Béla Nagy Jr1, Zsolt Bene2, Zsolt Fejes1, Sonya L. Heltshe3, David Reid4, Nicola J. Ronan5, 3, Yvonne McCarthy5, Daniel Smith4, Attila Nagy6, Elizabeth Joseloff7, György Balla2,8, János Kappelmayer1, Milan Macek Jr.9, Scott C. Bell4, Barry J. Plant5, Margarida D. Amaral10 and István Balogh1,11


1Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;

2Department of Pediatrics, Faculty of Medicine, University of Debrecen, Debrecen, Hungary;

3Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington, U.S.A;

4QIMR Berghofer Medical Research Institute and The Prince Charles Hospital, Brisbane, Australia;

5Cork Adult Cystic Fibrosis Centre, Cork University Hospital, Cork, Ireland; 6Department of Preventive Medicine, Faculty of Public Health, University of Debrecen, Debrecen, Hungary;

7Cystic Fibrosis Foundation, Bethesda, Maryland, U.S.A.;

8MTA-DE Vascular Biology, Thrombosis and Hemostasis Research Group, Hungarian Academy of Sciences, Debrecen, Hungary;

9Department of Biology and Medical Genetics, Charles University and Motol University Hospital, Prague, Czech Republic;

10University of Lisboa, Faculty of Sciences, BioISI-Biosystems & Integrative Sciences Institute, Lisboa, Portugal;

11Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary


What was your research question?

Human epididymis protein 4 (HE4) is a member of whey acidic protein four-disulfide core (WFDC) family. Normally this protein is produced by bronchial epithelial cells at a small quantity and acts as an antiproteinase in the frame of epithelial host defenses of the respiratory tract. In previous research, we found a correlation between increased HE4 levels and CF severity. In this study, we sought to confirm our previous finding of inverse correlation of HE4 levels with lung function parameter (FEV1) in CF patients, and to assess the changes in HE4 levels with the administration of ivacaftor.

Why is this important?

Currently, there are no unambiguous blood-based biomarkers for monitoring the efficacy of CFTR modulating therapy. Hence, there is an unmet clinical need to establish a sensitive and easily reproducible biomarker, which is simply performed and accessible, ideally plasma or serum based.

What did you do?

We have retrospectively analyzed HE4 levels in plasma samples obtained from three independent clinical cohorts, which were monitored for FEV1, sweat chloride and BMI under ivacaftor treatment. In contrast to lung function evaluation and special sweat chloride measurement, this test needs only a simple blood sampling with a general laboratory immunoassay analysis.

What did you find?

In response to ivacaftor therapy and independently of baseline concentrations, HE4 levels were significantly lower already after 1 month of therapy, and remained that way through the end of respective study periods (up to 6 months). Plasma HE4 negatively correlates with lung function improvement, and markedly alters in both mild and severe CF lung disease reflecting to ivacaftor.

What does this mean and reasons for caution?

Plasma HE4 as a potential biomarker may be of value for routine clinical and laboratory follow-up of CFTR modulating therapy in CF individuals. However, further studies are required to validate HE4 as a surrogate endpoint biomarker for treatment efficacy in CF not only for ivacaftor, but also for other CFTR potentiators and correctors. The mechanism of how CFTR impacts on HE4 levels in pulmonary epithelial cells need to be investigated as well as the direct effect of CFTR modulators.

What’s next?

We are going to investigate whether the beneficial effect of other CFTR specific therapy, such as lumacaftor, may be also monitored via measuring the plasma level of HE4 in CF.


Original manuscript citation in PubMed

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