Abstract
Background
Eosinophilic esophagitis (EoE) is a chronic inflammatory disorder which can respond to proton-pump inhibitors (PPIs). Genetic variation in the CYP2C19 metabolism gene influences PPI efficacy and adverse effects. Pharmacogenetic testing (PGx) can predict PPI response by analyzing genetic variation, particularly identifying patients categorized as CYP2C19 rapid or ultra-rapid metabolizers who might benefit from PPI dosage increases or changes to pharmacotherapy. Although PGx clinical practice guidelines have been established for PPI use, routine clinical implementation has been slow.
Methods
We conducted a non-interventional prospective cohort study of patients followed by a paediatric EoE clinic between 2020 and 2023. Eligible patients underwent CYP2C19 PGx testing, with results correlated to PPI use and histological outcomes assessed via endoscopic biopsies.
Results
Sixty-nine patients underwent PGx testing; 20 (29%) and 5 (7%) were determined to be rapid and ultra-rapid metabolizers, respectively. PGx-based management changes were made in 44 (64%) patients. Forty-three (62%) patients completed reassessment endoscopy, of which 21 (49%) demonstrated histological remission; 17 (40%) of these patients achieved remission after PGx-guided drug changes.
Conclusions
This study demonstrates that PPI non-response in patients with EoE may partly be due to inadequate PPI dosing in those with rapid or ultra-rapid CYP2C19 metabolizer status. Identifying CYP2C19 metabolizer status in pediatric patients with EoE for first-generation PPIs leads to therapeutic management changes and can improve histological remission rates. Clinicians treating EoE patients should consider routine PGx testing in combination with monitoring clinical factors to guide individualized PPI therapy and optimize dosing.
Keywords: eosinophilic esophagitis (EoE), CYP2C19, pharmacogenetics (PGx), precision medicine, second-generation proton-pump inhibitors (PPIs)
Graphical Abstract
Graphical Abstract.
Introduction
Genetic variation in CYP2C19 can affect enzyme activity, impacting the metabolism and bioavailability of first-generation proton pump inhibitors (PPIs), such as omeprazole, lansoprazole, and pantoprazole.1–4 The frequency and prevalence of 37 known genetic variants have been extensively studied and can be utilized in pharmacogenetic (PGx) testing to individualize pharmacotherapy. Combinations of these variants determine the metabolic status of individuals.5 Classification into 5 groups (poor metabolizers (PM); intermediate metabolizers (IM); normal metabolizers (NM); rapid metabolizers (RM); ultrarapid metabolizers (UM)) helps describe functional implications. Additionally, genetic ancestry plays a significant role in the population distribution of different CYP2C19 metabolizer statuses, although variation can be found across all ancestries. For example, East Asian populations exhibit higher rates of CYP2C19 PM (13%), while Afro-Caribbeans, Europeans, and Central and South Americans have increased prevalence of CYP2C19 RM (23%-27%) and UM (2%-4%).
Clinical PGx guidelines for PPI use recommend dose adjustments based on CYP2C19 metabolism to achieve desired plasma concentrations, therapeutic success, and reduce the risk of toxicity that is associated with long-term use, specifically at higher plasma concentrations. These guidelines are proposed in cases of routine PPI use such as Helicobacter pylori infections, gastroesophageal reflux disease (GERD), and eosinophilic esophagitis (EoE) in paediatric and adult populations.1–3,5–11 Recent studies have demonstrated that CYP2C19 PGx testing provided individualized PPI dosing for adult patients, which surpassed standard weight-based dosing and improved clinical outcomes.7,12
In the management of EoE, first-generation PPIs are used for initial treatment and maintenance of remission.1,2,13 Despite this and the recommendation by clinical practice guidelines, the uptake of PGx testing to guide PPI use in EoE has been slow. In this work, we aim to describe CYP2C19 metabolizer status determined by PGx testing and estimate the practical feasibility and clinical utility of such testing in paediatric EoE patients. We hypothesized that CYP2C19 PGx testing for patients commencing or continuing PPI therapy can guide EoE pharmacotherapy and improve clinical outcomes.
Methods
This non-interventional prospective cohort study investigated the feasibility and clinical utility of CYP2C19 PGx testing in patients followed by The Hospital for Sick Children (SickKids) EoE Clinic between October 2020 and December 2023. Patients aged 6 months–18 years with an EoE diagnosis based on previously published criteria were eligible.14 Clinical and demographic data were gathered from clinic and endoscopy visits via the electronic health record. Enrolled patients were categorized into 1 of 4 groups: (1) newly diagnosed patients with EoE naïve to PPI therapy, (2) patients with active disease on non-PPI therapy, (3) patients with active disease on standard high-dose PPI therapy (up to a maximum of 2 mg/kg/day divided into twice daily dosing, or 30 mg lansoprazole twice daily), or (4) patients in histological remission, either on or off an EoE treatment, who are being evaluated for the potential future use of PPIs. In this study, remission is defined histologically as a peak eosinophil count < 15/hpf in oesophageal biopsies at all levels (distal, mid, and proximal), along with improved clinical symptoms. Histological improvement was defined as the change from diffuse to localized disease or a reduction in eosinophil count of at least 50% in oesophageal biopsies at 1 or more levels while maintaining a peak count > 15/hpf.
Enrolled patients or a substitute decision-maker provided written consent for participation in this study. DNA was extracted via buccal swab for targeted CYP2C19 genotyping using mass spectrometry (MassARRAY MALDI-TOF, Agena BioScience). Haplotype reports were automatically generated using MassARRAY TyperAnalyzer software (v5.0.2) and iPLEX ADME PGx Pro software (v3.99.105, Agena BioScience), using the manufacturer’s standard protocols. Genotyping analysis was performed by a clinically accredited commercial genetic testing company (DNALabs).
Feasibility and clinical utility were further assessed. Feasibility was defined as completing the process of PGx test consent to test result consultation. Clinical usefulness was defined by management decisions based on CYP2C19 metabolism status in combination with clinical factors, such as continuing current PPI therapy or switching to a more suitable PPI and/or dose.1 Therapy changes were made by treating gastroenterologists and were additionally informed by histological examination of oesophageal biopsies and clinical symptoms to assess the improvement of therapeutic outcomes. Endoscopic reassessment occurred at least 3 months after therapeutic changes, following our standard of care.15 Descriptive statistical analysis was conducted using IBM SPSS Statistics software (v28.0.1.1(14), SPSS Inc).
This study was approved by the Research Ethics Board of SickKids (REB Number 1000053445).
Results
Seventy-two eligible patients were approached for PGx testing, and 69 (96%) were enrolled on this study and completed PGx testing, including a session to review results. Eighteen (26%) were newly diagnosed patients starting standard PPI therapy for the first time, 9 (13%) were known patients with active disease on non-PPI therapy, 33 (48%) were patients with active disease on standard high dose PPI, and 9 (13%) were patients who achieved histological remission, either on or off an EoE treatment, who were evaluated for the potential benefit of individualized PPI therapy. Table 1 outlines the basic characteristics and clinical features of this cohort. Among the 33 patients with active disease on high-dose PPI treatment, 14 (42%) were UM or RM (Table 2). Overall, changes to pharmacotherapy were made based on PGx test results for 44 (64%) patients.
Table 1.
Patient demographics.
| Patient characteristics (n = 69) | |
|---|---|
| Male (%) | 58 (84) |
| Age at diagnosis (years; median, IQR) | 9 (5-13) |
| Age at time of PGx testing (years; median, IQR) | 12 (8-14) |
| Patient categories at time of study inclusion, n (%) | |
| Group 1: Newly diagnosed with EoE and PPI therapy naïve | 18 (26) |
| Group 2: Known patients with active disease on non-PPI therapy | 9 (13) |
| Group 3: Known patients with active disease on standard high-dose PPI therapy | 33 (48) |
| Group 4: Known patients in histological remissiona, either on or off an EoE treatment, who are being evaluated for the potential future use of PPIs | 9 (13) |
| EoE therapy at the start of the study, n (%) | |
| First-generation PPI | 26 (38) |
| Topical steroid | 3 (4) |
| Dietary exclusion therapy (DET) | 8 (12) |
| Combination therapy | 19 (28) |
| No therapy | 13 (19) |
Abbreviations: EoE, eosinophilic esophagitis; IQR, interquartile range; PPI = proton-pump-inhibitor.
aHistological remission = peak eosinophil count < 15/hpf in oesophageal biopsies at all levels (distal, mid, and proximal) and improvement in symptoms confirmed by endoscopy.
Table 2.
Distribution of CYP2C19 metabolizer status and ethnic variability among study cohort.
| CYP2C19 metabolizer status | Total n (%) |
Group 1 n (%) |
Group 2 n (%) |
Group 3 n (%) |
Group 4 n (%) |
||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Ultra-rapid metabolizer (UM) | 5 (7) | 1 (20) | 1 (20) | 3 (60) | 0 | ||||||||
| Rapid metabolizer (RM) | 20 (29) | 4 (20) | 3 (15) | 11 (55) | 2 (10) | ||||||||
| Normal metabolizer (NM) | 25 (36) | 8 (32) | 2 (8) | 13 (52) | 2 (8) | ||||||||
| Intermediate metabolizer (IM) | 17 (25) | 4 (23.5) | 3 (18) | 6 (35) | 4 (23.5) | ||||||||
| Poor metabolizer (PM) | 2 (3) | 1 (50) | 0 | 0 | 1 (50) | ||||||||
| Self-reported ethnicity by metabolizer status | Totala n (%) |
Caucasian n (%) |
Asian n (%) |
Black n (%) |
Latin American n (%) |
East Indian/ South Asian n (%) |
Middle Eastern n (%) |
Mixed n (%) |
|||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| UM | 5 (9) | 4 (75) | 0 | 0 | 0 | 1 (25) | 0 | 0 | |||||
| RM | 16 (30) | 12 (75) | 0 | 0 | 0 | 3 (19) | 0 | 1 (6) | |||||
| NM | 19 (35) | 11 (58) | 1 (5) | 0 | 1 (5) | 3 (16) | 2 (11) | 1 (5) | |||||
| IM | 13 (24) | 7 (54) | 0 | 1 (8) | 0 | 3 (23) | 0 | 2 (15) | |||||
| PM | 1 (2) | 0 | 0 | 0 | 0 | 1 (100) | 0 | 0 | |||||
aData only available for 54 patients
Forty-three (62%) of the 69 patients underwent repeat endoscopy with biopsies. Twenty-eight (65%) of these patients had therapy adjustments before the procedure, directly guided by PGx results. The clinical outcome of these 43 patients is reported in Table 3. Twenty-five patients (58%) demonstrated significant clinical impact from PGx testing, with 17 (40%) achieving histological remission and 8 (19%) experiencing improved disease severity given PGx-informed management decisions. Among the 21 (49%) patients in histological remission during repeat endoscopy, 17 (40%) had medical management adjustments guided by PGx results before endoscopy.
Table 3.
Outcomes of patients who had a repeat endoscopic assessment after a management change, guided by both clinical judgement and PGx testing.
| Metabolizer phenotype (n = 43) |
Change in medical management based on PGx test result and clinical judgement (inclusion group stated)# |
Histological remission based on PGx-guided change in therapy (n = 17, 40%) |
Histological remission based on therapy changes led by clinical judgement* (n = 4, 9%) |
Total number of patients in histological remission (n = 21, 49%) |
|---|---|---|---|---|
| UM (n = 4) |
|
2/4 (50%) | – | 2/4 (50%) |
| RM (n = 13) |
|
4/13 (31%) | 3/13 (23%) | 7/13 (54%) |
| NM (n = 15) |
|
5/15 (33%) | – | 5/15 (33%) |
| IM (n = 10) |
|
6/10 (60%) | 1/10 (10%) | 7/10 (70%) |
| PM (n = 1) |
|
0 (0%) | 0 (0%) | 0 (0%) |
The number of patients who were found to be in histological remission is highlighted in bold font. Histological remission = peak eosinophil count < 15/hpf in oesophageal biopsies at all levels (distal, mid, and proximal) and improvement in symptoms. Histological improvement = change from diffuse to localized disease or reduction in eosinophil count of at least 50% in the oesophageal biopsies at 1 or more levels, while maintaining a peak count > 15/hpf. #This refers to inclusion groups as described in Methods. *Indicates patients (n = 6) who had a change in medical management based on the severity of their clinical symptoms and not independently based on the PGx test result. Abbreviations: IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; RM, rapid metabolizer; UM, ultra-rapid metabolizer.
Findings from patients with repeat endoscopy and biopsies post-PGx testing and treatment modification (N = 43)
CYP2C19 UM
Of the 5 UM, 4 patients had repeat endoscopic assessment of which 3 patients commenced second-generation PPI, such as rabeprazole or esomeprazole, after receiving PGx test results. Biopsies showed that 2 patients were in remission, 1 had improved disease and 1 had similar disease (Table 3).
CYP2C19 RM
Out of the 20 patients categorized as RM, 13 underwent repeat endoscopy with biopsies. Biopsies demonstrated that 7 were in histological remission, with 4 achieving remission as a result of following at least 12 weeks on PGx-guided therapy involving a switch to second-generation PPIs or an increased dose of first-generation PPIs. Additionally, 1 patient had improved disease and 5 had similar disease.
CYP2C19 NM
Fifteen out of 25 patients categorized as NM underwent repeat endoscopy with biopsies. Five of these patients achieved histologic remission, and 6 had improved disease. Of these 15 patients, 9 had PGx-guided treatment decisions that either maintained standard doses of first-generation PPIs or recommended changes to EoE treatment modality.
CYP2C19 IM and PM
Of the 17 patients categorized as IM, 10 underwent repeat endoscopy with biopsies. Of these 10 patients, 6 achieved histological remission, 1 had improved disease, and 3 had similar disease. Five out of 6 individuals demonstrating histological remission had their treatment directed by PGx findings, either by maintaining appropriately dosed first-generation PPIs or adding modalities, including topical steroids, diet elimination therapy (DET), or a combination. The single PM had worsened disease activity on repeat endoscopic assessment, possibly due to incorrect topical steroid slurry preparation.
PGx results and subsequent management of patients who did not undergo repeat endoscopy (N = 26)
Twenty-six (38%) out of 69 patients had not undergone repeat endoscopy. Twenty-four (92%) patients had their medical management adjusted directly based on their CYP2C19 metabolizer status. All 10 patients defined as CYP2C19 RM and UM were transitioned from first- to second-generation PPI therapy or had their first-generation PPI dose increased. Patients categorized as CYP2C19 IM and NM either remained on standard high dose first-generation PPI if clinically well or commenced alternative therapy. The single patient who did not have their management directly guided by PGx was an NM who had an increased PPI dose based on clinical GERD symptoms.
Discussion
This non-interventional observational study evaluated the clinical feasibility of using CYP2C19 metabolizer status to guide PPI therapy in paediatric EoE patients. Our study demonstrates that CYP2C19 RM or UM should not necessarily be considered PPI-non-responders; instead, may simply require higher dosing of first-generation PPIs or change in class to second-generation PPIs, like rabeprazole or esomeprazole, to achieve remission with appropriate drug exposure as they are less dependent on CYP2C19 metabolism. Of the 33 patients who were not in remission on PPI therapy, 14 (44%) were determined to be UM or RM. These PGx results highlight the potential advantage of a pre-emptive PGx testing approach at therapy onset as this patient population would benefit from a higher starting dose of first-generation PPIs or the initial use of a second-generation PPI. Our study contributes to the results of a similar Spanish study evaluating paediatric EoE patients on PPI therapy. They concluded that individuals with CYP2C19 *17 variants (RM or UM) were more likely to fail PPI therapy in comparison to those not carrying that variant and were classified as having PPI-non-responsive EoE.3
Moreover, we added valuable data substantiating the clinical significance of PGx testing in paediatric EoE patients. The feasibility of testing was high, as 69/72 (96%) approached patients who completed testing and received PGx results. We demonstrated that PGx testing influenced medical management for most patients, as 44/69 (64%) had PGx-guided management changes. These management decisions were made in combination with clinical judgment and patient-specific factors, aligning with our initial hypothesis that CYP2C19 PGx testing, when integrated with clinical considerations, may improve clinical outcomes. In addition, the 18/69 newly diagnosed patients with EoE naïve to PPI therapy underwent a pre-emptive PGx testing approach. In the absence of CYP2C19 genetic testing before commencing PPI therapy, these patients could have experienced clinical symptoms for a longer period, potentially requiring an additional trial of medical management and another reassessment endoscopy before achieving disease remission or improvement.
Our study supports the concept of PPI-responsive EoE, emphasizing the importance of optimizing serum drug concentrations for adequate disease control, leading to earlier disease remission and/or improvement. When PPI therapy is selected for treatment at our centre, standard practice is first-generation PPI use, partly given the lack of drug coverage and availability of suitable second-generation PPI formulation options. Our findings may provide decision support for both private and public insurance plans to cover the costs of second-generation PPIs as an initial drug of choice when one can demonstrate CPY2C19 rapid or ultra-rapid metabolizer status, including preparations appropriate for those too young to swallow pills or those with dysphagia. A cost-benefit decision analysis was not completed as part of this study but is a necessary next step to provide quantifiable evidence for PGx testing in paediatric EoE in various settings. Additionally, understanding the accessibility of PGx testing across different centres, including community practices, is needed to further assess its feasibility for routine clinical implementation. PGx testing to guide PPI use is not currently covered by public health plans in Canada, and access to such testing is generally limited to academic research centres or direct-to-consumer testing platforms that are paid out of pocket. Future studies may leverage our findings by recapitulating historical patient outcomes before and after PGx testing implementation, or by conducting site comparisons between locations where PGx testing is available and those where it is not, as current outcomes may not necessarily surpass those reported in other studies.
For compliant patients considered CYP2C19 NM, PM, or IM, determining their metabolizer status aids in selecting additional or alternative therapies if standard PPI treatment proves inadequate. Existing data suggests variable responses to PPIs among EoE patients, with therapeutic success rates ranging between 30% and 70%, likely influenced by additional factors such as food and environmental allergens.7,8,16–18 However, the term “PPI non-response” in literature might include individuals not receiving sufficient PPI doses, assuming normal CYP2C19 metabolism.
Our study is limited by a small population of 69 patients, which was related to decreased enrolment during the COVID-19 pandemic at the study’s outset; only 43 patients had repeat endoscopies given reduced procedure availability during the pandemic. The duration of medical therapy before reassessment endoscopy was prolonged due to these wait times. Moreover, only the most common CYP2C19 variants (*1,*2,*3,*4A,*4B,*5,*6,*7,*8,*17) were tested, limiting the detection of rare variants which may further influence CYP2C19 metabolizer status. Our study did not evaluate adherence to prescribed pharmacotherapy, nor did it address other drug–drug interactions or seasonal variations in disease activity.8,9,16,17
Conclusion
Our study demonstrates that understanding an individual’s CYP2C19 metabolizer status can not only optimize therapeutic management for paediatric EoE patients but is also feasible. In the era of precision medicine, the routine practice of PPI administration, which operates under the assumption that all individuals exhibit CYP2C19 normal metabolism, should not be considered a standard of care. Using genetic information can guide the selection of the most effective therapy upfront and expedite remission time. However, genetic variation in CYP2C19 alone cannot definitively determine an individual’s drug response, as other nongenetic factors may also contribute. Since this study began, SickKids has adopted CYP2C19 PGx testing as the standard of care in the EoE Clinic, and we strongly suggest healthcare professionals leverage PGx to optimize the care of patients considering PPI therapy. We propose a clinical management algorithm for PPI therapy in paediatric EoE, integrating PGx testing to help decision-making for both PPI-naïve individuals and those on standard PPI treatment not in remission (Figures 1 and 2). Future studies evaluating this algorithm are welcomed.19
Figure 1.
Proposed clinical management algorithm for newly diagnosed treatment naïve paediatric EoE patients or known EoE patients with active disease on non-PPI therapy based on CYP2C19 metabolizer status. Abbreviations: IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; PPI, proton-pump inhibitor; RM, rapid metabolizer; UM, ultra-rapid metabolizer. First-generation PPI includes lansoprazole, and omeprazole. Second-generation PPI (excluding dexlansoprazole) refers to rabeprazole and esomeprazole. *Histological remission = peak eosinophil count < 15/hpf in oesophageal biopsies and improvement in symptoms confirmed by endoscopy. **Histological improvement = change from diffuse to localized disease or a reduction in eosinophil count of at least 50% in oesophageal biopsies at 1 or more levels, while maintaining a peak count > 15/hpf.
Figure 2.
Proposed clinical management algorithm for paediatric EoE patients with active disease on first-generation PPI therapy based on CYP2C19 metabolizer status. Abbreviations: IM, intermediate metabolizer; NM, normal metabolizer; PM, poor metabolizer; PPI, proton-pump inhibitor; RM, rapid metabolizer; UM, ultra-rapid metabolizer. First-generation PPI includes lansoprazole and omeprazole. Second-generation PPI (excluding dexlansoprazole) refers to rabeprazole and esomeprazole.*Histological remission = peak eosinophil count < 15/hpf in oesophageal biopsies and improvement in symptoms confirmed by endoscopy. **Histological improvement = change from diffuse to localized disease or a reduction in eosinophil count of at least 50% in oesophageal biopsies at 1 or more levels, while maintaining a peak count > 15/hpf.
Supplementary Material
Contributor Information
Sierra Scodellaro, Department of Paediatrics, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Kristen A Bortolin, Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Margaret A Marcon, Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
Ruud H J Verstegen, Department of Paediatrics, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, Division of Rheumatology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.
Susana Da Silva, Temerty Faculty of Medicine, University of Toronto, Toronto, ON M5S 1A8, Canada.
Shinya Ito, Department of Paediatrics, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
Tamorah Lewis, Department of Paediatrics, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
Nicola L Jones, Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
Iris Cohn, Department of Paediatrics, Division of Clinical Pharmacology and Toxicology, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada.
Jessie M Hulst, Department of Paediatrics, Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, ON M5G 1X8, Canada; Department of Paediatrics, University of Toronto, Toronto, ON M5G 1X8, Canada; Department of Nutritional Sciences, University of Toronto, Toronto, ON M5S 1A8, Canada.
Author Contributions
Sierra Scodellaro and Dr Bortolin contributed equally as primary authors; Iris Cohn and Dr Hulst contributed equally as co-senior authors.
Funding
Sierra Scodellaro has no funding sources to declare. Kristen A. Bortolin has received speaker’s fees from Nutricia Canada. She has no funding sources to declare for this publication. Margaret A. Marcon has received speaker’s fees from Nutricia Canada and Sanofi. She has no funding sources to declare for this publication. Ruud H. J. Verstegen has no funding sources to declare. Susana Da Silva has no funding sources to declare. Shinya Ito has no funding sources to declare. Tamorah Lewis has no funding sources to declare. Nicola L. Jones has no funding sources to declare. Iris Cohn has no funding sources to declare. Jessie M. Hulst serves on the advisory board for the Canadian Malnutrition Taskforce (Canadian Nutrition Society) and has received speaker’s fees from Nutricia Canada and Abbott Canada. She has no funding sources to declare for this publication.
Conflict of Interest
Conflict of interest disclosure forms (ICMJE) have been collected for all co-authors and can be accessed as supplementary material here.
Data Availability
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.
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Data Availability Statement
The data underlying this article cannot be shared publicly due to the privacy of individuals that participated in the study. The data will be shared on reasonable request to the corresponding author.