hypersensitivity pneumonitis guidelines for diagnosis of
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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
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.
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
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.
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
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.
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
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.
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
1. Typical for HP2. Compatible with HP3. Indeterminate for HP4. Alternative Diagnosis
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
Image: Churg A, Muller NL. Atlas of interstitial lung disease pathology. Lippincott Williams & Wilkins; 2019 Sep 27.
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
1. Typical for HP2. Compatible with HP3. Indeterminate for HP4. Alternative Diagnosis
Non-fibrotic Fibrotic
1. Typical for HP2. Compatible with HP3. Indeterminate for HP4. Alternative Diagnosis
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
Image: Churg A, Muller NL. Atlas of interstitial lung disease pathology. Lippincott Williams & Wilkins; 2019 Sep 27.
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
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