Author + information
- Eliot G. Peyster, MD, MSc,
- Michael D. Feldman, MD, PhD and
- Kenneth B. Margulies, MD∗ ()
- ↵∗Perelman School of Medicine, University of Pennsylvania, Translational Research Center, Room 11-101, 3400 Civic Center Boulevard, Building 421, Philadelphia, Pennsylvania 19104
We appreciate the interest shown by Dr. Napoli and colleagues in our recent publication in JACC: Basic to Translational Science. We also appreciate their clear recognition of the need for improved biological characterization of transplanted endomyocardial biopsy tissues, as well as their appreciation of the in situ methodology we used in our work. Their letter raises several important points which we address in this response.
In our publication, approximately one-fourth of cases failed technical quality control. There were several reasons for this, some of which are mentioned in our paper (e.g., sample age), but other more technical factors are likely to improve with further experience and optimization. For example, the automated quantitative multiplex immunofluorescence (QmIF) staining workflow had not previously been applied to samples of heart tissue, and the default temperature of a heating step used for most tissues caused coverslips to become loose in heart tissues and created artifacts. Issues like this are relatively easily addressed once identified, and we expect a higher quality control pass rate moving forward.
The second point by Dr. Napoli and colleagues refers to the difficulty in determining if a high-grade asymptomatic case is truly “discordant” or the development of overt graft dysfunction is avoided by early treatment. It is true that the widespread convention of treating high-grade endomyocardial biopsy tissue with augmented immunosuppression based on histology alone makes it difficult to control for this potential confounder in retrospective investigations. Nevertheless, the clear differences in in situ immune profiles between high-grade endomyocardial biopsies with and without evidence of graft dysfunction and much higher expression of the anti-inflammatory mediators PD-L1 and FoxP3 in the clinically silent cases suggests that there are real biological differences between these groups. Although this cannot be proven conclusively until a prospective investigation is performed, it is compelling circumstantial evidence.
Finally, Dr. Napoli and colleagues discuss the issue of cost containment in the context of advanced diagnostic approaches such as QmIF. Although cost considerations may influence adoption of new technologies, if QmIF substantially improves the accuracy of rejection diagnosis and aids in risk stratification, then initial assay costs may be offset by reduced complications and improved patient outcomes. In low-risk populations, minimizing low-yield procedures saves money, especially if associated with reductions in excess immunosuppression which can predispose patients to iatrogenic injury. In high-risk populations, more aggressive surveillance, prevention, and treatment strategies can reduce hospitalizations and major complications and potentially reduce cost. Whether this potential will be realized will, of course, require further investigation.
Please note: Supported by National Center for Advancing Translational Sciences of the National Institutes of Health award TL1TR001880 and Akoya Biosciences. Dr. Feldman is an equity holder and has technology licensed to both Elucid Bioimaging and Inspirata; and is a consultant for Inspirata, Phillips Healthcare, XFIN, and Virbio; and is a member of the advisory board of Inspirata. Dr. Feldman is a consultant for Phillips Healthcare, XFIN, and Virbio. Dr. Margulies has received research grants from Sanofi-Aventis USA and GlaxoSmithKline; and is a consultant for and an advisory board member for Pfizer and MyoKardia.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- 2020 The Authors