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Upper GI acute GvHD adds minimal prognostic value
patients (20.4%) with Grade II disease would be downgraded, potentially impacting the interpretation of clinical trial outcomes. Defining upper gastrointestinal acute graft-versus-host disease as a Grade II entity, as it is currently diagnosed and treated, is not strongly supported by this analysis. The general approach to diagnosis, treatment and grading of upper gastrointestinal symptoms and their impact on subsequent acute graft-versus-host disease therapy warrants reevaluation.
Introduction
Upper gastrointestinal acute graft-versus-host disease (UGI aGvHD) is a clinical syndrome of anorexia, food intolerance, nausea and vomiting, first described by Weisdorf et al. in 1990.1 In that cohort of 469 related- donor allogeneic hematopoietic stem cell transplant (HSCT) recipients, UGI symptoms were found in at least 13% of recipients and in almost half of those cases were the only reason for initiating systemic immunosuppres- sion. Of note, all those diagnoses were confirmed by endoscopic biopsy and histological evaluation. In subse- quent studies, UGI involvement has been consistently seen in up to 27% of recipients with aGvHD, with per- haps a quarter of those having UGI symptoms in isolation.2,3 There is a large differential diagnosis for patients presenting with nausea, vomiting and/or anorexia post-allogeneic HSCT including prolonged effects of con- ditioning treatment and medication side effects. In addi- tion, endoscopic appearance and histological changes such as single cell epithelial necrosis with karyorrhexis, dilation of mucosal crypts or glands, and crypt abscesses or oblit- eration are not specific.4-6 Thus, defining and differentiat- ing UGI aGvHD from conditioning toxicity, cytomegalovirus (CMV) or cryptosporidium infection, mycophenolate mofetil (MMF)-related damage/ulcera- tion, and proton-pump inhibitor use can be challenging.7-9
In the original series describing this entity, the percent- age of those with UGI symptoms (in isolation or plus Grade I skin aGvHD) who developed chronic GvHD
Table 1. Incidence of acute GvHD in entire cohort.
(cGvHD) was similar to that seen after non-UGI Grade II
aGvHD (74% and 65%) and higher than in those
patients with no aGvHD (13%) or Grade I skin aGvHD
(50%).1 Based on this finding, UGI symptoms were
incorporated into the “Consensus” or modified
Glucksberg grading system as a criterion for Stage 1 GI,
overall Grade II aGvHD.10-12 UGI symptoms are not
reflected in the International Bone Marrow Transplant
Registry (IBMTR) grading schema. Many subsequent
publications used the modified “Consensus” grading
report incidence of Grades II-IV aGvHD without delving
into the organs involved, while others defined the indi-
vidual organ systems involved but did not differentiate
UGI versus lower GI (LGI) symptoms.13-15 Even when the
distribution of GI involvement is specified, only occa-
sionally are aGvHD responses and long-term prognosis
differentially followed based on specific involvement;
however, certain centers are increasingly focusing on UGI aGvHD.2,3,16-20
The prognostic implications and corresponding staging for UGI aGvHD, either in isolation or in combination with other manifestations, have not to our knowledge been val- idated in a large multi-center population. The need for such evaluation is highlighted by several findings. First, one study involving routine endoscopic evaluation demonstrated that UGI aGvHD, seen in 12 of 26 subjects, uniformly resolved if treated with steroids, did not progress to symptomatic LGI aGvHD, and in almost one- third of patients resolved without alteration in baseline immunosuppression. In that study, the presence of UGI
Maximum grade of aGvHD
None
I II
III-IV
Isolated UGI
Any UGI
involvement
Entire cohort (8567)
n (%)
3428 (40.0%)
1344 (15.7%) 2083 (24.3%)
1712 (20.0%)
229 (2.7%)
1039 (12.1%)
MRD (4183) n (%)
2038 (48.7%)
654 (15.6%) 835(19.9%)
656 (15.7%)
81 (1.9%)
430 (10.3%)
URD (4384) n (%)
1390 (31.7%)
690 (15.7%) 1248 (28.5%)
1056 (24.1%)
148 (3.4%)
609 (13.9%)
Biopsy reported as obtained to confirm organ involvement*
Organ Total involved n
Skin 1344 Skin 1498 Liver 252 UGI 872 LGI 914 Skin 1316 Liver 1003 UGI 167 LGI 1333 UGI 229 UGI 1039
Biopsied #Biopsies n (%) positive
218 (16.2%) 212 295 (19.7%) 263 25 (9.9%) 12 311 (35.7%) 286 327 (35.8%) 301 267 (20.2%) 231 138 (13.8%) 71 84 (50.3%) 75 361 (27.1%) 337 49 (21.3%) 42 395 (38.0%) 361
Systemic steroid use^
0 (0%)
956 (79.9%)
1896 (94.7%)
1628 (97.3%)
207 (95.4%)
966 (95.5%)
*Biopsy was reported as negative, positive, inconclusive, not tested or missing. Total number of biopsies reported excludes those not tested or missing. ^% Systemic steroid use excludes patients missing relevant data. aGvHD: acute graft-versus-host disease; MRD: matched related donor; URD: unrelated donor; UGI: upper gastrointestinal; LGI: lower gas- trointestinal.
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