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ORIGINAL ARTICLE
Year : 2021 | Volume
: 46
| Issue : 3 | Page : 151-154
Role of early estimation of regenerating islet-derived 3-α in hematopoietic stem cell transplantation patients as a prognostic marker for acute lower gastrointestinal graft-vs-host disease
Shaza A El Kourashy1, Soha R Youssef2, Hanaa F. Abdel-Samie1, Haitham M. Abdel-Bary1, Rania Radwan1, Basma S.M. Ali MSc 3
1 Department of Haematology, BMT and Internal Medicine, Ain Shams University, Cairo, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
3 Assistant Lecturer of Clinical Hematology and Bone Marrow Transplantation, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Correspondence Address:
Basma S.M. Ali
Postal/Zip Code 11833
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ejh.ejh_10_20
Background Regenerating islet-derived 3-α (REG3α) is an antimicrobial protein secreted by Paneth cells with protective effect on intestinal stem cells and prevents any gastrointestinal epithelial damage, as in GUT acute graft-vs-host disease (GVHD). As its plasma concentration correlates with GUT GVHD activity, it could be used as a biomarker for GUT GVHD.
Aim The aim was to evaluate the diagnostic and prognostic role of REG3α in hematopoietic stem cell transplantation (HSCT) patients with acute lower gut GVHD.
Patients and methods Serum level of REG3α was measured using enzyme-linked immunosorbent assay in 45 allogenic HSCT patients within one week after engraftment in comparison with 20 age-matched and sex-matched healthy controls. It was reevaluated again in a second sample in patients who developed diarrhea owing to acute GUT GVHD or any other causes. Then a third sample of REG3α was measured after 1 week of GUT GVHD treatment. The patients were recruited from Hematopoietic Stem Cells Transplantation Unit (BMT unit) at Ain shams university hospital over the period from 2017 to 2019.
Results Serum level of REG3α after engraftment was significantly elevated (>75 ng/l) in patients who developed later acute lower GUT GVHD compared with other patient groups, with a sensitivity 100% and specificity 93.3%. REG3α was elevated greater than 120 ng/l at the onset of lower GUT GVHD symptoms compared with diarrhea owing to other causes, with a sensitivity 93.33% and specificity 93.33%. After one week of treatment, patients with high levels, that is, greater than 160 ng/l, did not respond to treatment, whereas patients with levels less than or equal to 160 ng/l achieved complete or partial response within 90 days of follow-up.
Conclusion REG3α is a useful diagnostic and prognostic biomarker for acute lower GUT GVHD and could be used for early prediction of patients with acute LGI GVHD after HSCT before clinical presentation.
Keywords: acute lower GUT graft-vs-host disease, biomarkers, regenerating islet-derived 3-α
Allogeneic hematopoietic stem cell transplantation (alloHSCT) is a cornerstone treatment for many malignant and nonmalignant hematological diseases, often providing the only chance of cure [1].
Despite routine prophylaxis with immunosuppressive agents, approximately half of alloHSCT recipients develop acute graft-vs-host disease (aGVHD) [1], with up to 50% of aGVHD cases affecting the gastrointestinal tract [2].
The nonspecific clinical picture and invasive diagnostic tools of GUT GVHD led the researchers toward the biomarker field, seeking for noninvasive diagnostic and prognostic properties [3].
Regenerating islet-derived 3-α (REG3α), which is an antimicrobial protein expressed in Paneth cells and secreted into the crypt microenvironment with a protective effect for intestinal stem cells, has been studied and revealed good diagnostic and prognostic performance in acute lower GUT GVHD [4].
Patients and methodsThis study was performed at Ain Shams University Hematopoietic Stem Cells Transplantation Unit (BMT unit) from 2017 to 2019. A total of 65 adult subjects were enrolled after obtaining an informed consent (45 patients and 20 control). The study was conducted in accordance with the stipulations of the local ethical and scientific committees and the procedures respected the ethical standards in Helsinki declaration of 1964.
Study population
A total of 45 engrafted allogenic HSCT patients were included, who were divided into three groups as follows:
GUT GVHD group
It included 15 engrafted allogenic HSCT patients with lower GUT GVHD based on clinical criteria, endoscopic biopsy, and negative bacterial infection in stool samples.
Non-GUT GVHD diarrhea
It included 15 engrafted allogenic HSCT patients with diarrhea owing to other causes than lower GUT GVHD.
Non-GUT GVHD
It included 15 engrafted allogenic HSCT patients who did not have diarrhea but developed other types of GVHD.
Control group
It included 20 age-matched and sex-matched healthy adult individuals.
Serum level of the biomarker REG3α was evaluated in the four groups as follows:
In GUT GVHD group, REG3α was measured initially after engraftment (first sample), at onset of diarrhea (second sample), and after 1 week of treatment (third sample).
In non-GUT GVHD diarrhea group, REG3α was measured initially after engraftment (first sample) and at the onset of diarrhea (second sample).
In non-GUT GVHD group, REG3α was measured once after engraftment (first sample).
In control group, REG3α was measured once.
All patients were subjected to the following:
Full history taking.
Thorough physical examination.
Complete blood picture.
Routine laboratory tests (liver and renal functions, total proteins, s. albumin, bilirubin, s. electrolytes, erythrocyte sedimentation rate, C-reactive protein, and lactate dehydrogenase).
Stool analysis.
Stool culture and sensitivity.
Stool Clostridium difficile assay.
Quantitative PCR for cytomegalovirus.
LGI endoscopy for fit patients.
Serum level of REG3α by ELISA.
Inclusion criteria
The following were the inclusion criteria:
Adult patients.
All allogenic engrafted patients.
Exclusion criteria
The following were the inclusion criteria:
Nonengrafted patients.
Patients on laxative therapy.
Patients with vomiting or symptoms suggestive of upper GUT GVHD.
Patients on methylprednisolone more than 48 h (in second sample) in GUT GVHD group.
Autologous stem cell transplantation patients.
Statistical analysis
Data were analyzed using the Statistical Package for the Social Sciences (IBM SPSS) (IBM, Chicago, Delaware) version 23. The quantitative data were presented as mean, SD, and ranges when their distribution was found to be parametric and median with interquartile range when their distribution was found to be nonparametric. Moreover, qualitative variables were presented as number and percentages. P value less than 0.05 was considered significant, P value less than 0.001 was considered as highly significant, and P value greater than 0.05 was considered insignificant.
ResultsSerum levels of REG3α within 1 week after engraftment were highly elevated in patient groups in comparison with control group, with highly significant difference (P=0.000) ([Table 1]). In GUT GVHD group, REG3α ranged from 80 to 320 ng/l with a median of 120 ng/l. In non-GUT GVHD diarrhea group, REG3α ranged from 6 to 60 ng/l, with a median of 20 ng/l. In non-GUT GVHD group, REG3α ranged from 15 to 80 ng/l, with a median of 25 ng/l. In control group, REG3α ranged from 7 to 50 ng/l, with a median of 15 ng/l.
Table 1 Comparison between patient groups and control regarding regenerating islet-derived 3-α level at first sampleSerum levels of REG3α at onset of diarrhea were significantly elevated in GUT GVHD group compared with non-GUT GVHD diarrhea group (P=0.000) ([Table 2]). In GUT GVHD group, REG3α level ranged from 110 to 430 ng/l, with a median 200 ng/l. In non-GUT GVHD diarrhea group, REG3α ranged from 12 to 125 ng/l, with a median of 50 ng/l.
Table 2 Comparison between GUT GVHD group and non-GUT GVHD diarrhea group regarding regenerating islet-derived 3-α level at onset of diarrhea (second sample)Nonrelapse mortality (NRM) was related to serum level of REG3α after one week of GUT GVHD treatment, with highly statistical significance (P=0.008) ([Table 3]).
Table 3 The relation of regenerating islet-derived 3-α levels after one week of treatment in GUT GVHD group (third sample) to NRM and response to treatmentIn patients who did not respond to treatment, serum level of REG3α ranged from 200 to 500 ng/l, with a median of 300 ng/l, and in patients with good or partial response, serum level of REG3α ranged from 40 to 160 ng/l, with a median of 107 ng/l, with highly statistical significance (P=0.001) ([Table 3]).
DiscussionIn our study, REG3α was highly elevated greater than 120 ng/l in acute lower GUT GVHD patients in comparison with patients with diarrhea owing to other causes with highly significant difference (P=0.000), with a sensitivity of 93.33% and specificity of 93.33%. These results are compatible with Ferrara et al. [3], who reported that REG3α concentrations were three-fold higher in patients at lower gastrointestinal GVHD onset than other patients with non-GVHD enteritis. Sun et al. [5] also showed that REG3α is a specific biomarker for LGI-aGVHD.
In our study, REG3α was measured after one week of treatment in patients with acute lower GUT GVHD and revealed that patients with high levels greater than 160 ng/l did not respond to treatment, whereas patients with levels less than or equal to 160 ng/l achieved complete or partial response within 90 days of follow-up. High levels of REG3α were also related to NRM, with high significance (P=0.008). In accordance with our study, Harris et al. [6] revealed that REG3α has a predictive role for response to therapy, NRM, and overall survival. Levine et al. [7] also introduced REG3α within biomarker algorithm for risk stratification. Contrary to these results, Nelson et al. [8] reported that REG3α is predictive for aGVHD but cannot predict overall survival and NRM.In our study, we estimated the role of early measurement of REG3α after engraftment as a predictive biomarker for acute lower GUT GVHD. Serum level of REG3α was measured within one week after engraftment in all included allogenic HSCT patients in comparison with matched healthy volunteers. Serum level of REG3α after engraftment was highly elevated (>75 ng/l) in patients who developed later acute lower GUT GVHD in comparison with patients who developed diarrhea owing to other causes (P=0.000) or patients who did not develop any intestinal affection (P=0.000), with a sensitivity of 100% and specificity of 93.3%. In accordance with these results, Nelson et al. [8] assessed REG3α with other four biomarkers (ST2, elafin, TNFR1, and sIL2Rα) at days +7, +14, +21, and +30 after HSCT and reported that REG3α is predictive for aGVHD at days +14 and +21 but not before day +14. Shin et al. [1] used three biomarkers (tissue inhibitor of metalloproteinase 1, plastin-2, and regenerating islet-derived 3-α) as a screening algorithm within a median of 14 (range: 14–22) days after alloHSCT before the onset of clinical manifestations and reported that REG3α has a high predictive value for intestinal aGVHD.
ConclusionREG3α could be a reliable marker for early prediction of acute lower GUT GVHD, confirming its diagnosis and predicting disease severity and response to treatment.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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