Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation

Carol K. Conrad; Haley Hedlin; Hyunsook Chin; Don Hayes; Peter S. Heeger; Albert Faro; Samuel Goldfarb; Ernestina Melicoff-Portillo; Mohanakumar Thalachallour; Jonah Odim; Marc Schecter; Gregory A. Storch; Gary A. Visner; Nikki M. Williams; Karen Kesler; Lara Danziger-Isakov; Stuart C. Sweet

doi:10.1111/petr.14247

Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation

Carol K. Conrad, Haley Hedlin, Hyunsook Chin, Don Hayes, Peter S. Heeger, Albert Faro, Samuel Goldfarb, Ernestina Melicoff-Portillo, Mohanakumar Thalachallour, Jonah Odim, Marc Schecter, Gregory A. Storch, Gary A. Visner, Nikki M. Williams, Karen Kesler, Lara Danziger-Isakov, Stuart C. Sweet

Research output: Contribution to journal › Article › peer-review

Abstract

BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD).

METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients.

RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival.

CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

Original language	English (US)
Article number	e14247
Journal	Pediatric transplantation
Volume	26
Issue number	4
DOIs	https://doi.org/10.1111/petr.14247
State	Published - Jun 2022

Bibliographical note

Funding Information:
This research was performed under the auspices and guidance of the Clinical Trials in Organ Transplantation in Children, a collaborative clinical research project headquartered at the National Institute of Allergy and Infectious Diseases, supported by Grant U01 AI077810 “Viral Triggers of Alloimmunity and Autoimmunity in Pediatric Lung Transplantation” from the Division of Allergy, Immunology and Transplantation of the National Institutes of Health.

Funding Information:
The cytokine analysis was independently funded by the Arline and Pete Harmon Scholarhsip in Pediatric Pulmonary Biology at Stanford University awarded to Dr. Carol Conrad. For the CTOTC study—National Institute of Allergy and Infectious Diseases, Grant/Award Number: U01AI077810/AI/NIAID NIH HHS/United States. UM2 AI117870/AI/NIAID NIH HHS/United States. For analysis of the cytokines—Arline and Pete Harman Faculty Scholar in Pediatric Pulmonary Biology. This study was approved by the IRB of Stanford University H H

Publisher Copyright:
© 2022 Wiley Periodicals LLC.

Keywords

auto-inflammation
BOS
CLAD
pediatric lung transplant
Prospective Studies
Humans
Interleukin-23
Inflammation
Lung Transplantation
Bronchiolitis Obliterans/diagnosis
Adult
Cytokines/metabolism
Child

PubMed: MeSH publication types

Journal Article
Multicenter Study

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10.1111/petr.14247

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Conrad, C. K., Hedlin, H., Chin, H., Hayes, D., Heeger, P. S., Faro, A., Goldfarb, S., Melicoff-Portillo, E., Thalachallour, M., Odim, J., Schecter, M., Storch, G. A., Visner, G. A., Williams, N. M., Kesler, K., Danziger-Isakov, L., & Sweet, S. C. (2022). Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation. Pediatric transplantation, 26(4), Article e14247. https://doi.org/10.1111/petr.14247

Conrad, CK, Hedlin, H, Chin, H, Hayes, D, Heeger, PS, Faro, A, Goldfarb, S, Melicoff-Portillo, E, Thalachallour, M, Odim, J, Schecter, M, Storch, GA, Visner, GA, Williams, NM, Kesler, K, Danziger-Isakov, L & Sweet, SC 2022, 'Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation', Pediatric transplantation, vol. 26, no. 4, e14247. https://doi.org/10.1111/petr.14247

@article{f0bab6ef398a4831b6de0a1da0500796,

title = "Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation",

abstract = "BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD).METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients.RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival.CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of {"}classical{"} pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.",

keywords = "auto-inflammation, BOS, CLAD, pediatric lung transplant, Prospective Studies, Humans, Interleukin-23, Inflammation, Lung Transplantation, Bronchiolitis Obliterans/diagnosis, Adult, Cytokines/metabolism, Child",

author = "Conrad, {Carol K.} and Haley Hedlin and Hyunsook Chin and Don Hayes and Heeger, {Peter S.} and Albert Faro and Samuel Goldfarb and Ernestina Melicoff-Portillo and Mohanakumar Thalachallour and Jonah Odim and Marc Schecter and Storch, {Gregory A.} and Visner, {Gary A.} and Williams, {Nikki M.} and Karen Kesler and Lara Danziger-Isakov and Sweet, {Stuart C.}",

note = "Funding Information: This research was performed under the auspices and guidance of the Clinical Trials in Organ Transplantation in Children, a collaborative clinical research project headquartered at the National Institute of Allergy and Infectious Diseases, supported by Grant U01 AI077810 “Viral Triggers of Alloimmunity and Autoimmunity in Pediatric Lung Transplantation” from the Division of Allergy, Immunology and Transplantation of the National Institutes of Health. Funding Information: The cytokine analysis was independently funded by the Arline and Pete Harmon Scholarhsip in Pediatric Pulmonary Biology at Stanford University awarded to Dr. Carol Conrad. For the CTOTC study—National Institute of Allergy and Infectious Diseases, Grant/Award Number: U01AI077810/AI/NIAID NIH HHS/United States. UM2 AI117870/AI/NIAID NIH HHS/United States. For analysis of the cytokines—Arline and Pete Harman Faculty Scholar in Pediatric Pulmonary Biology. This study was approved by the IRB of Stanford University H H Publisher Copyright: {\textcopyright} 2022 Wiley Periodicals LLC.",

year = "2022",

month = jun,

doi = "10.1111/petr.14247",

language = "English (US)",

volume = "26",

journal = "Pediatric transplantation",

issn = "1397-3142",

publisher = "John Wiley and Sons Inc.",

number = "4",

}

TY - JOUR

T1 - Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation

AU - Conrad, Carol K.

AU - Hedlin, Haley

AU - Chin, Hyunsook

AU - Hayes, Don

AU - Heeger, Peter S.

AU - Faro, Albert

AU - Goldfarb, Samuel

AU - Melicoff-Portillo, Ernestina

AU - Thalachallour, Mohanakumar

AU - Odim, Jonah

AU - Schecter, Marc

AU - Storch, Gregory A.

AU - Visner, Gary A.

AU - Williams, Nikki M.

AU - Kesler, Karen

AU - Danziger-Isakov, Lara

AU - Sweet, Stuart C.

N1 - Funding Information: This research was performed under the auspices and guidance of the Clinical Trials in Organ Transplantation in Children, a collaborative clinical research project headquartered at the National Institute of Allergy and Infectious Diseases, supported by Grant U01 AI077810 “Viral Triggers of Alloimmunity and Autoimmunity in Pediatric Lung Transplantation” from the Division of Allergy, Immunology and Transplantation of the National Institutes of Health. Funding Information: The cytokine analysis was independently funded by the Arline and Pete Harmon Scholarhsip in Pediatric Pulmonary Biology at Stanford University awarded to Dr. Carol Conrad. For the CTOTC study—National Institute of Allergy and Infectious Diseases, Grant/Award Number: U01AI077810/AI/NIAID NIH HHS/United States. UM2 AI117870/AI/NIAID NIH HHS/United States. For analysis of the cytokines—Arline and Pete Harman Faculty Scholar in Pediatric Pulmonary Biology. This study was approved by the IRB of Stanford University H H Publisher Copyright: © 2022 Wiley Periodicals LLC.

PY - 2022/6

Y1 - 2022/6

N2 - BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD).METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients.RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival.CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

AB - BACKGROUND: Long-term survival after lung transplantation (LTx) is limited by chronic lung allograft dysfunction (CLAD).METHODS: We report an analysis of cytokine profiles in bronchoalveolar lavage samples collected during a prospective multicenter non-interventional trial primarily designed to determine the impact of community-acquired respiratory viral infections (CARV) in outcomes after pediatric LTx. In this analysis, we identify potential biomarkers of auto-inflammation and auto-immunity associated with survival and risk of bronchiolitis obliterans (BOS) after LTx with cytokine analysis of bronchoalveolar lavage fluid (BALF) from 61 pediatric recipients.RESULTS: Higher IL-23 (p = .048) and IL-31 (p = .035) levels were associated with the risk of BOS, and lower levels of epithelial growth factor (EGF) (p = .041) and eotaxin (EOX) (p = .017) were associated with BOS. Analysis using conditional inference trees to evaluate cytokines at each visit associated with survival identified soluble CD30 (p < .001), pro-inflammatory cytokine IL-23 (p = .02), and sTNFRI (p = .01) below cutoff levels as associated with BOS-free survival.CONCLUSIONS: Our results indicate that post-LTx survival in children may be linked to activation of alternate pathways of the immune system that affect airway remodeling in addition to activation of "classical" pathways that have been described in adult LTx recipients. These may indicate pathways to target for intervention.

KW - auto-inflammation

KW - BOS

KW - CLAD

KW - pediatric lung transplant

KW - Prospective Studies

KW - Humans

KW - Interleukin-23

KW - Inflammation

KW - Lung Transplantation

KW - Bronchiolitis Obliterans/diagnosis

KW - Adult

KW - Cytokines/metabolism

KW - Child

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UR - http://www.scopus.com/inward/citedby.url?scp=85124556977&partnerID=8YFLogxK

U2 - 10.1111/petr.14247

DO - 10.1111/petr.14247

M3 - Article

C2 - 35146849

AN - SCOPUS:85124556977

SN - 1397-3142

VL - 26

JO - Pediatric transplantation

JF - Pediatric transplantation

IS - 4

M1 - e14247

ER -

Auto-inflammation and auto-immunity pathways are associated with emergence of BOS in pediatric lung transplantation

Abstract

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