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Hypersensitivity Pneumonitis and Pulmonary Infiltrates with Eosinophilia

Chapter 299 | Part 7: Disorders of the Respiratory System · Part 7 – Respiratory Disorders · Chapter 299

Key Clinical Points

  1. Hypersensitivity pneumonitis (HP) is an immune-mediated response to inhaled antigens, requiring a history of exposure for diagnosis.
  2. Acute eosinophilic pneumonia (AEP) is characterized by rapid onset (<1 month), hypoxemic failure, and BAL eosinophilia >25%.
  3. Chronic eosinophilic pneumonia (CEP) presents with 'photographic negative pulmonary edema' (migratory bilateral peripheral or pleural-based opacities).
  4. Eosinophilic granulomatosis with polyangiitis (EGPA) is a multi-system disease involving asthma, peripheral eosinophilia, and vasculitis.
  5. Hypereosinophilic syndrome (HES) requires sustained eosinophilia >1000 cells/µL (>10% of WBC) and evidence of organ damage.
  6. Antigen avoidance is the primary treatment for HP; corticosteroids (prednisone 0.5–1 mg/kg/day) accelerate symptom resolution but do not change long-term outcomes in nonfibrotic cases.
  7. Fibrotic HP shares genetic markers (MUC5B) with IPF and may require antifibrotics (nintedanib, pirfenidone).
  8. AEP is often initially mistaken for ARDS until BAL confirms >25% eosinophils.
  9. EGPA typically progresses through three phases: prodromal (asthma/rhinitis), infiltrative (eosinophilia), and vasculitic (systemic involvement).
  10. Monoclonal antibodies against IL-5 are used for treatment of eosinophilic asthma, EGPA, and HES.

DEFINITION & OVERVIEW

• Hypersensitivity Pneumonitis (HP):

Definition: Hypersensitivity pneumonitis (HP), also referred to as extrinsic allergic alveolitis, is a pulmonary disease that occurs due to inhalational exposure to a variety of antigens leading to an inflammatory response of the alveoli and small airways.

• Pulmonary Infiltrates with Eosinophilia:

Definition: Pulmonary infiltrates with eosinophilia encompass several pulmonary eosinophilic syndemes characterized by pulmonary infiltrates on imaging along with an increased number of eosinophils in lung tissue, in sputum, and/or in BAL fluid, with resultant increased respiratory symptoms and the potential for systemic manifestations.

• Classification of Eosinophilic Syndromes:

  1. Primary Pulmonary Eosinophilic Disorders:
  2. Acute eosinophilic pneumonia (AEP)
  3. Chronic eosinophilic pneumonia (CEP)
  4. Eosinophilic granulomatosis with polyangiitis (EGPA/Churg-Strauss syndrome)
  5. Hypereosinophilic syndrome (HES)
  6. Pulmonary Disorders of Known Cause Associated with Eosinophilia:
  7. Asthma and eosinophilic bronchitis
  8. Allergic bronchopulmonary aspergillosis (ABPA)
  9. Bronchocentric granulomatosis
  10. Drug/toxin reaction
  11. Infections (Parasitic/helminthic or nonparasitic)
  12. Diseases Associated with Eosinophilia:
  13. Organizing pneumonia
  14. Hypersensitivity pneumonitis
  15. Idiopathic pulmonary fibrosis
  16. Pulmonary Langerhans cell granulomatosis
  17. Neoplasms Associated with Eosinophilia:
  18. Leukemia
  19. Lymphoma
  20. Lung cancer (Adenocarcinoma, Squamous cell carcinoma)
  21. Sarcoma of various organs
  22. Pleuropulmonary blastoma
  23. Systemic Disease Associated with Eosinophilia:
  24. Postradiation pneumonitis
  25. Rheumatoid arthritis
  26. Sarcoidosis
  27. Sjögren’s syndrome

EPIDEMIOLOGY

• HP Risk Factors:

• High-risk groups include farmers (grain/moldy hay), bird owners (feathers/droppings), industrial workers, and hot tub users.

• Specific conditions:

• Farmer's lung: exposure to bacterial or fungal antigens in grain or silage.

• Bird fancier's lung: exposure to parakeet, pigeon, or budgerigar proteins.

• Chemical worker's lung: exposure to isocyanates (e.g., diphenylmethane diisocyanate).

• Asthma in Elderly:

• Mortality of asthma in patients >65 years old is 5x higher than younger cohorts.

• ~50% of new-onset asthma cases are among current or former smokers.

• ~25% of adult-onset asthma is linked to occupational exposure.

• Eosinophilic inflammation correlates with more severe asthma symptoms.

• Eosinophilic Syndromes Demographics:

• EGPA: Mean age at diagnosis 48 years (range 14–74); average time from asthma onset to vasculitis is 9 years.

• HES: Typically occurs between ages 20 and 50; more common in men than in women.

ETIOLOGY & PATHOPHYSIOLOGY

• Hypersensitivity Pneumonitis (HP):

• Immune Response: Characterized by dysregulated T1 and T17 responses; innate immunity involves Toll-like receptors and MyD88 leading to neutrophil recruitment.

• Genetic Factors: No clear basis, but some cohorts show polymorphisms in TAP1 and MHC II. Chronic HP shares MUC5B polymorphism with IPF.

• Eosinophilic Syndromes:

• Pathophysiology: Likely result from dysregulated eosinophilopoiesis or autoimmune processes (high IgE, IgG4, and rheumatoid factor).

• IL-5 Role: Hypothesized to play a key role in eosinophilopoiesis; monoclonal antibodies against IL-5 are used for treatment.

• EGPA Specifics: ANCA present in 1/3 to 2/3 of patients; binding to vascular walls contributes to inflammation and injury.

• HP Antigens (Table 299-1):

• Fungal/Bacterial: Thermophilic actinomycetes, Aspergillus species, Penicillium species.

• Animal-derived: Proteins from birds (parakeets, pigeons), ducks, rats, and other animals.

• Environmental/Chemical: Isocyanates, Cladosporium (hot tubs), Aureobasidium (saunas), house dust mites, moldy hay.

CLINICAL FEATURES

• Hypersensitivity Pneumonitis (HP):

• Presentation: Variable; can be acute/intense or insidious/slowly progressive.

• Acute Form: Symptoms may resolve in hours to days if antigen is removed; can be recurrent/episodic.

• Chronic Form: Gradual onset of dyspnea, cough, fatigue, weight loss, and clubbing; often lacks an acute preceding episode.

• Acute Eosinophilic Pneumonia (AEP):

• Presentation: Fever, acute respiratory failure (requiring mechanical ventilation), diffuse infiltrates.

• Clinical Context: Often mistaken for ARDS until BAL reveals >25% eosinophils.

• Chronic Eosinophilic Pneumonia (CEP):

• Presentation: Indolent; cough, low-grade fever, weight loss, wheezing.

• Imaging: "Photographic negative pulmonary edema" (migratory bilateral peripheral or pleural-based opacities) in <25% of cases.

• Eosinophilic Granulomatosis with Polyangiitis (EGPA):

• Prodromal Phase: Asthma and allergic rhinitis (starts in 20s/30s, lasts years).

• Infiltrative Phase: Peripheral eosinophilia and tissue infiltration of lungs/GI tract.

• Vasculitic Phase: Constitutional symptoms (fever, weight loss, myalgias) and multi-organ involvement.

• Systemic Involvement:

• Respiratory: Severe asthma; alveolar hemorrhage/hemoptysis.

• Neurologic: >75% have manifestations; mononeuritis multiplex (peroneal nerve common); risk of cerebral hemorrhage.

• Dermatologic: ~50% develop palpable purpura, nodules, or urticarial rashes.

• Cardiovascular: Granulomas, vasculitis, cardiomyopathy (up to 50% of patients).

• Renal: ~25% have involvement (proteinuria, glomerulonephritis).

• Gastrointestinal: Abdominal pain, diarrhea, bleeding; ischemic bowel/pancreatitis portend poor prognosis.

DIFFERENTIAL DIAGNOSIS

• HP Differentiation:

• Distinguish from other interstitial lung diseases based on antigen exposure history and imaging (e.g., nonfibrotic vs. fibrotic patterns).

• Eosinophilic Syndromes Differentiation:

• AEP vs. ARDS: AEP is suspected when BAL shows >25% eosinophils.

• CEP vs. other infiltrates: Identified by peripheral/pleural-based opacities and high peripheral eosinophil count (>30%).

• EGPA vs. others: Distinguished by the triad of asthma, peripheral eosinophilia, and multi-organ involvement (vasculitis).

DIAGNOSTIC APPROACH

  1. Clinical Assessment:
  2. Identify exposure history for HP.
  3. Assess for asthma/allergy history in suspected eosinophilic syndromes.
  4. Imaging (Chest X-ray/CT):
  5. Nonfibrotic HP: Look for ground-glass opacities and centrilobular nodules.
  6. Fibrotic HP: Look for subpleural honeycombing sparing the lung bases.
  7. CEP: Identify "photographic negative pulmonary edema" (peripheral/pleural-based opacities).
  8. Bronchoalveolar Lavage (BAL):
  9. Perform to determine eosinophil percentage; >25% is a key threshold for AEP diagnosis.
  10. Laboratory Workup:
  11. Count peripheral eosinophils (AEP/CEP typically >30%; HES >1000 cells/µL).
  12. Check for ANCA (present in 1/3 to 2/3 of EGPA patients).
  13. Exclusionary Testing:
  14. Rule out parasitic, fungal, or other infections.
  15. Rule out drugs known to cause pulmonary eosinophilia.

MANAGEMENT & TREATMENT

  1. Hypersensitivity Pneumonitis (HP):
  2. Step 1: Antigen avoidance (primary management).
  3. Step 2: Corticosteroids (prednisone 0.5–1 mg/kg/day) to accelerate symptom resolution.

  4. Step 3: Antifibrotic agents (nintedanib, pirfenidone) for fibrotic HP cases.

  5. Eosinophilic Granulomatosis with Polyangiitis (EGPA):

  6. Step 1: Corticosteroids to control symptoms and potentially suppress vasculitic features.

  7. Step 2: Monoclonal antibodies against IL-5 for eosinophilic asthma/EGPA.

  8. Hypereosinophilic Syndrome (HES):

  9. Step 1: Monoclonal antibodies against IL-5.
  10. Step 2: Tyrosine kinase inhibitors (e.g., imatinib) for myeloproliferative variants.

COMPLICATIONS & PROGNOSIS

• HP Prognosis:

• Nonfibrotic: Good prognosis with antigen avoidance.

• Fibrotic: Prognosis similar to Idiopathic Pulmonary Fibrosis (IPF).

• Eosinophilic Syndromes Prognosis:

• AEP: Rapid response to corticosteroids; usually no relapse after discontinuation.

• EGPA: Neurologic sequelae often do not fully resolve; cardiac involvement portends worse prognosis; ischemic bowel/pancreatitis portend worse prognosis.

KEY PEARLS & HIGH-YIELD POINTS

• AEP vs. ARDS: AEP is often initially mistaken for ARDS until BAL confirms >25% eosinophils.

• HP Imaging Distinction: Nonfibrotic HP shows ground-glass/centrilobular nodules; Fibrotic HP shows subpleural honeycombing sparing the bases (unlike IPF).

• HES Threshold: Diagnosis requires sustained eosinophilia >1000 cells/µL (>10% of WBC) and organ damage.

• EGPA Progression: Follows a clinical continuum: Prodromal → Infiltrative → Vasculitic.

Reference Tables

TABLE 299-1 Examples of Hypersensitivity Pneumonitis DISEASE Farming/Food Processing Farmer’s lung

Harrison's 22e, p.2228

DISEASE ANTIGEN SOURCE
Farming/Food Processing
Farmer’s lung Thermophilic actinomycetes
(e.g., Saccharopolyspora
rectivirgula); fungus		 Grain, moldy hay,
silage
Bagassosis Thermophilic actinomycetes Sugarcane
Cheese washer’s lung Penicillium casei; Aspergillus
clavatus		 Cheese
Coffee worker’s lung Coffee bean dust Coffee beans
Malt worker’s lung Aspergillus species Barley
Miller’s lung Sitophilus granarius (wheat
weevil)		 Wheat flour
Mushroom worker’s lung Thermophilic actinomycetes;
mushroom spores		 Mushrooms
Potato riddler’s lung Thermophilic actinomycetes;
Aspergillus species		 Moldy hay around
potatoes
Tobacco grower’s lung Aspergillus species Tobacco
Wine maker’s lung Botrytis cinerea Grapes
Birds and Other Animals
Proteins derived by parakeets,
pigeons, budgerigars
Duck feathers, serum proteins
Fish meal dust
Dust from animal furs
Rat urine, serum, fur
Animal proteins
Chicken serum proteins
Turkey serum proteins
Other Occupational and Environmental Exposures
Chemical worker’s lung Isocyanates Polyurethane foam,
varnish, lacquer
Detergent worker’s lung Bacillus subtilis enzymes Detergent
Hot tub lung Cladosporium species;
Mycobacterium avium
complex		 Contaminated
water, mold on
ceiling
Humidifier fever (and air
conditioner lung)		 Several microorganisms
including: Aureobasidium
pullulans; Candida albicans;
thermophilic actinomycetes;
Mycobacterium species;
Klebsiella oxytoca; Naegleria
gruberi		 Humidifiers and
air conditioners
(contaminated
water)
Machine operator’s lung Pseudomonas species;
Mycobacteria species		 Metal working fluid
Sauna taker’s lung Aureobasidium species; other
antigens		 Sauna water
Suberosis Penicillium glabrum;
Chrysonilia sitophila		 Cork dust
Summer-type
pneumonitis		 Trichosporon cutaneum House dust mites,
bird droppings
Woodworker’s lung Alternaria species; Bacillus
subtilis		 Oak, cedar, pine,
mahogany dusts
299 Hypersensitivity
Pneumonitis and
Pulmonary Infiltrates
with Eosinophilia
Praveen Akuthota, Michael E. Wechsler

TABLE 299-2 Pulmonary Infiltrates with Eosinophilia Primary Pulmonary Eosinophilic Disorders Acute eosinophilic…

Harrison's 22e, p.2231

  • Primary Pulmonary Eosinophilic Disorders
  • Acute eosinophilic pneumonia
  • Chronic eosinophilic pneumonia
  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)
  • Hypereosinophilic syndrome
  • Pulmonary Disorders of Known Cause Associated with Eosinophilia
  • Asthma and eosinophilic bronchitis
  • Allergic bronchopulmonary aspergillosis
  • Bronchocentric granulomatosis
  • Drug/toxin reaction
  • Infection (Table 299-4)
  • Parasitic/helminthic disease
  • Nonparasitic infection
  • Lung Diseases Associated with Eosinophilia
  • Cryptogenic organizing pneumonia
  • Hypersensitivity pneumonitis
  • Idiopathic pulmonary fibrosis
  • Pulmonary Langerhans cell granulomatosis
  • Malignant Neoplasms Associated with Eosinophilia
  • Leukemia
  • Lymphoma
  • Lung cancer
  • Adenocarcinoma of various organs
  • Squamous cell carcinoma of various organs
  • Systemic Disease Associated with Eosinophilia
  • Postradiation pneumonitis
  • Rheumatoid arthritis
  • Sarcoidosis
  • Sjögren’s syndrome

TABLE 299-3 Diagnostic Criteria of Acute Eosinophilic Pneumonia Acute febrile illness with respiratory manifestations…

Harrison's 22e, p.2231

  • Acute febrile illness with respiratory manifestations of <1 month in duration
  • Hypoxemic respiratory failure
  • Diffuse pulmonary infiltrates on chest x-ray
  • Bronchoalveolar lavage eosinophilia >25%
  • Absence of parasitic, fungal, or other infection
  • Absence of drugs known to cause pulmonary eosinophilia
  • Quick clinical response to corticosteroids
  • Failure to relapse after discontinuation of corticosteroids