Hypersensitivity Pneumonitis Guidelines for Diagnosis of

Guidelines for Diagnosis of Hypersensitivity Pneumonitis

Soo-Ryum (Stew) Yang, MDAssistant Attending Pathologist

Molecular and Thoracic Pathology

No Relevant Disclosures

Outline

• Primer on Hypersensitivity Pneumonitis (HP)• Histologic Diagnostic Criteria for HP• Common Differential Diagnosis

Definition and Pathogenesis

• HP is a form of interstitial lung disease (ILD) resulting from an immune reaction provoked by an inhaled antigen in susceptible individuals

Inhaled Antigen• Organic

• Microbes (Mold)• Proteins (Avian)

• Inorganic• Chemicals• Drugs• Metals

Host Susceptibility • Polymorphisms

• MHC class II• MUC5B promoter• Telomere-related

genes• Preceding infection

Immune Reaction• Humoral• T-helper cell

type 1• Fibroblast

activity

Interstitial Lung Disease

• Bronchiolocentric interstitial inflammation and/or fibrosis

• Granulomatous inflammation

Raghu G et al. An official ATS/JRS/ALAT clinical practice guideline. American journal of respiratory and critical care medicine. 2020 Aug 1;202(3):e36-69.Pérez ER, Travis WD et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. 2021 Apr 20.

Churg A. Hypersensitivity pneumonitis: new concepts and classifications. Modern Pathology. 2021 Sep 16:1-3.Churg A, Muller NL. Atlas of interstitial lung disease pathology. Lippincott Williams & Wilkins; 2019 Sep 27.

Clinical Correlates

• Most patients present after fourth decade of life• Incidence: 1 – 2 cases per 100,000 per year in North America

and Europe• Common symptoms: dyspnea, cough, mid-expiratory squeaks

• Constitutional symptoms, chest tightness and wheezing• >50% of patients present with chronic symptoms and fibrosis• Poor prognosis: fibrosis and lack of identifiable inciting agent• Treatment: avoidance of inciting agent and immunosuppression


Churg A. Hypersensitivity pneumonitis: new concepts and classifications. Modern Pathology. 2021 Sep 16:1-3.Churg A, Muller NL. Atlas of interstitial lung disease pathology. Lippincott Williams & Wilkins; 2019 Sep 27.

Diagnostic Workup• Detailed exposure history

and clinical evaluation• High-resolution chest CT• Laboratory testing

• Serologic assays for IgG antibodies

• Bronchoalveolar lavage (BAL)

• Lymphocyte count >20% • Lung biopsy

• Surgical lung biopsy • Transbronchial (cryo)biopsy

Multidisciplinary Discussion (MDD)

Pulmonology

Radiology

Pathology

Rheumatology

MultidisciplinaryDiagnosis

Challenges in Diagnosis of HP

• Inciting agent is not identified in up to 50% of patients• Serologic testing and BAL have variable sensitivity/specificity• Poor agreement in clinical, radiologic, and pathologic criteria


Pérez Er et al. Identifying an inciting antigen is associated with improved survival in patients with chronic hypersensitivity pneumonitis. Chest. 2013 Nov 1Churg A. Hypersensitivity pneumonitis: new concepts and classifications. Modern Pathology. 2021 Sep 16:1-3.

Walsh SL et al. Multicentre evaluation of multidisciplinary team meeting agreement on diagnosis in diffuse parenchymal lung disease. The lancet Respiratory medicine. 2016 Jul 1

Diagnostic Guidelines for HPATS 2020 ACCP 2021


Diagnostic Classification

Acute• Febrile, self-limited illness

Subacute• Weeks to months• No fibrosis

Chronic• Months to years• Fibrosis

Non-fibrotic

Fibrotic

1. Typical2. Compatible3. Indeterminate4. Alternative

1. Typical2. Compatible3. Indeterminate4. Alternative

1. Typical2. Probable3. Indeterminate

1. Typical2. Probable3. Indeterminate

ATSHistologic

ACCPHistologic


ACCP Diagnostic Algorithm

Clinical

Radiology

BAL

Pathology

Pérez ER, Travis WD et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. 2021 Apr 20.

ACCP Histologic Classification

1. Typical for HP2. Compatible with HP3. Indeterminate for HP4. Alternative Diagnosis

Non-fibrotic Fibrotic


HP

Not HP

Typical Nonfibrotic HPMajor Features (All 4 required in at least 1 lobe)1. Small airway distribution (bronchioles and/or

alveolar ducts) “bronchiolocentricity”2. Uniform cellular interstitial inflammation of alveolar

walls and bronchioles (cellular bronchiolitis); may include cellular NSIP pattern

3. Inflammation consisting of mostly lymphocytes4. Interstitial scattered, poorly-formed non-necrotizing

granulomas and/or multinucleated giant cellsMust lack features suggesting alternative diagnosis

Minor Features (+/-)1. Organizing pneumonia, small foci2. Foamy macrophages3. Cholesterol clefts, Schaumann

bodies, calcium oxalate crystals

Typical Nonfibrotic HP#1 Small airway distribution (Bronchiolocentricity) #2 Uniform cellular interstitial inflammation, #3 mostly lymphocytic

Typical Nonfibrotic HP#4 Poorly-formed, non-necrotizing granulomas

(loose clusters of epithelioid histiocytes and multinucleated giant cells)

Middle: Pérez ER, Travis WD et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. 2021 Apr 20.Right: Churg A, Muller NL. Atlas of interstitial lung disease pathology. Lippincott Williams & Wilkins; 2019 Sep 27.

Typical Nonfibrotic HPOrganizing pneumonia Cholesterol clefts Foamy macrophages

Compatible with Nonfibrotic HPMajor Features (All 3 required in at least 1 lobe)1. Small airway distribution (bronchioles and/or

alveolar ducts) “bronchiolocentricity”2. Uniform cellular interstitial inflammation of alveolar

walls and bronchioles (cellular bronchiolitis); may include cellular NSIP pattern

3. Inflammation consisting of mostly lymphocytesLack of:1. Poorly-formed non-necrotizing granulomas2. Features suggesting alternative diagnosis

Minor Features (+/-)1. Organizing pneumonia, small foci2. Foamy macrophages3. Cholesterol clefts, Schaumann

bodies, calcium oxalate crystals

Compatible with Nonfibrotic HP#2 Uniform cellular interstitial inflammation#1 Chronic inflammation involving alveolar duct

#3 Mostly lymphocytes

No granulomas

Indeterminate for Nonfibrotic HPILD pattern that does not meet the criteria for:1. Typical nonfibrotic HP2. Compatible with nonfibrotic HP3. Alternative diagnosisBut is associated with radiologic and/or clinical features that suggest HP

• “Wastebasket” category• Multidisciplinary discussion is essential to consider whether this is nonfibrotic HP or other entity

Indeterminate for Nonfibrotic HP

Clinical• Positive exposure history

Pathology• Only cellular NSIP-pattern• No granulomas or bronchiolocentricity

Image: Churg A, Muller NL. Atlas of interstitial lung disease pathology. Lippincott Williams & Wilkins; 2019 Sep 27.

Alternative Diagnosis for Nonfibrotic HP• Sarcoidosis• Aspiration• Connective tissue disease• Immunodeficiency• Drug toxicity• Hot tub lung• Granulomatous infection• Small airway disease (bronchiolitis from other causes)

Aspiration vs. Nonfibrotic HP

• Bronchiolocentric cellular inflammation with granulomas

• Foreign material in granulomas• Not as uniform and diffuse as HP• Neutrophilic infiltrate if acute/subacute


Connective Tissue Disease vs. Nonfibrotic HP

• Scleroderma with CREST syndrome• Lymphoid hyperplasia with germinal

centers• Prominent plasma cell population• Peribronchiolar metaplasia is less

prominent• Granulomas less frequent (except

Sjögren’s)

Immunodeficiency vs. Nonfibrotic HP

• Common Variable Immunodeficiency (CVID)

• Lymphoid hyperplasia with germinal centers forming nodular infiltrates

• Can show features of lymphoid interstitial pneumonia (LIP)

• Well-formed granulomas

Hot Tub Lung vs. Nonfibrotic HP

• Variant of HP due to mycobacterial antigen exposure

• Granulomas are larger and mostly situated within airspaces and bronchiolar lumens

• Only moderate rim of chronic inflammatory cells

• Necrosis and acid-fast bacilli can be seen

ACCP Diagnostic Classification


Non-fibrotic Fibrotic


HP

Not HP

Typical Fibrotic HPMajor Features (All 3 required in at least 1 lobe)1. Small airway-centered fibrosis “bronchiolocentricity”

+/- peribronchiolar metaplasia2. Fibrosing interstitial pneumonia affecting at least 1

area/lobe, showing >1 following patterns:1. NSIP-fibrosing pattern2. UIP pattern3. Fibrosing pattern that is difficult to classify4. Fibrosis that is solely peribronchiolar

3. Poorly-formed, non-necrotizing granulomasLack features suggesting alternative diagnosis

Minor Features (+/-)1. Organizing pneumonia, small foci2. Focal peribronchiolar metaplasia3. Foamy macrophages4. Cholesterol clefts, Schaumann bodies,

calcium oxalate crystals

Fibrosing interstitial pneumonia1. Meets major criteria #22. All criteria for Typical Nonfibrotic HP in a

separate/same lobe Lack features suggesting alternative diagnosis

OR

Typical Fibrotic HP#2 Patchy, subpleural fibrosis with architectural

distortion and fibroblastic foci (UIP-pattern)#1 Bronchiolocentric fibrosis and inflammation

with #3 poorly-formed granulomas

Typical Fibrotic HP#2 Patchy interstitial fibrosis in a pattern that is

difficult to classify#1 Bronchiolocentric fibrosis and inflammation

with #3 poorly-formed granulomas

Compatible with Fibrotic HPMajor Features (All 3 required in at least 1 lobe)1. Small airway-centered fibrosis “bronchiolocentricity”

+/- widespread peribronchiolar metaplasia2. Fibrosing interstitial pneumonia affecting at least 1

area/lobe, showing >1 following patterns:1. NSIP-fibrosing pattern2. UIP pattern3. Fibrosing pattern that is difficult to classify4. Fibrosis that is solely peribronchiolar5. Could include some bronchiolocentric interstitial pneumonias

Lack of1. Poorly-formed, non-necrotizing granulomas

2. Features suggesting alternative diagnosis

Minor Features (+/-)1. Organizing pneumonia, small foci2. Focal peribronchiolar metaplasia3. Foamy macrophages4. Cholesterol clefts, Schaumann bodies,

calcium oxalate crystals

Fibrosing interstitial pneumonia1. Meets major criteria #22. All criteria for Compatible with Nonfibrotic

HP in a separate/same lobe Lack of1. Poorly-formed, non-necrotizing granulomas2. Features suggesting alternative diagnosis

OR

Compatible with Fibrotic HP

#2 Bronchiolar fibrosis#1 Bronchiole replaced by nodular fibrotic scar

(Bronchiolocentricity)

No granulomas

Indeterminate for Fibrotic HPFibrosing ILD pattern that does not meet the criteria for:1. Typical Fibrotic HP2. Compatible with Fibrotic HP3. Alternative diagnosisBut is associated with radiologic and/or clinical features that suggest HP

• “Wastebasket” category• Multidisciplinary discussion is essential to consider whether this is fibrotic HP or other entity

Indeterminate for Fibrotic HP

Radiology• Typical for fibrotic HP

Pathology• Only fibrotic NSIP-pattern• No granulomas or bronchiolocentricity

Alternative Diagnosis for Fibrotic HP• Idiopathic Pulmonary Fibrosis (IPF)/UIP• Fibrotic sarcoidosis• Aspiration with fibrosis• Connective tissue disease• Immunodeficiency• Drug toxicity• Fibrotic Langerhans Cell Histiocytosis (LCH)• Smoking-related patterns• Pneumoconiosis/occupational exposures

Idiopathic Pulmonary Fibrosis (IPF)/UIPvs. Fibrotic HP

Favor Fibrotic HP• Bronchiolocentricity• Prominent interstitial inflammation• Extensive peribronchiolar metaplasia (>50%)• Presence of granulomas/giant cells

Favor UIP/IPF• More fibroblastic foci• Increased subpleural fibrosis

Bridging fibrosis may be seen in bothPérez ER, Travis WD et al. Diagnosis and evaluation of hypersensitivity pneumonitis: CHEST guideline and expert panel report. Chest. 2021 Apr 20.

Churg A. Centrilobular Fibrosis in Fibrotic (Chronic) HP, UIP, and CTD–ILD. Archives of pathology & laboratory medicine. 2020 Dec 1;144(12):1509-16.Image: Churg A, Muller NL. Atlas of interstitial lung disease pathology. Lippincott Williams & Wilkins; 2019 Sep 27.

Sarcoidosis vs. Fibrotic HP

• Often with concentric fibrosis• Well-formed granulomas• Distribution along lymphatic

routes• Minimal cellular inflammation

Image: Raghu G et al. An official ATS/JRS/ALAT clinical practice guideline. American journal of respiratory and critical care medicine. 2020 Aug 1;202(3):e36-69.

Smoking-related ILD vs. Fibrotic HP

• Airspace Enlargement with Fibrosis (AEF)

• Accompanied by respiratory bronchiolitis and emphysema

• No granulomas

Fibrotic LCH vs. Fibrotic HP

• Centrilobular nodules and scarring that is more stellate than in HP

• Variable numbers of Langerhans cells with eosinophils

• Associated with respiratory bronchiolitis and smoking

• Lack of granulomas


Asbestosis vs. Fibrotic HP

• Patchy bilateral interstitial fibrosis with a bronchiolocentric distribution

• Pleural plaques or diffuse pleural thickening

• Asbestos/ferruginous bodies• No granulomas

Practical Diagnostic Approach

• Diagnostic categories do not represent pathologic diagnoses• Classification system to communicate the varying degrees of

diagnostic confidence for multidisciplinary discussion• Should not be used as pathologic diagnoses in reports

Practical Diagnostic Approach

“Bronchiolocentric fibrosing (± cellular) interstitial pneumonia with poorly-formed non-necrotizing

granulomas”

“Fibrosing (± cellular) interstitial pneumonia with bronchiolocentric features”

“Fibrosing (± cellular) interstitial pneumonia, not further classified”

Typical for Fibrotic HP

Compatible with Fibrotic HP

Indeterminate for Fibrotic HP

“Airspace enlargement with fibrosis and respiratory bronchiolitis”

Alternative Diagnosis

Pathology Report Multidisciplinary Discussion

HP

Not HP

Summary

• HP is a form of ILD resulting from an immune reaction provoked by an inhaled antigen in susceptible individuals

• Guidelines to improve diagnostic evaluation of HP• HP is classified as Fibrotic vs. Nonfibrotic• ACCP: Typical, Compatible, Indeterminate, and Alternative

1. Bronchiolocentricity2. Cellular interstitial inflammation and/or fibrosis3. Presence of granulomas

• Diagnostic categories for facilitating multidisciplinary discussion

Documents

Hypersensitivity Pneumonitis Guidelines for Diagnosis of