Introduction
(Article introduction authored by Conquest Editorial Team)
Graft versus host disease (GVHD) is a serious complication post-allogeneic hematopoietic stem cell transplantation, where donor cells attack the host tissues.
It commonly affects the skin, gastrointestinal tract, and liver, with acute and chronic phases distinguished by the time of occurrence.
Diagnosis relies on clinical features, lab data, and pathology, but biomarkers for acute GVHD prognosis and diagnosis are actively researched.
Elafin, a serine proteinase inhibitor, has shown promise as a potential biomarker for skin GVHD, reflecting skin damage. Despite varying study results, its diagnostic and prognostic role in skin GVHD warrants further investigation for clinical application.
Methods
The search for studies investigating the diagnostic or prognostic role of elafin in graft versus host disease (GVHD) involved a thorough exploration of PubMed and Google Scholar databases from January 1, 2000, to September 10, 2022. The search strategy incorporated terms such as ‘Elafin,’ ‘graft versus host disease,’ and ‘GVHD,’ utilizing Boolean operators ‘AND’ and ‘OR.’ Conducted by reviewers GD and RN, retrieved articles underwent meticulous screening, with duplicates removed manually and automatically.
The systematic review adhered to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines.
Eligibility criteria included studies exploring elafin’s role in acute GVHD, involving subjects of any age, gender, or nationality, and assessing its diagnostic and prognostic implications.
Exclusion criteria encompassed studies with irrelevant or insufficient information, non-English studies, unavailable full texts, review articles, correspondences, editorials, and poster/abstract presentations.
Data extraction followed a predetermined table format in Microsoft Excel, covering study characteristics, assay details, and key findings.
Quality assessment was performed using the QUIPS tool, and the primary outcome focused on comparing elafin levels between aGVHD and non-aGVHD samples, along with mortality based on initial elafin levels.
Descriptive statistics were employed for data synthesis, providing a comprehensive overview of the included studies.
Results
Study search results and study selection
A total number of 547 studies were retrieved after a systematic literature search using keywords. After screening the studies by title and abstract, and excluding the studies that do not meet our eligibility criteria, six original studies were included in our systematic review.
The details regarding the study selection process according to PRISMA guideline is given in Figure 1
Descriptive characteristics of the included studies
A total of six studies were included in our study. Three studies were from Asia, one study was from Europe and one study was from North America.
Five studies were cohort, one study was retrospective cohort, and one study was observational. A total of 1163 HSCT recipients were included in our review.
All participants were adults above 18 years of age with a median age of 19–61 years and males proportion were more than females.
Elafin assay in aGVHD
The description of the assay used in the measurement of elafin is shown in Table 3. In our review, a total of 753 patients develops aGVHD among HSCT recipients.
In most of the studies, calcineurin inhibitor-based drugs were given for prophylaxis. However, in two studies, recombinant thrombomodulin and antithymocyte globulin were given Elafin assay was done by ELISA in all studies.
Outcomes measurement
Diagnostic outcomes revealed that serum elafin levels were elevated in all 753 patients who developed graft versus host disease (GVHD) out of 1163 hematopoietic stem cell transplantation (HSCT) patients.
Multiple studies consistently reported significantly increased plasma elafin levels in acute GVHD (aGVHD) compared to non-GVHD cases. Li X et al. observed higher elafin levels in severe GVHD compared to less severe cases.
Metafuni et al. found increased elafin levels in aGVHD patients compared to non-GVHD cases, with lower levels in treatment-responsive cases. Nelson PR Jr. demonstrated an association between elevated serum elafin levels and increased GVHD risk.
However, some studies provided contrasting results, showing statistically distinct elafin increases in GVHD without rash but not in GVHD with non-GVHD rash. Patients with aGVHD exhibited higher median elafin levels compared to those without GVHD. In terms of prognostic outcomes, the evidence on the prognostic significance of serum elafin in GVHD is limited. Response to treatment was reported to be higher in the low elafin group compared to the high elafin group.
Nomura et al. found evidence of endothelial dysfunction related to elevated serum elafin levels. Elafin levels were higher in aGvHD patients compared to HSCT patients without GVHD.
However, conflicting results were reported by Zewde et al., where the low-risk elafin group unexpectedly showed a greater incidence of 6-month nonrelapse mortality.
Nelson Jr. did not find an association between serum elafin and overall survival or non-relapse mortality.
Higher elafin levels at the onset of aGvHD predicted a four times higher likelihood of developing steroid resistance. Overall, while diagnostic implications are consistent, further research is needed to establish the prognostic role of elafin in GVHD.
Discussion
This systematic review focuses on assessing the diagnostic and prognostic role of elafin in acute skin graft versus host disease (aGVHD).
The data indicate that 65.74% of individuals developed aGVHD after hematopoietic stem cell transplantation, with skin being the most commonly affected organ in about 80% of cases.
Elafin, while not specific to GVHD, is associated with various inflammatory conditions.
In the majority of studies, elafin levels were significantly elevated in GVHD, differing between GVHD and non-GVHD patients. Nelson et al. demonstrated a significant elevation of elafin at day 14, coinciding with other studies.
Prognostically, response to treatment was higher in the low elafin group, indicating its significance.
However, elafin did not consistently predict overall survival or non-relapse mortality in some studies.
The prognostic role of elafin was also supported by immunohistochemistry in skin biopsies, showing 100% sensitivity and 75% specificity for GVHD diagnosis.
Elafin outperformed other biomarkers in differentiating skin aGVHD, highlighting its specificity. This systematic review, the first of its kind, emphasizes the potential of elafin as a valuable biomarker for diagnosing and prognosticating skin aGVHD, although certain limitations and the need for further research are acknowledged.
Elafin can potentially be the specific biomarker associated with the diagnosis and prognosis of skin aGVHD and it should be investigated within 14 days of onset of aGVHD.
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