History: first described in 1932 (as Farmer’s Lung)
Age: most cases occur in adults (cases in children, especially associated with pigeons, may occur)
Tobacco Use: protective effect against HP (although >90% of patients are non-smokers at time of diagnosis)
Etiology
General Comments
Over 300 Different Etiologic Agents Have Been Associated with HP
However, Bird Fancier’s Lung Accounts for Approximately 66% of All HP Cases
Animal Products
Bird Fancier’s Lung (Feathers and Bird Droppings)
Avian Proteins (Intestinal Mucin, IgA, and IgG): these proteins are contained in both bird droppings and bloom (the waxy keratinous powder which waterproofs the feathers)
Pyrethrum Insecticide (see Pyrethrum, [[Pyrethrum]])
Pauli’s Reagent Alveolitis
Sodium Diazobenzene Sulfate: lab reagent
Water-Based Metal Working Fluid HP: pure petroleum oils, emulsion of petroleum in a water base (semi-synthetic fluids), or emulsion of synthetic oils in water (synthetic fluids) -> used in many industries (auto machinists, etc) to decrease heat from machine tools and the object in production
Unknown Antigen: although biocides are added to metal working fluids, resistant microorganisms survive, leading to selection of organisms such as Mycobacterium Immunogenum
Unlike hot tub lung, mycobacteria are not cultured from BAL fluid (measurement of M immunogenum-specific cell-mediated immunity using detection of specific antibodies against recombinant M immunogenum antigens by ELISA may be helpful)
Drugs
Intravesical Bacillus Calmette-Guerin (BCG) (see Bacillus Calmette-Guerin, [[Bacillus Calmette-Guerin]])
Flavocoxid (Limbrel) (see Flavocoxid, [[Flavocoxid]])
Sulfapyridine (see Sulfonamides, [[Sulfonamides]])
Physiology
Organic dust exposure with deposition in distal lung (injury mainly involves type 3, type 4 hypersensitivity)
Organic dusts as immunologic adjuvants (induce humoral and cell-mediated immunity):
Micropolyspora Faeni antigens induces IL-1 and TNF-α from macrophages (anti-TNF-α infihibits pulmonary inflammation)
Thermophilic Actinomycetes antigens activate alveolar macrophages and alternative complement (promoting PMN chemotaxis to lung)
Ag’s contain enzymatic substances, endotoxins, histamine releasers, and inducers of non-specific precipitins
Increased mast cells in BAL in normal farmers and in Farmer’s Lung (correlated with disease activity/ but no evidence for IgE-mediated type 1 mechanisms exists)
Micropolyspora Faeni Ag, complement, mononuclear cells, and Ig present in bronchial wall of Farmer’s Lung (possible type II cytotoxic component)
Sensitized lymphocyctes occur in both blood and lung
Animal models of HP show that repeated exposure may lead to improvement (possibly due to antigen-specific T-suppressor cells)
Type 3 immune-complex injury plays a major role in HP: immune complexex can induce IL-1 and TNF-alpha release from BAL cells, in-duce pulmonary granuloma formation, activate alveolar macrophages
Precipitating Ab are present to specific Ag (but these are related to environmental exposure, not necessarily to disease)
However, serum complement does not decrease with Ag exposure and histologic vasculitis is absent in lung tissue
Type 4 delayed hypersensitivity injury plays a major role:
Inhibitors of type 4 reaction (cortisone, CSA, antimacrophage sera, etc.) inhibit animal model granuloma formation
Host Factors
Less than 10% of exposed people develop HP
No association between HLA types and susceptibility
Wheel and flare seen in most Pigeon Breeder’s Lung (10% of these have bronchospasm on Ag challenge, possibly due to IgG4-mediated type 1 reaction)
Skin tests: non-specific (not used)
Angiotensin Converting Enzyme (ACE) Level
May be elevated (also seen in organic dust-exposed normals)
Arterial Blood Gas (ABG) (see Arterial Blood Gas, [[Arterial Blood Gas]])
Acute HP: hypoxemia with hypocapnia
Subacute HP:
Chronic HP:
Clinical
General Comments
Clinical Pattern is Determined by Intensity and Frequency of Antigen Exposure
The Traditional 3-Group Classification System Below is Controversial: since the subacute group is difficult to define, some authors suggest that the clinical data better fits a 2-group classification system (Chest, 2012) [MEDLINE]
Hypersensitivity Pneumonitis Study Group: Significant Predictors of Hypersensitivity Pneumonitis (Am J Respir Crit Care Med, 2003) [MEDLINE]
Exposure to Known Offending Antigen: Odds Ratio 38.8 (95% CI: 11.6-129.6)
Symptoms 4-8 hrs After Exposure: Odds Ratio 7.2 (95% CI: 1.8-28.6)
Positive Precipitating Antibodies: Odds Ratio 5.3 (95% CI: 2.7-10.4)
Inspiratory Crackles: Odds Ratio 4.5 (95% CI: 1.8-11.7)
Recurrent Episodes of Symptoms: Odds Ratio 3.3 (95% CI: 1.5-7.5)
Weight Loss: Odds Ratio 2.0 (95% CI: 1.8-28.6)
Acute Hypersensitivity Pneumonitis
Characteristics
Exposure: intermittent short duration exposure
Symptom Onset: occur 4-6 hrs after challenge, last for 18-24 hrs after exposure ceases
Presents like Acute Bacterial or Viral Pneumonia, But May Persist if Exposure Persists
High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]]): due to characteristic clinical manifestations and rapid resolution in acute HP, HRCT is not usually performed in this subset of HP patients
There are Case Reports of Normal HRCT in Biopsy-Proven HRCT: this may be related to the time interval between removal from the offending antigen and the performance of the HRCT
HP Study Group [MEDLINE]: only 4% of patients had a normal HRCT
Patchy or Diffuse Bilateral Ground-Glass Opacities: may be asymmetric in some cases
Ground-glass opacities in acute HP may be similar to those seen in desquamative interstitial pneumonia (see Desquamative Interstitial Pneumonia, [[Desquamative Interstitial Pneumonia]])
Small Poorly-Defined Ground-Glass Centrilobular Nodules (see Bronchiolar Disorders, [[Bronchiolar Disorders]]): characteristic feature
Lobular Areas of Decreased Attenuation and Vascularity: inspiratory HRCT
Focal Airspace Consolidation: may occur in some cases, due to organizing pneumonia or less commonly, diffuse alveolar damage
Areas of Decreased Attenuation and Vascularity Indicating Air Trapping (Represent Bronchiolar Obstruction): expiratory HRCT
Hilar/Mediastinal Lymphadenopathy (see Mediastinal Mass, [[Mediastinal Mass]]): occasionally seen
Typical Absence of Effusions/Solitary Nodules/Cavitation/Calcification/Atelectasis
Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]]): PFT’s have no discriminative ability to distinguish HP from other interstitial lung diseases
General Comments: may be normal if done after acute symptoms resolve
Restrictive Pattern with Decreased DLCO: typical pattern
However, Data from the HP Study Group Demonstrate that the DLCO is Normal in 22% of Cases (Chest, 2012) [MEDLINE]
Normal Raw
Induced Sputum: contains increased total cells and lymphocytes (cell count differential suggest that induced sputum and BAL reflected different compartments of inflammation)
The Clinical Utility of Induced Sputum in the Diagnosis of Acute HP is Unclear
Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy, [[Bronchoscopy]]): BAL technique is not standardized
BAL Lymphocytosis (>30% for Non-Smokers/Ex-Smokers, >20% for Current Smokers) is Mandatory for the Diagnosis of HP: a normal number of BAL lymphocytes rules out all but residual disease
However, BAL Lymphocytosis Can Also Be Seen in Exposed Asymptomatic Subjects
CD4/CD8 Ratio <1
Increased BAL CD4/CD8 Ratio Has Been Classically Associated with Sarcoidosis, But High CD4/CD8 Ratios Can Also Be Seen in HP (J Allergy Clin Immunol, 1991) [MEDLINE] (Eur Respir J, 1997) [MEDLINE]: making differentiation of these entities difficult by CD4/CD8 ratio alone
Open Lung Biopsy: not usually required for diagnosis
Neutrophilic Infiltration of the Respiratory Bronchioles and Alveoli
Diffuse Alveolar Damage and Temporally Uniform, Nonspecific, Chronic Interstitial Pneumonitis May Be Seen in Some Cases
Clinical Features
Fever/Chills(see Fever, [[Fever]]): fever may be up to 104°
There are Case Reports of Normal HRCT in Biopsy-Proven HRCT: this may be related to the time interval between removal from the offending antigen and the performance of the HRCT
HP Study Group [MEDLINE]: only 4% of patients had a normal HRCT
Patchy or Diffuse Bilateral Ground-Glass Opacities: may be asymmetric in some cases
Small Poorly-Defined Ground-Glass Centrilobular Nodules (see Bronchiolar Disorders, [[Bronchiolar Disorders]]): may be only finding in some subacute HP cases
Irregular nodules >10 mm are unusual (they usually represent areas of focal organizing pneumonia)
Lobular Areas of Decreased Attenuation and Vascularity: inspiratory HRCT
Focal Airspace Consolidation: may occur in some cases, due to organizing pneumonia or less commonly, diffuse alveolar damage
Areas of Decreased Attenuation and Vascularity Indicating Air Trapping (Represent Bronchiolar Obstruction): expiratory HRCT
Seen in up to 90% of cases
Cysts (3-25 mm) (see Cystic-Cavitary Lung Lesions, [[Cystic-Cavitary Lung Lesions]]): occur in 13% of patients with subacute HP
Usually Associated with Ground-Glass Opacities
Cysts Resemble Those of Lymphoid Interstitial Pneumonia: like the cysts of lymphoid interstitial pneumonia, they are presumably caused by partial bronchiolar obstruction by the peribronchiolar lymphocytic infiltrates
Hilar/Mediastinal Lymphadenopathy (see Mediastinal Mass, [[Mediastinal Mass]]): occasionally seen
Typical Absence of Effusions/Solitary Nodules/Cavitation/Calcification/Atelectasis
Patchy Interstitial Infiltrates: less common pattern
“Hilar Haze” Pattern: may mimic acute pulmonary edema
Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]]): PFT’s have no discriminative ability to distinguish HP from other interstitial lung diseases
Restrictive (and Sometimes Obstructive) Pattern
Obstructive Pattern is Especially Common in Farmer’s Lung
Methacholine Challenge: may be positive
Decreased DLCO
However, Data from the HP Study Group Demonstrate that the DLCO is Normal in 22% of Cases (Chest, 2012) [MEDLINE]
Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy, [[Bronchoscopy]]): BAL technique is not standardized
BAL Lymphocytosis (>30% for Non-Smokers/Ex-Smokers, >20% for Current Smokers) is Mandatory for the Diagnosis of HP: a normal number of BAL lymphocytes rules out all but residual disease
However, BAL Lymphocytosis Can Also Be Seen in Exposed Asymptomatic Subjects
CD4/CD8 Ratio <1
Increased BAL CD4/CD8 Ratio Has Been Classically Associated with Sarcoidosis, But High CD4/CD8 Ratios Can Also Be Seen in HP (J Allergy Clin Immunol, 1991) [MEDLINE] (Eur Respir J, 1997) [MEDLINE]: making differentiation of these entities difficult by CD4/CD8 ratio alone
Open Lung Biopsy
Cellular Bronchiolitis, Non-Caseating Granulomas, and Bronchiolocentric Interstitial Pneumonitis with a Predominance of Lymphocytes
Areas of Organizing Pneumonia May Be Seen
Clinical Features
Fever/Chills(see Fever, [[Fever]]): fever may be up to 104°
Clinical Features Which May Differentiate HP from Sarcoidosis [MEDLINE]
Inspiratory Crackles: HP more commonly presented with inspiratory crackles than sarcoidosis (87% vs 15%)
Hilar/Mediastinal Lymphadenopathy: hilar and/or mediastinal lymphadenopathy was more commonly observed in sarcoidosis than in HP (46% vs 2%)
Chronic Hypersensitivity Pneumonitis
Characteristics
Exposure: long duration exposure
Diagnosis
High-Resolution Chest CT (HRCT) (see High-Resolution Chest Computed Tomography, [[High-Resolution Chest Computed Tomography]]): radiographic changes in chronic HP may not allow accurate differentiation from idiopathic pulmonary fibrosis (with usual interstitial pneumonia pathology)
Reticulation and Traction Bronchiectasis and Bronchiolectasis Due to Fibrosis Superimposed on Findings of Acute/Subacute HP
Reticulation Be Patchy or Random
Reticulation May Have a Predominantly Subpleural/Peri-Bronchovascular Distribution
Reticulation Typically Spares the Lung Bases
Subpleural Honeycombing: occurs in a minority of chronic HP cases
Hilar/Mediastinal Lymphadenopathy (see Mediastinal Mass, [[Mediastinal Mass]]): occasionally seen
Emphysematous Changes: for unclear reasons, emphysematous changes are more common than interstitial fibrosis in chronic HP associated with farmer’s lung (without a smoking history) [MEDLINE]
Radiographic Features Which Best Differentiate Chronic HP from Idiopathic Pulmonary Fibrosis (IPF) and Non-Specific Interstitial Pneumonia (NSIP) [MEDLINE]
Lobular Areas with Decreased Attenuation and Vascularity
Absence of Lower-Zone Predominance of Abnormalities
Pulmonary Function Tests (PFT’s) (see Pulmonary Function Tests, [[Pulmonary Function Tests]]): PFT’s have no discriminative ability to distinguish HP from other interstitial lung diseases
Restrictive (and Sometimes Obstructive) Pattern
Obstructive Pattern is Especially Common in Farmer’s Lung
Decreased DLCO
However, Data from the HP Study Group Demonstrate that the DLCO is Normal in 22% of Cases (Chest, 2012) [MEDLINE]
Bronchoscopy with Bronchoalveolar Lavage (BAL) (see Bronchoscopy, [[Bronchoscopy]]): BAL technique is not standardized
BAL Lymphocytosis (>30% for Non-Smokers/Ex-Smokers, >20% for Current Smokers) is Mandatory for the Diagnosis of HP: a normal number of BAL lymphocytes rules out all but residual disease
However, BAL Lymphocytosis Can Also Be Seen in Exposed Asymptomatic Subjects
CD4/CD8 Ratio <1
Increased BAL CD4/CD8 Ratio Has Been Classically Associated with Sarcoidosis, But High CD4/CD8 Ratios Can Also Be Seen in HP (J Allergy Clin Immunol, 1991) [MEDLINE] (Eur Respir J, 1997) [MEDLINE]: making differentiation of these entities difficult by CD4/CD8 ratio alone
Open Lung Biopsy: may be required
Clinical Features
Fever/Chills (see Fever, [[Fever]]): fever may be up to 104°
Corticosteroids are usually used for more severe cases
Prednisone 60 mg/day usually x 2-3 weeks, then taper over 3-6 weeks
Typically result in rapid clinical response (over days)
Subacute/Chronic HP: may require >8 week course
Farmer’s Lung: steroids hasten acute recovery but do not have long-term clinical benefit
Hot Tub Lung: treatment with steroids OR treatment aimed at MAI appear to be equally effective -> dual therapy is currently recommended
Treatment of Bronchospasm
Albuterol and cromolyn are useful to treat obstructive component in some studies
Inhaled Corticosteroids (see Corticosteroids, [[Corticosteroids]])
Have not been shown to be useful (but high dose inhaled steroids have not been studied)
Avoidance of Exposure/Respiratory Protection
Symptoms usually resolve
Masks probably do limit exposure adequately though
Immunotherapy
Contraindicated (risk of causing immune-complex vasculitis)
Possible future role of Ag-specific inhalational or IV desensitization
Prognosis
Morbidity: 5-year morbidity is 30% (due to pulmonary fibrosis)
Overall, there is an increased mortality in patients with HP compared with the general population (hazard ratio, 2.98), even though these individuals are less likely to smoke [MEDLINE]
References
Difference in the phenotypes of bronchoalveolar lavage lymphocytes in patients with summer-type hypersensitivity pneumonitis, farmer’s lung, ventilation pneumonitis, and bird fancier’s lung: report of a nationwide epidemiologic study in Japan. J Allergy Clin Immunol. 1991;87(5):1002-1009 [MEDLINE]
Lung and blood T-cell receptor repertoire in extrinsic allergic alveolitis. Eur Respir J. 1997;10(4):772-779 [MEDLINE]
Hypersensitivity pneumonitis. AJR Am J Roentgenol. 2000;174(4):1061-1066 [MEDLINE]
High-resolution computed tomographic characteristics in acute farmer’s lung and in its follow-up. Eur Respir J 2000; 16:56–60 [MEDLINE]
Hypersensitivity pneumonitis: spectrum of high-resolution CT and pathologic findings. AJR Am J Roentgenol. 2007;188(2):334-344 [MEDLINE]
Extrinsic allergic alveolitis: incidence and mortality in the general population. QJM. 2007;100(4):233-237 [MEDLINE]
HP Study Group. Clinical diagnosis of hypersensitivity pneumonitis. Am J Respir Crit Care Med. 2003;168(8):952-958 [MEDLINE]
Chronic hypersensitivity pneumonitis: differentiation from idiopathic pulmonary fibrosis and nonspecific interstitial pneumonia by using thin-section CT. Radiology. 2008;246(1):288-297 [MEDLINE]
Recent advances in hypersensitivity pneumonitis. Chest 2012;142:208-217 [MEDLINE]
