543

Immunopathology, Diagnosis, and Management

of Hypersensitivity Pneumonitis
Moiss Selman, M.D. 1

Ivette Buenda-Roldn, M.D. 1

1 Instituto Nacional de Enfermedades Respiratorias Ismael Coso

Villegas, Mxico

Address for correspondence and reprint requests Moiss Selman,

M.D., Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502,
CP 14080, Mxico DF, Mxico (e-mail: mselmanl@yahoo.com.mx).

Abstract

Keywords

hypersensitivity
pneumonitis
extrinsic allergic
alveolitis
lung brosis

Hypersensitivity pneumonitis (HP) is an inammatory 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.
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 brosis. The pathology
is characterized by a bronchiolocentric interstitial mononuclear cell inltration, nonnecrotizing poorly formed granulomas, cellular pneumonitis and variable degrees of
brosis. However, morphological diagnosis of HP is complicated because the subacute/
chronic forms may be difcult to distinguish from idiopathic pulmonary brosis/usual
interstitial pneumonia and nonspecic interstitial pneumonia. In general, diagnosis of
HP represents a challenge for clinicians that need to weigh a constellation of clinical,
laboratory, radiographic and (when available) pathological evidence for each patient to
assess the certainty of the diagnosis. The cornerstone of therapy is antigen avoidance.
Although clinical trials are scanty, corticosteroids are usually indicated based upon
expert opinion. In this review we summarize the current evidence regarding the
diagnostic criteria and therapeutic strategies as well as the immunopathological
mechanisms putatively implicated in the development of the disease.

Hypersensitivity pneumonitis (HP) is a complex syndrome

that results from the exposure to a wide variety of nely
dispersed antigens of size suitable for reaching the alveolar
spaces (usually particles smaller than 5 m) that include
mammalian and avian proteins, fungi, thermophilic bacteria,
and certain small-molecular-weight chemical compounds that
combine with host proteins to form haptens.1 The incidence
and prevalence of HP are difcult to estimate precisely because
the disease represents a syndrome with different causative
agents, and epidemiological studies lack uniform diagnostic
criteria. Interestingly, however, the incidence of HP is low if we
consider that the offending antigens are numerous and widely
distributed around the world. Actually, an extensive number of
etiologic agents and sources of antigens capable of inducing HP
have been described, and the list of environments and agents is
always increasing (Tables 1, 2, 3). Thus, for example, in the

Issue Theme Orphan Lung Diseases;

Guest Editor, Jay H. Ryu, M.D.

last 10 years it has been demonstrated that heated water

colonized by Mycobacterium avium may provoke HP in hot tub
users.2 Likewise, Mycobacterium immunogenum may contaminate metal working uid (MWF), causing disease when they
become aerosolized, mostly in automotive industries.3 Workers with exposure to MWF are generally in the manufacturing
sector in processes like metal machining, forging, and stamping. HP has also been described in individuals exposed to
Cytophaga endotoxin in a nylon plant.4 In these workers
Cytophaga was isolated from the plant air-conditioning system,
and patients showed precipitins to Cytophaga antigen. Finally,
indirect exposure through a partner has been found to cause
HP, which can complicate the identication of the offending
antigen.
The low incidence of HP suggests that genetic or additional
environmental factors are necessary to develop the disease.

Copyright 2012 by Thieme Medical

Publishers, Inc., 333 Seventh Avenue,
New York, NY 10001, USA.
Tel: +1(212) 584-4662.

DOI http://dx.doi.org/
10.1055/s-0032-1325163.
ISSN 1069-3424.

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Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Selman, Buenda-Roldn

Table 1 Fungal and Bacterial Antigens Implicated in Hypersensitivity Pneumonitis

Disease

Antigen

Source

Farmers lung

Faeni rectivirgula

Moldy hay, grain, silage

Ventilation pneumonitis;
humidier lung; air conditioner
lung

Thermoactinomyces vulgaris,
Thermoactinomyces sacchari,
Thermoactinomyces candidus
Klebsiella oxytoca

Contaminated forced-air systems; water

reservoirs

Bagassosis

T. vulgaris

Moldy sugarcane (ie, bagasse)

Mushroom workers lung

T. sacchari

Moldy mushroom compost

Enoki mushroom workers lung

(Japan)

Penicillium citrinum

Moldy mushroom compost

Suberosis

Thermoactinomyces viridis, Aspergillus

fumigatus, Penicillium frequentans Penicillium
glabrum

Moldy cork

Detergent lung; washing

powder lung

Bacillus subtilis enzymes

Detergents (during processing or use)

Malt workers lung

Aspergillus fumigatus, Aspergillus clavatus

Moldy barley

Sequoiosis

Graphium, Pullularia, and Trichoderma spp.,

Aureobasidium pullulans

Moldy wood dust

Maple bark strippers lung

Cryptostroma corticale

Moldy maple bark

Cheese washers lung

Penicillium casei, A. clavatus

Moldy cheese

Woodworkers lung

Alternaria spp., wood dust

Oak, cedar, and mahogany dust, pine and

spruce pulp

Hardwood worker s lung

Paecilomyces

Kiln-dried wood

Paprika slicers lung

Mucor stolonifer

Moldy paprika pods

Sauna takers lung

Aureobasidium spp., other sources

Contaminated sauna water

Familial HP

B. subtilis

Contaminated wood dust in walls

Wood trimmers lung

Rhizopus spp., Mucor spp.

Contaminated wood trimmings

Composters 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 makers lung

Botrytis cincrea

Mold on grapes

Woodsmans disease

Penicillium spp.

Oak and maple trees

Thatched roof lung

Sacchoromonospora viridis

Dead grasses and leaves

Tobacco growers lung

Aspergillus spp.

Tobacco plants

Potato riddlers lung

Thermophilic actinomycetes, F. rectivirgula,

T. vulgaris, Aspergillus spp.

Moldy hay around potatoes

Summer-type pneumonitis

Trichosporon cutaneum

Contaminated old houses

Dry rot lung

Merulius lacrymans

Rotten wood

Stipatosis

Aspergillus fumigatus, T. actinomycetes

Esparto dust

Machine operators lung

Mycobacterium immunogenum, Pseudomona

uorescens

Aerosolized metalworking uid

Residential provoked
pneumonitis

Aureobasidium pullulans

Residential exposure

Humidier lung

Naegleria gruberi, Acanthamoeba polyphaga,

Acanthamoeba castellani, Bacillus spp., others

Contaminated water from home humidier,

ultrasonic misting fountains

Also, it is likely that a number of mild cases are misdiagnosed

as viral infections, and some severe advanced cases as idiopathic pulmonary brosis (IPF) or other brotic lung
disorders.
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According to several studies the prevalence of farmers

lung, one of the best-known types of HP, can be estimated in
0.5 to 3% of exposed farmers.5 Pigeon breeders disease (PBD),
another common form of HP, seems to occur frequently

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Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Selman, Buenda-Roldn

545

Table 2 Chemicals Implicated in Hypersensitivity Pneumonitis

Disease

Antigen

Source

Paulis reagent alveolitis

Sodium diazobenzene sulfate

Laboratory reagent

Chemical workers lung

Isocyanates; trimellitic anhydride

Polyurethane foams, spray paints, elastomers,

special glues

Dental technician s lung

Methyl methacrylate

Polishing and grinding prostheses

Vineyard sprayers lung

Copper sulfate

Bordeaux mixture

Pyrethrum HP

Pyrethrum

Pesticide

Epoxy resin lung

Phthalic anhydride

Heated epoxy resin

UNKNOWN
Moldy typesetting water

Coptic lung (mummy handlers lung)

Cloth wrappings of mummies

Grain measurers lung

Cereal grain

Coffee workers lung

Coffee bean dust

Tap water lung

Contaminated tap water

Tea growers lung

Tea plants

Mollusk shell HP

Sea snail shell

Swimming pool workers lung

Aerosolized endotoxin from pool

Water sprays and fountains

among bird fanciers taking care of hundreds or thousands of

pigeons (ie 20 to 20,000 per 100,000 persons at risk).1
However, the prevalence of PBD among people with only a
few birds at home is uncertain. Recently, in a large, generalpopulation-based cohort of HP patients, the overall incidence
rate was
1 per 100,000 in the UK population.6 The disease
appears to be a rare interstitial lung disease (ILD) in children,
and a recent report in Denmark showed an incidence of 2/
year and a point prevalence of 4/1,000,000 children.7 Incidence/prevalence seems to be even lower according to the
few pediatric cases reported worldwide and in relation to a
study of lung biopsy from 101 immunocompetent children
with diffuse interstitial lung disease in a North American
cohort derived from 13 pediatric centers over a 4 year period
in which only two children with HP were identied.8

Pathogenic Mechanisms
HP is an immunopathological disorder occurring in susceptible individuals where both humoral and cellular mechanisms
participate in the development of the lung lesions. However,
the genetic basis of the disease is poorly understood. Some
studies indicate that gene polymorphisms of major histocompatibility complex (MHC) class II alleles are implicated in the
risk to develop the disease.913 Also, polymorphisms in the
transporters associated with antigen processing (TAP) genes
may also be involved.14 TAP play an important role transporting peptides across the endoplasmic reticulum membrane for MHC class I molecule assembly. Almost every T cell
response is controlled by the molecular interaction between
the clonotypically expressed T cell receptor and cognate

Table 3 Animal Proteins Implicated in Hypersensitivity Pneumonitis

Disease

Antigen

Source

Pigeon breeders or pigeon fanciers

disease

Avian droppings, feathers, serum

Parakeets, budgerigars, pigeons, chickens,

turkeys

Pituitary snuff takers lung

Pituitary snuff

Bovine and porcine pituitary proteins

Fish meal workers lung

Fish meal

Fish meal dust

Bat lung

Bat serum protein

Bat droppings

Furriers lung

Animal fur dust

Animal pelts

Animal handlers lung, laboratory

workers lung, insect proteins

Rats, gerbils

Urine, serum, pelts, proteins

Millers lung

Sitophilus granarius (ie, wheat weevil)

Dust-contaminated grain

Lycoperdonosis

Puffball spores

Lycoperdon puffballs

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Bible printers lung

Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

peptide-MHC antigen. Typically, CD8 T cells recognize peptides bound to MHC class I molecules and mediate direct
target cell lysis, whereas CD4 T cells recognize pMHCIIrestricted ligands and play a more complex role in the
coordination of adaptive immune responses.15 Specic alleles
that differ from closely related alleles by only one or a few
amino acids in the peptide binding groove are frequently
strongly associated with disease susceptibility, including HP.
However, it is difcult to precisely dene which gene(s)
within the MHC are responsible for disease susceptibility
due to strong linkage disequilibrium across the region, which
contains a large number of genes relevant for immune
responses, including MHC class I and class II genes, tumor
necrosis factor (TNF) and complement genes, TAP genes and
human leukocyte antigen (HLA)-DM genes.16
Exposure to some environmental factors may also increase
the risk for HP. For example, high pesticide exposure and use
of organochlorine and carbamate pesticides have been associated with farmers lung in mutually adjusted models.17
Respiratory viral infection may also contribute to the development of HP. Thus proteins from the inuenza A virus have
been revealed in bronchoalveolar lavage (BAL) macrophages
from most patients with acute HP.18 Viral infection induces
the overexpression of B7 costimulatory molecules (CD80,
CD86), increasing the antigen-presenting capacity by alveolar
macrophages.19
Interestingly, strong evidence indicates that cigarette
smoking protects from HP. Accordingly, farmers lung, PBD,
and other types of HP occur more frequently in nonsmokers
than in smokers under the same risk of exposure.2025 The
reasons for this putative protection remain unclear. It has
been shown that nicotine has a signicant antiinammatory
effect in experimental HP, decreasing the lung lymphocyte
population and reducing the expression of TNF-, interleukin
(IL)-10, and interferon-gamma (IFN-) by alveolar macrophages.26 Also, nicotine has been shown to deplete the
calcium stores of T lymphocytes, probably impairing their
function.27 Similarly, stimulation of the nAChR 7 subtype
receptor led to decreased T cell proliferation.28 However,
although HP is less frequent in smokers, when it occurs in
them it appears to be more severe and chronic. Thus, for
example, in farmers who smoke and develop HP, the 10-year
survival rate is signicantly lower than in patients with
farmers lung who do not smoke.29

Mechanisms of Disease
In acute HP, lung inammation appears to be mediated by
immune complexes as evidenced by the presence of high
titers of antigen-specic precipitating serum immunoglobulin G (IgG), and an increase of lung neutrophils, most of them
primed for an enhanced respiratory burst.30 By contrast,
strong evidence supports that subacute and chronic HP is
characterized by an exaggerated T cellmediated immune
inammatory response. Increased migration, local proliferation, and decreased programmed cell death contribute to the
characteristic T-lymphocytic alveolitis.1,31,32 On the other
hand, several studies have indicated that the immune reSeminars in Respiratory and Critical Care Medicine

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Selman, Buenda-Roldn

sponse in HP is polarized toward a T-helper (Th)1-like reaction that is largely mediated by the hallmark cytokine IFN.32,33 This process is dependent on the transcription factor
STAT-4, which is activated by IL-12, and also on T-bet, which
is considered the master regulator of the Th1 lineage.34
Recent studies in experimental HP have revealed that IL-17
is associated with disease severity, suggesting that the Th17
cells are involved in this process.35 Importantly, the receptor
for IL-17 has been shown to be upregulated in lungs of
patients with HP, further suggesting that the Th17 pathway
is also relevant in human disease.36 The differentiation of
Th17 cells is induced by transforming growth factor- (TGF-)
and IL-6 or IL-21, which upregulate expression of the Th17
cell-specic transcription factor ROR.37 The prototypic Th17
IL-17A and IL-17F can both bind to the IL-17RA receptor and
induce various proinammatory cytokines/chemokines, including CXCL8, IL-6, CCL2, TNF-, IL-1, granulocyte-colony
stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF).38 However, the interplay of
T cell subsets in HP is complex, and the disease cannot be
easily categorized as a Th1- or Th17-mediated disease.
Immune abnormalities associated with progression to
brosis are unclear. An increase in CD4 :CD8 ratio, a
decrease of T cells, a skewing toward Th2 as opposed to
Th1, and exhaustion of effector CD8 T cells have been also
found in chronic patients that progress to brosis.32 Also,
increase of Th17 cells may promote collagen deposition in the
lung in response to chronic exposure of HP antigens.39

Clinical Presentation
The clinical behavior of HP is usually similar, regardless of the
type or nature of the inhaled dust. The disease has been
classically classied as acute, subacute, or chronic clinical
forms that seem to depend on several factors, including the
frequency, amount, and duration of antigen exposure; the
nature of the inhaled dust; and genetic or other factors that
participate in the immunopathological response.

Acute HP
Episodes of the acute form of HP usually result from intermittent and intense exposure of the provoking antigen. Symptoms of the acute disease occur abruptly, a few hours after
exposure, and consist of a ulike syndrome characterized by
fever, chills, headache, and malaise. Patients may present
with severe dyspnea, chest tightness, and nonproductive
cough; these symptoms may start after patients return (and
reexpose) to an environment from which they have been
absent for a short time. On physical examination patients
present with tachypnea and diffuse ne rales. Acute episodes
often follow exposure to the antigen within enclosed spaces
with poor ventilation, for example in farmers that feed
livestock in barns during the winter. In the absence of
exposure, this clinical form gradually improves and even
resolves over the next days but often recurs after the next
antigen contact.
Acute HP may be ignored because symptoms may be very
similar to those observed in an acute viral or bacterial

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Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Subacute HP
The subacute form of HP usually results from continual lowlevel exposure to inhaled antigens or more likely from the
progression of an undiagnosed acute HP. This clinical form is
characterized by gradual development of productive cough
and dyspnea over several days to weeks. Some patients
present with fever during the rst weeks, and fatigue, anorexia, and weight loss are commonly observed. Physical
examination usually reveals tachypnea and bibasilar inspiratory crackles. Wheezing, provoked by small airway obstruction, is not common, but it occurs in some patients. The
differential diagnosis includes granulomatous lung disorders,
primarily sarcoidosis, lymphocytic interstitial pneumonia
(LIP), drug-induced lung disease, idiopathic cellular nonspecic interstitial pneumonia (NSIP), and respiratory bronchiolitis/interstitial lung disease (RB-ILD) (a smoker-related lung
disorder) or other bronchiolar disorders.1

Chronic HP
It has been proposed that the chronic presentation of HP may
result from two different clinical scenarios: (1) from unrecognized acute/subacute episodes (recurrent chronic HP) and
(2) from a slowly progressive disease in patients exposed to
low levels of antigen and without history of acute episodes
(insidious chronic HP). Chronic HP presents as prolonged and
relentless pneumonitis with progressive dyspnea on exertion,
cough, fatigue, malaise, and weight loss. Despite chronicity,
these patients may stabilize or even improve after antigen
avoidance and antiinammatory/immunosuppressive treatment. However, they often progress, evolving to diffuse
brosis and end-stage lung disease. Digital clubbing may be
seen in advanced brotic HP and may help to predict poorer
outcome. Chronic HP may mimic idiopathic pulmonary brosis (IPF), and in this case the differential diagnosis may be
extremely difcult. Interestingly, some patients with HP,
primarily farmers with recurrent acute episodes, develop
an obstructive lung disease with emphysematous changes
instead of lung brosis. Differential diagnosis of chronic HP
includes brotic NSIP and, importantly, IPF.43
It is important to emphasize that, despite the wide use of
this clinical (acute, subacute, chronic) classication, signicant overlap between these interrelated categories often
occur, which is at least partially due to the lack of clear and
standardized criteria to differentiate between these various
forms. The classication is further complicated because
chronic HP may still be active and progressive. Actually,
cluster analysis of a large group of HP patients failed to
identify these three categories and proposed only two.44 In

547

the rst category, patients present with recurrent systemic

symptoms a few hours following antigen exposure (that is,
acute HP). The subacute presentation was considered only a
variant of the acute form of the disease, with similar but
attenuated symptoms remaining for days or weeks.40 Patients
in the second category correspond to chronic ones.

Acute Exacerbations in Chronic HP

Some patients with chronic HP may occasionally experience
an acute exacerbation (as described in IPF) characterized by
sudden and rapid deterioration of dyspnea, severe increase of
hypoxemia, and the appearance of new ground-glass opacities or consolidation. This severe process seems to be associated with male sex, smoking habit, more brosis and less
ground-glass opacities in initial high-resolution computed
tomographic (HRCT) scan, and worse pulmonary function
tests at the time of diagnosis. Lung biopsy/autopsy during the
acute exacerbation reveals predominantly diffuse alveolar
damage (DAD) but also organizing pneumonia.45,46

Pulmonary Function Tests

Lung function abnormalities play an important role in determining the severity of the disease during the rst evaluation
and follow-up but are neither specic nor diagnostic for HP
because similar modications are found in many other interstitial lung diseases (ILDs).1 HP patients show a restrictive
ventilatory defect characterized by a decrease of forced vital
capacity (FVC) and total lung capacity (TLC). However, because HP affects the small airways, a mixed obstructive/
restrictive functional pattern may be observed in some
patients, with decrease in forced expiratory ow in the
midexpiratory phase.47,48 An early reduction of diffusing
capacity for carbon monoxide (DLCO) is often found. HP
patients exhibit hypoxemia at rest that usually worsens
with exercise. Patients with mild/moderate disease may be
normoxemic at rest, but oxygen desaturation is usually
observed with exercise.
The correlation between pulmonary functional abnormalities and the prognosis of HP has not been properly evaluated,
but it is the general belief that patients with more severe
abnormalities have a worse outcome. However, some patients
with severe impairment may recover, whereas others with
relatively mild functional abnormalities at the onset of disease may develop progressive pulmonary brosis or airway
obstruction.

Imaging
Chest radiographs can be useful in the diagnostic evaluation
of suspected HP, but there are no specic ndings, and some
patients with HP may have normal chest radiographs. Abnormalities in acute and subacute HP patients include poorly
dened small nodules throughout both lungs and groundglass attenuation, either patchy or diffuse. Airspace consolidation can also be observed. In advanced chronic HP, ndings
also include pulmonary brosis with linear interstitial opacities, lung distortion, and honeycombing. In these cases,
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respiratory infection. Moreover, patients with proved HP may

show a rise of inuenza viruses or Mycoplasma pneumoniae
antibody titers.40,41 In farmers, the acute form of HP should be
distinguished from an inuenza-like illness resulting from
the nonimmunological reaction to inhaled mold dusts (bacterial or fungal toxins), called organic dust toxic syndrome.42
These patients, however, have no precipitins to antigens and
usually present with normal clinical ndings on respiratory
examination and chest radiographs.

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Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Figure 1 High-resolution computed tomographic scan in a patient

with acute hypersensitivity pneumonitis. The predominant nding is
ground-glass opacities and some centrilobular nodules (arrows).

cardiomegaly may develop as a result of chronic pulmonary

hypertension and cor pulmonale.

Computed Tomography
Computed tomography (CT) and HRCT provide a betterquality and more precise estimation of the pattern, extent,
and distribution of the disease and correlate better with
clinical and histopathological parameters.49
In acute HP, HRCT manifestations include a diffuse and
hazy increased parenchymal density and patchy or widespread airspace opacication (Fig. 1). The characteristic
features of subacute HP consist of patchy or diffuse bilateral
ground-glass attenuation, poorly dened small round centrilobular nodules (usually <5 mm in diameter), and lobular
areas of decreased attenuation and vascularity on inspiratory
images and of air trapping on expiratory images.49 A CT scan
obtained at the end of expiration is useful to improve the
visualization of the patchy air-trapping images (Fig. 2).
These hypoattenuated regions that persist on expiration are
indicative of bronchiolar inammation and obstruction. Air
trapping is also reected in pulmonary function tests as an
increased ratio of the residual volume (RV) to the total lung

Selman, Buenda-Roldn

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

mixed obstructive/restrictive pattern, whereas ground-glass
opacication and reticulation correlate with a restrictive
pattern.50,51 Bronchiolar wall thickening may also occur,
and thin-walled cysts have been found occasionally in patients with subacute HP.52 Patients with chronic disease have
subacute changes (ground-glass opacities and micronodules)
with both ne and coarse reticular opacities that may eventually evolve to honeycombing. Traction bronchiectasis and
bronchiolectasis frequently accompany these ndings
(Fig. 3). Often, the distinction of chronic brotic HP from
IPF and nonspecic interstitial pneumonia (NSIP), another
idiopathic interstitial pneumonia that mimics HP, may be
extremely difcult. It has been proposed that the presence of
lobular areas with decreased attenuation, centrilobular nodules, and a lack of lower zone predominance of the abnormalities are characteristics that best differentiate chronic HP
from IPF and NSIP.53 Thin-walled cysts located primarily in
areas of ground-glass opacities were also seen more commonly in patients with chronic HP than in those with IPF or
NSIP (Fig. 2). Nevertheless, it is important to emphasize that
honeycombing was seen in 64% of patients with chronic HP.53
It has been argued that the changes observed in HRCT may
correlate with the histopathological abnormalities.5456 Accordingly, ground-glass attenuation appears to reect the
presence of small granulomas within the alveolar septa and
with the partial lling of airspaces with inammatory cells.
Micronodules seem to correspond to cellular bronchiolitis,
noncaseating granulomas, and bronchiolocentric interstitial
pneumonitis. Finally, the reticular opacities, traction bronchiectasis, and honeycombing are related to the presence of
brosis, and conrm chronic, advanced disease.
For unclear reasons, patients with farmers lung may
evolve to a chronic obstructive pulmonary disease (COPD)like pattern more frequently than interstitial brosis.57,58

Lung Scintigraphy
Clearance of micronic aerosols of technetium 99m-labeled
diethylenetriamine pentaacetic acid (99mTc-DTPA) may evaluate alveolar epithelial integrity. Patients with PBD and
asymptomatic pigeon breeders with high specic antibody
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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Selman, Buenda-Roldn

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 nding in some chronic advanced patients is the presence of honeycombing (B and
C arrows).

whereas asymptomatic (antigen-exposed) subjects without

sensitization had intermediate rates of clearance.59 However,
the usefulness of this method is uncertain because there is
overlap in clearance rates of the radioisotope between ILD
patients and normal subjects and because cigarette smoking
and other variables inuence the respiratory clearance of
99mTc-DTPA.

Laboratory Tests
Routine laboratory tests are not useful either for diagnosis or
to monitor disease activity or progression.
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 asymptomatic individuals, and false-negative results may occur, mainly
in chronic cases.60,61 Avian antigen-specic 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.

represents a normal inammatory response or whether

the apparent normal individuals have a low-intensity alveolitis without clinical consequences.64 Although for a long
time it was considered that CD8 T cell subset was predominant, recent evidence demonstrates that the CD4:CD8 ratio
varied according to several variables, including, the type of
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 uids, mainly after
recent antigen exposure or subacute active disease.66,67 On
the other hand, an increase of neutrophils together with
lymphocytes characterizes the acute attacks.68,69 There is

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
asymptomatic HP-antigen-exposed individuals. In these
cases, it is unclear whether the increase of lymphocytes

Figure 4 Bronchoalveolar lavage cell prole in hypersensitivity

pneumonitis is characterized by a noteworthy increase of lymphocytes
(hematoxylin and eosin; 40).
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Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Selman, Buenda-Roldn

Figure 5 Photomicrographs of subacute hypersensitivity pneumonitis in lungs showing two common and characteristic histopathological
features. (A) Interstitial lymphocytic inltrate 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).

also an increase of mast cells that may be useful (together

with the increase of lymphocytes) for the differential diagnosis with other ILDs.70 Actually, although there is no unique
nding for HP, the described changes may eventually help to
distinguish HP from other frequent ILDs.71

Morphology
Little is know about the pathological changes of the acute
form of HP. A recent review of cases with new and rapid onset
of symptoms reported that, in addition to the bronchiolocentric lymphoplasmacytic inltrate, brin deposition and neutrophilic inltrates are usually present.72 However, hyaline
membranes, pneumocyte atypia, and broblastic proliferation as attributes of acute lung injury or diffuse alveolar
damage were not found.
Subacute HP is characterized by a bronchiolocentric pneumonitis with interstitial lymphoplasmacytic inltrates, cellular bronchiolitis, and small, poorly differentiated, loosely
arranged granulomas73 (Fig. 5). In the absence of granulomas, the histopathological pattern in subacute/chronic HP
can be very similar to that observed in NSIP.74 Occasional
areas of organizing pneumonia with Masson bodies are often
seen. Bronchiole pathology may vary, and while proliferative
bronchiolitis obliterans has been described in farmers lung,
constrictive bronchiolitis is primarily seen in PBD.75,76 Occasionally, peribronchiolar metaplasia (peribronchiolar proliferation of bronchial epithelium along thickened
peribronchiolar alveolar walls) can be the primary histological nding in the lung biopsy.77
Chronic HP is characterized by variable degrees of brotic
changes, and in advanced cases, brosis can be severe, with
destruction of the lung architecture, and honeycomb changes
that may be difcult to distinguish from usual interstitial
pneumonia (UIP) (Fig. 6).78,79 Also, some chronic patients
may show a relatively homogeneous linear brosis resembling brotic NSIP.79,80 In patients in whom the pattern of
brosis is consistent with UIP or NSIP, bronchiolocentric
localization of the brotic lesions and the presence of Schaumann bodies, giant multinucleated cells, or granulomas, may
support the diagnosis of chronic HP. It has been recently
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suggested that cathepsin-K is a sensitive immunohistochemical marker for detection of microgranulomas.81 Bridging
brosis between centrilobular and subpleural areas, and
areas close to the interlobular septa is frequently seen in
chronic HP. Interestingly, patients with concurrent histopathological features of pulmonary alveolar proteinosis and HP
have been recently reported, although the putative linkage is
unknown.82

Diagnosis
Clinicians should maintain a high index of suspicion for HP in
patients with clinical, radiological, and functional features of
ILD. An environmental antigen is essential for the development
of HP and must be considered when reviewing a patients
clinical history. Unfortunately, it is often impossible to identify
the causal antigen, or the interval between exposure and the
onset of symptoms is so long that the cause-and-effect relationship is difcult to establish. Alternatively, some patients
have a positive history of exposure to HP antigens, and even
specic circulating antibodies, but they have another ILD.
The elements that contribute to diagnosis have been
previously published.1 Diagnosis of acute HP based on (1)
evidence of exposure (usually substantial), documented by
history and specic antibodies against the offending antigen;
(2) a ulike syndrome; (3) increased BAL neutrophils and
lymphocytes; and (4) signicant improvement after removing the patient from the suspected environment, and worsening after reexposure.
Diagnosis of subacute HP includes (1) evidence of exposure
and specic antibodies against the offending antigen; (2)
progressive dyspnea; (3) BAL lymphocytosis (usually >40% in
nonsmokers); (4) ground-glass opacities, poorly dened centrilobular nodules, and mosaic attenuation on inspiratory
images and of air trapping on expiratory CT images; (5)
restrictive functional pattern plus hypoxemia and reduced
diffusing capacity for carbon monoxide (DLCO); and (6) partial
improvement after removing the patient from the suspected
environment, and worsening after reexposure.
Diagnosis of chronic HP is based on (1) evidence of
exposure and specic antibodies against the offending

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550

Selman, Buenda-Roldn

Figure 6 (A, B, C) Photomicrographs of three patients with chronic hypersensitivity pneumonitis. Lung tissues show chronic interstitial
mononuclear inammation, broblastic foci, interstitial brosis, 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)

clinical behavior of chronic ILD; (3) BAL lymphocytosis; (4)
reticular opacities superimposed to subacute changes on
HRCT; (5) restrictive functional pattern plus hypoxemia and
reduced DLCO; and (6) lung biopsy if there is insufcient
evidence for diagnosis.

Therapeutic Approach and Prognosis

Early diagnosis and avoidance of further antigen exposure are
crucial in the management of these patients. Although some
of them report complete remission of the disease despite
subsequent exposure to the offending antigen, in most cases
continued antigen inhalation is one of the identied causes of
an adverse prognosis.
Corticosteroids are recommended in acute, severe, and
subacute/chronic disease. However, long-term efcacy of these
agents has not been determined in appropriate clinical trials.
Old evidence suggests that in farmers lung corticosteroids did
not inuence the long-term outcome of the disease.83
In subacute/chronic progressive cases, the empirical
scheme consists of 0.5 mg/kg/d of prednisone for a month
followed by a gradual reduction until a maintenance dose of
10 to 15 mg per day is reached.1 This treatment should be
discontinued if there is no clinical or functional response after
1 year.
Inhaled steroids have been occasionally used to reduce the
severe side effects of prolonged systemic steroid therapy;
however, evidence of efcacy is scanty.8486 Patients with hot
tub lung provoked by Mycobacterium avium complex organisms contaminating hot tub water have been treated with

corticosteroids or with antimycobacterial therapy or both or

even simply by avoiding further exposure, with signicant
improvement.87,88 Also, no controlled studies of pediatric HP
have been performed, and treatment regimens are mainly
extrapolated from adults. Monthly high-dose intravenous
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
immediately, and other immunosuppressive drugs such as
azathioprine or cyclosporine were employed in severe cases
or in those with no obvious improvement in lung function
within 2 to 3 months or in cases of relapse.7 Most children
improved, and no mortality was seen.
Thalidomide, an antiinammatory and immunomodulatory drug, has proved useful in some immunopathological
disorders, including sarcoid skin lesions.89 This drug inhibits
the production of TNF-, IL-12p40, and IL-18 by alveolar
macrophages obtained from patients with diverse ILDs, including HP.90 However, there are no controlled clinical trials
in HP. Finally, in chronic progressive brotic HP patients, lung
transplantation should be considered.
If the diagnosis is correctly and timely done, outcome is
usually good in acute and subacute HP. By contrast, patients
with chronic disease often progress to irreversible pulmonary
brosis, and
30% of them die within a few years of diagnosis.91,92 In general, the risk of mortality increases with evidence of brosis at lung biopsy or HRCT or with a more severe
respiratory impairment on pulmonary function tests.9194
A report from the National Center for Health Statistics
showed that overall age-adjusted death rates increased signicantly between 1980 and 2002, from 0.09 to 0.29 per million.95
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Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Proportionate mortality ratios were signicantly high for agricultural production, livestock and agricultural production, crop.
The death rate was greater in farming states, where farmers
lung accounted for nearly 40% of all HP deaths. Importantly
however, the study demonstrated that nearly 56% of HP deaths
were due to unspecied organic dust/etiological agents.

HP is a complex and multifaceted disease that should be

included in the differential diagnosis of any patient consulting with an ILD. Early diagnosis and avoiding further antigen
exposure improve survival. The diagnosis requires a high
index of suspicion by the clinician and rests on the combination of ndings from environmental/occupational exposure
history, clinical behavior, serology, HRCT, BAL, and, if necessary, lung biopsy. Treatment with corticosteroids is usually
indicated, but their long-term effect in this disease is unclear.
In chronic patients with progressive brosis and refractory to
medical therapy, lung transplantation should be considered.
Experimental and clinical evidence points toward a T cell
mediated mechanism driving HP, but the role of the different
T cell subsets in the development of the disease needs to be
elucidated. A better understanding of the immunopathological mechanisms may help to nd HP-specic biomarkers and
may also open new therapeutic strategies.

1 Selman M. Hypersensitivity pneumonitis: a multifaceted deceiv-

5
6

10

11

ing disorder. Clin Chest Med 2004;25(3):531547, vi

Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot
tub lung: presenting features and clinical course of 21 patients.
Respir Med 2006;100(4):610615
Tillie-Leblond I, Grenouillet F, Reboux G, et al. Hypersensitivity
pneumonitis and metalworking uids contaminated by mycobacteria. Eur Respir J 2011;37(3):640647
Nordness ME, Zacharisen MC, Schlueter DP, Fink JN. Occupational
lung disease related to cytophaga endotoxin exposure in a nylon
plant. J Occup Environ Med 2003;45(4):385392
Girard M, Lacasse Y, Cormier Y. Hypersensitivity pneumonitis.
Allergy 2009;64(3):322334
Solaymani-Dodaran M, West J, Smith C, Hubbard R. Extrinsic
allergic alveolitis: incidence and mortality in the general population. QJM 2007;100(4):233237
Buchvald F, Petersen BL, Damgaard K, et al. Frequency, treatment,
and functional outcome in children with hypersensitivity pneumonitis. Pediatr Pulmonol 2011;46(11):10981107
Dishop MK, Askin FB, Galambos C, et al. Childrens Interstitial Lung
Disease (chILD) Network: classication of diffuse lung disease in
older children and adolescents: a multi-institutional study of the
Childrens Interstitial Lung Disease Network [abstract]. Mod
Pathol 2007;20:287288
Flaherty DK, Braun SR, Marx JJ, Blank JL, Emanuel DA, Rankin J.
Serologically detectable HLA-A, B, and C loci antigens in farmers
lung disease. Am Rev Respir Dis 1980;122(3):437443
Rittner C, Sennekamp J, Mollenhauer E, et al. Pigeon breeders
lung: association with HLA-DR 3. Tissue Antigens 1983;21(5):
374379
Selman M, Tern L, Mendoza A, et al. Increase of HLA-DR7 in
pigeon breeders lung in a Mexican population. Clin Immunol
Immunopathol 1987;44(1):6370

Seminars in Respiratory and Critical Care Medicine

13

15

16

17

18

19

20

21

References

12 Ando M, Hirayama K, Soda K, Okubo R, Araki S, Sasazuki T. HLA-

14

Conclusions

Vol. 33

No. 5/2012

Selman, Buenda-Roldn

22

23

24

25

26

27

28

29

30

31

DQw3 in Japanese summer-type hypersensitivity pneumonitis

induced by Trichosporon cutaneum. Am Rev Respir Dis
1989;140(4):948950
Camarena A, Jurez A, Meja M, et al. Major histocompatibility
complex and tumor necrosis factor-alpha polymorphisms in pigeon breeders disease. Am J Respir Crit Care Med 2001;
163(7):15281533
Aquino-Galvez A, Camarena A, Montao M, et al. Transporter
associated with antigen processing (TAP) 1 gene polymorphisms
in patients with hypersensitivity pneumonitis. Exp Mol Pathol
2008;84(2):173177
Bridgeman JS, Sewell AK, Miles JJ, Price DA, Cole DK. Structural and
biophysical determinants of T-cell antigen recognition. Immunology 2012;135(1):918
Wucherpfennig KW, Sethi D. T cell receptor recognition of self and
foreign antigens in the induction of autoimmunity. Semin Immunol 2011;23(2):8491
Hoppin JA, Umbach DM, Kullman GJ, et al. Pesticides and other
agricultural factors associated with self-reported farmers lung
among farm residents in the Agricultural Health Study. Occup
Environ Med 2007;64(5):334341
Dakhama A, Hegele RG, Laamme G, Isral-Assayag E, Cormier Y.
Common respiratory viruses in lower airways of patients with
acute hypersensitivity pneumonitis. Am J Respir Crit Care Med
1999;159(4 Pt 1):13161322
Isral-Assayag E, Dakhama A, Lavigne S, Laviolette M, Cormier Y.
Expression of costimulatory molecules on alveolar macrophages
in hypersensitivity pneumonitis. Am J Respir Crit Care Med
1999;159(6):18301834
Depierre A, Dalphin JC, Pernet D, Dubiez A, Faucompr C, Breton JL.
Epidemiological study of farmers lung in ve districts of the
French Doubs province. Thorax 1988;43(6):429435
Warren CPW. Extrinsic allergic alveolitis: a disease commoner in
non-smokers. Thorax 1977;32(5):567569
Baur X, Richter G, Pethran A, Czuppon AB, Schwaiblmair M.
Increased prevalence of IgG-induced sensitization and hypersensitivity pneumonitis (humidier lung) in nonsmokers exposed to
aerosols of a contaminated air conditioner. Respiration 1992;
59(4):211214
Arima K, Ando M, Ito K, et al. Effect of cigarette smoking on prevalence
of summer-type hypersensitivity pneumonitis caused by Trichosporon cutaneum. Arch Environ Health 1992;47(4):274278
Dalphin JC, Debieuvre D, Pernet D, et al. Prevalence and risk factors
for chronic bronchitis and farmers lung in French dairy farmers. Br
J Ind Med 1993;50(10):941944
Morell F, Roger A, Reyes L, Cruz MJ, Murio C, Muoz X. Bird fanciers
lung: a series of 86 patients. Medicine (Baltimore) 2008;
87(2):110130
Blanchet MR, Isral-Assayag E, Cormier Y. Inhibitory effect of
nicotine on experimental hypersensitivity pneumonitis in vivo
and in vitro. Am J Respir Crit Care Med 2004;169(8):903909
Sopori ML, Kozak W, Savage SM, Geng Y, Kluger MJ. Nicotineinduced modulation of T Cell function. Implications for inammation and infection. Adv Exp Med Biol 1998;437:279289
Nizri E, Irony-Tur-Sinai M, Lory O, Orr-Urtreger A, Lavi E, Brenner T.
Activation of the cholinergic anti-inammatory system by nicotine attenuates neuroinammation via suppression of Th1 and
Th17 responses. J Immunol 2009;183(10):66816688
Ohtsuka Y, Munakata M, Tanimura K, et al. Smoking promotes
insidious and chronic farmers lung disease, and deteriorates the
clinical outcome. Intern Med 1995;34(10):966971
Vogelmeier C, Krombach F, Mnzing S, et al. Activation of blood
neutrophils in acute episodes of farmers lung. Am Rev Respir Dis
1993;148(2):396400
Laamme C, Isral-Assayag E, Cormier Y. Apoptosis of bronchoalveolar lavage lymphocytes in hypersensitivity pneumonitis. Eur
Respir J 2003;21(2):225231

Downloaded by: Instituto Nacional de Enfermedades Respiratorias. Copyrighted material.

552

Selman, Buenda-Roldn

32 Barrera L, Mendoza F, Zuiga J, et al. Functional diversity of T-cell

54 Nakata H, Kimoto T, Nakayama T, Kido M, Miyazaki N, Harada S.

subpopulations in subacute and chronic hypersensitivity pneumonitis. Am J Respir Crit Care Med 2008;177(1):4455
Yamasaki H, Ando M, Brazer W, Center DM, Cruikshank WW.
Polarized type 1 cytokine prole in bronchoalveolar lavage T cells
of patients with hypersensitivity pneumonitis. J Immunol
1999;163(6):35163523
Glimcher LH. Trawling for treasure: tales of T-bet. Nat Immunol
2007;8(5):448450
Simonian PL, Roark CL, Wehrmann F, et al. Th17-polarized immune
response in a murine model of hypersensitivity pneumonitis and
lung brosis. J Immunol 2009;182(1):657665
Selman M, Pardo A, Barrera L, et al. Gene expression
proles distinguish idiopathic pulmonary brosis from hypersensitivity pneumonitis. Am J Respir Crit Care Med 2006;173(2):
188198
Lazarevic V, Glimcher LH. T-bet in disease. Nat Immunol 2011;
12(7):597606
Kolls JK, Lindn A. Interleukin-17 family members and inammation. Immunity 2004;21(4):467476
Simonian PL, Roark CL, Born WK, OBrien RL, Fontenot AP.
Gammadelta T cells and Th17 cytokines in hypersensitivity
pneumonitis and lung brosis. Transl Res 2009;154(5):
222227
Dakhama A, Hegele RG, Laamme G, Isral-Assayag E, Cormier Y.
Common respiratory viruses in lower airways of patients with
acute hypersensitivity pneumonitis. Am J Respir Crit Care Med
1999;159(4 Pt 1):13161322
Udwadia ZF, Wright MJ, McIntosh LG, Leitch AG. Confusing
serological abnormalities in bird fanciers lung. BMJ 1990;
300(6738):15191520
Seifert SA, Von Essen S, Jacobitz K, Crouch R, Lintner CP. Organic
dust toxic syndrome: a review. J Toxicol Clin Toxicol 2003;41
(2):185193
Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity
pneumonitis. Am J Surg Pathol 2006;30(2):201208
Lacasse Y, Selman M, Costabel U, et al; HP Study Group. Classication of hypersensitivity pneumonitis: a hypothesis. Int Arch
Allergy Immunol 2009;149(2):161166
Miyazaki Y, Tateishi T, Akashi T, Ohtani Y, Inase N, Yoshizawa Y.
Clinical predictors and histologic appearance of acute exacerbations in chronic hypersensitivity pneumonitis. Chest 2008;
134(6):12651270
Olson AL, Huie TJ, Groshong SD, et al. Acute exacerbations of
brotic hypersensitivity pneumonitis: a case series. Chest
2008;134(4):844850
Bourke SJ, Carter R, Anderson K, et al. Obstructive airways disease
in non-smoking subjects with pigeon fanciers lung. Clin Exp
Allergy 1989;19(6):629632
Selman M, Vargas MH. Airway involvement in hypersensitivity
pneumonitis. Curr Opin Pulm Med 1998;4(1):915
Silva CI, Churg A, Mller NL. Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic ndings. AJR Am J
Roentgenol 2007;188(2):334344
Hansell DM, Wells AU, Padley SPG, Mller NL. Hypersensitivity
pneumonitis: correlation of individual CT patterns with functional
abnormalities. Radiology 1996;199(1):123128
Chung MH, Edinburgh KJ, Webb EM, McCowin M, Webb WR. Mixed
inltrative and obstructive disease on high-resolution CT: differential diagnosis and functional correlates in a consecutive series. J
Thorac Imaging 2001;16(2):6975
Franquet T, Hansell DM, Senbanjo T, Remy-Jardin M, Mller NL.
Lung cysts in subacute hypersensitivity pneumonitis. J Comput
Assist Tomogr 2003;27(4):475478
Silva CI, Mller NL, Lynch DA, et al. Chronic hypersensitivity
pneumonitis: differentiation from idiopathic pulmonary brosis
and nonspecic interstitial pneumonia by using thin-section CT.
Radiology 2008;246(1):288297

Diffuse peripheral lung disease: evaluation by high-resolution

computed tomography. Radiology 1985;157(1):181185
Buschman DL, Gamsu G, Waldron JA Jr, Klein JS, King TE Jr. Chronic
hypersensitivity pneumonitis: use of CT in diagnosis. AJR Am J
Roentgenol 1992;159(5):957960
Sahin H, Brown KK, Curran-Everett D, et al. Chronic hypersensitivity pneumonitis: CT features comparison with pathologic evidence of brosis and survival. Radiology 2007;244(2):591598
Cormier Y, Brown M, Worthy S, Racine G, Mller NL. Highresolution computed tomographic characteristics in acute farmers lung and in its follow-up. Eur Respir J 2000;16(1):5660
Malinen AP, Erkinjuntti-Pekkanen RA, Partanen PL, Rytknen HT,
Vanninen RL. Long-term sequelae of Farmers lung disease in
HRCT: a 14-year follow-up study of 88 patients and 83 matched
control farmers. Eur Radiol 2003;13(9):22122221
Bourke SJ, Banham SW, McKillop JH, Boyd G. Clearance of 99mTcDTPA in pigeon fanciers hypersensitivity pneumonitis. Am Rev
Respir Dis 1990;142(5):11681171
McSharry C, Banham SW, Lynch PP, Boyd G. Antibody measurement in extrinsic allergic alveolitis. Eur J Respir Dis 1984;
65(4):259265
Cormier Y, Blanger J, Durand P. Factors inuencing the development of serum precipitins to farmers lung antigen in Quebec dairy
farmers. Thorax 1985;40(2):138142
Mendoza F, Baltazares M, Ramrez A, et al. Detection of salivary and
seric IgG and IgA antipooled pigeon sera activities in patients with
pigeon breeders disease. J Clin Lab Anal 1996;10(3):149154
McSharry C, MacLeod K, McGregor S, et al. Mucosal immunity in
extrinsic allergic alveolitis: salivary immunoglobulins and antibody against inhaled avian antigens among pigeon breeders. Clin
Exp Allergy 1999;29(7):957964
Cormier Y, Ltourneau L, Racine G. Signicance of precipitins and
asymptomatic lymphocytic alveolitis: a 20-yr follow-up. Eur Respir J 2004;23(4):523525
Ando M, Konishi K, Yoneda R, Tamura M. Difference in the
phenotypes of bronchoalveolar lavage lymphocytes in patients
with summer-type hypersensitivity pneumonitis, farmers lung,
ventilation pneumonitis, and bird fanciers lung: report of a
nationwide epidemiologic study in Japan. J Allergy Clin Immunol
1991;87(5):10021009
Drent M, van Velzen-Blad H, Diamant M, Wagenaar SS, Donckerwolck-Bogaert M, van den Bosch JM. Differential diagnostic
value of plasma cells in bronchoalveolar lavage uid. Chest
1993;103(6):17201724
Drent M, Wagenaar SS, van Velzen-Blad H, Mulder PG, Hoogsteden
HC, van den Bosch JM. Relationship between plasma cell levels and
prole of bronchoalveolar lavage uid in patients with subacute
extrinsic allergic alveolitis. Thorax 1993;48(8):835839
Haslam PL, Dewar A, Butchers P, Primett ZS, Newman-Taylor A,
Turner-Warwick M. Mast cells, atypical lymphocytes, and neutrophils in bronchoalveolar lavage in extrinsic allergic alveolitis.
Comparison with other interstitial lung diseases. Am Rev Respir
Dis 1987;135(1):3547
Drent M, van Velzen-Blad H, Diamant M, Wagenaar SS, Hoogsteden HC, van den Bosch JM. Bronchoalveolar lavage in extrinsic
allergic alveolitis: effect of time elapsed since antigen exposure.
Eur Respir J 1993;6(9):12761281
Schildge J, Klar B, Hardung-Backes M. Mast cells in bronchoalveolar
lavage uid of patients with interstitial lung diseases [in German].
Pneumologie 2003;57(4):202207
Drent M, Mulder PGH, Wagenaar SS, Hoogsteden HC, van VelzenBlad H, van den Bosch JM. Differences in BAL uid variables in
interstitial lung diseases evaluated by discriminant analysis. Eur
Respir J 1993;6(6):803810
Hariri LP, Mino-Kenudson M, Shea B, et al. Distinct histopathology
of acute onset or abrupt exacerbation of hypersensitivity pneumonitis. Hum Pathol 2012;43(5):660668

33

34
35

36

37
38
39

40

41

42

43
44

45

46

47

48
49

50

51

52

53

55

56

57

58

59

60

61

62

63

64

65

66

67

68

69

70

71

72

Seminars in Respiratory and Critical Care Medicine

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No. 5/2012

553

Downloaded by: Instituto Nacional de Enfermedades Respiratorias. Copyrighted material.

Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis

73 Barrios RJ. Hypersensitivity pneumonitis: histopathology. Arch
74

75
76

77

78

79
80

81

82

83

84

Pathol Lab Med 2008;132(2):199203

Gaxiola M, Buenda-Roldn I, Meja M, et al. Morphologic diversity
of chronic pigeon breeders disease: clinical features and survival.
Respir Med 2011;105(4):608614
Reyes CN, Wenzel FJ, Lawton BR, Emanuel DA. The pulmonary
pathology of farmers lung disease. Chest 1982;81(2):142146
Prez-Padilla R, Gaxiola MN, Salas J, Meja M, Ramos C, Selman M.
Bronchiolitis in chronic pigeon breeders disease: morphologic
evidence of a spectrum of small airway lesions in hypersensitivity
pneumonitis induced by avian antigens. Chest 1996;110(2):
371377
Fukuoka J, Franks TJ, Colby TV, et al. Peribronchiolar metaplasia: a
common histologic lesion in diffuse lung disease and a rare cause
of interstitial lung disease: clinicopathologic features of 15 cases.
Am J Surg Pathol 2005;29(7):948954
Katzenstein AL, Mukhopadhyay S, Myers JL. Diagnosis of usual
interstitial pneumonia and distinction from other brosing interstitial lung diseases. Hum Pathol 2008;39(9):12751294
Churg A, Muller NL, Flint J, Wright JL. Chronic hypersensitivity
pneumonitis. Am J Surg Pathol 2006;30(2):201208
Vourlekis JS, Schwarz MI, Cool CD, Tuder RM, King TE, Brown KK.
Nonspecic interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med 2002;112(6):
490493
Reghellin D, Poletti V, Tomassett S, et al. Cathepsin-K is a sensitive
immunohistochemical marker for detection of micro-granulomas
in hypersensitivity pneumonitis. Sarcoidosis Vasc Diffuse Lung Dis
2010;27(1):5763
Verma H, Nicholson AG, Kerr KM, et al. Alveolar proteinosis with
hypersensitivity pneumonitis: a new clinical phenotype. Respirology 2010;15(8):11971202
Kokkarinen JI, Tukiainen HO, Terho EO. Effect of corticosteroid
treatment on the recovery of pulmonary function in farmers lung.
Am Rev Respir Dis 1992;145(1):35
Ramrez A, Sansores R, Chapela R, et al. Inhaled beclomethasone
versus oral prednisone. A clinical trial in patients with hypersen-

Seminars in Respiratory and Critical Care Medicine

Vol. 33

No. 5/2012

85

86

87

88

89
90

91

92

93

94

95

Selman, Buenda-Roldn

sitivity pneumonitis [abstract]. Am J Respir Crit Care Med

1995;151:A605
Carlsen KH, Leegaard J, Lund OD, Skjaervik H. Allergic alveolitis in a
12-year-old boy: treatment with budesonide nebulizing solution.
Pediatr Pulmonol 1992;12(4):257259
Tanaka H, Tsunematsu K, Nakamura N, et al. Successful treatment
of hypersensitivity pneumonitis caused by Grifola frondosa (Maitake) mushroom using a HFA-BDP extra-ne aerosol. Intern Med
2004;43(8):737740
Khoor A, Leslie KO, Tazelaar HD, Helmers RA, Colby TV. Diffuse
pulmonary disease caused by nontuberculous mycobacteria in
immunocompetent people (hot tub lung). Am J Clin Pathol
2001;115(5):755762
Hanak V, Kalra S, Aksamit TR, Hartman TE, Tazelaar HD, Ryu JH. Hot
tub lung: presenting features and clinical course of 21 patients.
Respir Med 2006;100(4):610615
Baughman RP, Judson MA, Teirstein AS, Moller DR, Lower EE.
Thalidomide for chronic sarcoidosis. Chest 2002;122(1):227232
Ye Q, Chen B, Tong Z, et al. Thalidomide reduces IL-18, IL-8 and
TNF-alpha release from alveolar macrophages in interstitial lung
disease. Eur Respir J 2006;28(4):824831
Prez-Padilla R, Salas J, Chapela R, et al. Mortality in Mexican patients
with chronic pigeon breeders lung compared with those with usual
interstitial pneumonia. Am Rev Respir Dis 1993;148(1):4953
Vourlekis JS, Schwarz MI, Cherniack RM, et al. The effect of
pulmonary brosis on survival in patients with hypersensitivity
pneumonitis. Am J Med 2004;116(10):662668
Hanak V, Golbin JM, Hartman TE, Ryu JH. High-resolution CT
ndings of parenchymal brosis correlate with prognosis in
hypersensitivity pneumonitis. Chest 2008;134(1):133138
Lima MS, Coletta EN, Ferreira RG, et al. Subacute and chronic
hypersensitivity pneumonitis: histopathological patterns and survival. Respir Med 2009;103(4):508515
Bang KM, Weissman DN, Pinheiro GA, Antao VC, Wood JM, Syamlal
G. Twenty-three years of hypersensitivity pneumonitis mortality
surveillance in the United States. Am J Ind Med 2006;49(12):
9971004

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