All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional.

The GvHD Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Introducing

Now you can personalise
your GvHD Hub experience!

Bookmark content to read later

Select your specific areas of interest

View content recommended for you

Find out more
  TRANSLATE

The GvHD Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the GvHD Hub cannot guarantee the accuracy of translated content. The GvHD Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
LOADING
You're logged in! Click here any time to manage your account or log out.
LOADING
You're logged in! Click here any time to manage your account or log out.
2022-03-31T08:02:32.000Z

Editorial theme | Genetic predisposition and endoscopic diagnosis of aGvHD in pediatric patients

Mar 31, 2022
Share:
Learning objective: State genetic variants associated with Grade 2–4 aGvHD onset in pediatric patients, and discuss the sensitivities of gastrointestinal (GI) sites and the utility of upper and lower GI endoscopy for confirming a diagnosis of GI-aGvHD in pediatric patients.

Bookmark this article

Over the coming months, the GvHD Hub will be exploring different aspects of pediatric graft-versus-host disease (GvHD), including genetic predisposition, diagnosis, emerging therapies, and refining stem cell transplantation in this population. The first article of this editorial theme summarized consensus statements for pediatric GvHD, which you can read here. In this second article, we summarize two publications; one on the genetic susceptibility of pediatric patients to Grade 24 acute (a)GvHD1 and the other on the utility of upper and lower gastrointestinal (GI) endoscopy in GI aGvHD diagnosis.2

Genetic susceptibility1

The onset of aGvHD is attributed to many factors, including conditioning regimens, age, human leukocyte antigen HLA (matching), and stem cell source. Additionally, genetic variation may influence recipient susceptibility to aGvHD, independently or in association with these factors.1

An exome-wide association study, recently published by Ansari et al.1 in Bone Marrow Transplantation, investigated the association of genetic variants with the risk of Grade 24 aGvHD in pediatric patients.

Methods

A total of 255 patients who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) between 2000 and 2015 were included in either a discovery or replication cohort (Figure 1).

Figure 1. Study summary*

aGvHD, acute graft-versus-host disease; allo-HSCT, allogeneic hematopoietic stem cell transplantation; SJUHC, Sainte Justine University Health Center; SNP, single nucleotide polymorphism; UTR, untranslated region.
*Adapted from Ansari, et al.1
aGvHD was diagnosed up to 180 days post allo-HSCT
The independent cohort comprised 47 patients from SJUHC and 121 pediatric patients who underwent allo-HSCT between 2001 and 2015 in four different centers across Europe and Canada (Geneva University Hospital, University Medical Center Utrecht, Leiden University Medical Center, Robert Debré Hospital, and Alberta Children’s Hospital).

Results

Patient characteristics for the discovery and replication cohort are summarized in Table 1.

Table 1. Patient characteristics*

Characteristics, % (unless otherwise stated)

Discovery
(n = 87)

Replication
(n = 168)

Median age (range), years

7.4 (0.1–23.5)

4.7 (0.0–21.0)

Sex

 

 

              Female

54.0

39.9

              Male

46.0

60.1

Diagnosed with malignancy

51.7

56.0

HLA compatibility

 

 

              Unrelated donor

58.6

72.0

              Identical related donor

34.5

26.2

              Non-identical related donor

6.9

1.8

Stem cell source

 

 

              Bone marrow

49.4

41.7

              Peripheral blood

2.3

18.4

              Cord blood

48.3

37.5

              Bone marrow and peripheral blood

2.4

Total body irradiation

16.7

aGvHD Grade 24

12.6

26.8

Serotherapy

73.6

73.2

aGvHD, acute graft-versus-host disease; HLA, human leukocyte antigen.
*Adapted from Ansari, et al.1

Notable differences between the cohorts included median age, gender distribution, stem cell sources, the proportion of patients receiving total body irradiation, and Grade 2–4 aGvHD diagnosis (all p < 0.05).

Association analysis of the discovery cohort

A total of 11 loci were found to be associated with aGvHD onset after multiple testing, and nine of these were carried forward to the replication phase after correcting for multiple testing. Multivariate analysis confirmed a significant association of these variants with aGvHD onset (Table 2).

Table 2. Multivariate analysis of nine loci and Grade 24 aGvHD *

Variable

HR (95% CI)

p value

CASR rs1042636

31.2 (5.1191.5)

0.0002

SPRED1 rs11634702

22.7 (4.8107.4)

0.00008

NOP9 rs2332320

16.7 (3.286.2)

0.001

ERC1 rs1046473

13.1 (3.155.5)

0.001

PLEK rs3816281

11.4 (2.747.9)

0.001

ISG20 rs59188950

8.4 (2.6-27.4)

0.004

CCL8 rs1133763

7.4 (2.422.8)

0.001

ABC11 rs17822931

4.7 (1.911.5)

0.001

ERC1 rs1064125

4.6 (1.811.4)

0.001

aGvHD, acute graft-versus-host disease; CI, confidence interval; HR, hazard ratio.
*Adapted from Ansari, et al.1

The investigators next analyzed whether genetic variants were impacted by other risk factors for Grade 24 aGvHD onset. Nongenetic covariates included patient age, type of donor, serotherapy, and stem cell source. The genetic variants found to have a significant association with aGvHD when including these nongenetic factors included ERC1, PLEK, NOP9, and SPRED1. ERC1 was associated with aGvHD in patients receiving transplants from HLA-identical siblings, as well as in bone marrow recipients and in those who did not receive serotherapy. SPRED1 was associated with aGvHD in recipients who had received serotherapy, NOP9 was associated with aGvHD in patients receiving cord blood, and PLEK was associated with aGvHD in patients without previous serotherapy (Table 3).

Table 3. Risk of aGvHD in patient subgroups with top-ranking genetic variants*

Gene

Association group

HR (95% CI)

p value

ERC1

Serotherapy negative patients

3.4 (1.3–9.1)

0.004

ERC1

Stem cell source: bone marrow transplant

2.2 (1.2–4.1)

0.007

ERC1

HLA-identical siblings

2.8 (1.0–7.6)

0.03

SPRED1

Serotherapy positive patients

3.6 (1.1–12.1)

0.02

NOP1

Stem cell source: cord blood

5.8 (1.3–27.2)

0.01

PLEK1

Serotherapy negative

5.0 (0.9–28.5)

0.04

aGvHD, acute graft-versus-host disease; CI, confidence interval; HLA, human leukocyte antigen; HR, hazard ratio.
*Data from Ansari, et al.1

Replication cohort

The nine genetic variants were tested for an association with Grade 3–4 aGvHD. Not accounting for other clinical risk factors, both ERC1 (hazard ratio, 3.3; 95% confidence interval, 1.91–9.6; p = 0.02) and PLEK (hazard ratio, 4.7; 95% confidence interval, 1.3–16.9; p = 0.003) retained significance. Serotherapy and HLA histocompatibility were also associated with Grade 34 aGvHD (p = 0.0002 and p = 0.01, respectively).

Diagnosis of GI aGvHD with endoscopy2

There is a lack of consensus in GI aGvHD around which GI sites to analyze, with both upper and lower GI endoscopies used for diagnosis. Comparing these sites in terms of GI GvHD sensitivity could provide insights into the optimal approach for diagnosing aGvHD.

A single centre, retrospective review of pediatric patients undergoing allo-HSCT in New Zealand was recently published by Koh et al.2 in Pediatric Transplantation, in which they reviewed the variability of endoscopic approaches used over a 12-year period. They aimed to determine which sites and methods were most useful in diagnosing GI aGvHD.

Methods

The study design is summarized in Figure 2.

Figure 2. Study design*

aGvHD, acute graft-versus-host disease; allo-HSCT, allogeneic hematopoietic stem cell transplantation; GI, gastrointestinal.
*Adapted from Koh, et al.2
N = 216 refers to the total number of transplants; two separate transplants in the same patient were counted as two individual cases. 
A positive result was defined as histologically proven GI aGvHD at the GI site. A false negative result was defined as a negative biopsy when there was histologically proven GI GvHD elsewhere in the GI tract.

Results

A total of 216 transplants were performed in 199 patients, the characteristics of which are summarized in Table 4.

Table 4. Patient and donor characteristics*

Characteristics

All patients (N = 199)

Median age at transplant (IQR), years

6 (2–11)

Sex

 

              Female, %

40

              Male, %

60

Total number of transplants performed, N

216

              Related donor, n

72

              Unrelated donor, n

144

IQR, interquartile range.
*Adapted from Koh, et al.2

A total of 52 cases of GI aGvHD were suspected, with 36 exhibiting lower GI symptoms, 5 exhibiting upper GI symptoms, and 11 cases with both. A total of 37 of these patients underwent endoscopy (Figure 3). In total, 15 patients did not receive an endoscopy: 14 patients had other non-GI sites affected by GvHD and were already receiving immunotherapy, and one patient was too unwell to receive an endoscopy.

Figure 3. Patients undergoing endoscopy and the endoscopic techniques used*

LGIE, lower gastrointestinal endoscopy; UGIE, upper gastrointestinal endoscopy.
*Adapted from Koh, et al.2

The rectosigmoid and duodenum were the two most sensitive GI regions for GvHD detection, with a sensitivity of 86% and 76%, respectively. The sensitivity of upper GI endoscopy and lower GI endoscopy for aGvHD was comparable (86% and 90%, respectively).

A total of 21 cases had histologically proven GvHD, and 19 of these patients presented with symptoms affecting non-GI sites, with 10 patients presenting with concurrent infection(s). The most common concurrent infection was cytomegalovirus, observed in seven cases.

There was no difference in GI sites affected by GvHD between late onset (>100 days) and classic aGvHD (<100 days). 

Finally, there was no significant association observed between clinical symptoms and the GI site from which aGvHD was diagnosed. In 21 patients who had a positive GvHD biopsy, all had lower GI symptoms, but three of these patients did not have a positive colonic biopsy. Three out of four patients with upper GI symptoms who had an endoscopy in this site did not have a positive GI GvHD biopsy.

Conclusion

Increased risk of Grade 24 aGvHD in a cohort of pediatric patients was found to be associated with nine gene loci, of which the associations of four genes (ERC1, PLEK, NOP9, and SPRED1) were maintained in an interaction analysis with nongenetic covariates. Analysis for an association with Grade 34 aGvHD identified ERC1 and PLEK as significant independent of the nongenetic covariates studied. Study limitations included a small sample size, no genetic analysis of some donors, and a lack of an investigation into the relationship between GvHD prophylaxis and genetic variants due to heterogeneity.

In terms of diagnosis of aGvHD in pediatric patients, the retrospective study by Koh et al. demonstrated a lack of a standardized approach to endoscopy for GI aGvHD. Despite a higher occurrence of lower GI symptoms, both upper and lower GI endoscopies produced similar sensitivities for GI diagnosis. Given the lack of correlation between clinical symptoms and positive aGvHD biopsies, the authors felt that their data supported a standardized endoscopic approach utilizing upper GI endoscopy alongside sigmoidoscopy. The authors also highlighted that the study had limitations such as a small patient number, the retrospective nature of the study, and that sensitivity calculations did not account for variability in upper and lower GI endoscopic approaches.

  1. Ansari M, Petrykey K, Rezgui MA et al. Genetic susceptibility to acute graft versus host disease in pediatric patients undergoing HSCT. Bone marrow transplant. 2021;56(11):2697-704. DOI: 1038/s41409-021-01386-8
  2. Koh P, Cole N, Evans HM et al. Diagnostic utility of upper and lower gastrointestinal endoscopy for the diagnosis of acute graft‐versus‐host disease in children following stem cell transplantation: A 12‐year experience. Pediatr Transplantation. 2021;25(7):e14046. DOI: 1111/petr.14046

Newsletter

Subscribe to get the best content related to GvHD delivered to your inbox