What is the difference between hypersensitivity pneumonitis and idiopathic pulmonary fibrosis?

Distinguishing Hypersensitivity Pneumonitis from Idiopathic Pulmonary Fibrosis

The critical distinction between fibrotic hypersensitivity pneumonitis (fHP) and idiopathic pulmonary fibrosis (IPF) fundamentally determines treatment: IPF requires antifibrotic therapy as first-line management, while fHP demands antigen remediation followed by immunosuppressive therapy—immunosuppression being harmful and contraindicated in IPF. 1

Why This Distinction Matters for Patient Outcomes

Misdiagnosis directly impacts mortality and quality of life because immunosuppressive therapy used in fHP can worsen outcomes in IPF patients, while failure to identify and remove inciting antigens in fHP leads to continued disease progression. 1 Additionally, while fHP historically had better prognosis than IPF, recent evidence shows similar progression rates when fibrosis is established, making early accurate diagnosis essential. 1

Clinical Features That Distinguish These Diseases

Classic IPF Profile

• Male sex, age >60 years, and cigarette smoking history strongly favor IPF, with likelihood increasing when these features combine (e.g., older male smoker). 1
• Basal-predominant inspiratory crackles on examination. 1

Classic fHP Profile

• Identifiable antigen exposure that temporally parallels disease onset or activity is the hallmark of fHP. 1
• Any age, any sex, any smoking status (more heterogeneous than IPF). 1
• Inspiratory squeaks on auscultation suggest fHP over IPF. 1
• BAL lymphocytosis >30% strongly suggests fHP, though sensitivity decreases in established fibrosis. 1

Critical Exposure Assessment for fHP

Approximately 50% of fHP patients have no clearly identified antigen, so absence of exposure does not rule out fHP. 1 When evaluating exposures:

• Birds and molds are well-established high-suspicion antigens; feather bedding is a common occult source. 1, 2
• Assess exposure intensity (e.g., living with pet bird > using down bedding). 1
• Evaluate temporal relationship: exposure predates disease, symptoms worsen with exposure, improvement with avoidance. 1
• Use standardized questionnaires and consider serum-specific IgG testing for indeterminate exposures. 1, 3

Common pitfall: Many patients with other ILDs report exposures that are not causative—exposure alone does not equal fHP diagnosis and must be integrated with other clinical, radiologic, and pathologic features. 1

Radiologic Patterns

UIP Pattern (Suggests IPF)

• Basal and subpleural-predominant reticulation with honeycombing defines definite UIP pattern (>95% associated with histologic UIP). 1
• Probable UIP shows same distribution with traction bronchiectasis but lacks honeycombing. 1, 4
• Peripheral and lower lung zone predominance. 5
• Absence of micronodules favors IPF. 5

fHP Pattern

• Small airways abnormalities (mosaic attenuation, air trapping) with fibrosis suggest fHP. 1
• Presence of micronodules favors fHP over IPF. 5
• Ground-glass opacities with architectural distortion. 4
• May show less lower zone predominance than IPF. 5

Critical limitation: Chronic fHP can demonstrate identical UIP pattern to IPF on imaging, making CT alone insufficient for definitive diagnosis in many cases. 5, 6 CT distinguishes these diseases with high confidence in only 62% of cases. 5

Pathologic Patterns

fHP demonstrates broader pathologic spectrum than previously recognized, including not just the classic triad (bronchiolitis, interstitial infiltrates, granulomas) but also NSIP pattern, UIP pattern, organizing pneumonia, and airway-centric fibrosis. 6 This overlap makes histopathology challenging but still valuable when integrated with clinical and radiologic data. 1

Integrated Diagnostic Algorithm

Step 1: Clinical Phenotyping

Categorize patients into three profiles based on all available clinical features: 1

• Classic IPF profile (older male smoker, no exposure)
• Classic fHP profile (identifiable antigen with temporal relationship)
• Indeterminate profile (overlapping or non-distinguishing features)

Step 2: Multidisciplinary Discussion (MDD)

MDD is mandatory for all but the clearest cases, integrating clinical phenotype with radiologic pattern to generate leading diagnosis and confidence level. 1

• Concordant classic IPF profile + definite/probable UIP pattern = high-confidence IPF diagnosis without need for biopsy. 1
• Concordant classic fHP profile + fHP radiologic pattern = high-confidence fHP diagnosis. 1
• Indeterminate cases or discordant features require consideration of invasive testing. 1

Step 3: When to Pursue Tissue Diagnosis

Surgical lung biopsy should be considered when:

• MDD yields low diagnostic confidence (<70%). 1
• Clinical-radiologic features are discordant or indeterminate. 1
• Obtaining definitive diagnosis will change therapeutic management. 1

Important caveat: Even with biopsy, approximately 10% of fibrotic ILD remains unclassifiable, and diagnosis may require longitudinal observation. 1

Step 4: Repeat MDD with Pathology

When tissue is obtained, repeat MDD integrating pathologic findings with clinical and radiologic data—pathologic patterns must be contextualized, not interpreted in isolation. 1

Management Implications Based on Diagnosis

If IPF Diagnosed

• Initiate antifibrotic therapy (nintedanib or pirfenidone) as first-line treatment. 1
• Avoid immunosuppressive therapy—it is harmful in IPF. 1

If fHP Diagnosed

• Antigen remediation is the critical first intervention. 1, 3
• Immunosuppressive therapy commonly follows antigen removal (prednisone 1 mg/kg/day for moderate disease; methylprednisolone 2-4 mg/kg/day IV for severe disease). 3
• Antifibrotic agents are considered secondarily only in progressive fibrotic disease. 1

Key Diagnostic Pitfalls to Avoid

1. Do not diagnose IPF without excluding occult antigen exposures—one study found 43% of patients meeting 2011 IPF criteria actually had chronic fHP when rigorous exposure assessment was performed. 2

2. Do not rely on single domain (clinical, radiologic, or pathologic) alone—these must be integrated in MDD. 1

3. Do not assume absence of identified antigen rules out fHP—50% have no clear antigen. 1

4. Do not expect BAL lymphocytosis in all fHP cases—sensitivity decreases with established fibrosis. 1

5. Recognize that chronic fHP can have UIP pattern identical to IPF on both imaging and histology, requiring careful clinical correlation. 5, 6