Krebs von den lungen-6 as a clinical marker for hypersensitivity pneumonitis: A meta-analysis and bioinformatics analysis

Abstract

Aim: Hypersensitivity pneumonitis (HP), also referred to as exogenous allergic alveolitis, is one of the most common interstitial lung diseases (ILDs). A potential immune biomarker, Krebs von den lgen-6 (KL-6) characterizes the progression and severity of HP. The meta-analysis in this study was conducted to elucidate the variations in the concentrations of KL-6 in different types of HP.

Methods: A systematic search of various databases such as EMBASE, Pubmed, CNKI, VIP, Web of Science, and WanFang was carried out to find relevant published articles between January 1980 and August 2022 that explored the relationship between KL-6 and allergic pneumonia. Standardized mean difference (SMD) and 95% confidence interval (CI) were used as effect sizes for comparison among different groups. The GSE47460 and GSE150910 datasets were downloaded to extract and validate the differences in KL-6 mRNA expression between HP lung tissue and healthy controls. Furthermore, the single-cell sequencing dataset GSE135893 was downloaded to extract KL-6 mRNA expression in type II alveolar epithelial cells to validate the differences between HP and healthy controls. Two researchers evaluated the quality of the included studies by employing Newcastle-Ottawa Scale. All the qualified studies were subjected to statistical analyses carried out utilizing RevMan 5.2, Stata 11.0, and R software 4.1.3.

Results: Twenty studies aligned perfectly with the inclusion criteria of the meta. The concentrations of KL-6 were substantially higher in the blood of HP patients as compared to the control group. Subgroup analyses were carried out in accordance with the allergen source and the results revealed that patients with different allergens had higher blood KL-6 concentrations than healthy controls. Additionally, different subgroups of subjects were created for meta-analysis as per the fibrosis status, race, measurement method, and sample type. The concentration of KL-6 in blood was much higher in all HP subgroups than in healthy control groups. Moreover, the bioinformatics analysis revealed that KL-6 mRNA expression was higher in HP lung tissue and type II alveolar epithelial cells as compared to healthy controls.

Conclusion: The present meta-analysis and bioinformatics analysis suggested that the concentration levels of KL-6 varied between HP patients and healthy individuals, and the KL-6 concentrations may be higher in the blood samples of HP patients.

Systematic review registration: https://www.crd.york.ac.uk/prospero/, CRD42022355334.

Keywords: Krebs von den Lungen-6; bioinformatics analysis; hypersensitivity pneumonitis; meta-analysis; systematic review.

Figure 1

This flow chart illustrates the process of searching for literature and selecting studies.

Figure 2

The forest plot pooled the SMD (95%) of KL-6 level between HP patients and controls.

Figure 3

Subgroup analysis depended on different allergenic sources.

Figure 4

Begg’s funnel plot was to evaluate the publication bias among those included literatures about the association between KL-6 level and HP.

Figure 5

The scRNA-seq analysis in the GSE135893 (HP =3, control=8). (A) Feature plot of KL-6 in HP patients and controls. (B) Cell type annotation. (C) The different expressive analysis of KL-6 between HP and controls in AT2 cells.

Figure 6

The relationships between KL-6 mRNA levels and lung function in GSE47460. (A) KL-6 mRNA levels were negatively correlated with DLCO% predicted (r=-0.452, P=0.012); (B) KL-6 mRNA levels were negatively correlated with FEV1% predicted (r=-0.396, P=0.032).

Figure 7

The possible potential mechanism of KL-6 in HP.