Abstract
Identifying early stages of hypersensitivity pneumonitis (HP) is hampered by variable presentation, heterogeneous or undetected causal antigens and lack of gold-standard biomarkers. Krebs von den Lungen (KL)-6 is pathophysiological biomarker of alveolar epithelial damage. Pigeon fanciers, susceptible to HP, provide a model to investigate early HP. To test the hypothesis that plasma concentrations of KL-6 are increased in early-stage acute HP. Clinical history, spirometry and blood samples were obtained from pigeon fanciers, 20 with intermittent acute symptoms indicative of developing HP, 27 with no symptoms and 10 healthy subjects with no avian exposure. Plasma KL-6 (units/mL) and pigeon antigen-specific IgG antibody were quantified by enzyme immunoassay. Blood lymphocytes were quantified by flow cytometry and antigen specificity by in vitro cytokine production. KL-6 was higher in fanciers than controls, median (IQR) 452 (244, 632) vs 274 (151, 377), P=.01. Although fanciers with symptoms had similar antigen exposure and lung function, they had higher KL-6 than those without, 632 (468, 1314) vs 320 (200, 480), P<.001. KL-6 correlated with IgG antibody titre in those with symptoms, r=.591, P=.006. High KL-6, irrespective of symptom category, was associated with higher antibody (P=.006) and lymphocyte proliferation (P=.041), and lower CD4+ T lymphocyte proportion (P=.032). Raised KL-6 is associated with acute symptoms of early-stage HP, and its correlation with antibody may support therapeutic strategies when HP is suspected. KL-6 may act as a mechanistic biomarker of early pathogenesis by linking lung pathophysiological changes with an endotype of immune hypersensitivity.
Highlights
Detection of hypersensitivity pneumonitis (HP) is crucial for prompt intervention.[1,2] This can be compromised by heterogeneous clinical presentation and delay in identifying often cryptic causal antigens[3,4]; HP can become insidious and progress to treatment-refractory chronic cHP.[5]
We identified an endotype of increased Krebs von den Lungen (KL)-6 associated with IgG antibody and lymphocyte profile, linking lung pathophysiology with immunity that was indicative of early HP in this at-risk population
There were many asymptomatic subjects with evidence of immune reactivity, and several symptomatic subjects with relatively low immune reactivity and this overlap suggested that the immune response profile was insufficient to cleanly differentiate asymptomatic from early-stage acute HP; we investigated Krebs von den Lungen-6 (KL-6) as a pathophysiological biomarker between these categories
Summary
Detection of hypersensitivity pneumonitis (HP) is crucial for prompt intervention.[1,2] This can be compromised by heterogeneous clinical presentation and delay in identifying often cryptic causal antigens[3,4]; HP can become insidious and progress to treatment-refractory chronic cHP.[5] Objective tests to assess the pathophysiological significance of early mild symptoms would provide timely biomarkers for subjects at-risk of progression. This knowledge gap in the pathogenesis of early HP may be addressed by investigating HP among pigeon fanciers. KL-6 may act as a mechanistic biomarker of early
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