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Hypersensitivity Pneumonitis Whats New

PCCSU Volume 25, Lesson 11

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

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PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Mridu Gulati, MD, MPH

Dr. Gulati is Assistant Professor, Section of Pulmonary and Critical Care, Yale School of Medicine; and Associate Director, Yale Interstitial Lung Disease Program, Yale Occupational and Environmental Medicine Program, Yale University, New Haven, Connecticut.

Dr. Gulati has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within this chapter:

Centers for Disease Control (CDC)/National Institute for Occupational Safety and Health (NIOSH) K01 award – grant monies

Objectives

  1. Understand the critical components of the diagnostic evaluation of hypersensitivity pneumonitis (HP).
  2. Develop a general understanding of the pathogenesis of HP, as well as an appreciation for the factors that promote or protect against HP.
  3. Recognize the most common high-resolution chest CT scan findings for the acute, subacute, and chronic forms of HP.
  4. Recognize the most common histopathologic HP findings and the range of histopathologic patterns.
  5. Understand the differences in the clinical manifestations, as well as the radiographic and pathologic features that characterize the acute and chronic forms of HP.

Key words: bird fancier’s lung; bronchoprovocation testing; chronic pigeon breeder’s lung; diffuse parenchymal lung disease; extrinsic allergic alveolitis; farmer’s lung; hot tub lung; hypersensitivity pneumonitis; idiopathic pulmonary fibrosis; inhalation challenge testing; interstitial lung disease; nonspecific interstitial pneumonia; serum precipitating antibodies; summer-type hypersensitivity pneumonitis; thermophilic actinomycetes; usual interstitial pneumonia

Abbreviations: Dlco = diffusing capacity of lung for carbon monoxide; HP = hypersensitivity pneumonitis; HRCT = high-resolution CT; IL = interleukin; ILD = interstitial lung disease; IPF = idiopathic pulmonary fibrosis; ODTS = organic dust toxic syndrome; TNF = tumor necrosis factor; UIP = usual interstitial pneumonia

Hypersensitivity pneumonitis (HP), also known as extrinsic allergic alveolitis, is a form of interstitial lung disease (ILD) that is characterized by diffuse lung inflammation in the parenchyma and small airways of individuals sensitized to a variety of potential occupational and environmental antigens. A diagnosis of HP relies first on obtaining a thorough clinical history, with subsequent confirmatory testing including serum precipitating antibodies and high-resolution chest CT (HRCT) scans. When the exposure history is unclear, bronchoscopy and surgical lung biopsy may be indicated. Patients with more acute forms of HP often have a better prognosis than patients with chronic disease and established fibrosis.

Recently, investigators have uncovered associations between HP and novel agents in the occupational and environmental setting. In addition, several recent publications have shed light on the pathogenesis and immune mechanisms surrounding the development of HP. This article reviews the diagnostic assessment of HP and highlights recent research pertaining to the clinical presentation and pathogenesis of HP.

Epidemiology

Despite the fact that more than 300 agents have been associated with HP, the disorder’s prevalence is underappreciated. Exposures can be difficult to distinguish from common daily household exposures or may be so novel that they remain unrecognized. Several articles and reviews detail a more comprehensive list of agents.1,2

HP and ILD registries exist only in a few countries and show wide variability in prevalence data. For example, approximately 13% of prevalent ILD cases in Flanders were reported as HP,3 vs 0% of prevalent ILD cases in a New Mexico registry.4

Much of the epidemiologic data regarding HP have been derived from studies of farmers and bird fanciers. The prevalence of farmer’s lung varies widely (from 420 to 3,000 per 100,000 in the United States); this variation may be due to differences in farming practices and climate, with farmers living in more humid zones being at higher risk.5-8 Bird antigen may be more highly antigenic, with rates of HP ranging from 6% to 21% per year among individuals with bird exposure.9

Investigators from Mayo Clinic recently published their current experience with HP. Bird exposure and hot tub lung from Mycobacterium avium exposure accounted for 34% and 21% of cases, respectively. Farmer’s lung and household mold exposure accounted for 11% and 9% of cases, respectively. In 25% of all HP cases, the inciting antigen was not identified.10

Morell and colleagues11 recently published the largest known case series of 86 patients with bird fancier’s lung. Seventeen percent of patients presented with chronic disease after a median exposure interval of 16 years. While serum precipitating antibodies were also commonly found in asymptomatic control individuals exposed to avian antigens, inhalation challenge testing among patients with bird fancier’s lung had a sensitivity and specificity of >90%. Antigens used in challenge testing included specific bird antigens, such as pigeon and parakeet serum. None of the patients in the control groups had a positive bronchial challenge test. In this study, 8% of patients were <15 years of age, and three cases were caused by feather-filled bedding.11

Finally, high attack rates of HP have also been reported in other settings, ranging from public swimming pools with increased levels of gram-negative bacterial colonization and endotoxin12 to molding plants in which polyurethane parts are manufactured.13

Etiologic Agents

A wide array of environmental and occupational exposures has been reported to cause HP (Table 1). For example, workers in farming and agricultural industries and those in plastics and chemical industries may be at increased risk. The risk for developing disease depends on several factors, including the potency of the antigen, workplace environmental controls—such as personal protective equipment (respirators) and local exhaust ventilation—and individual susceptibility.

 


Table 1Select Causes of HP

Disease Type   Suspected Antigen Source of Settings
Fungal/bacterial Farmer’s lung Saccharopolyspora rectivirgula, Thermoactinomyces vulgaris Moldy hay and grain
Ventilation pneumonitis Thermoactinomyces species Contaminated forced-air systems, humidifiers
Metalworking fluid-associated HP Mycobacterium immunogenum Metalworking fluid
Hot tub lung Mycobacterium avium complex, Cladosporium Hot tubs
Animal protein Pigeon breeder’s disease, bird fancier’s lung Avian droppings, feathers, serum Direct contact with birds; indirect contact with proteinaceous avian material through ventilation systems; end products such as down comforters and duvets
Chemical Isocyanate-associated HP Isocyanates Polyurethane foams; spray paints

 


Numerous exposures can take place in agricultural settings, such as on farms or in grain- and flour-processing mills. Farmer’s lung has been well studied, and causation is most frequently linked to exposure to different mold species, such as Aspergillus species, and bacterial species, such as thermophilic actinomycetes, that contaminate hay and silage. Recent investigations remind clinicians that agricultural workers incur exposure to other possible antigens.14 In the Agricultural Health Study,15 organochlorine and carbamate pesticides were associated with HP in farmers.

In another agricultural setting, the cattle feed industry, exposure to the enzyme phytase was associated with HP.16

Occupational mold exposure in the agricultural industry has long been established as a cause of HP. Occupational mold exposure in an onion and potato sorter has also been reported.17 Residential mold exposure to organisms such as Cladosporium and Aureobasidium pullulans has been associated with HP. In the Mayo Clinic series, residential mold exposure caused 9% of cases.10

Exposure to avian antigens in excreta and proteinaceous material in the process of bird and poultry handling has been reported to cause HP. Exposure settings range from direct contact with birds to indirect contact with proteinaceous materials through bird house ventilation systems. The Mayo Clinic series should remind clinicians that exposure to avian antigens through down comforters or duvets can also cause HP.10,11

Metalworking fluids, composed of a complex mixture of a water-oil emulsion containing biocides and additives, can cause HP. Although the exact antigen is unclear, microbial contamination with species such as nontuberculous Mycobacterium species, Aspergillus, and Pseudomonas have been implicated. The aerosolization of metalworking fluids in the work setting may increase the potential for respiratory exposure.18

Exposure to medications, both older drugs and novel biologic agents, has been reported to cause HP. Newer therapeutic agents, such as rituximab,19 a chimeric anti-CD20 monoclonal antibody used to treat rheumatoid arthritis and non-Hodgkin’s lymphoma, and leflunomide,20 an immunomodulatory drug that inhibits dihydroorotate dehydrogenase, have been associated with the development of HP. Intravesical bacille Calmette-Guérin therapy for bladder cancer has also been associated with HP.21

Pathogenesis

The pathogenesis of HP is complex and both humoral and cell-mediated immunity may contribute. Initially, type III humoral mechanisms take place. Plasma cells produce precipitating antibody after exposure to a particular antigen, usually IgG, and then make an immune complex with the inhaled antigen. Immune complexes fix complement and stimulate alveolar macrophages to produce inflammatory mediators, including neutrophilic chemotactic factors, proteases, and reactive oxygen intermediates. After continued antigen exposure, a type IV cell-mediated immune response ensues. Activated macrophages secrete interleukin-12 (IL-12) and promote T-cell lymphocyte differentiation to the Th1 phenotype, which in turn produces interferon-γ. Interferon-γ then stimulates macrophages to produce greater amounts of IL-1 and tumor necrosis factor (TNF)-α.22-25 A recent study by Mroz and colleagues26 demonstrated that Th1 cell cytokine profile is unregulated in the BAL fluid of HP patients. Another study by Ye and colleagues27 also demonstrated an increase in Th1 cytokines (IL-12, IL-18, and TNF-α) by alveolar macrophages with both acute and chronic HP forms.

Simonian and coworkers28 have published several studies highlighting the importance of Th17-polarized CD4+ T lymphocytes in the immune response directed against a murine model of HP.

Promoting and Protective Factors

Several factors may work to enhance or mitigate risk for the development of HP in exposed individuals.

Cigarette Smoking
In certain settings, cigarette smoking may decrease the risk for developing HP. Smoking may reduce the risk of developing farmer’s lung, pigeon breeder’s lung, or Japanese summer-type HP. Cigarette smoke may have an immunosuppressive effect on alveolar macrophages, an effect that may result in decreased expression of several inflammatory cytokines, including TNF-α.29,30

Smoking may not be completely protective in the development of HP and may actually result in more chronic and severe disease in individuals in whom HP develops.31 Cigarette smoking may increase CD4+ T cells and increase the level of free radicals that may damage lung structural proteinases.1 A recent study of the effects of cigarette smoking in a murine model of pigeon breeder’s lung revealed that short-term cigarette smoking lessened lymphocytosis in BAL fluid and lymphocyte proliferation, while long-term smoking enhanced lung inflammation and fibrosis.32

In a recent report of metalworkers with HP, Dangman and colleagues33 suggested that smoking may reduce the ability to detect HP by simply masking some of HP’s common physical and test findings, such as crackles, elevated erythrocyte sedimentation rates, and spirometry results.

Viral Infections
Viral infections may increase risk for the development of HP. Viral antigens and higher concentrations of influenza virus proteins have been recovered in the lungs of HP patients. In animal models, mice infected with parainfluenza may be more responsive to a common HP antigen, Saccharopolyspora rectivirgula.34,35

Genetic Predisposition
Several gene polymorphisms have been found in patients with HP. Cytokine gene polymorphisms in major histocompatibility complex class II genes and TNF promoters have been found. Increased frequency of certain alleles on the TAP1 (transporter associated with antigen processing 1) gene have been reported in Mexican patients with HP and may be related to alterations in antigen processing and presentation, leading to enhanced immune response.36 Polymorphisms in IL-6 genes may be associated with higher levels of epithelial cell-derived neutrophil attractant 78, or ENA-78, an inflammatory chemokine that may attract and activate neutrophils.37 A polymorphism in the TNF-α gene at position –308 has been associated with higher TNF production in individuals with bird fancier’s lung.38

Classification of HP

Traditionally, HP has been classified into acute, subacute, and chronic categories. In the acute form of HP, such as in patients with farmer’s lung, flulike symptoms such as chills, fever, sweating, and myalgia develop between 6 and 24 h after exposure and last from hours to days. While patients with subacute HP develop symptoms over a period of days to weeks, patients with chronic HP, such as those with bird fancier’s lung, exhibit an insidious onset of cough and dyspnea over months to years.

These categories do not represent true “stages.” Patients with acute HP do not necessarily evolve over time to have chronic HP. Each classification may reflect differences in the variable clinical manifestations of exposure to different antigens as well as differing antigen exposure patterns. For example, agricultural workers with a “chronic history” of respiratory symptoms may actually be suffering from repeated episodes of acute HP and can have evidence of active inflammation that is substantially reversible away from exposure. Alternatively, individuals with chronic HP, such as those with bird fancier’s disease, can also have evidence of acute active alveolitis with inflammation superimposed on areas of more established fibrosis.

Recently, Lacasse and colleagues39 compared this traditional categorization with an alternative classification scheme that may more accurately reflect clinical situations. In one cluster, patients experienced more recurrent symptoms and often had normal findings on chest radiographs. In a second cluster, patients had more clubbing, hypoxemia, and fibrosis on CT scan. Nodular opacities were seen equally in both clusters. Patients in the first “acute” cluster tended to have a better prognosis.39

Diagnosis

While noninvasive and invasive testing is invaluable, the cornerstone of an HP diagnosis rests on a high index of suspicion and a thorough occupational and environmental history. More extensive testing—such as HRCT scanning, laboratory testing for serum precipitins, bronchoscopy with BAL, and lung biopsy—can be particularly helpful when the history of exposure is unclear or the level of exposure is low to intermediate (Table 2).

 


Table 2Diagnostic Evaluation of Patients With Suspected HP

Diagnostic Modality Findings Limitations
Clinical history Recurrent episodes of respiratory symptoms after exposure to suspected antigen; improvement away from exposure Requires high index of suspicion and thorough history; difficult to distinguish from daily exposures; identifying new causative antigens
HRCT scanning Patchy ground-glass opacities; centrilobular nodules; mosaic attenuation; upper to mid lung zone predominance Chronic forms of HP may demonstrate findings similar to other forms of ILD, such as IPF and nonspecific interstitial pneumonia
Serum precipitins Elevated titers False-positive test findings may be the result of exposure and not disease; false-negative results may be due to either failure to test for the correct antigen or removal from exposure
Inhalation challenge testing Respiratory symptoms immediately after exposure or with a delay Lack of standardized reference ranges; time consuming; requires close supervision in medically monitored setting
Bronchoscopy BAL reveals lymphocytosis and a CD4+/CD8+ ratio <1; transbronchial biopsy (see below) may reveal HP Invasive; limited sensitivity; transbronchial biopsy may yield insufficient tissue for diagnosis
Surgical lung biopsy Poorly formed granulomas; CD8+ lymphocyte predominance; bronchiolitis obliterans and organizing pneumonia; fibrosis in chronic cases Highly invasive; does not supplant clinical history, as alternative pathologic manifestations may be seen (similar to IPF or nonspecific interstitial pneumonia)

 


Pulmonary Function Testing
In HP, the results of pulmonary function testing generally reveal a restrictive ventilatory defect and reduced diffusing capacity of lung for carbon monoxide (Dlco). Isolated reductions in Dlco are sometimes seen. Obstructive ventilatory defects or reduction in mid-lung volume flow rates may be seen, reflecting the involvement of peripheral airways in HP.2

Radiology
While routine chest radiographs are often the first imaging study in HP patients, the abnormalities on plain chest radiographs are often subtle or nonspecific and sometimes the radiographic findings are even normal. Although plain chest radiographs may suffice for patients with acute HP, HRCT scans should be considered in all cases in which HP is suspected. This includes acute cases of HP, as subtle abnormalities may not be obvious on plain chest radiographs. HRCT scans more clearly delineate lung parenchymal abnormalities and may demonstrate findings that help distinguish HP from other forms of ILD (Figs 1, 2). Because HP disease can involve small airways, the interstitium, and the alveoli, HRCT scan findings can include ground-glass abnormalities (reflective of alveolar disease) and micronodules consisting of centrilobular or peribronchiolar nodules (reflecting small airway involvement) <5 mm in diameter. Given the presence of small-airway involvement in HP, air trapping on inspiratory and expiratory imaging is often found. In contrast to the lower lobe predominance seen in patients with idiopathic pulmonary fibrosis (IPF), HP typically shows HRCT scan evidence of disease in the upper- and mid-lung zones.

 


L11Fig1

Figure 1. HRCT scan in a patient with subacute HP demonstrates ground-glass abnormalities and centrilobular nodules.

 


L11Fig2

Figure 2. HRCT scan in a patient with chronic HP showing mosaic attenuation and some ground-glass pulmonary fibrosis with honeycombing in an upper- and mid-lung zone distribution.

 


Patients with pathologic fibrosis have more fibrotic changes on CT scan, such as a more extensive reticular pattern as well as traction bronchiectasis, honeycombing, and an IPF/usual interstitial pneumonia (UIP) pattern.

Although chronic HP can appear similar to a fibrotic IPF/UIP pattern on CT scan, certain radiologic features can help distinguish HP from IPF. For example, in a retrospective case series, chronic HP was associated with centrilobular nodules, mosaic attenuation, and the absence of lower lung zone predominance, in contrast to IPF.40,41

Serum Precipitating Antibodies
When clinicians have a strong or intermediate suspicion for antigen exposure, positive serum precipitins can lend further support to an HP diagnosis.

Serum precipitins generally measure the presence of IgG antibodies to specific antigens and can be measured by several methods, including immunodiffusion, immunoelectrophoresis, or enzyme-linked immunosorbent assays.

Serum precipitin testing is limited for several reasons. While negative test results may help clinicians rule out an exposure in patients with intermediate or indeterminate exposures who have ILD, negative results could also indicate that the specific exposure was not identified correctly, as most laboratory panels test for the presence of only certain specific antibodies. This standard set generally includes Aspergillus fumigatus IgG and Saccharopolyspora rectivirgula IgG. Because most centers do not routinely test for bird-specific antigens, health-care providers should specifically request testing for an antigen of interest.

Clinicians must also be cautious in their interpretation of positive precipitin test results. Positive results may confirm antigen exposure but may not correlate with or predict disease development. For example, 30% of farmers and 50% of pigeon breeders without HP have evidence of serum precipitating antibodies to antigens associated with HP.42,43

Inhalation Challenge
Inhalation challenge studies have been performed, particularly in research settings, to determine response to specific antigen exposure in patients with suspected HP. A positive inhalation challenge test involves the development of an acute response or even delayed response to a culprit antigen. Signs may include fevers, chills, shortness of breath, and cough. Physical examination and physiologic findings may include hypoxemia, crackles, changes in pulmonary function testing (FVC and Dlco), or the appearance of radiologic abnormalities (new ground-glass abnormalities).

Limitations of inhalation challenge testing include the lack of standard protocols as well as the lack of a clear definition of a “positive” or “negative” response. Other logistical and practical issues surrounding inhalation challenge testing include the fact that such testing is time consuming and expensive; furthermore, given the risk, such testing must take place in a closely supervised setting. Given these limitations, in the United States, inhalation challenge testing is generally unavailable or available only in a research setting.44,45

Bronchoalveolar Lavage
Contrary to the work-up of other forms of ILD, bronchoscopy with BAL can help support an HP diagnosis and is less invasive than a surgical lung biopsy.46 While neutrophilia (>5%) and mast cells (>1%) are often found acutely, BAL fluid typically reveals a lymphocytosis between 30% and 70% that can persist for years. Although sarcoid patients also have lymphocytosis, CD4+/CD8+ ratios in sarcoid are typically elevated (>3.5) and CD4+/CD8+ ratios <1 suggest HP. Several variables may influence the CD4+/CD8+ ratio, including the specific antigen, exposure cessation, and whether HP is chronic or acute. While low ratios are seen in patients with summer-type HP, HP associated with Mycobacterium avium complex is often characterized by an elevated CD4+/CD8+ ratio. BAL fluid may also contain increased levels of immunoglobulins—IgG, IgA, and IgM—or an increased IgG-to-albumin ratio. Investigators are actively searching for BAL-fluid biomarkers that could correlate with disease activity. For example, increased BAL levels of hyaluronic acid and procollagen 3 N-terminal peptide may indicate more active and severe HP.47

Lung Biopsy
In the setting of a classic history of antigen exposure, positive serum precipitins, and typical HRCT scan findings, an invasive lung biopsy is often unnecessary. When an exhaustive workup fails to fully support a diagnosis of HP, however, a lung biopsy can be useful. While transbronchial biopsy results may sometimes confirm the diagnosis, video-assisted thoracoscopic surgery may be required to obtain a large enough specimen to establish the diagnosis.48

Classically, the histopathologic condition in HP (Fig 3) is characterized by an inflammatory interstitial infiltrate of lymphocytes (principally CD8+ T cells), scattered poorly formed granulomas, and bronchiolitis obliterans and bronchiolitis obliterans with organizing pneumonia. The granulomas in HP are poorly formed as compared with those in sarcoidosis. Granulomas are frequently (perhaps in up to 60% of cases) but not uniformly found. In fact, biopsy specimens from patients with chronic HP may not reveal granulomas.49

 


L11Fig3

Figure 3. The pathologic finding's in HP are characterized by poorly formed granulomas and an inflammatory interstitial infiltrate (hematoxylin-eosin, original magnification x20).

 


Other pathologic forms of HP can be seen. Nonspecific interstitial pneumonia, another ILD histopathologic pattern characterized by a diffuse mononuclear infiltrate and fibrosis, has been described as an alternative pathologic manifestation of HP.50 In some cases, chronic HP may be similar to UIP, the pathologic pattern seen in IPF. Of note, even in HP patients in whom UIP/IPF patterns are seen on examination of lung biopsy specimens, there is often evidence of peribronchiolar fibrosis suggesting inhalational injury patterns not usually found in patients who have UIP/IPF.49

Finally, while the presence of antigen exposure in lung tissue is not routinely documented, a recent case report illustrated the potential use of immunohistochemistry in HP patients. León and coworkers51 reported positive cytoplasmic immunostaining in the multinucleated giant cells and histiocytes found in the granulomas of HP patients using a polyclonal antibody raised against pigeon serum.

Differential Diagnosis

The differential diagnosis for HP often varies depending on an acute vs chronic clinical presentation. Acute forms of HP should be differentiated from inhalation fever and organic dust toxic syndrome. In contrast to the allergic reaction that causes HP, inhalation fevers are toxic responses to a variety of exposures, including metal fumes (eg, zinc oxide fumes from welding). Organic dust toxic syndrome (ODTS) is a self-limiting flulike syndrome caused by exposure to organic materials, such as molds and bacteria that contaminate grain dust. While ODTS may occur in some of the same agricultural settings as HP, again, ODTS is not characterized by the immunologic response of HP and is self-limited without long-term sequelae.52

Differentiating chronic HP from other idiopathic interstitial pneumonias can be challenging, particularly in settings where exposure is intermediate or indeterminate. Insidious onset of chronic cough and dyspnea seen in patients with chronic HP can also occur in IPF patients. Patients with chronic HP can have a UIP-type pattern, the same pathologic pattern seen in patients with IPF. In such situations, certain pathologic clues, such as the finding of granulomas and centrilobular fibrosis, point towards chronic HP.49 Radiographically, the presence of decreased attenuation (mosaic attenuation), centrilobular nodules, ground-glass opacity, and a predominantly upper- and mid-lung zone distribution distinguishes chronic HP from IPF.53

Treatment

The cornerstone of HP treatment is antigen avoidance. While clinical and physiologic improvement may be dramatic and immediate in more acute forms of HP, improvement may occur over weeks to months for patients with subacute disease. In fact, patients with chronic HP who have established pulmonary fibrosis may not improve at all. Often, complete cessation of exposure may be difficult. For example, those with farmer’s lung may be financially unable to retire or change locations. Efforts to minimize exposure using respirators and engineering controls may help. Unfortunately, even small amounts of exposure may provoke symptoms given that HP is an immunologic reaction. In fact, continued bird antigen exposure has been reported in home environments long after the removal of the bird.

When symptoms are severe or complete exposure cessation is not feasible, clinicians should administer short courses of glucocorticoids, often for only 4 weeks. While steroids may result in a more rapid symptomatic improvement and physiologic function in the first several weeks, studies in the setting of farmer’s lung revealed no apparent differences in long-term outcome. While steroids may be highly effective in patients with acute or subacute disease, their effect may be limited or more prolonged courses required in individuals who have chronic or ongoing exposure.54-57

While alternative immunosuppressive or steroid-sparing agents such as azathioprine have been used in HP cases, data supporting their efficacy are limited.

Outcome

While most HP patients recover completely after exposure cessation, some individuals with HP have a poorer prognosis. Although recovery may continue for up to several years, patients with farmer’s lung often experience dramatic improvement soon after exposure cessation. Fifty percent of those with farmer’s lung have evidence of persistent physiologic impairment, but such derangements are often minor. Patients with chronic HP, such as those with bird fancier’s lung, may improve minimally or not at all. In a study of 18 patients with bird fancier’s lung followed for 10 years, five patients had persistent symptoms and four were left with physiologic derangements.56,57

In general, the prognosis in HP is better than for other forms of ILD, particularly IPF. The presence of established fibrosis predicts a poorer prognosis. In a recent study by Churg and coworkers,58 HP patients with no fibrosis had a median survival of 22.4 years, while patients with a fibrotic pattern had a survival of a little over 2 years. Given that pathologic data are often not available, it is notable that CT evidence of fibrosis also predicts poorer survival.59

As underscored by a recent study by Inase and colleagues,60 exposure cessation is critical; three of four patients with chronic summer-type HP who did not discontinue exposure died of respiratory failure.

Acute exacerbations (episodes of acute alveolitis) have also been reported in patients with HP. Miyazaki and coworkers61 reported acute exacerbations in 14 of 100 patients with bird fancier’s lung. Exacerbations were more common in patients with pathologic findings similar to those of IPF.

Summary

HP is underdiagnosed by both primary-care providers and pulmonary physicians. A wide array of potential antigens, ranging from a variety of mold species to proteinaceous material derived from birds, have been reported to be associated with the development of HP. Given this large range of potential antigens and the ongoing discovery of new antigens, the cornerstone of diagnosis rests upon a high index of clinical suspicion and a thorough occupational and environmental history. Classic HRCT scan findings—ground-glass and nodular opacities in an upper- and mid-lung zone distribution—and positive serum precipitins can support a diagnosis. When the exposure history is unclear, more invasive testing—such as bronchoscopy with BAL and even surgical lung biopsy—can help guide the clinician to the correct diagnosis. Unlike some forms of ILD, such as IPF, the prognosis for patients with acute and subacute HP can be quite good after exposure cessation. In patients with chronic HP, exposure cessation may be far less effective. In moderate to severe cases, steroid treatment may be indicated.


References

  1. Selman M. Hypersensitivity pneumonitis. In: King TE Jr, Schwarz MI, eds. Interstitial Lung Disease. 4th ed. Hamilton, Ontario, Canada: B.C. Decker; 2003:447-452.
  2. Vogelmeier C. Hypersensitivity pneumonitis. In: Costabel U, du Bois RM, Egan JJ, eds. Diffuse Parenchymal Lung Disease. Basel, Switzerland: S. Karger; 2007:139-147.
  3. Thomeer MJ, Costabe U, Rizzato G, Poletti V, Demedts D. Comparison of registries of interstitial lung diseases in three European countries. Eur Respir J Suppl. 2001;32:114s-118s.
  4. Coultas DB, Zumwalt RE, Black WC, Sobonya RE. The epidemiology of interstitial lung diseases. Am J Respir Crit Care Med. 1994;150(4):967-972.
  5. Dalphin JC, Debieuvre D, Pernet D, et al. Prevalence and risk factors for chronic bronchitis and farmer’s lung in French dairy farmers. Br J Ind Med. 1993;50(10):941-944.
  6. Grant IW, Blyth W, Wardrop VE, Gordon RM, Pearson JC, Mair A. Prevalence of farmer’s lung in Scotland: a pilot survey. Br Med J. 1972;1(5799):530-534.
  7. Gruchow HW, Hoffmann RG, Marx JJ Jr, Emanuel DA, Rimm AA. Precipitating antibodies to farmer’s lung antigens in a Wisconsin farming population. Am Rev Respir Dis. 1981;124(4):411-415.
  8. Madsen D, Klock LE, Wenzel FJ, Robbins JL, Schmidt CD. The prevalence of farmer's lung in an agricultural population. Am Rev Respir Dis. 1976;113(2):171-174.
  9. Christensen LT, Schmidt CD, Robbins L. Pigeon breeders’ disease—a prevalence study and review. Clin Allergy. 1975;5(4):417-430.
  10. Hanak V, Golbin JM, Ryu JH. Causes and presenting features in 85 consecutive patients with hypersensitivity pneumonitis. Mayo Clin Proc. 2007;82(7):812-816.
  11. Morell F, Roger A, Reyes L, Cruz M, Murio C, Muñoz X. Bird fancier’s lung: a series of 86 patients. Medicine. 2008;87(2):110-130.
  12. Rose CS, Martyny JW, Newman LS, et al. “Lifeguard lung”: endemic granulomatous pneumonitis in an indoor swimming pool. Am J Public Health. 1998;88(12):1795-1800.
  13. Simpson C, Garabrant D, Torrey S, Robins T, Franzblau A. Hypersensitivity pneumonitis-like reaction and occupational asthma associated with 1,3-bis(isocyanatomethyl) cyclohexane pre-polymer. Am J Ind Med. 1996;30(1):48-55.
  14. Malmberg P, Rask-Andersen A, Rosenhall L. Exposure to microorganisms associated with allergic alveolitis and febrile reactions to mold dust in farmers. Chest. 1993;103(4):1202-1209.
  15. Hoppin JA, Umbach DM, Kullman GJ, et al. Pesticides and other agricultural factors associated with self-reported farmer’s lung among farmer’s lung among farm residents in the Agricultural Health Study. Occup Environ Med. 2007;64(5):334-341.
  16. van Heemst RC, Sander I, Rooyackers J, et al. Hypersensitivity pneumonitis caused by occupational exposure to phytase. Eur Respir J. 2009;33(6):1507-1509.
  17. Merget R, Sander I, Rozynek P, Raulf-Heimsoth M, Bruening T. Occupational hypersensitivity pneumonitis to molds in an onion and potato sorter. Am J Ind Med. 2008;51(2):117-119.
  18. Gupta A, Rosenman KD. Hypersensitivity pneumonitis due to metal working fluids: sporadic or under reported? Am J Ind Med. 2006;49(6):423-433.
  19. Tonelli AR, Lottenberg R, Allan RW, Sriram PS. Rituximab-induced hypersensitivity pneumonitis. Respiration. 2009;78(2):225-229.
  20. Martin N, Innes JA, Lambert CM, Turnbull CM, Wallace WA. Hypersensitivity pneumonitis associated with leflunomide therapy. J Rheumatol. 2007;34(9):1934-1937.
  21. Um SJ, Lee SK, Yang DK. Hypersensitivity pneumonitis following intravesical bacille Calmette-Guérin immunotherapy for superficial bladder cancer. J Investig Allergol Clin Immunol. 2009;19(3):230-232.
  22. Bourke SJ, Dalphin JC, Boyd G, McSharry C, Baldwin CI, Calvert JE. Hypersensitivity pneumonitis: current concepts. Eur Respir J Suppl. 2001;32:81s-92s.
  23. McSharry C, Anderson K, Bourke SJ, Boyd G. Takes your breath away—the immunology of allergic alveolitis. Clin Exp Immunol. 2002;128(1):3-9.
  24. Patel AM, Ryu JH, Reed CE. Hypersensitivity pneumonitis: current concepts and future questions. J Allergy Clin Immunol. 2001;108(5):661-670.
  25. Shanley TP, Peters JL, Jones ML, Chensue SW, Kunkel SL, Ward PA. Regulatory effects of endogenous interleukin-1 receptor antagonist protein in immunoglobulin G immune complex-induced lung injury. J Clin Invest. 1996;97(4):963-970.
  26. Mroz RM, Korniluk M, Stasiak-Barmuta A, Ossolinska M, Chyczewska E. Increased levels of Treg cells in bronchoalveolar lavage fluid and induced sputum of patients with active pulmonary sarcoidosis. Eur J Med Res. 2009;14 Suppl 4:165-169.
  27. Ye Q, Nakamura S, Sarria R, Costabel U, Guzman J. Interleukin 12, interleukin 18, and tumor necrosis factor alpha release by alveolar macrophages: acute and chronic hypersensitivity pneumonitis. Ann Allergy Asthma Immunol. 2009;102(2):149-154.
  28. Simonian PL, Roark CL, Born WK, O'Brien RL, Fontenot AP. Gammadelta T cells and Th17 cytokines in hypersensitivity pneumonitis and lung fibrosis. Transl Res. 2009;154(5):222-227.
  29. 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):274-278.
  30. McSharry C, Banham SW, Boyd G. Effect of cigarette smoking on the antibody response to inhaled antigens and the prevalence of extrinsic allergic alveolitis among pigeon breeders. Clin Allergy. 1985;15(5):487-494.
  31. Ohtsuka Y, Munakata M, Tanimura K, et al. Smoking promotes insidious and chronic farmer’s lung disease and deteriorates the clinical outcome. Intern Med. 1995;34(10):966-971.
  32. Furuiye M, Mikake S, Miyazaki Y, et al. Effect of cigarette smoking on the development of murine chronic pigeon breeder’s lung: the difference between a short-term and a long-term exposure. J Med Dent Sci. 2007;54(1):87-95.
  33. Dangman KH, Storey E, Schenck P, Hodgson MJ. Effects of cigarette smoking on diagnostic tests for work-related hypersensitivity pneumonitis: data from an outbreak of lung disease in metalworkers. Am J Ind Med. 2004;45(5):455-467.
  34. Dakhama A, Hegele RG, Laflamme G, Israël-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):1316-1322.
  35. Cormier Y, Tremblay GM, Fournier M, Israël-Assayag E. Long-term viral enhancement of lung response to Saccharopolyspora rectivirgula. Am J Respir Crit Care Med. 1994;149(2 Pt 1):490-494.
  36. Aquino-Galvez A, Camarena A, Montaño M, et al. Transporter associated with antigen processing (TAP) 1 gene polymorphisms in patients with hypersensitivity pneumonitis. Exp Mol Pathol. 2008;84(2):173-177.
  37. Vasakova M, Sterclova M, Kolesar L, et al. Cytokine gene polymorphisms and BALF cytokine levels in interstitial lung diseases. Respir Med. 2009;103(5):773-779.
  38. Camarena A, Juárez A, Mejía M, et al. Major histocompatibility complex and tumor necrosis factor-alpha polymorphisms in pigeon breeder’s disease. Am J Respir Crit Care Med. 2001;163(7):1528-1533.
  39. Lacasse Y, Selman M, Costabel U, et al. Classification of hypersensitivity pneumonitis: a hypothesis. Int Arch Allergy Immunol. 2009;149(2):161-166.
  40. Adler BD, Padley SP, Müller NL, Remy-Jardin M, Remy J. Chronic hypersensitivity pneumonitis: high-resolution CT and radiographic features in 16 patients. Radiology. 1992;185(1):91-95.
  41. Cormier Y, Brown M, Worthy S, Racine G, Müller NL. High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J. 2000;16(1):56-60.
  42. Roberts RC, Wenzel FJ, Emanuel DA. Precipitating antibodies in a midwest dairy farming population toward the antigens associated with farmer’s lung disease. J Allergy Clin Immunol. 1976;57(6):518-524.
  43. McSharry C, Banham SW, Lynch PP, Boyd G. Antibody measurement in extrinsic allergic alveolitis. Eur J Respir Dis. 1984;65(4):259-265.
  44. Ohtani Y, Kojima K, Sumi Y, et al. Inhalation provocation tests in chronic bird fancier’s lung. Chest. 2000;118(5):1382-1389.
  45. Edwards JH, Davies BH. Inhalation challenge and skin testing in farmer’s lung. J Allergy Clin Immunol. 1981;68(1):58-64.
  46. Semenzato G, Bjermer L, Costabel U, Haslam PL, Olivieri D. Clinical guidelines and indications for bronchoalveolar lavage (BAL): extrinsic allergic alveolitis. Eur Respir J. 1990;3(8):945-946, 961-969.
  47. Larsson K, Eklund A, Malmberg P, Bjermer L, Lundgren R, Belin L. Hyaluronic acid (hyaluronan) in BAL fluid distinguishes farmers with allergic alveolitis from farmers with asymptomatic alveolitis. Chest. 1992;101(1):109-114.
  48. Trahan S, Hanak V, Ryu JH, Myers JL. Role of surgical lung biopsy in separating chronic hypersensitivity pneumonia from usual interstitial pneumonia/idiopathic pulmonary fibrosis: analysis of 31 biopsies from 15 patients. Chest. 2008;134(1):126-132.
  49. Akashi T, Takemura T, Ando N, et al. Histopathologic analysis of sixteen autopsy cases of chronic hypersensitivity pneumonitis and comparison with idiopathic pulmonary fibrosis/usual interstitial pneumonia. Am J Clin Pathol. 2009;131(3):405-415.
  50. Vourlekis JS, Schwarz MI, Cool CD, Tuder RM, King TE, Brown KK. Nonspecific interstitial pneumonitis as the sole histologic expression of hypersensitivity pneumonitis. Am J Med. 2002;112(6):490-493.
  51. León D, Retana VN, Hernández-Pando R, et al; Interdisciplinary group for the study of extrinsic allergic alveolitis. Pigeon hypersensitivity pneumonitis: immunohistochemical demonstration of the causative antigen in the lung. Prim Care Respir J. 2007;16(4):252-256.
  52. Blanc PD. Inhalation fever. In: Rom WN, Markowitz S, eds. Environmental and Occupational Medicine. Philadelphia, PA: Lippincott Williams & Wilkins; 2007:402-415.
  53. Silva CI, Müller NL, Lynch DA, et al. Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology. 2008;246(1):288-297.
  54. Cormier Y, Israël-Assayag E, Desmeules M, Lesur O. Effect of contact avoidance or treatment with oral prednisolone on bronchoalveolar lavage surfactant protein A levels in subjects with farmer’s lung. Thorax. 1996;51(12):1210-1215.
  55. Mönkäre S, Haahtela T. Farmer’s lung—a 5-year follow-up of eighty-six patients. Clin Allergy. 1987;17(2):143-151.
  56. Zacharisen MC, Schlueter DP, Kurup VP, Fink JN. The long-term outcome in acute, subacute, and chronic forms of pigeon breeder’s disease hypersensitivity pneumonitis. Ann Allergy Asthma Immunol. 2002;88(2):175-182.
  57. Lalancette M, Carrier G, Laviolette M, et al. Farmer’s lung: long-term outcome and lack of predictive value of bronchoalveolar lavage fibrosing factors. Am Rev Respir Dis. 1993;148(1):216-221.
  58. Churg A, Sin DD, Everett D, Brown K, Cool C. Pathologic patterns and survival in chronic hypersensitivity pneumonitis. Am J Surg Pathol. 2009;33(12):1765-1770.
  59. Hanak V, Golbin JM, Hartman TE, Ryu JH. High-resolution CT findings of parenchymal fibrosis correlate with prognosis in hypersensitivity pneumonitis. Chest. 2008;134(1):133-138.
  60. Inase N, Ohtani Y, Usui Y, Miyazaki Y, Takemura T, Yoshizawa Y. Chronic summer- type hypersensitivity pneumonitis: clinical similarities to idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis. 2007;24(2):141-147.
  61. 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):1265-1270.