2159Asthma CHAPTER

can be achieved by starting at lower levels of exercise (warming up) and

287

by using a mask in colder weather to condition the air. Pretreatment

with an SABA can increase the threshold of ventilation required to

induce bronchoconstriction. LABAs may extend the period of protection, but their use alone in asthma is to be discouraged. For occasional

exercise, ICS/LABA can be used, but regular use may expose the

patient to unnecessary doses of ICS. If regular exercise is undertaken,

then LTRAs may provide protection and can be used regularly. A SABA

(or ICS/formoterol) should always be available for quick relief.

Exercise-induced airway narrowing in elite athletes may be related

to direct epithelial injury. In addition to the above, conditioning

of incoming air may be of major assistance. Ipratropium has been

reported to be of utility as well.

■ PREGNANCY

Asthma may improve, deteriorate, or remain unchanged during pregnancy. Poor asthma control, especially exacerbations, is associated with

poor fetal outcomes. The general principles of asthma management

and its goals are unchanged. Avoidance of triggers, especially smoking

environments, is critical in view of the risk of loss of control and, in

the case of smoking, its clear effects on risk of development of asthma

in the child. There is extensive experience suggesting the safety of

inhaled albuterol, beclomethasone, budesonide, and fluticasone, with

reassuring information on formoterol and salmeterol in pregnancy.

Animal studies have not suggested toxicity for montelukast, zafirlukast,

omalizumab, and ipratropium. Antibodies cross the placenta, and there

are few human data on the safety of IL-5–active drugs or anti–IL-4Rα.

Chronic use of OCS has been associated with neonatal adrenal insufficiency, preeclampsia, low birth weight, and a slight increase in the frequency of cleft palate. However, it is clear that poorly controlled asthma

during pregnancy carries greater risk to the fetus and mother than

these effects. There should be no hesitancy in administering routine

pharmacotherapy for acute exacerbations. Initiation of allergen immunotherapy or omalizumab during pregnancy is not recommended. In

cases where prostaglandins are needed to manage pregnancy, PGF2-α

should be avoided since it is associated with bronchoconstriction.

■ ASPIRIN-EXACERBATED RESPIRATORY DISEASE

A subset of patients (5–10%) present in adulthood with difficult-tocontrol asthma and type 2 inflammation with eosinophilia, sinusitis,

nasal polyposis, and severe asthma exacerbations that are precipitated

by ingesting inhibitors of cyclooxygenase, with aspirin being the

most prominent of such inhibitors. Such patients, classified as having aspirin-exacerbated respiratory disease, overproduce leukotrienes

in response to inhibition of cyclooxygenase-1, probably secondary

to inhibition of PGE2

. These patients should avoid inhibitors of

cyclooxygenase-1, (aspirin and NSAIDs) but can generally tolerate

inhibitors of cyclooxygenase-2 and acetaminophen. They should be

treated with leukotriene modifiers. Aspirin desensitization can be

undertaken to decrease upper respiratory symptoms and to allow

chronic administration of aspirin or NSAIDs for those that require

it. Dupilumab and the IL-5–active biologics appear to be particularly

helpful and appear to be superseding aspirin desensitization in management except when chronic administration of aspirin or NSAIDs is

required for another therapeutic indication.

■ SEVERE ASTHMA

Severe and difficult-to-treat asthma, which composes ~5–10% of

asthma, is defined as asthma that, having undergone appropriate evaluation for comorbidities and mimics, education, and trigger mitigation,

remains uncontrolled on step 5 therapy or requires step 5 therapy for

its control. Severe asthma can account for almost 50% of the cost of

asthma care in the United States. A significant proportion of these

patients have trouble with adherence and/or inhaler technique, and

these factors need to be investigated vigorously. Almost half of these

patients have evidence of persistent eosinophilic inflammation as

evidenced by peripheral blood eosinophils and/or induced sputum.

Those with recurrent exacerbations have a substantially increased

likelihood of responding to the type 2 targeted biologics. Treatment

for those with mixed inflammation, isolated neutrophilic inflammation, or pauci-granulocytic inflammation remains to be determined.

Some data suggest that many of these patients may have aberrations

in the pathways responsible for resolution of inflammation. A rare

patient may have biochemical abnormalities that interfere with steroid

response pathways. Macrolides are of use in a subset. Studies targeting

mast cells, IL-6, IL-33, and other pathways illustrated in Fig. 287-3 are

underway. Therapies aimed at improving pro-resolving pathways may

also be promising.

■ ELDERLY PATIENTS WITH ASTHMA

Asthma may present at or persist into older age. The mortality of

asthma in those >65 years old is five times greater than that of younger

cohorts even when adjusting for comorbidities. Many of these patients

had asthma as children, some with quiescent periods as they entered

adulthood. Of those with new-onset asthma, almost half were smokers or are currently smoking. One-quarter of adult-onset asthma is

believed to be due to occupational exposure. Patients presenting with

eosinophilic inflammation appear to have more severe asthma. Besides

investigations of comorbidities, these patients may require adjustment

to step therapy based on intolerance of β2

-agonist therapy due to

arrhythmia or tremulousness. The coexistence of COPD needs to be

carefully considered (see below).

■ ASTHMA-COPD OVERLAP

Most clinicians agree that asthma-COPD overlap is not a syndrome,

but rather recognize that it may be useful to identify patients who

present with symptoms related to airway dysfunction that may be

due to simultaneous coexistence of both asthma and COPD. From an

asthma perspective, recognition that COPD and smoking can alter the

response to asthma therapies may be important. Smoking can blunt the

response to ICS. Further, it has been difficult to demonstrate the effectiveness of biologic agents targeted at type 2 inflammation in patients

with COPD despite the presence of ≥300 circulating eosinophils/μL.

Additionally, in patients with both diseases, earlier initiation of anticholinergics may be considered.

Acknowledgment

Peter J. Barnes contributed to this chapter in the 20th edition, and some

material from that chapter has been retained here.

■ FURTHER READING

Cloutier MM et al: 2020 focused updates to the asthma management

guidelines: A report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working

Group. J Allergy Clin Immunol 146:1217, 2020.

Global Initiative for Asthma: 2020 GINA Report, global strategy

for asthma management and prevention. https://ginasthma.org/

gina-reports/.

Israel E, Reddel HK: Severe and difficult-to-treat asthma in adults.

N Engl J Med 377:965, 2017.

Kaur R, Chupp G: Phenotypes and endotypes of adult asthma: Moving

toward precision medicine. J Allergy Clin Immunol 144:1, 2019.

Zaidan MF et al: Management of acute asthma in adults in 2020.

JAMA 323:563, 2020.

TABLE 287-6 Patients at Greater Risk for Asthma Mortality

1. History of intensive care unit admission for asthma

2. History of intubation for asthma

3. Illicit drug use

4. Depression

5. New diagnosis

6. ≥2 emergency unit visits in past 6 months

7. Severe psychosocial problems

8. Lower socioeconomic status

9. On daily prednisone prior to admission

2160 PART 7 Disorders of the Respiratory System

HYPERSENSITIVITY PNEUMONITIS

■ INTRODUCTION AND DEFINITION

Hypersensitivity pneumonitis (HP), also referred to as extrinsic allergic alveolitis, is a pulmonary disease that occurs due to inhalational

exposure to a variety of antigens leading to an inflammatory response

of the alveoli and small airways. Systemic manifestations such as fever

and fatigue can accompany respiratory symptoms. Although sensitization to an inhaled antigen as manifested by specific circulating IgG

antibodies is necessary for the development of HP, sensitization alone

is not sufficient as a defining characteristic, because many sensitized

individuals do not develop HP. The incidence and prevalence of HP are

variable, depending on geography, occupation, avocation, and environment of the cohort being studied. As yet unexplained is the decreased

risk of developing HP in smokers.

■ OFFENDING ANTIGENS

HP can be caused by any of a large list of potential offending inhaled

antigens (Table 288-1). The various antigens and environmental conditions described to be associated with HP give rise to an expansive

list of monikers given to specific forms of HP. Antigens derived from

fungal, bacterial, mycobacterial, bird-derived, and chemical sources

have all been implicated in causing HP.

Categories of individuals at particular risk in the United States

include farmers, bird owners, industrial workers, and hot tub users.

Farmer’s lung occurs as a result of exposure to one of several possible

sources of bacterial or fungal antigens such as grain, moldy hay, or

silage. Potential offending antigens include thermophilic actinomycetes or Aspergillus species. Bird fancier’s lung (also referred to by

names corresponding to specific birds) must be considered in patients

who give a history of keeping birds in their home and is precipitated

by exposure to antigens derived from feathers, droppings, and serum

proteins. Occupational exposure to birds may also cause HP, as is

seen in poultry worker’s lung. Chemical worker’s lung is provoked by

exposure to occupational chemical antigens such as diphenylmethane

diisocyanate and toluene diisocyanate. Mycobacteria may cause HP

rather than frank infection, a phenomenon observed in hot tub lung

and in HP due to metalworking fluid.

■ PATHOPHYSIOLOGY

While much remains to be learned regarding the pathophysiology of

HP, it has been established that HP is an immune-mediated condition

that occurs in response to inhaled antigens that are small enough

to deposit in distal airways and alveoli. From an immunologic perspective, HP is characterized by dysregulated TH1 and TH17 immune

responses. Although the presence of precipitating IgG antibodies

against specific antigens in HP suggests a prominent role for adaptive

immunity in the pathophysiology of HP, innate immune mechanisms

likely also make an important contribution. This is highlighted by the

observation that Toll-like receptors and downstream signaling proteins such as MyD88 are activated in HP, leading to neutrophil recruitment. Although no clear genetic basis for HP has been established,

in specific cohorts, polymorphisms in genes involved in antigen

processing and presentation, including TAP1 and major histocompatibility complex type II, have been observed. In chronic HP, bone

marrow–derived fibrocytes may contribute to lung inflammation and

fibrosis.

288 Hypersensitivity

Pneumonitis and

Pulmonary Infiltrates with

Eosinophilia

Praveen Akuthota, Michael E. Wechsler

■ CLINICAL PRESENTATION

Given the heterogeneity among patients, variability in offending

antigens, and differences in the intensity and duration of exposure to

antigen, the presentation of HP is accordingly variable. Although these

categories are not fully satisfactory in capturing this variability, HP has

been traditionally categorized as having acute, subacute, and chronic

forms. Acute HP usually manifests itself 4–8 h following exposure

to the inciting antigen, often intense in nature. Systemic symptoms,

TABLE 288-1 Examples of Hypersensitivity Pneumonitis

DISEASE ANTIGEN SOURCE

Farming/Food Processing

Farmer’s lung Thermophilic actinomycetes

(e.g., Saccharopolyspora

rectivirgula); fungus

Grain, moldy hay,

silage

Bagassosis Thermophilic actinomycetes Sugarcane

Cheese washer’s lung Penicillium casei; Aspergillus

clavatus

Cheese

Coffee worker’s lung Coffee bean dust Coffee beans

Malt worker’s lung Aspergillus species Barley

Miller’s lung Sitophilus granarius (wheat

weevil)

Wheat flour

Mushroom worker’s

lung

Thermophilic actinomycetes;

mushroom spores

Mushrooms

Potato riddler’s lung Thermophilic actinomycetes;

Aspergillus species

Moldy hay around

potatoes

Tobacco grower’s lung Aspergillus species Tobacco

Wine maker’s lung Botrytis cinerea Grapes

Birds and Other Animals

Bird fancier’s lung (also

named by specific bird

exposures)

Proteins derived by parakeets,

pigeons, budgerigars

Bird feathers,

droppings, serum

proteins

Duck fever Duck feathers, serum proteins Ducks

Fish meal worker’s lung Fish meal dust Fish meal

Furrier’s lung Dust from animal furs Animal furs

Laboratory worker’s

lung

Rat urine, serum, fur Laboratory rats

Pituitary snuff taker’s

lung

Animal proteins Pituitary snuff from

bovine and porcine

sources

Poultry worker’s lung Chicken serum proteins Chickens

Turkey handling disease Turkey serum proteins Turkeys

Other Occupational and Environmental Exposures

Chemical worker’s lung Isocyanates Polyurethane foam,

varnish, lacquer

Detergent worker’s lung Bacillus subtilis enzymes Detergent

Hot tub lung Cladosporium species;

Mycobacterium avium

complex

Contaminated water,

mold on ceiling

Humidifier fever (and air

conditioner lung)

Several microorganisms

including: Aureobasidium

pullulans; Candida albicans;

thermophilic actinomycetes;

Mycobacterium species;

Klebsiella oxytoca; Naegleria

gruberi

Humidifiers and

air conditioners

(contaminated water)

Machine operator’s lung Pseudomonas species;

Mycobacteria species

Metal working fluid

Sauna taker’s lung Aureobasidium species; other

antigens

Sauna water

Suberosis Penicillium glabrum;

Chrysonilia sitophila

Cork dust

Summer-type

pneumonitis

Trichosporon cutaneum House dust mites,

bird droppings

Woodworker’s lung Alternaria species; Bacillus

subtilis

Oak, cedar, pine,

mahogany dusts

2161Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia CHAPTER 288

including fevers, chills, and malaise, are prominent and are accompanied by dyspnea. Symptoms resolve within hours to days if no further

exposure to the offending antigen occurs. In subacute HP resulting

from ongoing antigen exposure, the onset of respiratory and systemic

symptoms is typically more gradual over the course of weeks. A similar presentation may occur as a culmination of intermittent episodes

of acute HP. Although respiratory impairment may be quite severe,

antigen avoidance generally results in resolution of the symptoms, but

with a slower time course, on the order of weeks to months, than that

seen with acute HP. Chronic HP can present with an even more gradual onset of symptoms than subacute HP, with progressive dyspnea,

cough, fatigue, weight loss, and clubbing of the digits. The insidious

onset of symptoms and frequent lack of an anteceding episode of acute

HP make diagnosing chronic HP a challenge. Unlike with the other

forms of HP, there can be an irreversible component to the respiratory

impairment that is not responsive to removal of the responsible antigen

from the patient’s environment. The disease progression of chronic HP

to lung fibrosis with honeycombing on chest imaging and hypoxemic

respiratory failure can mirror that seen in idiopathic pulmonary fibrosis (IPF), with a similar prognosis. Diagnostic uncertainty between

these two entities is not uncommon. Fibrotic lung disease is a potential

feature of chronic HP due to exposure to bird antigens, whereas an

emphysematous phenotype may be seen in farmer’s lung.

The categories of acute, subacute, and chronic HP are not completely

sufficient in classifying HP. The HP Study Group found on cluster analysis that a cohort of HP patients is best described in bipartite fashion,

with one group featuring recurrent systemic signs and symptoms and

the other featuring more severe respiratory findings. Some experts

have argued for a reclassification of HP into acute/inflammatory and

chronic/fibrotic categories.

Concordant with the variability in the presentation of HP is the

observed variability in outcome. HP that has not progressed to chronic

lung disease has a more favorable outcome with likely resolution if

antigen avoidance can be achieved. However, chronic HP resulting in

lung fibrosis has a poorer prognosis, with patients with chronic pigeon

breeder’s lung having demonstrated a similar mortality as seen in IPF.

■ DIAGNOSIS

Although there is no set of universally accepted criteria for arriving at

a diagnosis of HP, diagnosis depends foremost on establishing a history

of exposure to an offending antigen that correlates with respiratory and

systemic symptoms. A careful occupational and home exposure history

should be taken and may be supplemented if necessary by a clinician

visit to the work or home environment. Specific inquiries will be influenced by geography and the occupation of the patient. When HP is

suspected by history, the additional workup is aimed at establishing an

immunologic and physiologic response to inhalational antigen exposure with chest imaging, pulmonary function testing (PFT), serologic

studies, bronchoscopy, and, on occasion, lung biopsy. Re-exposure to

the offending environment may be performed to aid in confirming the

diagnosis of HP.

Chest Imaging Chest x-ray findings in HP are nonspecific and can

even lack any discernible abnormalities. In cases of acute and subacute

HP, findings may be transient and can include ill-defined micronodular opacities or hazy ground-glass airspace opacities. Findings on

chest x-ray will often resolve with removal from the offending antigen,

although the time course of resolution may vary. With chronic HP, the

abnormalities seen on the chest radiograph are frequently more fibrotic

in nature and may be difficult to distinguish from IPF.

High-resolution computed tomography (HRCT) is a common

component in the diagnostic workup for HP. Although the HRCT may

be normal in acute forms of HP, this may be due to lack of temporal

correlation between exposure to the offending antigen and obtaining

the imaging. Additionally, because of the transient nature of acute

HP, HRCT is not always performed. In subacute forms of the disease,

ground-glass airspace opacities are characteristic, as is the presence

of centrilobular nodules. Expiratory images may show areas of air

trapping that are likely caused by involvement of the small airways

(Fig. 288-1). Reticular changes and traction bronchiectasis can be

observed in chronic HP. Subpleural honeycombing similar to that seen

in IPF may be present in advanced cases, although unlike in IPF, the

lung bases are frequently spared.

Pulmonary Function Testing Either restrictive or obstructive

PFTs can be present in HP, so the pattern of PFT change is not useful

in establishing the diagnosis of HP. However, obtaining PFTs is of use

in characterizing the physiologic impairment of an individual patient

and in gauging the response to antigen avoidance and/or corticosteroid

therapy. Diffusion capacity for carbon monoxide may be significantly

impaired, particularly in cases of chronic HP with fibrotic pulmonary

parenchymal changes.

Serum Precipitins Assaying for IgG antibodies against specific

antigens, either through precipitin testing or direct serum measurement, can be a useful adjunct in the diagnosis of HP. However, the presence of an immunologic response alone is not sufficient for establishing

the diagnosis, because many asymptomatic individuals with high levels

of exposure to antigen may display specific IgG, as has been observed

in farmers and in pigeon breeders. It should also be noted that panels that test for several specific antigens often provide false-negative

results, because they represent an extremely limited proportion of the

universe of potential offending environmental antigens.

Bronchoscopy Bronchoscopy with bronchoalveolar lavage (BAL)

may be used in the evaluation of HP. Although not a specific finding,

BAL lymphocytosis is characteristic of HP. However, in active smokers,

a lower threshold should be used to establish BAL lymphocytosis,

because smoking will result in lower lymphocyte percentages. Most

cases of HP have a CD4+/CD8+ lymphocyte ratio of <1, but again, this

is not a specific finding and has limited utility in the diagnosis of HP.

Lung Biopsy Tissue samples may be obtained by a bronchoscopic

approach using transbronchial biopsy, or more architecturally preserved

specimens may be obtained by a surgical approach (video-assisted

thoracoscopy or open approach). As is the case with BAL, histologic

specimens are not absolutely necessary to establish the diagnosis of

HP, but they can be useful in the correct clinical context. A common

histologic feature in HP is the presence of noncaseating granulomas in

the vicinity of small airways (Fig. 288-2). As opposed to pulmonary

sarcoidosis, in which noncaseating granulomas are well defined, the

granulomas seen in HP are loose and poorly defined in nature. Within

the alveolar spaces and in the interstitium, a mixed cellular infiltrate

with a lymphocytic predominance is observed that is frequently patchy

FIGURE 288-1 Chest computed tomography scan of a patient with subacute

hypersensitivity pneumonitis in which scattered regions of ground-glass infiltrates

in a mosaic pattern consistent with air trapping are seen bilaterally. This patient had

bird fancier’s lung. (Courtesy of TJ Gross; with permission.)

2162 PART 7 Disorders of the Respiratory System

FIGURE 288-2 Open-lung biopsy from a patient with subacute hypersensitivity

pneumonitis demonstrating a loose, nonnecrotizing granuloma made up of

histiocytes and multinucleated giant cells. Peribronchial inflammatory infiltrate

made up of lymphocytes and plasma cells is also seen. (Courtesy of TJ Gross; with

permission.)

in distribution. Bronchiolitis with the presence of organizing exudate

is also often observed. Fibrosis may be present as well, particularly in

chronic HP. Fibrotic changes may be focal but can be diffuse and severe

with honeycombing in advanced cases, similar to findings in IPF.

Clinical Prediction Rule Although not meant as a set of validated

diagnostic criteria, a clinical prediction rule for predicting the presence

of HP has been published by the HP Study Group. They identified six

statistically significant predictors for HP, the strongest of which was

exposure to an antigen known to cause HP. Other predictive criteria

were the presence of serum precipitins, recurrent symptoms, symptoms occurring 4–8 h after antigen exposure, crackles on inspiration,

and weight loss.

■ DIFFERENTIAL DIAGNOSIS

Differentiating HP from other conditions that cause a similar constellation of respiratory and systemic symptoms requires an increased index

of suspicion based on obtaining a history of possible exposure to an

offending antigen. Presentations of acute or subacute HP can be mistaken for respiratory infection. In cases of chronic disease, HP must be

differentiated from interstitial lung disease, such as IPF or nonspecific

interstitial pneumonitis (NSIP); this can be a difficult task even with

lung biopsy. Given the presence of pulmonary infiltrates and noncaseating granulomas on biopsy, sarcoidosis is also a consideration in the

differential diagnosis of HP. Unlike in HP, however, hilar adenopathy

may be prominent on chest x-ray, organs other than the lung may be

involved, and noncaseating granulomas in pathologic specimens tend

to be well formed. Other inhalational syndromes, such as organic toxic

dust syndrome (OTDS), can be misdiagnosed as HP. OTDS occurs

with exposure to organic dusts, including those produced by grains

or mold silage, but neither requires prior antigen sensitization nor is

characterized by positive specific IgG antibodies.

TREATMENT

Hypersensitivity Pneumonitis

The mainstay of treatment for HP is antigen avoidance, if possible.

A careful exposure history must be obtained to attempt to identify

the potential offending antigen and to identify the location where

a patient is exposed. Once a potential antigen and location are

identified, efforts should be made to modify the environment to

minimize patient exposure. This may be accomplished with measures such as removal of birds, removal of molds, and improved

ventilation. Personal protective equipment including respirators

and ventilated helmets can be used but may not provide adequate

protection for sensitized individuals. In some cases, fully avoiding

specific environments may be necessary, although such a recommendation must be balanced against the effects to an individual’s

lifestyle or occupation. It is not uncommon for patients with HP

due to exposure to household birds to be unwilling to remove them

from the home.

Because acute HP is generally a self-limited disease after a discrete exposure to an offending antigen, pharmacologic therapy is

generally not necessary. However, in so-called subacute and chronic

forms of the disease, there is a role for glucocorticoid therapy. In

patients with particularly severe symptoms as a result of subacute

HP, antigen avoidance may be insufficient after establishing the

diagnosis. Although glucocorticoids do not change the long-term

outcome in these patients, they can accelerate the resolution of

symptoms. While there is significant variability in the approach to

glucocorticoid therapy by individual clinicians, prednisone therapy can be initiated at 0.5–1 mg/kg of ideal body weight per day

(not to exceed 60 mg/d or alternative glucocorticoid equivalent)

over a duration of 1–2 weeks, followed by a taper over the next

2–6 weeks. In chronic HP, a similar trial of corticosteroids may be

used, although a variable component of fibrotic disease may be

irreversible. In advanced cases of chronic HP with extensive lung

fibrosis, lung transplantation may be necessary.

■ GLOBAL CONSIDERATIONS

As the ever-expanding list of antigens and exposures associated with

the development of HP suggests, populations at risk for HP will vary

globally based on specifics of local occupational, avocational, and

environmental factors. Specific examples of geographically limited HP

include summer-type pneumonitis seen in Japan and suberosis seen in

cork workers in Portugal and Spain.

PULMONARY INFILTRATES WITH

EOSINOPHILIA

Although eosinophils are normal constituents of the lungs, there are

several pulmonary eosinophilic syndromes that are characterized by

pulmonary infiltrates on imaging along with an increased number of

eosinophils in lung tissue, in sputum, and/or in BAL fluid, with resultant increased respiratory symptoms and the potential for systemic

manifestations. Because the eosinophil plays such an important role

in each of these syndromes, it is often difficult to distinguish between

them, but there are important clinical and pathologic differences as

well as differences in prognosis and treatment paradigms.

■ CLASSIFYING PULMONARY INFILTRATES WITH

EOSINOPHILIA AND GENERAL APPROACH

Because there are so many different diagnoses associated with pulmonary infiltrates with eosinophilia, the first step in classifying pulmonary eosinophilic syndromes is distinguishing between primary

pulmonary eosinophilic lung disorders and those with eosinophilia

that are secondary to a specific cause such as a drug reaction, an infection, a malignancy, or another pulmonary condition such as asthma.

Table 288-2 lists primary and secondary pulmonary eosinophilic

disorders.

For each patient, a detailed history is of utmost importance and can

help elucidate what the underlying disease is. Details regarding onset,

timing, and precipitants of specific symptoms can help discern one diagnosis from another. History regarding pharmacologic, occupational, and

environmental exposures is instructive, and family and travel history are

crucial. In addition to details about the sinuses and lungs, it is important

to inquire about systemic manifestations and assess for physical findings of cardiac, gastrointestinal (GI), neurologic, dermatologic, and

genitourinary involvement, all of which may give clues to specific diagnoses. Once the details from history and physical are teased out, laboratory testing (including measurements of blood eosinophils, cultures,

and markers of inflammation), spirometry, and radiographic imaging

2163Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia CHAPTER 288

can help distinguish between different diseases. Often, however, BAL,

transbronchial, or open lung biopsies are required. In many cases,

biopsies or noninvasive diagnostic studies of other organs (e.g., echocardiogram, electromyogram, or bone marrow biopsy) can be helpful.

■ PATHOPHYSIOLOGY

Pathologically, the pulmonary eosinophilic syndromes are characterized by tissue infiltration by eosinophils (Fig. 288-2). In eosinophilic

granulomatosis with polyangiitis (EGPA), extravascular granulomas

and necrotizing vasculitis may occur in the lungs, as well as in the

heart, skin, muscle, liver, spleen, and kidneys, and may be associated

with fibrinoid necrosis and thrombosis.

The exact etiology of the various pulmonary eosinophilic syndromes is unknown; however, it is felt that these syndromes result from

dysregulated eosinophilopoiesis or an autoimmune process because of

the prominence of allergic features and the presence of immune complexes, heightened T-cell immunity, and altered humoral immunity as

evidenced by elevated IgE, IgG4, and rheumatoid factor. Because of

its integral involvement in eosinophilopoiesis, interleukin 5 (IL-5) has

been hypothesized to play an etiologic role. Monoclonal antibodies

against IL-5 are now in clinical use for the treatment of eosinophilic

asthma and eosinophilic granulomatosis with polyangiitis and are

under investigation for other conditions characterized by pulmonary

infiltrates with eosinophilia. Antineutrophil cytoplasmic antibodies

(ANCAs) are present in about one-third to two-thirds of patients with

EGPA; binding of ANCAs to vascular walls likely contributes to vascular inflammation and injury as well as chemotaxis of inflammatory cells.

■ ACUTE EOSINOPHILIC PNEUMONIA

Acute eosinophilic pneumonia is a syndrome characterized by fevers,

acute respiratory failure that often requires mechanical ventilation,

diffuse pulmonary infiltrates, and pulmonary eosinophilia in a previously healthy individual (Table 288-3).

Clinical Features and Etiology At presentation, acute eosinophilic pneumonia is often mistaken for acute lung injury or acute

respiratory distress syndrome (ARDS), until a BAL is performed and

reveals >25% eosinophils. Although the predominant symptoms of

acute eosinophilic pneumonia are cough, dyspnea, malaise, myalgias,

night sweats, and pleuritic chest pain, physical examination findings

include high fevers, basilar rales, and rhonchi on forced expiration.

Acute eosinophilic pneumonia most often affects males between age

20 and 40 with no history of asthma. Although no clear etiology has

been identified, several case reports have linked acute eosinophilic

pneumonia to recent initiation of tobacco smoking or even electronic

cigarette inhalation (vaping), or exposure to other environmental stimuli including dust from indoor renovations.

In addition to a suggestive history, the key to establishing a diagnosis

of acute eosinophilic pneumonia is the presence of >25% eosinophilia

on BAL fluid. While lung biopsies show eosinophilic infiltration with

acute and organizing diffuse alveolar damage, it is generally not necessary to proceed to biopsy to establish a diagnosis. Although patients

present with an elevated white blood cell count, in contrast to other

pulmonary eosinophilic syndromes, acute eosinophilic pneumonia is

often not associated with peripheral eosinophilia upon presentation.

However, between 7 and 30 days of disease onset, peripheral eosinophilia often occurs with mean eosinophil counts of 1700. Erythrocyte

sedimentation rate (ESR), C-reactive protein, and IgE levels are high

but nonspecific, whereas HRCT is always abnormal with bilateral random patchy ground-glass or reticular opacities and small pleural effusions in as many as two-thirds of patients. Pleural fluid is characterized

by a high pH with marked eosinophilia.

Clinical Course and Response to Therapy Although some

patients improve spontaneously, most patients require admission to

an intensive care unit and respiratory support with either invasive

(intubation) or noninvasive mechanical ventilation. However, what

distinguishes acute eosinophilic pneumonia from both other cases of

acute lung injury as well as some of the other pulmonary eosinophilic

syndromes is the absence of organ dysfunction or multisystem organ

failure other than respiratory failure. One of the characteristic features

of acute eosinophilic pneumonia is the high degree of corticosteroid

responsiveness and the excellent prognosis. Another distinguishing

feature of acute eosinophilic pneumonia is that complete clinical and

radiographic recovery without recurrence or residual sequelae occurs

in almost all patients within several weeks of initiation of therapy.

■ CHRONIC EOSINOPHILIC PNEUMONIA

In contrast to acute eosinophilic pneumonia, chronic eosinophilic

pneumonia is a more indolent syndrome that is characterized by pulmonary infiltrates and eosinophilia in both the tissue and blood. Most

patients are female nonsmokers with a mean age of 45, and patients do

not usually develop the acute respiratory failure and significant hypoxemia appreciated in acute eosinophilic pneumonia. Similar to EGPA, a

majority have asthma, with many having a history of allergies.

Patients present with a subacute illness over weeks to months, with

cough, low-grade fevers, progressive dyspnea, weight loss, wheezing,

malaise, and night sweats, and a chest x-ray with migratory bilateral

peripheral or pleural-based opacities. Although this “photographic

TABLE 288-2 Pulmonary Infiltrates with Eosinophilia

Primary Pulmonary Eosinophilic Disorders

Acute eosinophilic pneumonia

Chronic eosinophilic pneumonia

Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

Hypereosinophilic syndrome

Pulmonary Disorders of Known Cause Associated with Eosinophilia

Asthma and eosinophilic bronchitis

Allergic bronchopulmonary aspergillosis

Bronchocentric granulomatosis

Drug/toxin reaction

Infection (Table 288-4)

Parasitic/helminthic disease

Nonparasitic infection

Lung Diseases Associated with Eosinophilia

Cryptogenic organizing pneumonia

Hypersensitivity pneumonitis

Idiopathic pulmonary fibrosis

Pulmonary Langerhans cell granulomatosis

Malignant Neoplasms Associated with Eosinophilia

Leukemia

Lymphoma

Lung cancer

Adenocarcinoma of various organs

Squamous cell carcinoma of various organs

Systemic Disease Associated with Eosinophilia

Postradiation pneumonitis

Rheumatoid arthritis

Sarcoidosis

Sjögren’s syndrome

TABLE 288-3 Diagnostic Criteria of Acute Eosinophilic Pneumonia

Acute febrile illness with respiratory manifestations of <1 month in duration

Hypoxemic respiratory failure

Diffuse pulmonary infiltrates on chest x-ray

Bronchoalveolar lavage eosinophilia >25%

Absence of parasitic, fungal, or other infection

Absence of drugs known to cause pulmonary eosinophilia

Quick clinical response to corticosteroids

Failure to relapse after discontinuation of corticosteroids

2164 PART 7 Disorders of the Respiratory System

negative pulmonary edema” appearance on chest x-ray and chest CT is

pathognomonic of chronic eosinophilic pneumonia, <25% of patients

present with this finding. Other radiographic findings include atelectasis, pleural effusions, lymphadenopathy, and septal line thickening.

Almost 90% of patients have peripheral eosinophilia, with mean

eosinophil counts of over 30% of total white blood cell count. BAL

eosinophilia is also an important distinguishing feature with mean

BAL eosinophil counts of ~60%. Both peripheral and BAL eosinophilia

are very responsive to treatment with corticosteroids. Other laboratory features of chronic eosinophilic pneumonia include increased

ESR, C-reactive protein, platelets, and IgE. Lung biopsy is also often

not required to establish a diagnosis but may show accumulation of

eosinophils and histiocytes in the lung parenchyma and interstitium,

as well as cryptogenic organizing pneumonia, but with minimal fibrosis. Nonrespiratory manifestations are uncommon, but arthralgias,

neuropathy, and skin and GI symptoms have all been reported; their

presence may suggest EGPA or a hypereosinophilic syndrome. Another

similarity is the rapid response to corticosteroids with quick resolution

of peripheral and BAL eosinophilia and improvement in symptoms. In

contrast to acute eosinophilic pneumonia, though, >50% of patients

relapse, and many require prolonged courses of corticosteroids for

months to years.

■ EOSINOPHILIC GRANULOMATOSIS WITH

POLYANGIITIS (EGPA)

Previously known as allergic angiitis granulomatosis or Churg-Strauss

syndrome, this complex syndrome is characterized by eosinophilic

vasculitis that may involve multiple organ systems including the lungs,

heart, skin, GI tract, and nervous system. Although EGPA is characterized by peripheral and pulmonary eosinophilia with infiltrates on

chest x-ray, the primary features that distinguish EGPA from other

pulmonary eosinophilic syndromes are the presence of eosinophilic

vasculitis in the setting of asthma and involvement of multiple end

organs (a feature it shares with hypereosinophilic syndrome). Although

perceived to be quite rare, in the last few years, there has appeared to be

an increased incidence of this disease, particularly in association with

various asthma therapies, including leukotriene modifiers and antiIGE therapy with omalizumab, possibly due to concurrent systemic

corticosteroid withdrawal (forme fruste EGPA).

The primary features of EGPA include asthma, peripheral eosinophilia, neuropathy, pulmonary infiltrates, paranasal sinus abnormality,

and presence of eosinophilic vasculitis. The mean age at diagnosis is

48 years, with a range of 14–74 years; the average length of time

between diagnosis of asthma and vasculitis is 9 years. EGPA typically

occurs in several phases. The prodromal phase is characterized by

asthma and allergic rhinitis, and usually begins when the individual

is in his or her twenties or thirties, typically persisting for many years.

The eosinophilic infiltrative phase is characterized by peripheral eosinophilia and eosinophilic tissue infiltration of various organs including

the lungs and GI tract. The third phase is the vasculitic phase and may

be associated with constitutional signs and symptoms including fever,

weight loss, malaise, and fatigue. This phasic progression supports the

hypothesis that there is a pathophysiologic continuum between eosinophilic asthma, chronic eosinophilic asthma, and EGPA.

Similar to other pulmonary eosinophilic syndromes, constitutional

symptoms are very common in EGPA and include weight loss of

10–20 lb, fevers, and diffuse myalgias and migratory polyarthralgias.

Myositis may be present with evidence of vasculitis on muscle biopsies. In contrast to the eosinophilic pneumonias, EGPA involves many

organ systems including the lungs, skin, nerves, heart, GI tract, and

kidneys.

Symptoms and Clinical Manifestations •  RESPIRATORY

Most EGPA patients have asthma that arises later in life and in individuals who have no family history of atopy. The asthma can often be

severe, and oral corticosteroids are often required to control symptoms

but may lead to suppression of vasculitic symptoms. In addition to the

more common symptoms of cough, dyspnea, sinusitis, and allergic

rhinitis, alveolar hemorrhage and hemoptysis may also occur.

NEUROLOGIC Over three-fourths of EGPA patients have neurologic

manifestations. Mononeuritis multiplex most commonly involves the

peroneal nerve, but also involves the ulnar, radial, internal popliteal,

and occasionally, cranial nerves. Cerebral hemorrhage and infarction

may also occur and are important causes of death. Despite treatment,

neurologic sequelae often do not completely resolve.

DERMATOLOGIC Approximately half of EGPA patients develop dermatologic manifestations. These include palpable purpura, skin nodules, urticarial rashes, and livedo.

CARDIOVASCULAR Granulomas, vasculitis, and widespread myocardial damage may be found on biopsy or at autopsy, and cardiomyopathy and heart failure may be seen in up to half of all patients but are

often at least partially reversible. Acute pericarditis, constrictive pericarditis, myocardial infarction, and other electrocardiographic changes

all may occur. The heart is a primary target organ in EGPA, and cardiac

involvement often portends a worse prognosis.

GI GI symptoms are common in EGPA and likely represent an eosinophilic gastroenteritis characterized by abdominal pain, diarrhea, GI

bleeding, and colitis. Ischemic bowel, pancreatitis, and cholecystitis

have also been reported in association with EGPA and usually portend

a worse prognosis.

RENAL Renal involvement is more common than once thought, and

~25% of patients have some degree of renal involvement. This may

include proteinuria, glomerulonephritis, renal insufficiency, and rarely,

renal infarct.

Lab Abnormalities Systemic eosinophilia is the hallmark laboratory finding in patients with EGPA and reflects the likely pathogenic

role that the eosinophil plays in this disease. Eosinophilia >10% is one

of the defining features of this illness and may be as high as 75% of the

peripheral white blood cell count. It is present at the time of diagnosis

in >80% of patients, but may respond quickly (often within 24 h) to

initiation of systemic corticosteroid therapy. Even in the absence of

systemic eosinophilia, tissue eosinophilia may be present.

Although not specific to EGPA, ANCAs are present in approximately one-third to two-thirds of patients, mostly in a perinuclear

staining pattern, with specific antibodies against myeloperoxidase

detected. Nonspecific lab abnormalities that may be present in patients

with EGPA include a marked elevation in ESR, a normochromic normocytic anemia, an elevated IgE, hypergammaglobulinemia, and positive rheumatoid factor and antinuclear antibodies (ANA). Although

BAL often reveals significant eosinophilia, this may be seen in other

eosinophilic lung diseases. Similarly, PFT often reveals an obstructive

defect similar to asthma.

Radiographic Features Chest x-ray abnormalities are extremely

common in EGPA and consist of bilateral, nonsegmental, patchy

infiltrates that often migrate and may be interstitial or alveolar in

appearance. Reticulonodular and nodular disease without cavitation

can be seen, as can pleural effusions and hilar adenopathy. The most

common CT findings include bilateral ground-glass opacity and

airspace consolidation that is predominantly subpleural. Other CT

findings include bronchial wall thickening, hyperinflation, interlobular septal thickening, lymph node enlargement, and pericardial and

pleural effusions. Angiography may be used diagnostically and may

show signs of vasculitis in the coronary, central nervous system, and

peripheral vasculature.

Treatment and Prognosis of EGPA Most patients diagnosed

with EGPA have previously been diagnosed with asthma, rhinitis, and

sinusitis, and have received treatment with inhaled or systemic corticosteroids. Because these agents are also the initial treatment of choice

for EGPA patients, institution of these therapies in patients with EGPA

who are perceived to have severe asthma may delay the diagnosis of

EGPA because signs of vasculitis may be masked. Corticosteroids

dramatically alter the course of EGPA: up to 50% of those who are

untreated die within 3 months of diagnosis, whereas treated patients

have a 6-year survival of >70%. Common causes of death include

2165Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia CHAPTER 288

heart failure, cerebral hemorrhage, renal failure, and GI bleeding.

Recent data suggest that clinical remission may be obtained in >90% of

patients treated; ~25% of those patients may relapse, often due to corticosteroid tapering, with a rising eosinophil count heralding the relapse.

Myocardial, GI, and renal involvement most often portend a poor

prognosis. In such cases, treatment with higher doses of corticosteroids

or the addition of cytotoxic agents such as cyclophosphamide is often

warranted. Although survival does not differ between those treated

or untreated with cyclophosphamide, cyclophosphamide is associated

with a reduced incidence of relapse and an improved clinical response

to treatment. Recent studies examining the efficacy of anti-IL-5 therapy with mepolizumab compared with placebo have shown promise,

indicating that mepolizumab is a safe and effective corticosteroidsparing agent that can reduce relapses. Other therapies that have been

used successfully in the management of EGPA include azathioprine,

methotrexate, rituximab, omalizumab, intravenous gamma globulin,

and interferon α. Plasma exchange has not been shown to provide any

additional benefit.

■ HYPEREOSINOPHILIC SYNDROMES

Hypereosinophilic syndromes (HES) constitute a heterogeneous group of

disease entities manifest by persistent eosinophilia >1500 eosinophils/μL

in association with end organ damage or dysfunction, in the absence

of secondary causes of eosinophilia. In addition to familial, undefined,

and overlap syndromes with incomplete criteria, the predominant HES

subtypes are the myeloproliferative and lymphocytic variants. The

myeloproliferative variants may have acquired genetic abnormalities,

including of platelet-derived growth factor receptor α (PDGFRα),

attributed to a constitutively activated tyrosine kinase fusion protein

(Fip1L1-PDGFRα) due to a chromosomal deletion on 4q12; this

variant is often responsive to imatinib. Myeloproliferative HES may

also be associated with mutations involving platelet-derived growth

factor β (PDGFRβ), Janus kinase 2 (JAK2), and fibroblast growth factor

receptor 1 (FGFR1). Chronic eosinophilic leukemia with demonstrable

cytogenetic abnormalities and/or blasts on peripheral smear is often

categorized with the myeloproliferative HES. Clinical and laboratory

findings in myeloproliferative HES may include dysplastic peripheral

eosinophils, increased serum vitamin B12, increased tryptase, anemia, thrombocytopenia, splenomegaly, bone marrow cellularity >80%,

spindle-shaped mast cells, and myelofibrosis. The evaluation for

lymphocytic HES includes searching for abnormal T-cell clonal

populations.

Extrapulmonary Manifestations of HES More common in

men than in women, HES occurs between the ages of 20 and 50 and

is characterized by significant extrapulmonary involvement, including

infiltration of the heart, GI tract, kidney, liver, joints, and skin. Cardiac

involvement includes myocarditis and/or endomyocardial fibrosis, as

well as a restrictive cardiomyopathy.

Pulmonary Manifestations of HES Similar to the other pulmonary eosinophilic syndromes, these HES are manifested by high levels

of blood, BAL, and tissue eosinophilia. Lung involvement occurs in

40% of these patients and is characterized by cough and dyspnea, as

well as pulmonary infiltrates. Although it is often difficult to discern

the pulmonary infiltrates and effusions seen on chest x-ray from pulmonary edema resulting from cardiac involvement, CT scan findings

include interstitial infiltrates, ground-glass opacities, and small nodules. HES are typically not associated with ANCA. IgE may be elevated

in lymphocytic HES variants.

Course and Response to Therapy Unlike the other pulmonary

eosinophilic syndromes, less than half of patients with these HES

respond to corticosteroids as first-line therapy. Although other treatment options include hydroxyurea, cyclosporine, and interferon, the

tyrosine kinase inhibitor imatinib has emerged as an important therapeutic option for patients with the myeloproliferative variant, particularly in individuals with the Fip1L1-PDGFRA gene fusion. Anti-IL-5

therapy with mepolizumab or benralizumab also holds promise for

these patients and is currently being investigated.

■ ALLERGIC BRONCHOPULMONARY

ASPERGILLOSIS

Allergic bronchopulmonary aspergillosis (ABPA) is an eosinophilic

pulmonary disorder that occurs in response to allergic sensitization

to antigens from Aspergillus species fungi. The predominant clinical

presentation of ABPA is an asthmatic phenotype, often accompanied

by cough with production of brownish plugs of mucus. ABPA has also

been well described as a complication of cystic fibrosis. A workup for

ABPA may be beneficial in patients who carry a diagnosis of asthma

but have proven refractory to usual therapy. ABPA is a distinct diagnosis from simple asthma, characterized by prominent peripheral

eosinophilia and elevated circulating levels of IgE (often >1000 IU/mL).

Establishing a diagnosis of ABPA also requires establishing sensitivity

to Aspergillus antigens by skin test reactivity and/or direct measurement

of circulating specific IgE to Aspergillus. Positive serum precipitins for

Aspergillus or direct measurement of circulating specific IgG to Aspergillus can be used as an adjunct diagnostic criterion. Central bronchiectasis is described as a classic finding on chest imaging in ABPA but is

not necessary for making a diagnosis. Other possible findings on chest

imaging include patchy infiltrates and evidence of mucus impaction.

Systemic glucocorticoids may be used in the treatment of ABPA

that is persistently symptomatic despite the use of inhaled therapies for

asthma. Courses of glucocorticoids should be tapered over 3–6 months,

and their use must be balanced against the risks of prolonged steroid

therapy. Antifungal agents such as itraconazole and voriconazole given

over a 4-month course reduce the antigenic stimulus in ABPA and may

therefore modulate disease activity in selected patients. Newer azole

agents may be used as well. The use of monoclonal antibody against IgE

(omalizumab) has been described in treating severe ABPA, particularly

in individuals with ABPA as a complication of cystic fibrosis. Other

monoclonal antibodies used in severe eosinophilic asthma, such as

those targeting IL-5 (or its receptor) or targeting IL-4-receptor-alpha,

may be considered as well in refractory cases.

ABPA-like syndromes have been reported as a result of sensitization

to several non-Aspergillus species fungi. However, these conditions are

substantially rarer than ABPA, which may be present in a significant

proportion of patients with refractory asthma.

■ INFECTIOUS PROCESSES

Infectious etiologies of pulmonary eosinophilia are largely due to helminths and are of particular importance in the evaluation of pulmonary

eosinophilia in tropical environments and in the developing world

(Table 288-4). These infectious conditions may also be considered in

recent travelers to endemic regions. Loffler syndrome refers to transient

pulmonary infiltrates with eosinophilia that occurs in response to passage of helminthic larvae through the lungs, most commonly larvae of

Ascaris species (roundworm). Symptoms are generally self-limited and

may include dyspnea, cough, wheeze, and hemoptysis. Loffler syndrome

may also occur in response to hookworm infection with Ancylostoma

duodenale or Necator americanus. Chronic Strongyloides stercoralis infection can lead to recurrent respiratory symptoms with peripheral eosinophilia between flares. In immunocompromised hosts, including patients

on glucocorticoids, a severe, potentially fatal, hyperinfection syndrome

can result from Strongyloides infection. Paragonimiasis, filariasis, and

visceral larval migrans can all cause pulmonary eosinophilia as well.

■ DRUGS AND TOXINS

A host of medications are associated with the development of pulmonary infiltrates with peripheral eosinophilia. Therefore, drug reaction

must always be included in the differential diagnosis of pulmonary eosinophilia. Although the list of medications associated with pulmonary

eosinophilia is ever expanding, common culprits include nonsteroidal

anti-inflammatory medications and systemic antibiotics. Additionally,

various and diverse environmental exposures such as particulate metals, scorpion stings, and inhalational drugs of abuse may also cause

pulmonary eosinophilia. Radiation therapy for breast cancer has been

linked with eosinophilic pulmonary infiltration as well. The mainstay

of treatment is removal of the offending exposure, although glucocorticoids may be necessary if respiratory symptoms are severe.

2166 PART 7 Disorders of the Respiratory System

TABLE 288-4 Infectious Causes of Pulmonary Eosinophilia

Löffler Syndrome

Ascaris

Hookworm

Schistosomiasis

Heavy Parasite Burden

Strongyloidiasis

Direct Pulmonary Penetration

Paragonimiasis

Visceral larval migrans

Immunologic Response to Organisms in Lungs

Filariasis

Dirofilariasis

Cystic Disease

Echinococcus

Cysticercosis

Other Nonparasitic

Coccidioidomycosis

Basidiobolomycosis

Paracoccidioidomycosis

Tuberculosis

Source: Adapted from P Akuthota, PF Weller: Clin Microbiol Rev 25:649, 2012.

Occupational and environmental lung diseases are difficult to distinguish from those of nonenvironmental origin. Virtually all major

categories of pulmonary disease can be caused by environmental

agents, and environmentally related disease usually presents clinically

in a manner indistinguishable from that of disease not caused by such

agents. In addition, the etiology of many diseases may be multifactorial; occupational and environmental factors may interact with other

289 Occupational and

Environmental Lung Disease

John R. Balmes

■ GLOBAL CONSIDERATIONS

In the United States, drug-induced eosinophilic pneumonias are the

most common cause of eosinophilic pulmonary infiltrates. A travel

history or evidence of recent immigration should prompt the consideration of parasite-associated disorders. Tropical eosinophilia is

usually caused by filarial infection; however, eosinophilic pneumonias

also occur with other parasites such as Ascaris spp., Ancylostoma spp.,

Toxocara spp., and Strongyloides stercoralis. Tropical eosinophilia due

to Wuchereria bancrofti or Wuchereria malayi occurs most commonly

in southern Asia, Africa, and South America and is treated successfully

with diethylcarbamazine. In the United States, Strongyloides is endemic

to the southeastern and Appalachian regions.

■ FURTHER READING

Akuthota P, Weller PF: Eosinophilic pneumonias. Clin Microbiol

Rev 25:649, 2012.

Cottin V: Eosinophilic lung diseases. Clin Chest Med 37:535, 2016.

Vasakova M et al: Hypersensitivity pneumonitis: Perspectives in diagnosis and management. Am J Respir Crit Care Med 196:680, 2017.

Wechsler ME et al: Mepolizumab or placebo for eosinophilic granulomatosis with polyangiitis. N Engl J Med 376:1921, 2017.

factors (such as smoking and genetic risk). It is often only after a careful exposure history is taken that the underlying workplace or general

environmental exposure is uncovered.

Why is knowledge of occupational or environmental etiology so

important? Patient management and prognosis are affected significantly by such knowledge. For example, patients with occupational

asthma or hypersensitivity pneumonitis often cannot be managed

adequately without cessation of exposure to the offending agent. Establishment of cause may have significant legal and financial implications

for a patient who no longer can work in his or her usual job. Other

exposed people may be identified as having the disease or prevented

from getting it. In addition, new associations between exposure and

disease may be identified (e.g., nylon flock worker’s lung disease and

diacetyl-induced bronchiolitis obliterans).

Although the exact proportion of lung disease due to occupational

and environmental factors is unknown, a large number of individuals

are at risk. For example, 15–20% of the burden of adult asthma and

chronic obstructive pulmonary disease (COPD) has been estimated to

be due to occupational factors.

■ HISTORY AND EXPOSURE ASSESSMENT

The patient’s history is of paramount importance in assessing any

potential occupational or environmental exposure. Inquiry into specific

work practices should include questions about the specific contaminants involved, the presence of visible dusts, chemical odors, the size

and ventilation of workspaces, the use of respiratory protective equipment, and whether coworkers have similar complaints. The temporal

association of exposure at work and symptoms may provide clues to

occupation-related disease. In addition, the patient must be questioned

about alternative sources of exposure to potentially toxic agents, including hobbies, home characteristics, exposure to secondhand smoke, and

proximity to traffic or industrial facilities. Short-term and long-term

exposures to potential toxic agents in the distant past also must be

considered.

Workers in the United States have the right to know about potential

hazards in their workplaces under federal Occupational Safety and

Health Administration (OSHA) regulations. Employers must provide

specific information about potential hazardous agents in products

being used through Safety Data Sheets as well as training in personal

protective equipment and environmental control procedures. However,

the introduction of new processes and/or new chemical compounds

may change exposure significantly, and often only the employee on the

production line is aware of the change. For the physician caring for a

patient with a suspected work-related illness, a visit to the work site

can be very instructive. Alternatively, an affected worker can request an

inspection by OSHA. If reliable environmental sampling data are available, that information should be used in assessing a patient’s exposure.

Because chronic diseases may result from exposure over many years,

current environmental measurements should be combined with work

histories to arrive at estimates of past exposure.

■ LABORATORY TESTS

Exposures to inorganic and organic dusts can cause interstitial lung

disease that presents with a restrictive pattern and a decreased diffusing capacity (Chap. 285). Similarly, exposures to a number of dusts or

chemical agents may result in occupational asthma or COPD that is

characterized by airway obstruction. Measurement of change in forced

expiratory volume in 1 s (FEV1

) before and after a working shift can be

used to detect an acute bronchoconstrictive response.

The chest radiograph is useful in detecting and monitoring the

pulmonary response to mineral dusts, certain metals, and organic

dusts capable of inducing hypersensitivity pneumonitis. The International Labour Organisation (ILO) International Classification of

Radiographs of Pneumoconioses classifies chest radiographs by the

nature and size of opacities seen and the extent of involvement of the

parenchyma. In general, small rounded opacities are seen in silicosis

or coal worker’s pneumoconiosis, and small linear opacities are seen

in asbestosis. Although useful for epidemiologic studies and screening

large numbers of workers, the ILO system can be problematic when

2167Occupational and Environmental Lung Disease CHAPTER 289

Particle size of air contaminants must also be considered. Because

of their settling velocities in air, particles >10–15 μm in diameter do

not penetrate beyond the nose and throat. Particles <10 μm in size

are deposited below the larynx. These particles are divided into three

size fractions on the basis of their size characteristics and sources.

Particles ~2.5–10 μm (coarse-mode fraction) contain crustal elements

such as silica, aluminum, and iron. These particles mostly deposit

relatively high in the tracheobronchial tree. Although the total mass

of an ambient sample is dominated by these larger respirable particles, the number of particles, and therefore the surface area on which

potential toxic agents can deposit and be carried to the lower airways,

is dominated by particles <2.5 μm (fine-mode fraction). These fine

particles are created primarily by the burning of fossil fuels or hightemperature industrial processes resulting in condensation products

from gases, fumes, or vapors. The smallest particles, those <0.1 μm in

size, represent the ultrafine fraction and make up the largest number

of particles; they tend to remain in the airstream and deposit in the

lung only on a random basis as they come into contact with the alveolar walls. If they do deposit, however, particles of this size range may

penetrate into the circulation and be carried to extrapulmonary sites.

New technologies create particles of this size (“nanoparticles”) for use

in many commercial applications. Besides the size characteristics of

particles and the solubility of gases, the actual chemical composition,

mechanical properties, and immunogenicity or infectivity of inhaled

material determine in large part the nature of the diseases found

among exposed persons.

OCCUPATIONAL EXPOSURES AND

PULMONARY DISEASE

Table 289-1 provides broad categories of exposure in the workplace

and diseases associated with chronic exposure in those industries.

■ ASBESTOS-RELATED DISEASES

Asbestos is a generic term for several different mineral silicates, including chrysolite, amosite, anthophyllite, and crocidolite. In addition to

applied to an individual worker’s chest radiograph. With dusts causing

rounded opacities, the degree of involvement on the chest radiograph

may be extensive, whereas pulmonary function may be only minimally

impaired. In contrast, in pneumoconiosis causing linear, irregular

opacities like those seen in asbestosis, the radiograph may lead to

underestimation of the severity of the impairment until relatively late

in the disease. For patients with a history of asbestos exposure, conventional computed tomography (CT) is more sensitive for the detection

of pleural thickening, and high-resolution CT (HRCT) improves the

detection of asbestosis.

Other procedures that may be of use in identifying the role of environmental exposures in causing lung disease include skin prick testing

or specific IgE antibody titers for evidence of immediate hypersensitivity to agents capable of inducing occupational asthma (e.g., flour

antigens in bakers), specific IgG precipitating antibody titers for agents

capable of causing hypersensitivity pneumonitis (e.g., pigeon antigen in

bird handlers), and assays for specific cell-mediated immune responses

(e.g., beryllium lymphocyte proliferation testing in nuclear workers or

tuberculin skin testing in health care workers). Sometimes a bronchoscopy to obtain transbronchial biopsies of lung tissue may be required

for histologic diagnosis (chronic beryllium disease [CBD]). Rarely,

video-assisted thoracoscopic surgery to obtain a larger sample of lung

tissue may be required to determine the specific diagnosis of environmentally induced lung disease (hypersensitivity pneumonitis or giant

cell interstitial pneumonitis due to cobalt exposure).

■ DETERMINANTS OF INHALATIONAL EXPOSURE

The chemical and physical characteristics of inhaled agents affect

both the dose and the site of deposition in the respiratory tract.

Water-soluble gases such as ammonia and sulfur dioxide are absorbed

in the lining fluid of the upper and proximal airways and thus tend

to produce irritative and bronchoconstrictive responses. In contrast,

nitrogen dioxide and phosgene, which are less soluble, may penetrate

to the bronchioles and alveoli in sufficient quantities to produce acute

chemical pneumonitis.

TABLE 289-1 Categories of Occupational Exposure and Associated Respiratory Conditions

OCCUPATIONAL EXPOSURES NATURE OF RESPIRATORY RESPONSES COMMENT

Inorganic Dusts

Asbestos: mining, processing, construction, ship

repair

Fibrosis (asbestosis), pleural disease, cancer,

mesothelioma

Virtually all new mining and construction with asbestos done

in developing countries

Silica: mining, stone cutting, sandblasting,

quarrying, artificial stone manufacture and

installation

Fibrosis (silicosis), progressive massive fibrosis

(PMF), cancer, tuberculosis, chronic obstructive

pulmonary disease (COPD)

Improved protection in United States; persistent risk in

developing countries

Coal dust: mining Fibrosis (coal worker’s pneumoconiosis), PMF,

COPD

Risk persists in certain areas of United States, increasing in

countries where new mines open

Beryllium: processing alloys for nuclear power and

weapons, aerospace, and electronics

Acute pneumonitis (rare), chronic granulomatous

disease, lung cancer (highly suspect)

Risk in high-tech industries persists

Other metals: aluminum, chromium, cobalt, nickel,

titanium, tungsten carbide, or “hard metal”

(contains cobalt)

Wide variety of conditions from acute pneumonitis

to lung cancer and asthma

New diseases appear with new process development

Organic Dusts

Cotton dust: milling, processing Byssinosis (an asthma-like syndrome), chronic

bronchitis, COPD

Increasing risk in developing countries with drop in

United States as jobs shift overseas

Grain dust: elevator agents, dock workers, milling,

bakers

Asthma, chronic bronchitis, COPD Risk shifting more to migrant labor pool

Other agricultural dusts: fungal spores, vegetable

products, insect fragments, animal dander, bird and

rodent feces, endotoxins, microorganisms, pollens

Hypersensitivity pneumonitis (farmer’s lung),

asthma, chronic bronchitis

Important in migrant labor pool but also resulting from

in-home exposures

Toxic chemicals: wide variety of industries; see

Table 289-2

Asthma, chronic bronchitis, COPD,

hypersensitivity pneumonitis, pneumoconiosis,

and cancer

Reduced risk with recognized hazards; increasing risk for

developing countries where controlled labor practices are

less stringent

Other Environmental Agents

Uranium and radon daughters, secondhand tobacco

smoke, polycyclic aromatic hydrocarbons (PAHs),

biomass smoke, diesel exhaust, welding fumes,

wood finishing

Occupational exposures estimated to contribute

to up to 10% of all lung cancers; chronic

bronchitis, COPD, and fibrosis

In-home exposures important; in developing countries,

biomass smoke is a major risk factor for COPD among

women in these countries

2168 PART 7 Disorders of the Respiratory System

workers involved in the production of asbestos products (mining,

milling, and manufacturing), many workers in the shipbuilding and

construction trades, including pipe fitters and boilermakers, were

occupationally exposed because asbestos was widely used during the

twentieth century for its thermal and electrical insulation properties.

Asbestos also was used in the manufacture of fire-resistant textiles,

in cement and floor tiles, and in friction materials such as brake and

clutch linings.

Exposure to asbestos is not limited to persons who directly handle

the material. Cases of asbestos-related diseases have been encountered

in individuals with only bystander exposure, such as painters and electricians who worked alongside insulation workers in a shipyard. Community exposure resulted from the use of asbestos-containing mine

and mill tailings as landfill, road surface, and playground material (e.g.,

Libby, MT, the site of a vermiculite mine in which the ore was contaminated with asbestos). Finally, exposure can occur from the disturbance

of naturally occurring asbestos (e.g., from increasing residential development in the foothills of the Sierra Mountains in California).

Asbestos has largely been replaced in the developed world with synthetic mineral fibers such as fiberglass and refractory ceramic fibers, but

it continues to be used in the developing world. The major health effects

from exposure to asbestos are pleural and pulmonary fibrosis, cancers

of the respiratory tract, and pleural and peritoneal mesothelioma.

Asbestosis is a diffuse interstitial fibrosing disease of the lung that is

directly related to the intensity and duration of exposure. The disease

resembles other forms of diffuse interstitial fibrosis (Chap. 293). Usually, exposure has taken place for at least 10 years before the disease

becomes manifest. The mechanisms by which asbestos fibers induce

lung fibrosis are not completely understood but are known to involve

oxidative injury due to the generation of reactive oxygen species by

the transition metals on the surface of the fibers as well as from cells

engaged in phagocytosis.

Past exposure to asbestos is specifically indicated by pleural plaques

on chest radiographs, which are characterized by either thickening

or calcification along the parietal pleura, particularly along the lower

lung fields, the diaphragm, and the cardiac border. Without additional

manifestations, pleural plaques imply only exposure, not pulmonary

impairment. Benign pleural effusions also may occur.

Irregular or linear opacities that usually are first noted in the lower

lung fields are the chest radiographic hallmark of asbestosis. An indistinct heart border or a “ground-glass” appearance in the lung fields may

be seen. HRCT may show distinct changes of subpleural curvilinear

lines 5–10 mm in length that appear to be parallel to the pleural surface

(Fig. 289-1).

Pulmonary function testing in asbestosis reveals a restrictive pattern

with a decrease in both lung volumes and diffusing capacity. There may

also be evidence of mild airflow obstruction (due to peribronchiolar

fibrosis).

Because no specific therapy is available for asbestosis, supportive

care is the same as that given to any patient with diffuse interstitial

fibrosis of any cause. In general, newly diagnosed cases will have

resulted from exposures that occurred many years before.

Lung cancer (Chap. 78) is the most common cancer associated with

asbestos exposure. The excess frequency of lung cancer (all histologic

types) in asbestos workers is associated with a minimum latency of

15–19 years between first exposure and development of the disease.

Persons with more exposure are at greater risk of disease. In addition,

there is a significant interactive effect of smoking and asbestos exposure that results in greater risk than what would be expected from the

additive effect of each factor.

Mesotheliomas (Chap. 294), both pleural and peritoneal, are also

associated with asbestos exposure. In contrast to lung cancers, these

tumors do not appear to be associated with smoking. Relatively shortterm asbestos exposures of ≤1–2 years, occurring up to 40 years in the

past, have been associated with the development of mesotheliomas (an

observation that emphasizes the importance of obtaining a complete

environmental exposure history). Although the risk of mesothelioma

is much less than that of lung cancer among asbestos-exposed workers,

~3000 cases per year are diagnosed in the United States.

Because epidemiologic studies have shown that >80% of mesotheliomas may be associated with asbestos exposure, documented mesothelioma in a patient with occupational or environmental exposure to

asbestos may be compensable.

■ SILICOSIS

Despite being one of the oldest known occupational pulmonary hazards, free silica (SiO2

), or crystalline quartz, is still a major cause of

disease. The major occupational exposures include mining; stonecutting; sand blasting; glass and cement manufacturing; foundry work;

packing of silica flour; and quarrying, particularly of granite. Most

often, pulmonary fibrosis due to silica exposure (silicosis) occurs in a

dose-response fashion after many years of exposure. Two recent outbreaks of silicosis have involved sandblasting of denim jeans to make

FIGURE 289-1 Asbestosis. A. Frontal chest radiograph shows bilateral calcified

pleural plaques consistent with asbestos-related pleural disease. Poorly defined

linear and reticular abnormalities are seen in the lower lobes bilaterally. B. Axial

high-resolution computed tomography of the thorax obtained through the lung

bases shows bilateral, subpleural reticulation (black arrows), representing fibrotic

lung disease due to asbestosis. Subpleural lines are also present (arrowheads),

characteristic of, though not specific for, asbestosis. Calcified pleural plaques

representing asbestos-related pleural disease (white arrows) are also evident.