of asthma and

allergic rhinitis might suggest a diagnosis of eosinophilic GPA.

ILD of known cause ILD of unknown cause

Granulomatous lung disease:

Sarcoidosis

Hypersensitivity pneumonia

Idiopathic pulmonary

fibrosis

Treatment related:

Radiation

Methotrexate

Amiodarone

Nitrofurantoin

Chemotherapeutics

Granulomatous disease with

vasculitis:

Granulomatosis with polyangiitis

Churg-Strauss

Connective tissue

disease:

Rheumatoid

arthritis

Scleroderma

Polymyositis/

Dermatomyositis

Idiopathic interstitial

pneumonias

Lymangioleiomyomatosis

Pulmonary alveolar proteinosis

Langerhan’s cell histiocytosis

Pleural parenchymal fibroelastosis

Other

Occupational:

Asbestosis

Silicosis

Systemic

disease

Nonspecific interstitial pneumonia

Respiratory bronchiolitis—associated

interstitial lung disease

Desquamative interstitial pneumonia

Cryptogenic organizing pneumonia

Acute interstitial pneumonia

Lymphocytic interstitial pneumonia

Exposure

FIGURE 293-1 Classification of interstitial lung disease. This algorithm represents a common approach to subclassifying the interstitial lung diseases. It is typical to divide

the interstitial lung diseases into those of known and unknown causes (although it is important to note that genetic studies demonstrate that a significant portion of familial

and idiopathic pulmonary fibrosis [classically described as diseases of unknown cause] may be explained, in part, by genetic factors). The idiopathic interstitial pneumonias

were more precisely defined by a 2002 study as described in Am J Respir Crit Care Med 165:277, 2002, referenced in the Further Reading list.

2192 PART 7 Disorders of the Respiratory System

Medications Many medications have been associated with ILD,

and to complicate matters further, many medications commonly

used to treat inflammatory and granulomatous lung disease are also

associated with ILD development (e.g., methotrexate, azathioprine,

rituximab, and the tumor necrosis factor α–blocking agents). Specific

medications in many classes are also known to cause ILD, including

antibiotics (e.g., nitrofurantoin), antiarrhythmics (e.g., amiodarone),

and many of the antineoplastic agents (e.g., bleomycin).

Family History A family history of ILD (of almost any type) is

important to ascertain. The percentage of pulmonary fibrosis that is

familial, as opposed to idiopathic, varies by study, with estimates ranging from <5% to as high as 20%. Despite this variability, most agree

that the presence of a close relative with an IIP is among the strongest

risk factors for IPF. Family studies have consistently noted familial

aggregation of diverse forms of IIP (such as IPF, nonspecific interstitial

pneumonia [NSIP], and DIP running in the same family) and, in some

cases, other forms of ILD. To date, the most well-replicated genetic

factors for pulmonary fibrosis (a promoter variant of a mucin gene

[MUC5B]) and various genetic determinants known to influence telomere length (e.g., variants in the telomerase reverse transcriptase gene

[TERT]) (Chap. 482) appear to be associated with both familial and

idiopathic forms of pulmonary fibrosis similarly.

Social History A history of smoking is nearly always present in

some forms of ILD (e.g., respiratory bronchiolitis and desquamative

interstitial pneumonia [DIP]—sometimes referred by pathologists

jointly as smoking-related ILD) where it is felt to be causative. A history of smoking is also noted in approximately three-quarters of IPF

patients. Occupational and environmental exposure histories are also

important to obtain as they might identify exposures known to cause

pulmonary fibrosis (e.g., significant asbestos exposure) or HP (pigeon

breeder’s lung).

■ PHYSICAL EXAMINATION

End-inspiratory fine crackles, or rales, noted at the lung bases are

found in most patients with IPF and may be one of the earliest signs of

the disease. However, rales are nonspecific and can be found in many

forms of ILD and other disorders. Wheezing is uncommon in most

forms of ILD but can be present in some disorders, such as sarcoidosis,

HP, and eosinophilic GPA. Signs of advanced disease include cyanosis,

digital clubbing, and cor pulmonale.

■ LABORATORY STUDIES

Laboratory studies can be particularly helpful in the workup for an

underlying CTD-associated ILD. As noted previously, these tests can

reveal the presence of an underlying CTD as the cause of an ILD (e.g.,

a positive anti-cyclic citrullinated peptide [anti-CCP] antibody for RA)

even when no other symptomatology or physical examination findings

suggestive of the disorder are present. However, the cost-effectiveness

and the extent of laboratory testing that should be ordered in various

clinical contexts have yet to be determined (as there is a relatively long

list of autoantibody tests that could be ordered).

■ PULMONARY FUNCTION TESTS

Most forms of ILD will eventually result in a restrictive deficit on pulmonary function testing. A restrictive deficit is typified by a reduced

total lung capacity (TLC) and symmetrically reduced measures of

forced expiratory volume in 1 s (FEV1

) and forced vital capacity (FVC).

A reduction in the diffusing capacity of the lung for carbon monoxide

(DlCO) is also common and may precede a reduction in lung volumes;

however, there is more measurement variability in DlCO measurement

and the test is less specific for ILD. A reduced FEV1

 to FVC ratio, which

is diagnostic of airway obstruction, is unusual in many forms of ILD but

can be present as an isolated finding or in conjunction with an additional

restrictive deficit in ILDs involving the airways such as sarcoidosis, HP,

and LAM. Although pulmonary function testing is rarely diagnostic,

reductions in lung function help to characterize the extent of disease,

and evidence for decline in repeated measures of pulmonary function

(e.g., FVC) has been correlated with an elevated rate of mortality.

■ CHEST IMAGING STUDIES

Chest X-Ray Findings on CXR can be the first clinical indication

that an ILD might be present. For example, enlarged hilar lymph nodes

and a pattern of central nodular opacities in the mid to upper lung

zones can suggest sarcoidosis. A basilar reticular pattern, with small

cystic spaces, in the absence of clinical evidence for heart failure, might

suggest IPF. With a few exceptions, CXR alone rarely leads to a specific

diagnosis.

Chest CT High-resolution CT (HRCT) chest imaging is now considered to be standard of care in the initial evaluation of a patient with

a suspected ILD. HRCT can be diagnostic for some ILDs (e.g., IPF) in

the right clinical context and may preclude the need for, and spare the

patient the risk of, a lung biopsy. HRCT also helps to define the extent

of the ILD, determine the presence of more concerning features suggestive of advanced disease (e.g., honeycombing), provide information

on coexisting diseases (e.g., emphysema and lung cancer), and when

not diagnostic, provide the most useful locations for obtaining lung

biopsy specimens.

■ LUNG BIOPSY

Fiberoptic Bronchoscopy Bronchoscopy can be helpful in establishing a specific ILD diagnosis, and can help to establish an alternate

diagnosis, in select cases. Examination of serial lavage fluid can be

helpful in establishing DAH, which can be present in ILDs with

vasculitis (e.g., GPA), and in some cases, cellular examination can

suggest a specific diagnosis (eosinophilia >25% in chronic eosinophilic

pneumonia or fat globules in macrophages in lipoid pneumonia).

Transbronchial lung biopsies and lymph node biopsies (in sarcoidosis

in particular) can lead to a confident diagnosis in patients with likely

granulomatous lung disease (e.g., sarcoidosis and HP). However, in

general, bronchoscopically obtained tissue samples are often felt to be

insufficient to diagnose most of the IIPs. To date, studies have been

mixed on whether bronchoscopically obtained cryobiopsies, which can

result in yields larger than those obtained by transbronchial forceps

biopsies, could improve the diagnostic yield of bronchoscopy; however,

the precise role of cryobiopsies in the diagnostic workup of ILD has yet

to be clarified.

Surgical Lung Biopsy A surgically obtained lung biopsy specimen

can help solidify the diagnosis of ILD. In many cases, these are now

obtained through a video-assisted thoracoscopic (VATS) approach (as

compared to an open thoracotomy), which tends to reduce the length

of operative times and hospital stays. The diagnostic yield of biopsies

tends to be higher if obtained prior to treatment. The desire to obtain

a surgical lung biopsy should be weighed against the risks, which can

include a short-term mortality rate of as high as 5%. These risks are

reported to be higher in biopsies of patients ultimately diagnosed with

IPF and in those presenting acutely.

■ INDIVIDUAL FORMS OF ILD

The ILDs include a diverse group of lung pathologies that can be subclassified into those disorders of unknown cause (e.g., IIPs) and those

of known cause (e.g., sometimes referred to as secondary interstitial

pneumonias [CTD-associated ILDs]) (see Fig. 293-1). Although this

remains a useful approach to classifying this diverse group of disorders,

it is important to recognize that genetic studies are challenging this

classic categorization. For example, numerous ILDs commonly listed as

having an “unknown cause” have been determined to have significant

genetic underpinnings (e.g., IPF and LAM), while the pathophysiologic

processes that result in ILDs of “known cause” (e.g., CTD) remain

incompletely understood. Diagnosis is based on combined information

obtained from a patient’s clinical presentation, measures of pulmonary function, imaging, immune serologies, and histopathology. It is

important to remember that prognosis and treatment vary widely by

disorder (and disease extent). In some cases, medical therapy that is felt

to be effective for some ILDs has been proven to be harmful for others.

Medical treatments range from immune modulators to antifibrotic

2193 Interstitial Lung Disease CHAPTER 293

medications, whereas lung transplantation remains the standard of care

for patients with advanced and rapidly progressive ILDs.

IDIOPATHIC INTERSTITIAL PNEUMONIAS

■ IDIOPATHIC PULMONARY FIBROSIS

Clinical Manifestations IPF is the most common ILD of

unknown cause. Prevalence increases with age and is estimated at

50–200:100,000. IPF is commonly diagnosed in the fifth or sixth

decade in life, affects men more than women, and is frequently associated with a history of smoking or other environmental exposures. IPF

is a variably progressive disease that carries a poor prognosis with an

estimated 50% 3- to 5-year survival.

HRCT Image Findings Chest CT findings include subpleural

reticulation with a posterior basal predominance usually including

more advanced fibrotic features, such as honeycombing and traction

bronchiectasis. Collectively, these imaging findings are referred to as

a UIP pattern. The presence of extensive ground-glass opacities, bronchovascular changes, micronodules, mosaic attenuation, or an upper

lung predominance should raise suspicion for an alternative diagnosis

(Fig. 293-2).

Histopathology Diagnostic VATS biopsy findings include subpleural reticulation associated with honeycomb changes and fibroblast

foci (subepithelial collections of myofibroblasts and collagen). These

fibrotic changes alternate with areas of preserved normal alveolar architecture consistent with temporal and spatial heterogeneity (Fig. 293-3).

Collectively, these pathologic findings are referred to as UIP.

Treatment Historically, IPF was felt to be refractory to medical

therapy with lung transplantation the only viable therapeutic option.

This dogma changed in 2014 with large clinical trials that demonstrated that antifibrotic therapy (pirfenidone and nintedanib) can slow

decline of lung function in IPF patients. Further meta-analyses have

suggested that antifibrotic therapy may also improve survival. Trials

now suggest that antifibrotic therapy may be broadly effective in other

forms of progressive pulmonary fibrosis as well. In contrast, treatment

with immunosuppression, which had been commonly prescribed to

many IPF patients, has now been demonstrated (in some cases) to be

associated with increased morbidity and mortality. Physical therapy

and supplemental oxygen, when indicated, can improve exercise tolerance and reduce likelihood of developing pulmonary hypertension.

Lung transplantation can extend survival and improve the quality of

life in a subset of IPF patients who meet criteria to undergo transplant.

■ NONSPECIFIC INTERSTITIAL PNEUMONIA

Clinical Manifestations Idiopathic NSIP is a distinct clinical

entity with characteristic clinical, radiologic, and pathologic features;

however, NSIP is also commonly observed in patients with CTD and

less frequently with familial interstitial pneumonia, drug toxicity, and

infection. Although the prevalence of NSIP is not well established, it is

A B

C D

FIGURE 293-2 Chest CT imaging and interstitial lung disease. A. Idiopathic pulmonary fibrosis (IPF): Classic findings of IPF (apparent on this image) include a posterior,

basilar predominance of subpleural reticular markings and more advanced features of pulmonary fibrosis including traction bronchiectasis and honeycombing. This

constellation of findings is often referred to as a usual interstitial pneumonia (UIP) pattern. B. Nonspecific interstitial pneumonia (NSIP): Chest CT findings of NSIP can

overlap with those of a UIP pattern but tend to include a bilateral, symmetric pattern that presents with a greater percentage of ground-glass opacities than is apparent in

a UIP pattern. Additional unique findings include more diffuse imaging abnormalities with a predominance not limited to the lung bases, imaging abnormalities that spare

the subpleural regions, and thickening of the bronchovascular bundles (as is apparent in the right mid lung zone on this image). C. Cryptogenic organizing pneumonia:

Chest CT findings include patchy, sometimes migratory, subpleural consolidative opacities (as is apparent on this image) often with associated ground-glass opacities.

Peribronchiolar or perilobar opacities can be present, and sometimes a rim of subpleural sparing (often referred to as a reversed halo or atoll sign) can be seen, which

can help to aid in the diagnosis. D. Sarcoidosis: Sarcoidosis can present with varied imaging abnormalities, but a pattern of mediastinal and hilar lymphadenopathy with a

pattern of reticular-nodular opacities involving the bronchovascular bundles (apparent in this image) are common features. Additional findings can include diffuse small

nodules in a miliary pattern, larger nodular opacities, extensive ground-glass infiltrates, and mosaic attenuation suggestive of small airways involvement, and, in more

advanced cases, signs of pulmonary fibrosis.

2194 PART 7 Disorders of the Respiratory System

commonly diagnosed in nonsmoking females in their fifth decade of

life. Positive serologic tests for CTD are frequently observed. Idiopathic

NSIP has a relatively good prognosis, with a 5-year survival of >80%;

patients with a predominant cellular NSIP pattern have a more favorable prognosis than those with a fibrosing NSIP pattern.

HRCT Image Findings Diffuse subpleural, symmetric, groundglass, and reticular opacities are common. Volume loss and traction

bronchiectasis involving the lower lung zones can also be found. Occasionally subpleural sparing is noted, while peribronchiolar thickening

and honeycombing are uncommon.

Histopathology Diagnostic lung biopsy findings include varying

amounts of interstitial inflammation and fibrosis with a uniform appearance. Honeycomb changes are usually absent and fibroblast foci are rare.

NSIP is often referred to histopathologically as being either predominantly cellular (and potentially more responsive to medical therapy)

or fibrotic (and potentially less likely to resolve with medical therapy).

Treatment Pulmonary fibrosis associated with CTD is commonly

treated with immunosuppression despite the paucity of randomized

clinical trials to demonstrate efficacy. Idiopathic NSIP is often treated

with oral steroids (prednisone), cytotoxic agents (mycophenolate,

azathioprine, and cyclophosphamide), or biologics (rituximab). Trials

now suggest that NSIP patients with progressive pulmonary fibrosis

may benefit from antifibrotic therapy. Oxygen therapy, pulmonary

rehabilitation, and lung transplantation may be required in patients

with progressive disease.

■ SMOKING-RELATED ILD

Although smoking-related ILDs, including respiratory bronchiolitis

with interstitial lung disease (RB-ILD), and DIP are frequently subclassified with the IIPs, these disorders (along with PLCH, an ILD with

unique clinical, imaging, and histopathologic manifestations) are commonly felt to be the result of active or prior tobacco smoke exposure.

DIP has also been known to occur in children with familial pulmonary

fibrosis (FPF). Smokers, particularly elderly smokers, frequently have

radiologic (centrilobular) interstitial abnormalities. These interstitial

abnormalities are often incidentally found on routine CXR or chest

CT studies in asymptomatic or minimally symptomatic individuals.

Respiratory bronchiolitis is felt to correlate histopathologically with

these imaging findings. However, in some cases, these imaging findings

can progress to more advanced radiologic changes where more diffuse

signs of interstitial pneumonia tend to be present.

Clinical Manifestations These disorders predominantly occur in

active, and in many cases heavy, smokers who are typically between 40

and 50 years of age. In those ultimately diagnosed with RB-ILD or DIP,

dyspnea and cough are relatively common and symptomatic wheezing

is not rare. The prevalence of smoking-related ILDs is not well understood, but they are generally felt to account for <10% of the IIPs. While

there are minimal data on the natural histories and prognoses of these

conditions, prolonged survival can be expected in most patients with

RB-ILD and death secondary to progressive ILD is felt to be rare.

HRCT Image Findings Prominent and common findings in

RB-ILD include central bronchial wall thickening, peripheral bronchial

A B

C D

FIGURE 293-3 Histopathology of interstitial lung disease. A. Idiopathic pulmonary fibrosis (IPF): Histopathologic findings include subpleural reticulation associated with

honeycomb changes alternating with areas of preserved normal lung architecture referred to as temporal and spatial heterogeneity (as is apparent in the low-power

image above). Additional important diagnostic findings include fibroblast foci, which are subepithelial collections of myofibroblasts and collagen (as is apparent in the

higher-powered inset of this image). Collectively, these pathologic findings are referred to as usual interstitial pneumonia (UIP). B. Nonspecific interstitial pneumonia

(NSIP): Histopathologic findings of NSIP include varying amounts of interstitial inflammation and fibrosis with a uniform appearance (as is apparent in this image).

Honeycomb changes are usually absent and fibroblast foci are rare. NSIP is often referred to histopathologically as being either predominantly cellular or fibrotic.

C. Cryptogenic organizing pneumonia (COP): Histopathologic findings of COP include patchy regions of organizing pneumonia with granulation tissue that commonly

involves the small airways, alveolar ducts, and alveoli with surrounding inflammation that can involve the alveolar walls (as is apparent in this image). D. Sarcoidosis: The

hallmark histopathologic feature of sarcoidosis is presence of granulomas (as are apparent numerously in the low-powered image and more closely visualized in the higherpowered inset image). Typically, these are referred to as noncaseating, which suggests the absence of necrosis. Caseating granulomas are rare in sarcoid and should

prompt additional evaluation for an underlying infection. Because malignancy can result in a granulomatous reaction, it is important to closely survey biopsy specimens

with granulomatous involvement for additional signs of malignancy.

2195 Interstitial Lung Disease CHAPTER 293

wall thickening, centrilobular nodules, and ground-glass opacities.

Septal lines and a reticular pattern are also not uncommon. Honeycombing is generally felt to be rare (and indicates a worse prognosis).

Similar findings are noted in patients with DIP where diffuse (or

patchy) bilateral symmetric ground-glass opacities tend to be even

more prominent.

Histopathology Common features of RB-ILD include the accumulation of pigmented macrophages within the lumens of respiratory

bronchioles and alveolar ducts, accompanied by chronic inflammation

of the respiratory bronchiolar walls and both bronchiolar and peribronchiolar alveolar fibrosis causing architectural distortion. These

features are patchy and confined to the peribronchiolar region. DIP

tends to include similar changes but has a more diffuse pattern characterized by pigmented macrophage accumulation, pneumocyte hyperplasia, and prominent interstitial thickening.

Treatment All patients with smoking-related ILD should be counseled to discontinue smoking and/or encouraged to enroll in a formal

smoking cessation program. Small studies have evaluated, and patients

are often treated with, immunosuppressive (e.g., prednisone) and cytotoxic (e.g., azathioprine, and cyclophosphamide) agents and, in some

cases, bronchodilators. To date, there is no strong evidence that these

therapies result in significant improvements in symptoms or measures

of pulmonary function or prevent clinical deterioration.

■ CRYPTOGENIC ORGANIZING PNEUMONIA

Clinical Manifestations COP typically involves patients in their

50–60s and often presents as a subacute flulike illness, with cough,

dyspnea, fever, and fatigue. Inspiratory rales are often present on

examination, and most patients are noted to have restrictive lung deficits on pulmonary function testing with hypoxemia. COP is commonly

mistaken for pneumonia. It is important to note that this syndrome can

occur in isolation, can be secondary to an underlying CTD (e.g., polymyositis) or medications, or can result from an underlying malignancy.

Laboratory testing for various CTDs is helpful as testing can both be

diagnostic and suggest the need for prolonged medical therapy.

HRCT Image Findings The most common imaging findings

include patchy, sometimes migratory, subpleural consolidative opacities often with associated ground-glass opacities. Peribronchiolar or

perilobar opacities can be present, and sometimes a rim of subpleural

sparing (often referred to as a reversed halo or atoll sign) can be seen,

which can aid in the diagnosis.

Histopathology Surgical lung biopsy specimens tend to reveal

patchy regions of organizing pneumonia with granulation tissue that

commonly involves the small airways, alveolar ducts, and alveoli with

surrounding inflammation that can involve the alveolar walls (see

Fig. 293-3).

Treatment Corticosteroids can result in substantial clinical

improvement in many patients but usually need to be continued for at

least 6 months as relapse rates are high. Evidence is growing that alternate cytotoxic (e.g., mycophenolate, cyclophosphamide) or biologic

(e.g., rituximab) therapies can be helpful in both treating the disease

and reducing the need for steroids. In some patients with secondary

forms of the disease, long-term therapy may be needed.

ACUTE OR SUBACUTE IIPS

■ ACUTE INTERSTITIAL PNEUMONIA

(HAMMAN-RICH SYNDROME)

Clinical Manifestations AIP is a rare and often fatal lung disorder that is characterized by an acute onset of respiratory distress and

hypoxemia. A prodromal period of symptoms consistent with an acute

upper respiratory infection is common. The mortality rate within

6 months of presentation can be quite high (>50%), and recurrences

are common. In those who recover, lung function improvement can be

substantial. AIP can be difficult to distinguish from acute respiratory

distress syndrome (ARDS) and an acute exacerbation of an unsuspected underlying pulmonary fibrotic process.

HRCT Image Findings The most common imaging findings are

patchy bilateral ground-glass opacities. Dependent regions of air-space

consolidation are also common.

Histopathology Similar to ARDS and acute exacerbations of

underlying pulmonary fibrosis, AIP presents histopathologically as diffuse alveolar damage (DAD) demonstrated on a surgical lung biopsy.

Treatment Treatment is mostly supportive and often includes

mechanical ventilation. There is no proven drug therapy for AIP. Glucocorticoids are often given, but they are not clearly effective and data

on their use in other forms of DAD (e.g., ARDS) is controversial.

■ ACUTE EXACERBATIONS OF IIPS

Clinical Manifestations Acute exacerbations are not separate

disorders, but rather an accelerated phase of lung injury that can

occur in any ILD resulting in pulmonary fibrosis. Acute exacerbations are most commonly described and most severe in patients with

known IPF. Acute exacerbations are characterized by an acute onset

(<30 days) of respiratory distress and hypoxemia occurring in a patient

with underlying pulmonary fibrosis not explained by an alternate cause

(e.g., pneumonia, left heart failure). Reported mortality rates are very

high (>85%), and mean survival periods range from as little as days to

months.

HRCT Image Findings The most common imaging findings

include patchy bilateral ground-glass opacities and dependent regions

of air-space consolidation. Sometimes these new changes can be

appreciated on the background of the imaging findings typified by

the underlying IIP, although sometimes they obscure the preceding

imaging findings.

Histopathology Acute exacerbations of underlying pulmonary

fibrosis present histopathologically as DAD, although sometimes organizing pneumonia can also be demonstrated on a surgical lung biopsy.

Treatment Treatment is mostly supportive. Mechanical ventilation,

when not being used as a bridge to lung transplantation, is controversial as the survival rate in these patients tends to be poor. There is some

evidence that drug therapy (e.g., nintedanib) may reduce the rate of

acute exacerbations in patients with IPF. Drug therapy, in the context

of an acute exacerbation, is also controversial. Immunosuppressive

(e.g., prednisone) and cytotoxic (e.g., cyclophosphamide) therapies are

commonly used without proven benefit.

ILD ASSOCIATED WITH CONNECTIVE

TISSUE DISEASE

ILD is a common disease manifestation of many CTDs. Disease progression, response to therapy, and survival are variable and associated

with specific radiologic and histopathologic patterns. ILD occurs most

commonly in patients with scleroderma (systemic sclerosis form, or

SSc), RA, polymyositis/dermatomyositis, and less frequently Sjögren’s

syndrome and systemic lupus erythematosus (SLE). ILD may precede

the development of extrapulmonary manifestations of a specific CTD

or may present as part of a poorly defined CTD. In rare cases, lung manifestations may be the sole feature of the patient’s clinical presentation.

■ SYSTEMIC SCLEROSIS

Clinical Manifestations (Chap. 360) ILD is the most common

pulmonary manifestation of SSc. ILD occurs in ~50% of SSc patients

with diffuse disease and in ~30% of patients with limited disease. Pulmonary hypertension can occur separately or concomitantly with ILD

and is more frequent in patients with limited SSc.

HRCT Image Findings Similar imaging findings noted in both

patients with NSIP and IPF can be present, although findings consistent

with COP and DAD may also be present. Additional HRCT findings

may include a dilated esophagus and pulmonary artery enlargement.

2196 PART 7 Disorders of the Respiratory System

Histopathology Comparable to the imaging overlap, histopathologic changes commonly noted in patients with NSIP and IPF are

frequently identified. Additionally, aspiration related to esophageal

dysmotility is common in SSc, and in these patients, histopathologic

findings consistent with COP and DAD may be observed.

Treatment Cyclophosphamide has a modest benefit in preservation

of lung function and is associated with significant toxicity. Mycophenolate has recently been shown to have similar efficacy and improved

tolerability. Clinical trials have demonstrated that antifibrotic therapy

(e.g., nintedanib) may benefit patients with systemic sclerosis associated pulmonary fibrosis. Minimizing the risk of reflux by using

high-dose proton pump inhibitors or antireflux surgery should be

considered in SSc with progressive ILD. Lung transplantation can

potentially be offered to select patients without significant aspiration

or chest wall restriction.

■ RHEUMATOID ARTHRITIS

Clinical Manifestations (Chap. 358) A common extraarticular

complication of RA is ILD. Although RA is more common in females,

RA-ILD is more frequent in males and in patients with a history of

tobacco exposure. In a small subset of patients, ILD is the first disease

manifestation of RA. Clinically evident RA-ILD occurs in nearly 10%

of the RA population; however, up to 40–50% of RA patients have

radiologic abnormalities on chest CT, suggesting that ILD in the context of RA may be underdiagnosed.

HRCT Image Findings The most common imaging pattern of

ILD in patients with RA is a UIP pattern, although NSIP patterns are

not uncommon. There is evidence that survival in patients with RA is

decreased in patients with a UIP pattern and among those with more

extensive fibrosis in general.

Histopathology Histopathologic findings of UIP and NSIP are

most common. Some studies suggest that UIP in the context of RA (as

compared to IPF) may present with a reduced number of fibroblastic

foci and an increased amount of germinal centers. Comparable to the

imaging findings, UIP (and DAD) patterns in patients with RA are

associated with reduced survival.

Treatment In contrast with SSc, there are no randomized clinical

trials testing the role of immune suppression in RA-ILD. Extrapolating from the scleroderma experience, immunosuppressive (e.g.,

prednisone) and cytotoxic (e.g., mycophenolate, azathioprine, cyclophosphamide, and calcineurin inhibitors) agents have been used with

variable success. Clinical trials testing antifibrotic therapies (pirfenidone and nintedanib) are presently being conducted. Lung transplantation is a viable therapeutic approach for eligible patients with

progressive disease that is not responsive to medical therapy.

■ DERMATOMYOSITIS/POLYMYOSITIS

Clinical Manifestations (Chap. 365) The idiopathic inflammatory myopathies are disorders characterized by immune-mediated

destruction and dysfunction of muscle; however, these disorders can

affect the skin, joints, cardiovascular system, and lung. The prevalence of ILD associated with inflammatory myopathy varies by report;

however, ILD is present in up to 45% of patients with positive antisynthetase antibodies. The anti-synthetase syndrome is characterized

by positive anti-synthetase antibodies, myositis, fever, Raynaud’s phenomenon, mechanic’s hands, arthritis, and progressive ILD. There is a

subset of anti–Jo-1 antibody–positive individuals who can develop a

rapidly progressive form of ILD consistent with an acute exacerbation.

Some studies have suggested that ILD may be even more common

in those with other antibodies (e.g., anti-PL-12). Dermatomyositis/

polymyositis can occur as an isolated CTD or as a process associated

with an underlying malignancy.

HRCT Image Findings Common imaging patterns of ILD in

patients with dermatomyositis/polymyositis include those consistent

with NSIP with or without evidence for COP. A UIP pattern can also

occur. Some studies have suggested that a UIP pattern may be more

common among those with anti-PL-12 antibodies.

Histopathology The anti-synthetase syndrome is associated with

multiple histopathologic subtypes including NSIP, COP, and UIP. DAD,

a histopathologic pattern observed in AIP and acute exacerbations, is

associated with rapidly progressive ILD in myositis patients.

Treatment Immunosuppressive (e.g., prednisone) and cytotoxic

(e.g., mycophenolate, azathioprine, cyclophosphamide, and calcineurin

inhibitors) agents are often used in patients with progressive ILD. Some

patients (particularly those with less fibrosis) have been noted to have

improved or resolved ILD in response to medical therapy. In small

studies, relapses have been more common in patients treated with

prednisone alone. Patients who fail immune-suppressive therapy can

benefit from lung transplantation.

■ GRANULOMATOUS ILDS

The most common granulomatous ILD is sarcoidosis, a multisystem

disorder of unknown cause where lung involvement is often the most

dominant feature; sarcoidosis is discussed in Chap. 367. HP, a granulomatous reaction due to inhalation of organic (e.g., bird fancier’s lung

secondary to exposure to bird feathers) and inorganic (e.g., coal worker’s

pneumoconiosis secondary to exposure to coal dusts) dusts, is also an

important and common cause of ILD and is discussed in Chap. 288.

Granulomatous Vasculitides (See Chap. 64) These disorders

are characterized by blood vessels with inflammatory infiltrates and

associated granulomatous lesions with or without the presence of tissue necrosis. The lungs are commonly involved, and a unique feature

of these disorders is that hemoptysis can be a presenting symptom.

Although laboratory testing is often helpful and can provide specific

information, biopsies of involved tissue can be essential for making the

diagnosis. Many of these disorders include additional systemic manifestations. GPA, also referred to as Wegener’s disease, is an example of

a granulomatous vasculitis that commonly affects the lung (including

inflammatory infiltrates in small to medium-sized vessels), ears, nose,

throat, and kidney (resulting in glomerulonephritis). Common imaging

abnormalities of GPA include nodules, patchy ground-glass and consolidative opacities that can be migratory, and hilar lymphadenopathy.

Eosinophilic GPA (EG; also referred to as Churg-Strauss syndrome)

is another example of a granulomatous vasculitis that affects the lung

(including eosinophilic infiltrates in small to medium-sized vessels)

and can result in numerous clinical manifestations but frequently

includes chronic sinusitis, asthma, and peripheral blood eosinophilia.

Common imaging abnormalities of EG include peripheral consolidative opacities that can be migratory and small pleural effusions.

■ GENETICS AND ILD

Studies of genetic epidemiology have led to important insights in our

understanding of ILD. First, studies of families with FPF have demonstrated that unique IIPs can cosegregate with specific genetic variants

known to be associated with IPF. This suggests that many genetic

variants appear to predispose to interstitial lung injury patterns more

broadly than to unique diagnoses specifically. Second, most of the

genetic variants known to be associated with FPF are also associated

with more sporadic forms of the disease. Third, at least one of the

genetic factors most strongly associated with FPF and IPF is both common and confers a large increase in the risk of these diseases. At least

one copy of a mucin 5B (MUC5B) promoter variant is present in ~20%

of Caucasian populations and 35–45% of patients with IPF and confers

an approximate sixfold increase in the risk of this disease. Fourth,

studies of general population samples demonstrate that imaging abnormalities suggestive of an early stage of pulmonary fibrosis in research

participants without known ILD are not uncommon (occurring in

~7–9% of adults) and are also associated with the same genetic variants

known to be associated with IPF (e.g., the MUC5B promoter variant).

This latter finding suggests a path forward toward an early detection of

IPF. Additional genetic findings demonstrating replicable associations

with pulmonary fibrosis include numerous genetic variants in, and

2197 Disorders of the Pleura CHAPTER 294

adjacent to, genes known to be involved in the regulation of telomere

length (e.g., the TERT gene, the telomerase RNA component [TERC]

gene, and the regulator of telomere elongation helicase 1 [RTEL1] gene)

and surfactant protein genes (e.g., surfactant protein A2 [SFTPA2]

gene) (Chap. 482).

Genetic studies have also provided some insights into other forms

of ILD. Genome-wide association studies of sarcoidosis have demonstrated numerous variants in genes and in genomic regions that are

associated with the disease. Some of these disease-associated variants in sarcoidosis fall in human leukocyte antigen (HLA) regions,

in regions of genes involved in immune regulation (e.g., interleukin

12B [IL12B]), and in regions of genes that are less well understood

(butyrophilin-like 2 [BTNL2]) but also appear to be involved in T-cell

activation. LAM is often associated with genetic variants in the tuberous sclerosis complex genes (e.g., TSC1 and TSC2), consistent with

the known evidence that this disease can occur in isolation but also

in patients with known tuberous sclerosis. Many genetic factors for

rare diseases such as Hermansky-Pudlak syndrome (a rare autosomal

recessive disorder that results in pulmonary fibrosis but also includes

oculocutaneous albinism, bleeding diatheses, and horizontal nystagmus) have also been discovered (e.g., HSP1, and HSP3-7).

■ GLOBAL CONSIDERATIONS

The prevalence, clinical presentation, and natural history of most ILDs

in European countries resemble those described in the United States.

However, as expected, there is growing evidence for racial differences

in clinical (rate of acute exacerbations) and genetic (MUC5B) attributes

between Caucasian and Asian populations. To date, there are limited

data on the prevalence of ILD in Hispanics, subjects of African descent,

and many other ethnic groups.

■ FURTHER READING

American Thoracic Society/European Respiratory Society:

Consensus classification of the idiopathic interstitial pneumonias.

Am J Respir Crit Care Med 165:277, 2002.

Raghu G et al; ATS/ERS/JRS/ALAT Committee on Idiopathic

Pulmonary Fibrosis: An official ATS/ERS/ JRS/ALAT statement:

Idiopathic pulmonary fibrosis: Evidence-based guidelines for the

diagnosis and management. Am J Respir Crit Care Med 183:788,

2011.

Travis WD et al: Idiopathic nonspecific interstitial pneumonia: Report

of an American Thoracic Society project. Am J Respir Crit Care Med

177:1338, 2008.

Travis WD et al: An official American Thoracic Society/European

Respiratory Society Statement: Ten decade update on IIP’s, potential

areas for future investigation are proposed (ATS/ERS update of the

international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 188:733, 2013.

■ PLEURAL EFFUSION

The pleural space lies between the lung and the chest wall and normally

contains a very thin layer of fluid, which serves as a coupling system.

A pleural effusion is present when there is an excess quantity of fluid

in the pleural space.

Etiology Pleural fluid accumulates when pleural fluid formation

exceeds pleural fluid absorption. Normally, fluid enters the pleural

294 Disorders of the Pleura

Richard W. Light*

*

Deceased.

space from the capillaries in the parietal pleura and is removed via

the lymphatics in the parietal pleura. Fluid also can enter the pleural

space from the interstitial spaces of the lung via the visceral pleura or

from the peritoneal cavity via small holes in the diaphragm. The lymphatics have the capacity to absorb 20 times more fluid than is formed

normally. Accordingly, a pleural effusion may develop when there is

excess pleural fluid formation (from the interstitial spaces of the lung,

the parietal pleura, or the peritoneal cavity) or when there is decreased

fluid removal by the lymphatics.

Diagnostic Approach Patients suspected of having a pleural effusion should undergo chest imaging to diagnose its extent. Chest

ultrasound has replaced the lateral decubitus x-ray in the evaluation

of suspected pleural effusions and as a guide to thoracentesis. When a

patient is found to have a pleural effusion, an effort should be made to

determine the cause (Fig. 294-1). The first step is to determine whether

the effusion is a transudate or an exudate. A transudative pleural effusion

occurs when systemic factors that influence the formation and absorption

of pleural fluid are altered. The leading causes of transudative pleural

Perform diagnostic thoracentesis

Measure pleural fluid protein and LDH

Exudate

Further diagnostic procedures

Transudate

Treat CHF, cirrhosis, nephrosis

Measure PF glucose

Obtain PF cytology

Obtain differential cell count

Culture, stain PF

PF marker for TB

Consider: Malignancy

Bacterial infections

Rheumatoid

pleuritis

Glucose <60 mg/dL

No diagnosis

Consider pulmonary

embolus (spiral CT

or lung scan)

Treat for PE

PF marker for TB Treat for TB

Observe

Consider thoracoscopy

or image-guided

pleural biopsy

Any of following met?

PF/serum protein >0.5

PF/serum LDH >0.6

PF LDH >2/3 upper normal serum limit

Pleural effusion

Yes No

Yes

Yes

Yes

No

No

No

SYMPTOMS IMPROVING

FIGURE 294-1 Approach to the diagnosis of pleural effusions. CHF, congestive heart

failure; CT, computed tomography; LDH, lactate dehydrogenase; PE, pulmonary

embolism; PF, pleural fluid; TB, tuberculosis.

2198 PART 7 Disorders of the Respiratory System

If the fluid recurs after the initial therapeutic thoracentesis and if

any of these characteristics is present, a repeat thoracentesis should

be performed. If the fluid cannot be completely removed with the

therapeutic thoracentesis, consideration should be given to inserting a

chest tube and instilling the combination of a fibrinolytic agent (e.g.,

tissue plasminogen activator, 10 mg) and deoxyribonuclease (5 mg) or

performing a thoracoscopy with the breakdown of adhesions. Decortication should be considered when these measures are ineffective.

Effusion Secondary to Malignancy Malignant pleural effusions

secondary to metastatic disease are the second most common type of

exudative pleural effusion. The three tumors that cause ~75% of all

malignant pleural effusions are lung carcinoma, breast carcinoma, and

lymphoma. Most patients complain of dyspnea, which is frequently out

of proportion to the size of the effusion. The pleural fluid is an exudate,

and its glucose level may be reduced if the tumor burden in the pleural

space is high.

The diagnosis usually is made via cytology of the pleural fluid. If the

initial cytologic examination is negative, thoracoscopy is the best next

procedure if malignancy is strongly suspected. At the time of thoracoscopy, a procedure such as pleural abrasion should be performed to effect a

pleurodesis. An alternative to thoracoscopy is CT- or ultrasound-guided

needle biopsy of pleural thickening or nodules. Patients with a malignant pleural effusion are treated symptomatically for the most part,

since the presence of the effusion indicates disseminated disease and

most malignancies associated with pleural effusion are not curable with

chemotherapy. The only symptom that can be attributed to the effusion

itself is dyspnea. If the patient’s lifestyle is compromised by dyspnea

and if the dyspnea is relieved with a therapeutic thoracentesis, one of

the following procedures should be considered: (1) insertion of a small

indwelling catheter or (2) tube thoracostomy with the instillation of a

sclerosing agent such as doxycycline (500 mg).

Mesothelioma Malignant mesotheliomas are primary tumors that

arise from the mesothelial cells that line the pleural cavities; most are

related to asbestos exposure. Patients with mesothelioma present with

chest pain and shortness of breath. The chest radiograph reveals a

pleural effusion, generalized pleural thickening, and a shrunken hemithorax. The diagnosis is usually established with image-guided needle

biopsy or thoracoscopy (Fig. 294-2).

Effusion Secondary to Pulmonary Embolization The diagnosis most commonly overlooked in the differential diagnosis of a

patient with an undiagnosed pleural effusion is pulmonary embolism.

Dyspnea is the most common symptom. The pleural fluid is almost

always an exudate. The diagnosis is established by spiral CT scan or

pulmonary arteriography (Chap. 279). Treatment of a patient with a

pleural effusion secondary to pulmonary embolism is the same as it is

FIGURE 294-2 CT scan from a patient with mesothelioma demonstrating a mass

in the left lung, a pleural effusion, pleural thickening, and a shrunken hemithorax.

effusions in the United States are left ventricular failure and cirrhosis.

An exudative pleural effusion occurs when local factors that influence the

formation and absorption of pleural fluid are altered. The leading causes

of exudative pleural effusions are bacterial pneumonia, malignancy, viral

infection, and pulmonary embolism. The primary reason for making

this differentiation is that additional diagnostic procedures are indicated

with exudative effusions to define the cause of the local disease.

Transudative and exudative pleural effusions are distinguished by

measuring the lactate dehydrogenase (LDH) and protein levels in

the pleural fluid. Exudative pleural effusions meet at least one of the

following criteria, whereas transudative pleural effusions meet none:

1. Pleural fluid protein/serum protein >0.5

2. Pleural fluid LDH/serum LDH >0.6

3. Pleural fluid LDH more than two-thirds the normal upper limit for

serum

These criteria misidentify ~25% of transudates as exudates. If one

or more of the exudative criteria are met and the patient is clinically

thought to have a condition producing a transudative effusion, the

difference between the protein levels in the serum and the pleural fluid

should be measured. If this gradient is >31 g/L (3.1 g/dL), the exudative

categorization by these criteria can be ignored because almost all such

patients have a transudative pleural effusion.

If a patient has an exudative pleural effusion, the following tests on the

pleural fluid should be obtained: description of the appearance of the fluid,

glucose level, differential cell count, microbiologic studies, and cytology.

Effusion Due to Heart Failure The most common cause of

pleural effusion is left ventricular failure. The effusion occurs because

the increased amounts of fluid in the lung interstitial spaces exit in

part across the visceral pleura; this overwhelms the capacity of the

lymphatics in the parietal pleura to remove fluid. In patients with heart

failure, a diagnostic thoracentesis should be performed if the effusions

are not bilateral and comparable in size, if the patient is febrile, or

if the patient has pleuritic chest pain to verify that the patient has a

transudative effusion. Otherwise, the patient’s heart failure is treated. If

the effusion persists despite therapy, a diagnostic thoracentesis should

be performed. A pleural fluid N-terminal pro-brain natriuretic peptide

(NT-proBNP) level >1500 pg/mL is virtually diagnostic of an effusion

that is secondary to congestive heart failure.

Hepatic Hydrothorax Pleural effusions occur in ~5% of patients

with cirrhosis and ascites. The predominant mechanism is the direct

movement of peritoneal fluid through small openings in the diaphragm into the pleural space. The effusion is usually right-sided and

frequently is large enough to produce severe dyspnea.

Parapneumonic Effusion Parapneumonic effusions are associated with bacterial pneumonia, lung abscess, or bronchiectasis and are

probably the most common cause of exudative pleural effusion in the

United States. Empyema refers to a grossly purulent effusion.

Patients with aerobic bacterial pneumonia and pleural effusion present with an acute febrile illness consisting of chest pain, sputum production, and leukocytosis. Patients with anaerobic infections present

with a subacute illness with weight loss, a brisk leukocytosis, mild anemia, and a history of some factor that predisposes them to aspiration.

The possibility of a parapneumonic effusion should be considered

whenever a patient with bacterial pneumonia is initially evaluated.

The presence of free pleural fluid can be demonstrated with a lateral

decubitus radiograph, computed tomography (CT) of the chest, or

ultrasound. If the free fluid separates the lung from the chest wall by

>10 mm, a therapeutic thoracentesis should be performed. Factors

indicating the likely need for a procedure more invasive than a thoracentesis (in increasing order of importance) include the following:

1. Loculated pleural fluid

2. Pleural fluid pH <7.20

3. Pleural fluid glucose <3.3 mmol/L (<60 mg/dL)

4. Positive Gram stain or culture of the pleural fluid

5. Presence of gross pus in the pleural space

2199 Disorders of the Pleura CHAPTER 294

for any patient with pulmonary emboli. If the pleural effusion increases

in size after anticoagulation, the patient probably has recurrent emboli

or another complication, such as a hemothorax or a pleural infection.

Tuberculous Pleuritis (See also Chap. 178) In many parts of

the world, the most common cause of an exudative pleural effusion

is tuberculosis (TB), but tuberculous effusions are relatively uncommon in the United States. Tuberculous pleural effusions usually are

associated with primary TB and are thought to be due primarily to a

hypersensitivity reaction to tuberculous protein in the pleural space.

Patients with tuberculous pleuritis present with fever, weight loss,

dyspnea, and/or pleuritic chest pain. The pleural fluid is an exudate

with predominantly small lymphocytes. The diagnosis is established

by demonstrating high levels of TB markers in the pleural fluid (adenosine deaminase >40 IU/L or interferon γ >140 pg/mL). Alternatively,

the diagnosis can be established by culture of the pleural fluid, needle

biopsy of the pleura, or thoracoscopy. The recommended treatments of

pleural and pulmonary TB are identical (Chap. 178).

Effusion Secondary to Viral Infection Viral infections are

probably responsible for a sizable percentage of undiagnosed exudative

pleural effusions. In many series, no diagnosis is established for ~20%

of exudative effusions, and these effusions resolve spontaneously with

no long-term residua. The importance of these effusions is that one

should not be too aggressive in trying to establish a diagnosis for the

undiagnosed effusion, particularly if the patient is improving clinically.

Chylothorax A chylothorax occurs when the thoracic duct is disrupted and chyle accumulates in the pleural space. The most common

cause of chylothorax is trauma (most frequently thoracic surgery),

but it also may result from tumors in the mediastinum. Patients with

chylothorax present with dyspnea, and a large pleural effusion is

present on the chest radiograph. Thoracentesis reveals milky fluid,

and biochemical analysis reveals a triglyceride level that exceeds

1.2 mmol/L (110 mg/dL). Patients with chylothorax and no obvious

trauma should have a lymphangiogram and a mediastinal CT scan to

assess the mediastinum for lymph nodes. The treatment of choice for

most chylothoraces is insertion of a chest tube plus the administration

of octreotide. If these modalities fail, percutaneous transabdominal

thoracic duct blockage effectively controls most chylothoraces. An

alternative treatment is ligation of the thoracic duct. Patients with

chylothoraces should not undergo prolonged tube thoracostomy with

chest tube drainage because this will lead to malnutrition and immunologic incompetence.

Hemothorax When a diagnostic thoracentesis reveals bloody

pleural fluid, a hematocrit should be obtained on the pleural fluid. If

the hematocrit is more than one-half of that in the peripheral blood,

the patient is considered to have a hemothorax. Most hemothoraces

are the result of trauma; other causes include rupture of a blood vessel

or tumor. Most patients with hemothorax should be treated with tube

thoracostomy, which allows continuous quantification of bleeding. If

the bleeding emanates from a laceration of the pleura, apposition of

the two pleural surfaces is likely to stop the bleeding. If the pleural

hemorrhage exceeds 200 mL/h, consideration should be given to angiographic coil embolization, thoracoscopy, or thoracotomy.

Miscellaneous Causes of Pleural Effusion There are many

other causes of pleural effusion (Table 294-1). Key features of some

of these conditions are as follows: If the pleural fluid amylase level is

elevated, the diagnosis of esophageal rupture or pancreatic disease is

likely. If the patient is febrile, has predominantly polymorphonuclear

cells in the pleural fluid, and has no pulmonary parenchymal abnormalities, an intraabdominal abscess should be considered.

The diagnosis of an asbestos pleural effusion is one of exclusions.

Benign ovarian tumors can produce ascites and a pleural effusion

(Meigs’ syndrome), as can the ovarian hyperstimulation syndrome.

Several drugs can cause pleural effusion; the associated fluid is usually eosinophilic. Pleural effusions commonly occur after coronary

artery bypass surgery. Effusions occurring within the first weeks are

typically left-sided and bloody, with large numbers of eosinophils, and

respond to one or two therapeutic thoracenteses. Effusions occurring

after the first few weeks are typically left-sided and clear yellow, with

predominantly small lymphocytes, and tend to recur. Other medical

TABLE 294-1 Differential Diagnoses of Pleural Effusions

Transudative Pleural Effusions

1. Congestive heart failure

2. Cirrhosis

3. Nephrotic syndrome

4. Peritoneal dialysis

5. Superior vena cava obstruction

6. Myxedema

7. Urinothorax

Exudative Pleural Effusions

1. Neoplastic diseases

a. Metastatic disease

b. Mesothelioma

2. Infectious diseases

a. Bacterial infections

b. Tuberculosis

c. Fungal infections

d. Viral infections

e. Parasitic infections

3. Pulmonary embolization

4. Gastrointestinal disease

a. Esophageal perforation

b. Pancreatic disease

c. Intraabdominal abscesses

d. Diaphragmatic hernia

e. After abdominal surgery

f. Endoscopic variceal sclerotherapy

g. After liver transplant

5. Collagen vascular diseases

a. Rheumatoid pleuritis

b. Systemic lupus erythematosus

c. Drug-induced lupus

d. Sjögren syndrome

e. Granulomatosis with polyangiitis (Wegener)

f. Churg-Strauss syndrome

6. Post–coronary artery bypass surgery

7. Asbestos exposure

8. Sarcoidosis

9. Uremia

10. Meigs’ syndrome

11. Yellow nail syndrome

12. Drug-induced pleural disease

a. Nitrofurantoin

b. Dantrolene

c. Methysergide

d. Bromocriptine

e. Procarbazine

f. Amiodarone

g. Dasatinib

13. Trapped lung

14. Radiation therapy

15. Post–cardiac injury syndrome

16. Hemothorax

17. Iatrogenic injury

18. Ovarian hyperstimulation syndrome

19. Pericardial disease

20. Chylothorax

2200 PART 7 Disorders of the Respiratory System

manipulations that induce pleural effusions include abdominal surgery; radiation therapy; liver, lung, or heart transplantation; and the

intravascular insertion of central lines.

■ PNEUMOTHORAX

Pneumothorax is the presence of gas in the pleural space. A spontaneous pneumothorax is one that occurs without antecedent trauma to the

thorax. A primary spontaneous pneumothorax occurs in the absence

of underlying lung disease, whereas a secondary pneumothorax occurs

in its presence. A traumatic pneumothorax results from penetrating or

nonpenetrating chest injuries. A tension pneumothorax is a pneumothorax in which the pressure in the pleural space is positive throughout

the respiratory cycle.

Primary Spontaneous Pneumothorax Primary spontaneous

pneumothoraces are usually due to rupture of apical pleural blebs,

small cystic spaces that lie within or immediately under the visceral

pleura. Primary spontaneous pneumothoraces occur almost exclusively in smokers; this suggests that these patients have subclinical lung

disease. Approximately one-half of patients with an initial primary

spontaneous pneumothorax will have a recurrence. The initial recommended treatment for primary spontaneous pneumothorax is simple

aspiration. If the lung does not expand with aspiration or if the patient

has a recurrent pneumothorax, thoracoscopy with stapling of blebs

and pleural abrasion is indicated. Thoracoscopy or thoracotomy with

pleural abrasion is almost 100% successful in preventing recurrences.

Secondary Pneumothorax Most secondary pneumothoraces are

due to chronic obstructive pulmonary disease, but pneumothoraces

have been reported with virtually every lung disease. Pneumothorax in

patients with lung disease is more life-threatening than it is in normal

individuals because of the lack of pulmonary reserve in these patients.

Nearly all patients with secondary pneumothorax should be treated

with tube thoracostomy. Most should also be treated with thoracoscopy

or thoracotomy with the stapling of blebs and pleural abrasion. If the

patient is not a good operative candidate or refuses surgery, pleurodesis

should be attempted by the intrapleural injection of a sclerosing agent

such as doxycycline.

Traumatic Pneumothorax Traumatic pneumothoraces can result

from both penetrating and nonpenetrating chest trauma. Traumatic

pneumothoraces should be treated with tube thoracostomy unless

they are very small. If a hemopneumothorax is present, one chest tube

should be placed in the superior part of the hemithorax to evacuate the

air and another should be placed in the inferior part of the hemithorax

to remove the blood. Iatrogenic pneumothorax is a type of traumatic

pneumothorax that is becoming more common. The leading causes

are transthoracic needle aspiration, thoracentesis, and the insertion of

central intravenous catheters. Most can be managed with supplemental

oxygen or aspiration, but if these measures are unsuccessful, a tube

thoracostomy should be performed.

Tension Pneumothorax This condition usually occurs during

mechanical ventilation or resuscitative efforts. The positive pleural

pressure is life-threatening both because ventilation is severely compromised and because the positive pressure is transmitted to the mediastinum, resulting in decreased venous return to the heart and reduced

cardiac output.

Difficulty in ventilation during resuscitation or high peak inspiratory pressures during mechanical ventilation strongly suggest the

diagnosis. The diagnosis is made by physical examination showing an

enlarged hemithorax with no breath sounds, hyperresonance to percussion, and shift of the mediastinum to the contralateral side. Tension

pneumothorax must be treated as a medical emergency. If the tension

in the pleural space is not relieved, the patient is likely to die from

inadequate cardiac output or marked hypoxemia. A large-bore needle

should be inserted into the pleural space through the second anterior

intercostal space. If large amounts of gas escape from the needle after

insertion, the diagnosis is confirmed. The needle should be left in place

until a thoracostomy tube can be inserted.

■ FURTHER READING

Feller-Koppman D, Light R: Pleural disease. N Engl J Med 378:740,

2018.

Light RW: Pleural Diseases, 6th ed. Lippincott, Williams and Wilkins,

Baltimore, 2013.

Rahman NM et al: Intrapleural use of tissue plasminogen activator

and DNase in pleural infection. N Engl J Med 365:518, 2011.

The mediastinum is the region between the pleural sacs. It is separated

into three compartments (Table 295-1). The anterior mediastinum

extends from the sternum anteriorly to the pericardium and brachiocephalic vessels posteriorly. It contains the thymus gland, the anterior

mediastinal lymph nodes, and the internal mammary arteries and

veins. The middle mediastinum lies between the anterior and posterior

mediastina and contains the heart; the ascending and transverse arches

of the aorta; the venae cavae; the brachiocephalic arteries and veins;

the phrenic nerves; the trachea, the main bronchi, and their contiguous lymph nodes; and the pulmonary arteries and veins. The posterior

mediastinum is bounded by the pericardium and trachea anteriorly and

the vertebral column posteriorly. It contains the descending thoracic

aorta, the esophagus, the thoracic duct, the azygos and hemiazygos

veins, and the posterior group of mediastinal lymph nodes.

■ MEDIASTINAL MASSES

The first step in evaluating a mediastinal mass is to place it in one of the

three mediastinal compartments, since each has different characteristic

lesions (Table 295-1).

Computed tomography (CT) scanning is the most valuable imaging

technique for evaluating mediastinal masses and is the only imaging

technique that should be done in most instances. Barium studies of

the gastrointestinal tract are indicated in many patients with posterior

mediastinal lesions, becauseg hernias, diverticula, and achalasia are

readily diagnosed in this manner. An iodine-131 scan can efficiently

establish the diagnosis of intrathoracic goiter.

A definite diagnosis can be obtained with mediastinoscopy or

anterior mediastinotomy in many patients with masses in the anterior

or middle mediastinal compartments. A diagnosis can be established

without thoracotomy via percutaneous fine-needle aspiration biopsy

or endoscopic transesophageal or endobronchial ultrasound-guided

biopsy of mediastinal masses in most cases. An alternative way to

establish the diagnosis is video-assisted thoracoscopy. In many cases,

the diagnosis can be established and the mediastinal mass removed

with video-assisted thoracoscopy.

■ ACUTE MEDIASTINITIS

Cases of acute mediastinitis are usually due to esophageal perforation,

occur after median sternotomy for cardiac surgery, or are infections

descending from the neck, oral cavity, or facial area. Patients with

295 Disorders of the

Mediastinum

Richard W. Light*

*

Deceased.