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Immunopathology, Diagnosis, and Managementof Hypersensitivity Pneumonitis
Moisés Selman, M.D. 1 Ivette Buendía-Roldán, M.D. 1
1 Instituto Nacional de Enfermedades Respiratorias “Ismael Cosío
Villegas,” México
Semin Respir Crit Care Med 2012;33:543–554.
Address for correspondence and reprint requests Moisés Selman,
M.D., Instituto Nacional de Enfermedades Respiratorias, Tlalpan 4502,
CP 14080, México DF, México (e-mail: [email protected]).
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 µm) 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 HPare dif cult 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
etiologicagents and sources of antigenscapableof inducing HP
have been described, and the listof environments and agents is
always increasing (► Tables 1, 2 , 3). Thus, for example, in the
last 10 years it has been demonstrated that heated water
colonized by Mycobacterium avium may provoke HPin hot tub
users.2 Likewise, Mycobacterium immunogenum may contam-
inate metal working uid (MWF), causing disease when they
become aerosolized, mostly in automotive industries.3 Work-
ers with exposure to MWF are generally in the manufacturing
sector in processes like metal machining, forging, and stamp-
ing. HP has also been described in individuals exposed to
Cytophaga endotoxin in a nylon plant.4 In these workers
Cytophaga wasisolated fromthe 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.
Thelow incidence of HP suggests that geneticor additional
environmental factors are necessary to develop the disease.
Keywords
► hypersensitivity
pneumonitis
► extrinsic allergic
alveolitis
►
lung
brosis
Abstract 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, non-necrotizing poorly formed granulomas, cellular pneumonitis and variable degrees of
brosis. However, morphological diagnosis of HP is complicated because the subacute/
chronic forms may be dif cult 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.
Issue Theme Orphan Lung Diseases;
Guest Editor, Jay H. Ryu, M.D.
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.
543
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Also, it is likely that a number of mild cases are misdiagnosed
as viral infections, and some severe advanced cases as idio-
pathic pulmonary brosis (IPF) or other brotic lung
disorders.
According to several studies the prevalence of farmer’s
lung, one of the best-known types of HP, can be estimated in
0.5 to 3% of exposed farmers.5 Pigeon breeder’s disease (PBD),
another common form of HP, seems to occur frequently
Table 1 Fungal and Bacterial Antigens Implicated in Hypersensitivity Pneumonitis
Disease Antigen Source
Farmer’s lung Faeni rectivirgula Moldy hay, grain, silage
Ventilation pneumonitis;humidier lung; air conditionerlung
Thermoactinomyces vulgaris,Thermoactinomyces sacchari,Thermoactinomyces candidus
Klebsiella oxytoca
Contaminated forced-air systems; waterreservoirs
Bagassosis T. vulgaris Moldy sugarcane (ie, bagasse)
Mushroom worker’s lung T. sacchari Moldy mushroom compost
Enoki mushroom worker’s lung(Japan)
Penicillium citrinum Moldy mushroom compost
Suberosis Thermoactinomyces viridis, Aspergillusfumigatus, Penicillium frequentans Penicillium
glabrum
Moldy cork
Detergent lung; washingpowder lung
Bacillus subtilis enzymes Detergents (during processing or use)
Malt worker’s lung Aspergillus fumigatus, Aspergillus clavatus Moldy barley
Sequoiosis Graphium, Pullularia, and Trichoderma spp.,
Aureobasidium pullulans
Moldy wood dust
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 andspruce 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 ac tinomycetes, 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 dustMachine operator’s lung Mycobacterium immunogenum, Pseudomona
uorescensAerosolized metalworking uid
Residential provokedpneumonitis
Aureobasidium pullulans Residential exposure
Humidier lung Naegleria gruberi, Acanthamoeba polyphaga, Acanthamoeb a castellani, Bacillus spp., others
Contaminated water from home humidier,ultrasonic misting fountains
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Immunopathology, Diagnosis, and Management of Hypersensitivity Pneumonitis Selman, Buendía-Roldán544
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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, general-
population-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 Inci-
dence/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 suscepti-
ble 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 histocom-patibility complex (MHC) class II alleles are implicated in the
risk to develop the disease.9–13 Also, polymorphisms in the
transporters associated with antigen processing (TAP) genes
may also be involved.14 TAP play an important role trans-
porting peptides across the endoplasmic reticulum mem-
brane for MHC class I molecule assembly. Almost every T cell
response is controlled by the molecular interaction between
the clonotypically expressed αβ T cell receptor and cognate
Table 2 Chemicals Implicated in Hypersensitivity Pneumonitis
Disease Antigen Source
Pauli’s reagent alveolitis Sodium diazobenzene sulfate La borator y 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
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 poolWater sprays and fountains
Table 3 Animal Proteins Implicated in Hypersensitivity Pneumonitis
Disease Antigen Source
Pigeon breeder’s or pigeon fancier’sdisease
Avian droppings, feathers, serum Parakeets, budgerigars, pigeons, chickens,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 worker’s lung, insect proteins
Rats, gerbils Urine, serum, pelts, proteins
Miller’s lung Sitophilus granarius (ie, wheat weevil) Dust-contaminated grain
Lycoperdonosis Puffball spores Lycoperdon puffballs
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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 Infarmers, the acute form ofHP should be
distinguished from an inuenza-like illness resulting from
the nonimmunological reaction to inhaled mold dusts (bac-
terial 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 respiratoryexamination and chest radiographs.
Subacute HP
The subacute form of HP usually results from continual low-
level 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, an-
orexia, and weight loss are commonly observed. Physical
examination usually reveals tachypnea and bibasilar inspira-
tory crackles. Wheezing, provoked by small airway obstruc-
tion, is not common, but it occurs in some patients. Thedifferential diagnosis includes granulomatous lung disorders,
primarily sarcoidosis, lymphocytic interstitial pneumonia
(LIP), drug-induced lung disease, idiopathic cellular nonspe-
cic interstitial pneumonia (NSIP), and respiratory bronchi-
olitis/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 unrec-
ognized acute/subacute episodes (recurrent chronic HP) and
(2) from a slowly progressive disease in patients exposed tolow levels of antigen and without history of acute episodes
(insidious chronic HP). Chronic HP presents as prolonged and
relentlesspneumonitis with progressivedyspnea on exertion,
cough, fatigue, malaise, and weight loss. Despite chronicity,
these patients may stabilize or even improve after antigen
avoidance and antiinammatory/immunosuppressive treat-
ment. 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 bro-
sis (IPF), and in this case the differential diagnosis may be
extremely dif cult. Interestingly, some patients with HP,
primarily farmers with recurrent acute episodes, developan 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, signi-
cant 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
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 daysor weeks.40 Patients
in the second category correspond to chronic ones.
Acute Exacerbations in Chronic HPSome 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 opaci-
ties or consolidation. This severe process seems to be associ-
ated 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 deter-
mining 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 inter-
stitial 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, be-
cause 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 diffusingcapacity for carbon monoxide (DL CO) 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 abnormal-
ities and the prognosis of HP has not been properly evaluated,
but it is the general belief that patients with more severe
abnormalitieshave a worse outcome. However,some patients
with severe impairment may recover, whereas others with
relatively mild functional abnormalities at the onset of dis-
ease 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. Abnor-
malities in acute and subacute HP patients include poorly
dened small nodules throughout both lungs and ground-
glass attenuation, either patchy or diffuse. Airspace consoli-
dation can also be observed. In advanced chronic HP, ndings
also include pulmonary brosis with linear interstitial opaci-
ties, lung distortion, and honeycombing. In these cases,
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cardiomegaly may develop as a result of chronic pulmonaryhypertension and cor pulmonale.
Computed Tomography
Computed tomography (CT) and HRCT provide a better-
quality 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 wide-
spread airspace opacication (►Fig. 1). The characteristic
features of subacute HP consist of patchy or diffuse bilateral
ground-glass attenuation, poorly de
ned small round cen-trilobular nodules (usually
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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 smokingand 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 carefullybecause
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-specic IgG and IgA canbe 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
asymptomatic HP-antigen-exposed individuals. In these
cases, it is unclear whether the increase of lymphocytes
represents a “normal” inammatory response or whether
the apparent “normal” individuals have a low-intensity al-
veolitis without clinical consequences.64 Although for a long
time it was considered that CD8þ T cell subset was predomi-
nant, recent evidence demonstrates that the CD4:CD8 ratiovaried 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 plasmacellscan also bepresent inBAL 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
Figure 3 Three different levels of a high-resolut ion computed tomographic scan in a patient with chronic hypersensitivity pneumonit is. (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 remarkablending in some chronic advanced patients is the presence of honeycombing (B and
C arrows).
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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also an increase of mast cells that may be useful (together
with the increase of lymphocytes) for the differential diagno-
sis with other ILDs.70 Actually, although there is no unique
nding for HP, the described changes may eventually help todistinguish 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 bronchiolocen-
tric lymphoplasmacytic inltrate, brin deposition and neu-
trophilic inltrates are usually present.72 However, hyaline
membranes, pneumocyte atypia, and broblastic prolifera-
tion as attributes of acute lung injury or diffuse alveolar
damage were not found.Subacute HP is characterized by a bronchiolocentric pneu-
monitis with interstitial lymphoplasmacytic inltrates, cel-
lular bronchiolitis, and small, poorly differentiated, loosely
arranged granulomas73 (►Fig. 5). In the absence of granulo-
mas, 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 farmer’s lung,
constrictive bronchiolitis is primarily seen in PBD.75,76 Occa-
sionally, peribronchiolar metaplasia (peribronchiolar prolif-
eration of bronchial epithelium along thickened
peribronchiolar alveolar walls) can be the primary histologi-cal 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 dif cult to distinguish from usual interstitial
pneumonia (UIP) (►Fig. 6).78,79 Also, some chronic patients
may show a relatively homogeneous linear brosis resem-
bling 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 Schau-
mann bodies, giant multinucleated cells, or granulomas, may
support the diagnosis of chronic HP. It has been recently
suggested that cathepsin-K is a sensitive immunohistochem-
ical marker for detection of microgranulomas.81 Bridging
brosis between centrilobular and subpleural areas, and
areas close to the interlobular septa is frequently seen inchronic HP. Interestingly, patients with concurrent histopath-
ological 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 patient’s
clinical history. Unfortunately, it is often impossible to identifythe causal antigen, or the interval between exposure and the
onset of symptoms is so long that the cause-and-effect rela-
tionship is dif cult 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 remov-
ing the patient from the suspected environment, and wors-
ening after reexposure.Diagnosisof 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 cen-
trilobular nodules, and mosaic attenuation on inspiratory
images and of air trapping on expiratory CT images; (5)
restrictive functional pattern plus hypoxemia and reduced
diffusingcapacity forcarbon monoxide (DL CO); 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
Figure 5 Photomicrographs of subacute hypersensitivity pneumonitis in lungs showing two common and characteristic histopathological
features. (A)Interstitial lymphocytic inltrate anda poorly formedgranuloma (arrowhead). (B)The granuloma is typicallyfound 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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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 DL CO; and (6) lung biopsy if there is insuf cient
evidence for diagnosis.
Therapeutic Approach and Prognosis
Early diagnosis andavoidance of further antigenexposure 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 ef cacy of these
agents has not been determined in appropriate clinical trials.
Old evidence suggests that in farmer’s lung corticosteroids didnot 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 functionalresponse after
1 year.
Inhaled steroids have been occasionally used to reduce the
severe side effects of prolonged systemic steroid therapy;
however, evidence of ef cacyis scanty.84–86 Patients with hot
tub lung provoked by Mycobacterium avium complex organ-
isms 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 asmall 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 immunomodula-
tory drug, has proved useful in some immunopathological
disorders, including sarcoid skin lesions.89 This drug inhibits
the production of TNF-α, IL-12p40, and IL-18 by alveolar
macrophages obtained from patients with diverse ILDs, in-
cluding HP.90 However, there are no controlled clinical trialsin HP. Finally, in chronic progressivebrotic 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 diagno-
sis.91,92 In general, the risk of mortality increases with evi-
dence of brosis at lungbiopsyor HRCTor with a more severe
respiratory impairment on pulmonary function tests.91–94
A report from the National Center for Health Statistics
showed that overall age-adjusted death rates increased signi-
cantly between 1980 and 2002, from 0.09 to 0.29 per million.95
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.)
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Proportionate mortality ratios were signicantly high for agri-
cultural production, livestock and agricultural production, crop.
The death rate was greater in farming states, where farmer’s
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.
Conclusions
HP is a complex and multifaceted disease that should be
included in the differential diagnosis of any patient consult-
ing 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 combina-
tion of ndings from environmental/occupational exposure
history, clinical behavior, serology, HRCT, BAL, and, if neces-
sary, 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 immunopathologi-
cal mechanisms may help to nd HP-specic biomarkers and
may also open new therapeutic strategies.
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