543

Immunopathology, Diagnosis, and Management

of Hypersensitivity Pneumonitis
Moisés Selman, M.D. 1 Ivette Buendía-Roldán, M.D. 1

1 Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío Address for correspondence and reprint requests Moisés Selman,
Villegas,” México M.D., Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502,
CP 14080, México DF, México (e-mail: mselmanl@yahoo.com.mx).
Semin Respir Crit Care Med 2012;33:543–554.

Abstract Hypersensitivity pneumonitis (HP) is an inflammatory interstitial lung disease caused by

a wide variety of organic particles and certain small-molecular weight chemical
compounds that provoke an exaggerated immune response in susceptible individuals.

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The clinical manifestations are heterogeneous and have been classically described as
acute, subacute and chronic. The chronic form has an insidious onset over a period of
months or years, with progressive dyspnea and often evolves to fibrosis. The pathology
is characterized by a bronchiolocentric interstitial mononuclear cell infiltration, non-
necrotizing poorly formed granulomas, cellular pneumonitis and variable degrees of
fibrosis. However, morphological diagnosis of HP is complicated because the subacute/
chronic forms may be difficult to distinguish from idiopathic pulmonary fibrosis/usual
interstitial pneumonia and nonspecific interstitial pneumonia. In general, diagnosis of
HP represents a challenge for clinicians that need to weigh a constellation of clinical,
Keywords laboratory, radiographic and (when available) pathological evidence for each patient to
► hypersensitivity assess the certainty of the diagnosis. The cornerstone of therapy is antigen avoidance.
pneumonitis Although clinical trials are scanty, corticosteroids are usually indicated based upon
► extrinsic allergic expert opinion. In this review we summarize the current evidence regarding the
alveolitis diagnostic criteria and therapeutic strategies as well as the immunopathological
► lung fibrosis mechanisms putatively implicated in the development of the disease.

Hypersensitivity pneumonitis (HP) is a complex syndrome last 10 years it has been demonstrated that heated water
that results from the exposure to a wide variety of finely colonized by Mycobacterium avium may provoke HP in hot tub
dispersed antigens of size suitable for reaching the alveolar users.2 Likewise, Mycobacterium immunogenum may contam-
spaces (usually particles smaller than 5 µm) that include inate metal working fluid (MWF), causing disease when they
mammalian and avian proteins, fungi, thermophilic bacteria, become aerosolized, mostly in automotive industries.3 Work-
and certain small-molecular-weight chemical compounds that ers with exposure to MWF are generally in the manufacturing
combine with host proteins to form haptens.1 The incidence sector in processes like metal machining, forging, and stamp-
and prevalence of HP are difficult to estimate precisely because ing. HP has also been described in individuals exposed to
the disease represents a syndrome with different causative Cytophaga endotoxin in a nylon plant.4 In these workers
agents, and epidemiological studies lack uniform diagnostic Cytophaga was isolated from the plant air-conditioning system,
criteria. Interestingly, however, the incidence of HP is low if we and patients showed precipitins to Cytophaga antigen. Finally,
consider that the offending antigens are numerous and widely indirect exposure through a partner has been found to cause
distributed around the world. Actually, an extensive number of HP, which can complicate the identification of the offending
etiologic agents and sources of antigens capable of inducing HP antigen.
have been described, and the list of environments and agents is The low incidence of HP suggests that genetic or additional
always increasing (►Tables 1, 2, 3). Thus, for example, in the environmental factors are necessary to develop the disease.

Issue Theme Orphan Lung Diseases; Copyright © 2012 by Thieme Medical DOI http://dx.doi.org/
Guest Editor, Jay H. Ryu, M.D. Publishers, Inc., 333 Seventh Avenue, 10.1055/s-0032-1325163.
New York, NY 10001, USA. ISSN 1069-3424.
Tel: +1(212) 584-4662.
544 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán

Table 1 Fungal and Bacterial Antigens Implicated in Hypersensitivity Pneumonitis

Disease Antigen Source

Farmer’s lung Faeni rectivirgula Moldy hay, grain, silage
Ventilation pneumonitis; Thermoactinomyces vulgaris, Contaminated forced-air systems; water
humidifier lung; air conditioner Thermoactinomyces sacchari, reservoirs
lung Thermoactinomyces candidus
Klebsiella oxytoca
Bagassosis T. vulgaris Moldy sugarcane (ie, bagasse)
Mushroom worker’s lung T. sacchari Moldy mushroom compost
Enoki mushroom worker’s lung Penicillium citrinum Moldy mushroom compost
(Japan)
Suberosis Thermoactinomyces viridis, Aspergillus Moldy cork
fumigatus, Penicillium frequentans Penicillium
glabrum
Detergent lung; washing Bacillus subtilis enzymes Detergents (during processing or use)

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powder lung
Malt worker’s lung Aspergillus fumigatus, Aspergillus clavatus Moldy barley
Sequoiosis Graphium, Pullularia, and Trichoderma spp., Moldy wood dust
Aureobasidium pullulans
Maple bark stripper’s lung Cryptostroma corticale Moldy maple bark
Cheese washer’s lung Penicillium casei, A. clavatus Moldy cheese
Woodworker’s lung Alternaria spp., wood dust Oak, cedar, and mahogany dust, pine and
spruce pulp
Hardwood workeŕ s lung Paecilomyces Kiln-dried wood
Paprika slicer’s lung Mucor stolonifer Moldy paprika pods
Sauna taker’s lung Aureobasidium spp., other sources Contaminated sauna water
Familial HP B. subtilis Contaminated wood dust in walls
Wood trimmer’s lung Rhizopus spp., Mucor spp. Contaminated wood trimmings
Composter’s lung T. vulgaris, Aspergillus Compost
Basement shower HP Epicoccum nigrum Mold on unventilated shower
Hot tub lung Mycobacterium avium complex Hot tub mists; mold on ceiling
Wine maker’s lung Botrytis cincrea Mold on grapes
Woodsman’s disease Penicillium spp. Oak and maple trees
Thatched roof lung Sacchoromonospora viridis Dead grasses and leaves
Tobacco grower’s lung Aspergillus spp. Tobacco plants
Potato riddler’s lung Thermophilic actinomycetes, F. rectivirgula, Moldy hay around potatoes
T. vulgaris, Aspergillus spp.
Summer-type pneumonitis Trichosporon cutaneum Contaminated old houses
Dry rot lung Merulius lacrymans Rotten wood
Stipatosis Aspergillus fumigatus, T. actinomycetes Esparto dust
Machine operator’s lung Mycobacterium immunogenum, Pseudomona Aerosolized metalworking fluid
fluorescens
Residential provoked Aureobasidium pullulans Residential exposure
pneumonitis
Humidifier lung Naegleria gruberi, Acanthamoeba polyphaga, Contaminated water from home humidifier,
Acanthamoeba castellani, Bacillus spp., others ultrasonic misting fountains

Also, it is likely that a number of mild cases are misdiagnosed According to several studies the prevalence of farmer’s
as viral infections, and some severe advanced cases as idio- lung, one of the best-known types of HP, can be estimated in
pathic pulmonary fibrosis (IPF) or other fibrotic lung 0.5 to 3% of exposed farmers.5 Pigeon breeder’s disease (PBD),
disorders. another common form of HP, seems to occur frequently

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 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán 545

Table 2 Chemicals Implicated in Hypersensitivity Pneumonitis

Disease Antigen Source

Pauli’s reagent alveolitis Sodium diazobenzene sulfate Laboratory reagent
Chemical worker’s lung Isocyanates; trimellitic anhydride Polyurethane foams, spray paints, elastomers,
special glues
Dental techniciań s lung Methyl methacrylate Polishing and grinding prostheses
Vineyard sprayer’s lung Copper sulfate Bordeaux mixture
Pyrethrum HP Pyrethrum Pesticide
Epoxy resin lung Phthalic anhydride Heated epoxy resin
UNKNOWN
Bible printer’s lung Moldy typesetting water
Coptic lung (mummy handler’s lung) Cloth wrappings of mummies
Grain measurer’s lung Cereal grain

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Coffee worker’s lung Coffee bean dust
Tap water lung Contaminated tap water
Tea grower’s lung Tea plants
Mollusk shell HP Sea snail shell
Swimming pool worker’s lung Aerosolized endotoxin from pool
Water sprays and fountains

among bird fanciers taking care of hundreds or thousands of Pathogenic Mechanisms

pigeons (ie 20 to 20,000 per 100,000 persons at risk).1
However, the prevalence of PBD among people with only a HP is an immunopathological disorder occurring in suscepti-
few birds at home is uncertain. Recently, in a large, general- ble individuals where both humoral and cellular mechanisms
population-based cohort of HP patients, the overall incidence participate in the development of the lung lesions. However,
rate was
1 per 100,000 in the UK population.6 The disease the genetic basis of the disease is poorly understood. Some
appears to be a rare interstitial lung disease (ILD) in children, studies indicate that gene polymorphisms of major histocom-
and a recent report in Denmark showed an incidence of 2/ patibility complex (MHC) class II alleles are implicated in the
year and a point prevalence of 4/1,000,000 children.7 Inci- risk to develop the disease.9–13 Also, polymorphisms in the
dence/prevalence seems to be even lower according to the transporters associated with antigen processing (TAP) genes
few pediatric cases reported worldwide and in relation to a may also be involved.14 TAP play an important role trans-
study of lung biopsy from 101 immunocompetent children porting peptides across the endoplasmic reticulum mem-
with diffuse interstitial lung disease in a North American brane for MHC class I molecule assembly. Almost every T cell
cohort derived from 13 pediatric centers over a 4 year period response is controlled by the molecular interaction between
in which only two children with HP were identified.8 the clonotypically expressed αβ T cell receptor and cognate

Table 3 Animal Proteins Implicated in Hypersensitivity Pneumonitis

Disease Antigen Source

Pigeon breeder’s or pigeon fancier’s Avian droppings, feathers, serum Parakeets, budgerigars, pigeons, chickens,
disease turkeys
Pituitary snuff taker’s lung Pituitary snuff Bovine and porcine pituitary proteins
Fish meal worker’s lung Fish meal Fish meal dust
Bat lung Bat serum protein Bat droppings
Furrier’s lung Animal fur dust Animal pelts
Animal handler’s lung, laboratory Rats, gerbils Urine, serum, pelts, proteins
worker’s lung, insect proteins
Miller’s lung Sitophilus granarius (ie, wheat weevil) Dust-contaminated grain
Lycoperdonosis Puffball spores Lycoperdon puffballs

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546 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán

peptide-MHC antigen. Typically, CD8þ T cells recognize pep- sponse in HP is polarized toward a T-helper (Th)1-like reac-
tides bound to MHC class I molecules and mediate direct tion that is largely mediated by the hallmark cytokine IFN-
target cell lysis, whereas CD4þ T cells recognize pMHCII- γ.32,33 This process is dependent on the transcription factor
restricted ligands and play a more complex role in the STAT-4, which is activated by IL-12, and also on T-bet, which
coordination of adaptive immune responses.15 Specific alleles is considered the master regulator of the Th1 lineage.34
that differ from closely related alleles by only one or a few Recent studies in experimental HP have revealed that IL-17
amino acids in the peptide binding groove are frequently is associated with disease severity, suggesting that the Th17
strongly associated with disease susceptibility, including HP. cells are involved in this process.35 Importantly, the receptor
However, it is difficult to precisely define which gene(s) for IL-17 has been shown to be upregulated in lungs of
within the MHC are responsible for disease susceptibility patients with HP, further suggesting that the Th17 pathway
due to strong linkage disequilibrium across the region, which is also relevant in human disease.36 The differentiation of
contains a large number of genes relevant for immune Th17 cells is induced by transforming growth factor-β (TGF-β)
responses, including MHC class I and class II genes, tumor and IL-6 or IL-21, which upregulate expression of the Th17
necrosis factor (TNF) and complement genes, TAP genes and cell-specific transcription factor RORγ.37 The prototypic Th17
human leukocyte antigen (HLA)-DM genes.16 IL-17A and IL-17F can both bind to the IL-17RA receptor and
Exposure to some environmental factors may also increase induce various proinflammatory cytokines/chemokines, in-

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the risk for HP. For example, high pesticide exposure and use cluding CXCL8, IL-6, CCL2, TNF-α, IL-1β, granulocyte-colony
of organochlorine and carbamate pesticides have been asso- stimulating factor (G-CSF) and granulocyte-macrophage col-
ciated with farmer’s lung in mutually adjusted models.17 ony-stimulating factor (GM-CSF).38 However, the interplay of
Respiratory viral infection may also contribute to the devel- T cell subsets in HP is complex, and the disease cannot be
opment of HP. Thus proteins from the influenza A virus have easily categorized as a Th1- or Th17-mediated disease.
been revealed in bronchoalveolar lavage (BAL) macrophages Immune abnormalities associated with progression to
from most patients with acute HP.18 Viral infection induces fibrosis are unclear. An increase in CD4 þ :CD8þ ratio, a
the overexpression of B7 costimulatory molecules (CD80, decrease of γδT cells, a skewing toward Th2 as opposed to
CD86), increasing the antigen-presenting capacity by alveolar Th1, and exhaustion of effector CD8þ T cells have been also
macrophages.19 found in chronic patients that progress to fibrosis.32 Also,
Interestingly, strong evidence indicates that cigarette increase of Th17 cells may promote collagen deposition in the
smoking protects from HP. Accordingly, farmer’s lung, PBD, lung in response to chronic exposure of HP antigens.39
and other types of HP occur more frequently in nonsmokers
than in smokers under the same risk of exposure.20–25 The
Clinical Presentation
reasons for this putative protection remain unclear. It has
been shown that nicotine has a significant antiinflammatory The clinical behavior of HP is usually similar, regardless of the
effect in experimental HP, decreasing the lung lymphocyte type or nature of the inhaled dust. The disease has been
population and reducing the expression of TNF-α, interleukin classically classified as acute, subacute, or chronic clinical
(IL)-10, and interferon-gamma (IFN-γ) by alveolar macro- forms that seem to depend on several factors, including the
phages.26 Also, nicotine has been shown to deplete the frequency, amount, and duration of antigen exposure; the
calcium stores of T lymphocytes, probably impairing their nature of the inhaled dust; and genetic or other factors that
function.27 Similarly, stimulation of the nAChR α7 subtype participate in the immunopathological response.
receptor led to decreased T cell proliferation.28 However,
although HP is less frequent in smokers, when it occurs in Acute HP
them it appears to be more severe and chronic. Thus, for Episodes of the acute form of HP usually result from intermit-
example, in farmers who smoke and develop HP, the 10-year tent and intense exposure of the provoking antigen. Symp-
survival rate is significantly lower than in patients with toms of the acute disease occur abruptly, a few hours after
farmer’s lung who do not smoke.29 exposure, and consist of a flulike syndrome characterized by
fever, chills, headache, and malaise. Patients may present
with severe dyspnea, chest tightness, and nonproductive
Mechanisms of Disease
cough; these symptoms may start after patients return (and
In acute HP, lung inflammation appears to be mediated by reexpose) to an environment from which they have been
immune complexes as evidenced by the presence of high absent for a short time. On physical examination patients
titers of antigen-specific precipitating serum immunoglobu- present with tachypnea and diffuse fine rales. Acute episodes
lin G (IgG), and an increase of lung neutrophils, most of them often follow exposure to the antigen within enclosed spaces
primed for an enhanced respiratory burst.30 By contrast, with poor ventilation, for example in farmers that feed
strong evidence supports that subacute and chronic HP is livestock in barns during the winter. In the absence of
characterized by an exaggerated T cell–mediated immune exposure, this clinical form gradually improves and even
inflammatory response. Increased migration, local prolifera- resolves over the next days but often recurs after the next
tion, and decreased programmed cell death contribute to the antigen contact.
characteristic T-lymphocytic alveolitis.1,31,32 On the other Acute HP may be ignored because symptoms may be very
hand, several studies have indicated that the immune re- similar to those observed in an acute viral or bacterial

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 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán 547

respiratory infection. Moreover, patients with proved HP may the first category, patients present with recurrent systemic
show a rise of influenza viruses or Mycoplasma pneumoniae symptoms a few hours following antigen exposure (that is,
antibody titers.40,41 In farmers, the acute form of HP should be acute HP). The subacute presentation was considered only a
distinguished from an influenza-like illness resulting from variant of the acute form of the disease, with similar but
the nonimmunological reaction to inhaled mold dusts (bac- attenuated symptoms remaining for days or weeks.40 Patients
terial or fungal toxins), called organic dust toxic syndrome.42 in the second category correspond to chronic ones.
These patients, however, have no precipitins to antigens and
usually present with normal clinical findings on respiratory Acute Exacerbations in Chronic HP
examination and chest radiographs. Some patients with chronic HP may occasionally experience
an acute exacerbation (as described in IPF) characterized by
Subacute HP sudden and rapid deterioration of dyspnea, severe increase of
The subacute form of HP usually results from continual low- hypoxemia, and the appearance of new ground-glass opaci-
level exposure to inhaled antigens or more likely from the ties or consolidation. This severe process seems to be associ-
progression of an undiagnosed acute HP. This clinical form is ated with male sex, smoking habit, more fibrosis and less
characterized by gradual development of productive cough ground-glass opacities in initial high-resolution computed
and dyspnea over several days to weeks. Some patients tomographic (HRCT) scan, and worse pulmonary function

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present with fever during the first weeks, and fatigue, an- tests at the time of diagnosis. Lung biopsy/autopsy during the
orexia, and weight loss are commonly observed. Physical acute exacerbation reveals predominantly diffuse alveolar
examination usually reveals tachypnea and bibasilar inspira- damage (DAD) but also organizing pneumonia.45,46
tory crackles. Wheezing, provoked by small airway obstruc-
tion, is not common, but it occurs in some patients. The
Pulmonary Function Tests
differential diagnosis includes granulomatous lung disorders,
primarily sarcoidosis, lymphocytic interstitial pneumonia Lung function abnormalities play an important role in deter-
(LIP), drug-induced lung disease, idiopathic cellular nonspe- mining the severity of the disease during the first evaluation
cific interstitial pneumonia (NSIP), and respiratory bronchi- and follow-up but are neither specific nor diagnostic for HP
olitis/interstitial lung disease (RB-ILD) (a smoker-related lung because similar modifications are found in many other inter-
disorder) or other bronchiolar disorders.1 stitial lung diseases (ILDs).1 HP patients show a restrictive
ventilatory defect characterized by a decrease of forced vital
Chronic HP capacity (FVC) and total lung capacity (TLC). However, be-
It has been proposed that the chronic presentation of HP may cause HP affects the small airways, a mixed obstructive/
result from two different clinical scenarios: (1) from unrec- restrictive functional pattern may be observed in some
ognized acute/subacute episodes (recurrent chronic HP) and patients, with decrease in forced expiratory flow in the
(2) from a slowly progressive disease in patients exposed to midexpiratory phase.47,48 An early reduction of diffusing
low levels of antigen and without history of acute episodes capacity for carbon monoxide (DLCO) is often found. HP
(insidious chronic HP). Chronic HP presents as prolonged and patients exhibit hypoxemia at rest that usually worsens
relentless pneumonitis with progressive dyspnea on exertion, with exercise. Patients with mild/moderate disease may be
cough, fatigue, malaise, and weight loss. Despite chronicity, normoxemic at rest, but oxygen desaturation is usually
these patients may stabilize or even improve after antigen observed with exercise.
avoidance and antiinflammatory/immunosuppressive treat- The correlation between pulmonary functional abnormal-
ment. However, they often progress, evolving to diffuse ities and the prognosis of HP has not been properly evaluated,
fibrosis and end-stage lung disease. Digital clubbing may be but it is the general belief that patients with more severe
seen in advanced fibrotic HP and may help to predict poorer abnormalities have a worse outcome. However, some patients
outcome. Chronic HP may mimic idiopathic pulmonary fibro- with severe impairment may recover, whereas others with
sis (IPF), and in this case the differential diagnosis may be relatively mild functional abnormalities at the onset of dis-
extremely difficult. Interestingly, some patients with HP, ease may develop progressive pulmonary fibrosis or airway
primarily farmers with recurrent acute episodes, develop obstruction.
an obstructive lung disease with emphysematous changes
instead of lung fibrosis. Differential diagnosis of chronic HP
Imaging
includes fibrotic NSIP and, importantly, IPF.43
It is important to emphasize that, despite the wide use of Chest radiographs can be useful in the diagnostic evaluation
this clinical (acute, subacute, chronic) classification, signifi- of suspected HP, but there are no specific findings, and some
cant overlap between these interrelated categories often patients with HP may have normal chest radiographs. Abnor-
occur, which is at least partially due to the lack of clear and malities in acute and subacute HP patients include poorly
standardized criteria to differentiate between these various defined small nodules throughout both lungs and ground-
forms. The classification is further complicated because glass attenuation, either patchy or diffuse. Airspace consoli-
chronic HP may still be active and progressive. Actually, dation can also be observed. In advanced chronic HP, findings
cluster analysis of a large group of HP patients failed to also include pulmonary fibrosis with linear interstitial opaci-
identify these three categories and proposed only two.44 In ties, lung distortion, and honeycombing. In these cases,

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548 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán

capacity (TLC), and its extent correlates with the presence of a

mixed obstructive/restrictive pattern, whereas ground-glass
opacification and reticulation correlate with a restrictive
pattern.50,51 Bronchiolar wall thickening may also occur,
and thin-walled cysts have been found occasionally in pa-
tients with subacute HP.52 Patients with chronic disease have
subacute changes (ground-glass opacities and micronodules)
with both fine and coarse reticular opacities that may even-
tually evolve to honeycombing. Traction bronchiectasis and
bronchiolectasis frequently accompany these findings
(►Fig. 3). Often, the distinction of chronic fibrotic HP from
IPF and nonspecific interstitial pneumonia (NSIP), another
idiopathic interstitial pneumonia that mimics HP, may be
extremely difficult. It has been proposed that the presence of
lobular areas with decreased attenuation, centrilobular nod-
ules, and a lack of lower zone predominance of the abnor-

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Figure 1 High-resolution computed tomographic scan in a patient malities are characteristics that best differentiate chronic HP
with acute hypersensitivity pneumonitis. The predominant finding is from IPF and NSIP.53 Thin-walled cysts located primarily in
ground-glass opacities and some centrilobular nodules (arrows). areas of ground-glass opacities were also seen more com-
monly in patients with chronic HP than in those with IPF or
cardiomegaly may develop as a result of chronic pulmonary NSIP (►Fig. 2). Nevertheless, it is important to emphasize that
hypertension and cor pulmonale. honeycombing was seen in 64% of patients with chronic HP.53
It has been argued that the changes observed in HRCT may
Computed Tomography correlate with the histopathological abnormalities.54–56 Ac-
Computed tomography (CT) and HRCT provide a better- cordingly, ground-glass attenuation appears to reflect the
quality and more precise estimation of the pattern, extent, presence of small granulomas within the alveolar septa and
and distribution of the disease and correlate better with with the partial filling of airspaces with inflammatory cells.
clinical and histopathological parameters.49 Micronodules seem to correspond to cellular bronchiolitis,
In acute HP, HRCT manifestations include a diffuse and noncaseating granulomas, and bronchiolocentric interstitial
hazy increased parenchymal density and patchy or wide- pneumonitis. Finally, the reticular opacities, traction bron-
spread airspace opacification (►Fig. 1). The characteristic chiectasis, and honeycombing are related to the presence of
features of subacute HP consist of patchy or diffuse bilateral fibrosis, and confirm chronic, advanced disease.
ground-glass attenuation, poorly defined small round cen- For unclear reasons, patients with farmer’s lung may
trilobular nodules (usually <5 mm in diameter), and lobular evolve to a chronic obstructive pulmonary disease (COPD)-
areas of decreased attenuation and vascularity on inspiratory like pattern more frequently than interstitial fibrosis.57,58
images and of air trapping on expiratory images.49 A CT scan
obtained at the end of expiration is useful to improve the Lung Scintigraphy
visualization of the patchy air-trapping images (►Fig. 2). Clearance of micronic aerosols of technetium 99m-labeled
These hypoattenuated regions that persist on expiration are diethylenetriamine pentaacetic acid (99mTc-DTPA) may eval-
indicative of bronchiolar inflammation and obstruction. Air uate alveolar epithelial integrity. Patients with PBD and
trapping is also reflected in pulmonary function tests as an asymptomatic pigeon breeders with high specific antibody
increased ratio of the residual volume (RV) to the total lung levels exhibit increased rates of clearance of 99mTc-DTPA,

Figure 2 Subacute phase of hypersensitivity pneumonitis due to exposure to avian antigens (pigeons). (A) Inspiratory high-resolution computed
tomographic (HRCT) image shows extensive ground-glass attenuation and small centrilobular nodules (arrows). (B) Expiratory HRCT scan showing
air trapping (arrows) that can be seen as a failure of an area to increase in attenuation.

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 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán 549

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Figure 3 Three different levels of a high-resolution computed tomographic scan in a patient with chronic hypersensitivity pneumonitis. (A) On a
background of ground-glass attenuation, extensive reticular opacities and traction bronchiectasis are frequently observed. (B) There is also
architectural distortion of the lung parenchyma. A remarkable finding in some chronic advanced patients is the presence of honeycombing (B and
C arrows).

whereas asymptomatic (antigen-exposed) subjects without represents a “normal” inflammatory response or whether
sensitization had intermediate rates of clearance.59 However, the apparent “normal” individuals have a low-intensity al-
the usefulness of this method is uncertain because there is veolitis without clinical consequences.64 Although for a long
overlap in clearance rates of the radioisotope between ILD time it was considered that CD8þ T cell subset was predomi-
patients and normal subjects and because cigarette smoking nant, recent evidence demonstrates that the CD4:CD8 ratio
and other variables influence the respiratory clearance of varied according to several variables, including, the type of
99mTc-DTPA. causative antigen, the clinical status (ie, acute/subacute vs
chronic), smoking habit, and others.32,65 A few B lymphocytes
and plasma cells can also be present in BAL fluids, mainly after
Laboratory Tests
recent antigen exposure or subacute active disease.66,67 On
Routine laboratory tests are not useful either for diagnosis or the other hand, an increase of neutrophils together with
to monitor disease activity or progression. lymphocytes characterizes the acute attacks.68,69 There is
Serum-precipitating IgG antibodies against the offending
antigen are usually detectable. However, the presence or
absence of these antibodies should be taken carefully because
similar antibodies may be found in exposed but asymptom-
atic individuals, and false-negative results may occur, mainly
in chronic cases.60,61 Avian antigen-specific IgG and IgA can
be easily detectable in saliva samples,62,63 which may be a
useful approach, especially in children, and can also facilitate
sampling for epidemiological studies.

Bronchoalveolar Lavage
Patients with HP usually display an increase in the total cell
count with a remarkable elevation in the percentage of
lymphocytes, usually T cells (►Fig. 4). Importantly however,
an increase in BAL lymphocytes is also observed in some Figure 4 Bronchoalveolar lavage cell profile in hypersensitivity
asymptomatic HP-antigen-exposed individuals. In these pneumonitis is characterized by a noteworthy increase of lymphocytes
cases, it is unclear whether the increase of lymphocytes (hematoxylin and eosin; 40).

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550 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán

Figure 5 Photomicrographs of subacute hypersensitivity pneumonitis in lungs showing two common and characteristic histopathological
features. (A) Interstitial lymphocytic infiltrate and a poorly formed granuloma (arrowhead). (B) The granuloma is typically found in peribronchiolar
localization (arrow). Epithelioid and multinucleated giant cells form a loosely organized aggregate without the compact architecture that
characterizes other granulomatous disorders such as sarcoidosis (hematoxylin and eosin).

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also an increase of mast cells that may be useful (together suggested that cathepsin-K is a sensitive immunohistochem-
with the increase of lymphocytes) for the differential diagno- ical marker for detection of microgranulomas.81 Bridging
sis with other ILDs.70 Actually, although there is no unique fibrosis between centrilobular and subpleural areas, and
finding for HP, the described changes may eventually help to areas close to the interlobular septa is frequently seen in
distinguish HP from other frequent ILDs.71 chronic HP. Interestingly, patients with concurrent histopath-
ological features of pulmonary alveolar proteinosis and HP
have been recently reported, although the putative linkage is
Morphology
unknown.82
Little is know about the pathological changes of the acute
form of HP. A recent review of cases with new and rapid onset
Diagnosis
of symptoms reported that, in addition to the bronchiolocen-
tric lymphoplasmacytic infiltrate, fibrin deposition and neu- Clinicians should maintain a high index of suspicion for HP in
trophilic infiltrates are usually present.72 However, hyaline patients with clinical, radiological, and functional features of
membranes, pneumocyte atypia, and fibroblastic prolifera- ILD. An environmental antigen is essential for the development
tion as attributes of acute lung injury or diffuse alveolar of HP and must be considered when reviewing a patient’s
damage were not found. clinical history. Unfortunately, it is often impossible to identify
Subacute HP is characterized by a bronchiolocentric pneu- the causal antigen, or the interval between exposure and the
monitis with interstitial lymphoplasmacytic infiltrates, cel- onset of symptoms is so long that the cause-and-effect rela-
lular bronchiolitis, and small, poorly differentiated, loosely tionship is difficult to establish. Alternatively, some patients
arranged granulomas73 (►Fig. 5). In the absence of granulo- have a positive history of exposure to HP antigens, and even
mas, the histopathological pattern in subacute/chronic HP specific circulating antibodies, but they have another ILD.
can be very similar to that observed in NSIP.74 Occasional The elements that contribute to diagnosis have been
areas of organizing pneumonia with Masson bodies are often previously published.1 Diagnosis of acute HP based on (1)
seen. Bronchiole pathology may vary, and while proliferative evidence of exposure (usually substantial), documented by
bronchiolitis obliterans has been described in farmer’s lung, history and specific antibodies against the offending antigen;
constrictive bronchiolitis is primarily seen in PBD.75,76 Occa- (2) a flulike syndrome; (3) increased BAL neutrophils and
sionally, peribronchiolar metaplasia (peribronchiolar prolif- lymphocytes; and (4) significant improvement after remov-
eration of bronchial epithelium along thickened ing the patient from the suspected environment, and wors-
peribronchiolar alveolar walls) can be the primary histologi- ening after reexposure.
cal finding in the lung biopsy.77 Diagnosis of subacute HP includes (1) evidence of exposure
Chronic HP is characterized by variable degrees of fibrotic and specific antibodies against the offending antigen; (2)
changes, and in advanced cases, fibrosis can be severe, with progressive dyspnea; (3) BAL lymphocytosis (usually >40% in
destruction of the lung architecture, and honeycomb changes nonsmokers); (4) ground-glass opacities, poorly defined cen-
that may be difficult to distinguish from usual interstitial trilobular nodules, and mosaic attenuation on inspiratory
pneumonia (UIP) (►Fig. 6).78,79 Also, some chronic patients images and of air trapping on expiratory CT images; (5)
may show a relatively homogeneous linear fibrosis resem- restrictive functional pattern plus hypoxemia and reduced
bling fibrotic NSIP.79,80 In patients in whom the pattern of diffusing capacity for carbon monoxide (DLCO); and (6) partial
fibrosis is consistent with UIP or NSIP, bronchiolocentric improvement after removing the patient from the suspected
localization of the fibrotic lesions and the presence of Schau- environment, and worsening after reexposure.
mann bodies, giant multinucleated cells, or granulomas, may Diagnosis of chronic HP is based on (1) evidence of
support the diagnosis of chronic HP. It has been recently exposure and specific antibodies against the offending

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 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán 551

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Figure 6 (A, B, C) Photomicrographs of three patients with chronic hypersensitivity pneumonitis. Lung tissues show chronic interstitial
mononuclear inflammation, fibroblastic foci, interstitial fibrosis, and distortion of the lung architecture. These lesions may be misinterpreted as
usual interstitial pneumonia. ((A) Masson trichrome staining, (B, C) hematoxylin and eosin staining.)

antigen (or antigen-induced lymphocyte proliferation); (2) corticosteroids or with antimycobacterial therapy or both or
clinical behavior of chronic ILD; (3) BAL lymphocytosis; (4) even simply by avoiding further exposure, with significant
reticular opacities superimposed to subacute changes on improvement.87,88 Also, no controlled studies of pediatric HP
HRCT; (5) restrictive functional pattern plus hypoxemia and have been performed, and treatment regimens are mainly
reduced DLCO; and (6) lung biopsy if there is insufficient extrapolated from adults. Monthly high-dose intravenous
evidence for diagnosis. methylprednisolone constituted the basic treatment in a
small cohort of patients in Denmark (15 mg/kg OD [every
day] for 3 days). Additionally, oral prednisolone was initiated
Therapeutic Approach and Prognosis
immediately, and other immunosuppressive drugs such as
Early diagnosis and avoidance of further antigen exposure are azathioprine or cyclosporine were employed in severe cases
crucial in the management of these patients. Although some or in those with no obvious improvement in lung function
of them report complete remission of the disease despite within 2 to 3 months or in cases of relapse.7 Most children
subsequent exposure to the offending antigen, in most cases improved, and no mortality was seen.
continued antigen inhalation is one of the identified causes of Thalidomide, an antiinflammatory and immunomodula-
an adverse prognosis. tory drug, has proved useful in some immunopathological
Corticosteroids are recommended in acute, severe, and disorders, including sarcoid skin lesions.89 This drug inhibits
subacute/chronic disease. However, long-term efficacy of these the production of TNF-α, IL-12p40, and IL-18 by alveolar
agents has not been determined in appropriate clinical trials. macrophages obtained from patients with diverse ILDs, in-
Old evidence suggests that in farmer’s lung corticosteroids did cluding HP.90 However, there are no controlled clinical trials
not influence the long-term outcome of the disease.83 in HP. Finally, in chronic progressive fibrotic HP patients, lung
In subacute/chronic progressive cases, the empirical transplantation should be considered.
scheme consists of 0.5 mg/kg/d of prednisone for a month If the diagnosis is correctly and timely done, outcome is
followed by a gradual reduction until a maintenance dose of usually good in acute and subacute HP. By contrast, patients
10 to 15 mg per day is reached.1 This treatment should be with chronic disease often progress to irreversible pulmonary
discontinued if there is no clinical or functional response after fibrosis, and
30% of them die within a few years of diagno-
1 year. sis.91,92 In general, the risk of mortality increases with evi-
Inhaled steroids have been occasionally used to reduce the dence of fibrosis at lung biopsy or HRCT or with a more severe
severe side effects of prolonged systemic steroid therapy; respiratory impairment on pulmonary function tests.91–94
however, evidence of efficacy is scanty.84–86 Patients with hot A report from the National Center for Health Statistics
tub lung provoked by Mycobacterium avium complex organ- showed that overall age-adjusted death rates increased signifi-
isms contaminating hot tub water have been treated with cantly between 1980 and 2002, from 0.09 to 0.29 per million.95

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552 Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán

Proportionate mortality ratios were significantly high for agri- 12 Ando M, Hirayama K, Soda K, Okubo R, Araki S, Sasazuki T. HLA-
cultural production, livestock and agricultural production, crop. DQw3 in Japanese summer-type hypersensitivity pneumonitis
The death rate was greater in farming states, where farmer’s induced by Trichosporon cutaneum. Am Rev Respir Dis
1989;140(4):948–950
lung accounted for nearly 40% of all HP deaths. Importantly
13 Camarena A, Juárez A, Mejía M, et al. Major histocompatibility
however, the study demonstrated that nearly 56% of HP deaths complex and tumor necrosis factor-alpha polymorphisms in pi-
were due to unspecified organic dust/etiological agents. geon breeder’s disease. Am J Respir Crit Care Med 2001;
163(7):1528–1533
14 Aquino-Galvez A, Camarena A, Montaño M, et al. Transporter
Conclusions associated with antigen processing (TAP) 1 gene polymorphisms
in patients with hypersensitivity pneumonitis. Exp Mol Pathol
HP is a complex and multifaceted disease that should be
2008;84(2):173–177
included in the differential diagnosis of any patient consult- 15 Bridgeman JS, Sewell AK, Miles JJ, Price DA, Cole DK. Structural and
ing with an ILD. Early diagnosis and avoiding further antigen biophysical determinants of αβ T-cell antigen recognition. Immu-
exposure improve survival. The diagnosis requires a high nology 2012;135(1):9–18
index of suspicion by the clinician and rests on the combina- 16 Wucherpfennig KW, Sethi D. T cell receptor recognition of self and
foreign antigens in the induction of autoimmunity. Semin Immu-
tion of findings from environmental/occupational exposure
nol 2011;23(2):84–91
history, clinical behavior, serology, HRCT, BAL, and, if neces- 17 Hoppin JA, Umbach DM, Kullman GJ, et al. Pesticides and other

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sary, lung biopsy. Treatment with corticosteroids is usually agricultural factors associated with self-reported farmer’s lung
indicated, but their long-term effect in this disease is unclear. among farm residents in the Agricultural Health Study. Occup
In chronic patients with progressive fibrosis and refractory to Environ Med 2007;64(5):334–341
medical therapy, lung transplantation should be considered. 18 Dakhama A, Hegele RG, Laflamme G, Israël-Assayag E, Cormier Y.
Common respiratory viruses in lower airways of patients with
Experimental and clinical evidence points toward a T cell–
acute hypersensitivity pneumonitis. Am J Respir Crit Care Med
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T cell subsets in the development of the disease needs to be 19 Israël-Assayag E, Dakhama A, Lavigne S, Laviolette M, Cormier Y.
elucidated. A better understanding of the immunopathologi- Expression of costimulatory molecules on alveolar macrophages
cal mechanisms may help to find HP-specific biomarkers and in hypersensitivity pneumonitis. Am J Respir Crit Care Med
1999;159(6):1830–1834
may also open new therapeutic strategies.
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