Serum Biomarkers of Lung Fibrosis in Interstitial Pneumonia: Comparison
View Latest Version
Please note this is a comparison between Version 3 by Bruce Ren and Version 2 by Bruce Ren.

Interstitial pneumonia with autoimmune features (IPAF) belongs to a group of diseases called interstitial lung diseases (ILDs), which are disorders of a varied prognosis and course. Finding sufficiently specific and sensitive biomarkers would enable the progression to be predicted, the natural history to be monitored and patients to be stratified according to their treatment. 

  • interstitial pneumonia with autoimmune features
  • IPAF
  • pulmonary fibrosis
  • biomarkers
  • KL-6
  • SP-A
  • SP-D
  • circulating fibrocytes
  • CXCL

1. Introduction

Interstitial pneumonia with autoimmune features (IPAF) is a relatively novel disorder developed in 2015 by the European Respiratory Society/American Thoracic Society Task Force on Undifferentiated Forms of Connective Tissue Disease-Associated Interstitial Lung Disease [1]. This document sparked scientific interest in IPAF and multiple, mainly retrospective, studies on IPAF cohorts. The mentioned publication aimed to identify, describe and study patients with interstitial lung disease (ILD) who display some symptoms of autoimmunity, but do not meet established criteria for any connective tissue disease.
It is estimated that approximately 7% of ILD patients may be diagnosed with IPAF [2]. It affects mostly women in the 6–7th decades of their lives. The most commonly reported extrapulmonary symptoms are Raynaud’s phenomenon, arthritis, morning stiffness and “mechanic’s hands”. Often, patients may also present with a dry cough, shortness of breath and fatigue. Anti-nuclear antibodies (ANA) were the most frequently identified antibodies in blood serum serological tests in patients with IPAF. The predominant pattern in high-resolution computed tomography (HRCT) was nonspecific interstitial pneumonia (NSIP), which is also characteristic of lesions accompanying most systemic connective tissue diseases [3][4][5][6][7][8]. Distinct results were described in Oldham’s research—the cohort study reports a high proportion of usual interstitial pneumonia (UIP). This is mostly likely due to the fact that the study was conducted retrospectively in the reference centre for IPF patients.

2. Biomarkers

The term “biomarker” can be defined as “a specific characteristic that is measured as an indicator of normal biologic processes, pathogenic processes, or responses to an exposure or intervention, including therapeutic interventions” [9]. A broader definition of pulmonary fibrosis biomarkers may include the results of respiratory function tests, imaging or biochemical molecules that are detectable in blood, bronchoalveolar lavage or lung tissue. Biomarkers could be used for a variety of purposes: diagnostic, prognostic, therapeutic or to identify patients with a predisposition to developing a certain disease.
IPAF belongs to a group of diseases called interstitial lung diseases (ILDs), which are disorders of a varied prognosis and course. They are characterised by the destruction of lung tissue by inflammation and fibrosis. The pathogenesis of pulmonary fibrosis is not fully understood. It is known to be caused by immune system activation, diffuse remodelling of the lung parenchyma, the presence of excess extracellular matrix or irreversible scarring [10][11].
Four main groups of circulating ILD candidate biomarkers, categorised by the pathophysiology pathways, can be distinguished as follows [12][13]:
-alveolar epithelial cell damage and dysfunction (KL-6, SP-A, SP-D);
-aberrant fibrogenesis and matrix remodelling (MMP7, MMP3, LOXL2, HSP47, IGFBPs, periostin, circulating fibrocytes, fibrillin-1, osteopontin);
-damaged endothelium (IL-8, ET-1, VEGF);
-immune dysregulation and inflammation (CCL18, YKL-40, ICAM, VCAM, E-
alveolar epithelial cell damage and dysfunction (KL-6, SP-A, SP-D);
selectin, IL-
aberrant fibrogenesis and matrix remodelling (MMP7, MMP3, LOXL2, HSP47, IGFBPs, periostin, circulating fibrocytes, fibrillin-1, osteopontin);
6, CXCL-
damaged endothelium (IL-8, ET-1, VEGF);
13, anti-
immune dysregulation and inflammation (CCL18, YKL-40, ICAM, VCAM, E-selectin, IL-6, CXCL-13, anti-HSP70 IgG, BLyS, serum RAGE).
HSP70 IgG, BLyS, serum RAGE).
A growing body of evidence suggests their role in pulmonary fibrosis in patients with idiopathic pulmonary fibrosis (IPF), which is the most extensively studied fibrotic interstitial lung disease, but also in patients with CTD-ILD.

3. KL-6

Krebs von den Lungen-6 (KL-6), a high molecular weight glycoprotein, also known as human mucin-1 (MUC1), is mainly produced by damaged or regenerating alveolar type II pneumocytes. It can also be found on the epithelial cells of the stomach, pancreas and oesophagus. The glycoprotein, described for the first time by Kohno et al., plays an important role in the morphogenesis and development of foetal lungs and exhibits chemotactic properties for fibroblasts [14][15].
KL-6 levels were significantly higher in the patients with IPAF than in the patients with non-IPF interstitial fibrosis, non-fibrotic lung diseases, pneumonia and a healthy group [16][17][18][19]. The biomarker level, when compared to IPF, was varied depending on the study: it was significantly higher in IPAF in Kameda’s study, but comparable in Xue’s study [16][17].
Moreover, in three studies, the serum KL-6 levels showed a negative correlation with the transfer factor for carbon monoxide (TLCO) [17][18][19]. The results of the studies regarding the correlation between KL-6 and the percentage of predicted forced vital capacity value (%FVC) differed from study to study: there was no significant correlation with %FVC and the percentage of predicted forced expiratory volume in one second value (%FEV1) in Wang’s publication, whilst the association with %FVC was described in Xue’s article [18][19].
A significant positive correlation with the severity of interstitial lung lesions in the IIP group (including IPAF, although the disease was not separately analysed) was also observed [17].
Furthermore, Wang proved that the post-treatment KL-6 serum levels were significantly increased compared to the pre-treatment ones in patients with progressive disease. The opposite effect was noted in the improvement group. The results suggest that KL-6 may be used as a biomarker to monitor the progression of pulmonary fibrosis in patients with IPAF [18]. However, the results were not fully confirmed by Yamakawa’s study [20].
In Xue’s prospective study with a 52-week follow-up, there was a positive correlation between the KL-6 serum levels and CT scores in the aggravation group. The investigators did not observe any correlation in the improvement or stable groups. Furthermore, there was no significant correlation between KL-6 and autoimmune factors [19].
To sum up, the KL-6 level seems to be higher in IPAF than in a healthy group and non-fibrotic lung diseases. There is a negative correlation between the serum level of this molecule and TLCO. In the aggravation groups, the KL-6 levels correlate with the degree of lung involvement.

4. SP-A and SP-D

Surfactant proteins SP-A and SP-D are large hydrophilic proteins—collagen-containing C-type lectins called collectins. They are produced by Clara cells and type II alveolar epithelial cells. SP-A and SP-D are important for innate immune mechanisms and help to resolve inflammation on the alveolar surface [21][22][23]. They are among the most thoroughly studied biomarkers in IPAF.
The SP-A and SP-D levels were higher in the IPAF patients than in a healthy group, the patients with pneumonia or non-fibrotic lung diseases [17][18][19]. Furthermore, the SP-D serum levels were lower in the IIP non-IPF group than in the IPAF patients [17]. The SP-A level cannot be used to distinguish between IPAF and CTD-ILD patients [19].
In Xue’s publication, a negative correlation of SP-A serum levels and TLCO was observed in the IIP group (including 27/69 patients with IPAF, although this group was not separately investigated). A negative correlation was also noted with FEV1 and FVC pulmonary ventilatory function parameters in that group [17]. The observation was partially confirmed by Wang’s study: the investigators proved a negative correlation between SP-A serum levels and changes in TLCO, FEV1 and FVC (delta TLCO, delta FEV1, delta FVC) results after treatment. However, there was no significant correlation between the serum SP-A levels and %FVC or %FEV1 in the said article and Xue’s prospective study [18][19].
Moreover, in his article, Wang described a suspected prognostic role of SP-A: the pre-treatment biomarker levels were significantly lower than the post-treatment ones in patients with the progressive type of IPAF. Additionally, a significant positive correlation was found between changes in the KL-6 and SP-A levels [18]. Unfortunately, the prognostic role was not confirmed in the case of the SP-D serum level in the other studies: the biomarker slope was not significantly different between disease courses.
In Xue’s prospective study, a significant difference was noted in the SP-A serum levels at baseline and 52 weeks. In the aggravation group, the biomarker also correlated with HRCT scores. In contrast, the correlation was not found in the improvement and stable groups. Additionally, no relationship was observed between the SP-A serum levels and autoantibodies [19].
In conclusion, it can be said that there is a negative correlation between the level of SP-A and the results of respiratory function tests (TLCO, FEV1, FVC) in patients with IPAF. In the progressive group, the level of this molecule increases over time. Moreover, in IPAF, the SP-A and SP-D levels were higher than in the patients with pneumonia, non-fibrotic lung diseases and a healthy group.

5. Circulating Fibrocytes

Circulating fibrocytes are cells derived from bone marrow. They have the features of hematopoietic and mesenchymal cells. The cells are involved in inflammatory reactions, including autoimmune ones, as well as fibrosis and wound healing [24].
There is one study in which scientists examined the concentration of circulating fibrocytes in patients with autoimmune interstitial lung diseases (including IPAF). Unfortunately, the IPAF group was not separately analysed; hence, it is impossible to draw any conclusions. Interestingly, the concentrations of circulating fibrocytes were higher in the patients with autoimmune interstitial lung disease than in the control group. The biomarker serum levels declined with the use of immunosuppressive therapy [12].

6. CCL2

Chemokine ligand 2—monocyte chemoattractant protein-1 (MCP-1)—is another profibrotic chemokine associated with pulmonary fibrosis. CCL2 is expressed in macrophages, alveolar epithelial cells and lung vascular endothelium in pulmonary fibrosis [17][25][26].
The CCL2 serum levels showed a negative correlation with TLCO in the IIP group including IPAF, although IPAF patients were not distinguished. The CCL2 levels were notably higher in the IPAF group than in a healthy one [17].

7. CXCL13

Similar to CCL2, in Xue’s study, the serum levels of CXCL13 were significantly lower in the patients with pneumonia and the normal controls than in the IIP group (including IPAF patients). Their negative correlation with TLCO was also noted. Additionally, the CXCL13 serum levels were higher in the IPAF group than in the IPF group [17].

8. CXCL9, CXCL10, CXCL11

CXCL9 (C-X-C motif chemokine), CXCL10 and CXCL11 are cytokines responsible for the recruitment of immune cells at inflammation sites. They also have an impact on angiogenesis [27].
Kameda’s study showed that the serum levels of the biomarkers in the IPAF patients were significantly elevated compared to the IPF patients. CXCL9, CXCL10 and CXCL11 serum levels correlated with %FVC, C-reactive protein and alveolar-arterial oxygen difference. Furthermore, the CXCL9 and CXCL10 serum levels also correlated with the bronchoalveolar lavage fluid (BALF) levels.
It is worth noting that a positive correlation was observed between the CXCL9 and CXCL11 pre-treatment serum levels and the annual changes in FVC in the patients with IPAF treated with immunosuppressive drugs. This observation provides the basis for further studies of the prognostic significance of these biomarkers [16].

9. Other Biomarkers

Kameda reported that the TNF-alpha levels in IPAF patients were higher than in the IPF group and lower than in patients with collagen vascular diseases–associated interstitial lung disease (CVD-ILD), however, without statistical significance [16].
In Liang’s study, the investigators noted that the CXCL1, IL-4, IL-13, IL-6 and IL-17 serum levels were higher in the patients with IPAF than in those with other types of IIP, COPD and healthy individuals. Furthermore, the CXCL1 levels in the acute exacerbation phase were notably higher than in the stable phase. The biomarkers were also negatively correlated with TLCO [28].

References

  1. Fischer, A.; Antoniou, K.M.; Brown, K.K.; Cadranel, J.; Corte, T.J.; Du Bois, R.M.; Lee, J.S.; Leslie, K.O.; Lynch, D.A.; Matteson, E.L.; et al. An official European Respiratory Society/American Thoracic Society research statement: Interstitial pneumonia with autoimmune features. Eur. Respir. J. 2015, 46, 976–987.
  2. Ahmad, K.; Barba, T.; Gamondes, D.; Ginoux, M.; Khouatra, C.; Spagnolo, P.; Strek, M.; Thivolet-Béjui, F.; Traclet, J.; Cottin, V. Interstitial pneumonia with autoimmune features: Clinical, radiologic, and histological characteristics and outcome in a series of 57 patients. Respir. Med. 2017, 123, 56–62.
  3. Oldham, J.M.; Adegunsoye, A.; Valenzi, E.; Lee, C.; Witt, L.; Chen, L.; Husain, A.N.; Montner, S.; Chung, J.H.; Cottin, V.; et al. Characterisation of patients with interstitial pneumonia with autoimmune features. Eur. Respir. J. 2016, 47, 1767–1775.
  4. Chartrand, S.; Swigris, J.J.; Stanchev, L.; Lee, J.S.; Brown, K.K.; Fischer, A. Clinical features and natural history of interstitial pneumonia with autoimmune features: A single center experience. Respir. Med. 2016, 119, 150–154.
  5. Dai, J.; Wang, L.; Yan, X.; Li, H.; Zhou, K.; He, J.; Meng, F.; Xu, S.; Liang, G.; Cai, H. Clinical features, risk factors, and outcomes of patients with interstitial pneumonia with autoimmune features: A population-based study. Clin. Rheumatol. 2018, 37, 2125–2132.
  6. Ito, Y.; Arita, M.; Kumagai, S.; Takei, R.; Noyama, M.; Tokioka, F.; Nishimura, K.; Koyama, T.; Notohara, K.; Ishida, T. Serological and morphological prognostic factors in patients with interstitial pneumonia with autoimmune features. BMC Pulm. Med. 2017, 17, 111.
  7. Sambataro, G.; Sambataro, D.; Torrisi, S.E.; Vancheri, A.; Colaci, M.; Pavone, M.; Pignataro, F.; Del Papa, N.; Palmucci, S.; Vancheri, C. Clinical, serological and radiological features of a prospective cohort of Interstitial Pneumonia with Autoimmune Features (IPAF) patients. Respir. Med. 2019, 150, 154–160.
  8. Kelly, B.T.; Moua, T. Overlap of interstitial pneumonia with autoimmune features with undifferentiated connective tissue disease and contribution of UIP to mortality. Respirology 2018, 23, 600–605.
  9. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: Preferred definitions and conceptual framework. Clin. Pharmacol. Ther. 2001, 69, 89–95.
  10. Travis, W.D.; Costabel, U.; Hansell, D.M.; King, T.E., Jr.; Lynch, D.A.; Nicholson, A.G.; Ryerson, C.J.; Ryu, J.H.; Selman, M.; Wells, A.U.; et al. An official American Thoracic Society/European Respiratory Society statement: Update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am. J. Respir. Crit. Care Med. 2013, 188, 733–748.
  11. King, T.E., Jr.; Pardo, A.; Selman, M. Idiopathic pulmonary fibrosis. Lancet 2011, 378, 1949–1961.
  12. Odackal, J.; Yu, V.; Gomez-Manjerres, D.; Field, J.J.; Burdick, M.D.; Mehrad, B. Circulating fibrocytes as prognostic biomarkers of autoimmune interstitial lung disease. ERJ Open Res. 2020, 6.
  13. Jee, A.S.; Sahhar, J.; Youssef, P.; Bleasel, J.; Adelstein, S.; Nguyen, M.; Corte, T.J. Review: Serum biomarkers in idiopathic pulmonary fibrosis and systemic sclerosis associated interstitial lung disease—Frontiers and horizons. Pharmacol. Ther. 2019, 202, 40–52.
  14. Kohno, N.; Kyoizumi, S.; Awaya, Y.; Fukuhara, H.; Yamakido, M.; Akiyama, M. New serum indicator of interstitial pneu-monitis activity. Sialylated carbohydrate antigen KL-6. Chest 1989, 96, 68–73.
  15. Ohshimo, S.; Yokoyama, A.; Hattori, N.; Ishikawa, N.; Hirasawa, Y.; Kohno, N. KL-6, a human MUC1 mucin, promotes proliferation and survival of lung fibroblasts. Biochem. Biophys. Res. Commun. 2005, 338, 1845–1852.
  16. Kameda, M.; Otsuka, M.; Chiba, H.; Kuronuma, K.; Hasegawa, T.; Takahashi, H. CXCL9, CXCL10, and CXCL11; biomarkers of pulmonary inflammation associated with autoimmunity in patients with collagen vascular diseases–associated interstitial lung disease and interstitial pneumonia with autoimmune features. PLoS ONE 2020, 15, e0241719.
  17. Xue, M.; Guo, Z.; Cai, C.; Sun, B.; Wang, H. Evaluation of the Diagnostic Efficacies of Serological Markers KL-6, SP-A, SP-D, CCL2, and CXCL13 in Idiopathic Interstitial Pneumonia. Respiration 2019, 98, 534–545.
  18. Wang, J.; Zheng, P.; Huang, Z.; Huang, H.; Xue, M.; Liao, C.; Sun, B.; Zhong, N. Serum SP-A and KL-6 levels can predict the improvement and deterioration of patients with interstitial pneumonia with autoimmune features. BMC Pulm. Med. 2020, 20, 1–10.
  19. Xue, M.; Cai, C.; Zeng, Y.; Xu, Y.; Chen, H.; Hu, H.; Zhou, L.; Sun, B. Krebs von den Lungen-6 and surfactant protein-A in interstitial pneumonia with autoimmune features. Medicine 2021, 100, e24260.
  20. Yamakawa, H.; Hagiwara, E.; Ikeda, S.; Iwasawa, T.; Otoshi, R.; Tabata, E.; Okuda, R.; Sekine, A.; Baba, T.; Iso, S.; et al. Evaluation of changes in the serum levels of Krebs von den Lungen-6 and surfactant protein-D over time as important biomarkers in idiopathic fibrotic nonspecific interstitial pneumonia. Respir. Investig. 2019, 57, 422–429.
  21. Barlo, N.P.; Van Moorsel, C.H.M.; Ruven, H.J.T.; Zanen, P.; Bosch, J.M.M.V.D.; Grutters, J.C. Surfactant protein-D predicts survival in patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc. Diffus. Lung Dis. 2009, 26, 155–161.
  22. Maher, T.M.; Oballa, E.; Simpson, J.K.; Porte, J.; Habgood, A.; Fahy, W.; Flynn, A.; Molyneaux, P.L.; Braybrooke, R.; Divyateja, H.; et al. An epithelial biomarker signature for idiopathic pulmonary fibrosis: An analysis from the multicentre PROFILE cohort study. Lancet Respir. Med. 2017, 5, 946–955.
  23. Kinder, B.W.; Brown, K.K.; McCormack, F.X.; Ix, J.H.; Kervitsky, A.; Schwarz, M.I.; King, T.E. Serum Surfactant Protein-A Is a Strong Predictor of Early Mortality in Idiopathic Pulmonary Fibrosis. Chest 2009, 135, 1557–1563.
  24. Galligan, C.L.; Fish, E.N. The role of circulating fibrocytes in inflammation and autoimmunity. J. Leukoc. Biol. 2013, 93, 45–50.
  25. Suga, M.; Iyonaga, K.; Ichiyasu, H.; Saita, N.; Yamasaki, H.; Ando, M. Clinical significance of MCP-1 levels in BALF and serum in patients with interstitial lung diseases. Eur. Respir. J. 1999, 14, 376–382.
  26. DePianto, D.J.; Chandriani, S.; Abbas, A.R.; Jia, G.; N’Diaye, E.N.; Caplazi, P.; E Kauder, S.; Biswas, S.; Karnik, S.K.; Ha, C.; et al. Heterogeneous gene expression signatures correspond to distinct lung pathologies and biomarkers of disease severity in idiopathic pulmonary fibrosis. Thorax 2015, 70, 48–56.
  27. Lacotte, S.; Brun, S.; Muller, S.; Dumortier, H. CXCR3, Inflammation, and Autoimmune Diseases. Ann. N. Y. Acad. Sci. 2009, 1173, 310–317.
  28. Liang, M.; Jiang, Z.; Huang, Q.; Liu, L.; Xue, Y.; Zhu, X.; Yu, Y.; Wan, W.; Yang, H.; Zou, H. Clinical Association of Chemokine (C-X-C motif) Ligand 1 (CXCL1) with Interstitial Pneumonia with Autoimmune Features (IPAF). Sci. Rep. 2016, 6, 38949.
More
© Text is available under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/)
ScholarVision Creations
Feedback