4 neumonitis por hipersensibilidad 2012 dr. selman ya leido muy bueno.pdf

8/8/2019 4 neumonitis por hipersensibilidad 2012 dr. Selman YA LEIDO MUY BUENO.pdf

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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

Seminars in Respiratory and Critical Care Medicine Vol. 33 No. 5/2012

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


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


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


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


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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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