Familial fibrotic hypersensitivity pneumonitis: A distinct clinical phenotype with shorter leukocyte telomere length

BACKGROUND: Family history is an important factor in recognizing the prognosis of interstitial lung disease (ILD), however, its significance in fibrotic hypersensitivity pneumonitis (HP), as based on the latest international guidelines, remains unclear. This study aimed to investigate the distinct clinical profile and leukocyte telomere length (LTL) of familial fibrotic HP. METHODS: We retrospectively reviewed 490 patients who underwent leukocyte telomere length (LTL) measurement, and identified 131 patients with fibrotic HP, including 19 familial cases. Chest HRCT images were reviewed using automatic deep learning-based lung analysis. RESULTS: Familial fibrotic HP patients were younger (age ≥60: 68.4 % vs. 91.9 %, p = 0.02) and had lower diffusing capacity for carbon monoxide (DLco) (mean [SD]: 70.9 [23.6] vs. 82.9 [23.2], p = 0.031) compared to non-familial cases. Despite similar imaging patterns and AI-based CT analysis, pathological features of usual interstitial pneumonia (UIP) were more frequent in familial cases. Age-adjusted LTL was significantly shorter in the familial group (mean [SD]: -0.26 [0.26] vs. -0.06 [0.28], p = 0.004). Furthermore, LTL correlated with serum KL-6 (r = -0.603, p = 0.006), %DLco(r = 0.629, p = 0.007), and fibrotic features according to deep learning-based CT analysis; the consolidation with traction bronchiectasis ratio (r = -0.48, p = 0.038) and the traction bronchiectasis ratio (r = -0.489, p = 0.034). CONCLUSION: Familial fibrotic HP may represent a distinct clinical phenotype characterized by shorter telomeres, with LTL emerging as a potential biomarker for disease severity.