Ethical dilemma: ELX/TEZ/IVA or Lung Transplantation in Cystic Fibrosis and End Stage Lung Disease?
Oded Breuer, MD, David Shoseyov, MD, Shifra Koretz, Nadia Alyan, Joel Reiter, MD, Malena Cohen-Cymberknoh, MD, Isaiah Wexler, MD, PhD, Eitan Kerem, MD
PII: S0012-3692(21)03846-0
DOI: https://doi.org/10.1016/j.chest.2021.08.073 Reference: CHEST 4596
To appear in: CHEST
Received Date: 28 April 2021
Revised Date: 3 August 2021
Accepted Date: 31 August 2021
Please cite this article as: Breuer O, Shoseyov D, Koretz S, Alyan N, Reiter J, Cohen-Cymberknoh M, Wexler I, Kerem E, Ethical dilemma: ELX/TEZ/IVA or Lung Transplantation in Cystic Fibrosis and End Stage Lung Disease?, CHEST (2021), doi: https://doi.org/10.1016/j.chest.2021.08.073.
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Copyright © 2021 Published by Elsevier Inc under license from the American College of Chest Physicians.
Ethical dilemma: ELX/TEZ/IVA or Lung Transplantation in Cystic Fibrosis and End Stage Lung Disease?
Oded Breuer MD1,2, David Shoseyov MD1, Shifra Koretz2,3, Nadia Alyan1,3, Joel Reiter MD1,2, Malena Cohen-Cymberknoh MD1, Isaiah Wexler, MD, PhD1, Eitan Kerem MD1,2
1Department of Pediatrics, 2Pediatric Pulmonology and CF Center, 3Department of Social Work Services, all from the Hadassah Medical Center and Faculty of Medicine, Hebrew University of Jerusalem, Israel
Corresponding Author: Oded Breuer, Pediatric Pulmonology, Hadassah-Hebrew University Medical Center, 91120 Jerusalem, Israel, Tel: 972-2-5845026, Fax: 972-2-6435897, e-mail: [email protected]
ABSTRACT
Cystic fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Novel, highly effective, modulator therapies correcting and potentiating CFTR function are changing the course of the disease.We present an ethical dilemma involving an 11-year-old child with CF and end stage lung disease. Shortly after starting treatment with Elexacaftor-Tezacaftor-Ivacaftor, the family received notification that a matched donor lung had been allocated.
Clinical decision-making in this case is challenging as definitive data to medically support one treatment option over the other is limited. A survey of CF center team members was conducted for the purpose of this manuscript. Ethical principles that may guide us in these situations are discussed.Overall, results of the survey present a lack of agreement as to the best approach in this situation. Physicians, when compared to other team members, are more likely to provide a specific recommendation vs. to present the information and let the family decide (odds ratio (95% confidence interval)=4.0 (1.2-12.8), p=0.021). A shared decision-making model, stressing our moral obligation as clinicians to respect autonomy by appreciating family values while offering to participate in the decision-making process and ensuring non-maleficence, is presented.In summary, CFTR modulators affect the outcomes of CF disease and influence clinical decision-making. Current lack of data on long-term outcomes, in young patients with CF receiving effective modulator therapy, should not preclude CF team participation in decision- making. Shared decision-making which is focused on respecting autonomy is our preferred approach in these situations.
INTRODUCTION
Cystic fibrosis is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene1. In the past decade, small molecules collectively named CFTR modulators, were developed to improve CFTR function2. In 2012, the first clinical use of a modulator, ivacaftor, targeting CFTR channel gating was approved 3-5. Thereafter, long-term benefits of ivacaftor have been observed changing the face of CF care6-13. Since then, modulators correcting CFTR protein folding, processing and trafficking to the cell membrane were also developed allowing treatment of a wider range of CFTR mutations2,14-19. Recently, a triple modulator combination (Elexacaftor-tezacaftor-ivacaftor) was approved based on clinical trials that included patients above 12 years of age carrying at least one Phe508del mutation, showing significant improvement in multiple outcomes. As a result, the majority of patients with CF worldwide can now be offered disease modifying treatment20,21.
We present an ethical dilemma involving an 11-year-old child with CF and end stage lung disease. While awaiting lung transplantation, she was started on Elexacaftor-Tezacaftor- Ivacaftor therapy with an initial improvement. Shortly after treatment initiation, the family received notification that a matched donor lung had been allocated.
CASE PRESENTATION
The patient is a child with cystic fibrosis, homozygous for the CFTR p.(Phe508del) mutation. She has been in our care since infancy. Her course has been marked by frequent respiratory exacerbations and respiratory compromise, early pseudomonas aeruginosa infection, CF related diabetes (CFRD) from 8 years of age, and complex social challenges with parent separation, learning disabilities and behavioural difficulties requiring psychosocial interventions.
At 9 years of age the patient’s FEV1 reached 30% predicted with a BMI of 14 (z- score=-1). She soon required day time oxygen therapy and subsequently nocturnal non- invasive ventilation.Due to lack of improvement despite additional treatment with Lumacaftor-Ivacaftor and later Tezacaftor-Ivacaftor, with persistent FEV1 of below 30% predicted, she was referred for lung transplantation at the age of 10-years.
In November 2019, she was admitted with a severe, life threatening exacerbation associated with hemoptysis and a FEV1 of 21% predicted. During this admission, gradual modest improvements in lung function and nutritional status were observed (figure 1).
In October 2019 Elexacaftor-Tezacaftor-Ivacaftor was approved for patients with CF, 12 years and above. In view of promising individual reports from adult patients with severe lung disease who improved considerably after starting therapy and because of the unavailability of pediatric donor lungs in our country, this treatment option was pursued. Due to her young age, 10 years and 7 months at that time, she was denied both expanded access and insurer covered therapy. A national and social media campaign allowed for crowdfunding with private purchase of 2 months of Elexacaftor-Tezacaftor-Ivacaftor therapy for proof of concept. Treatment was started on the 1st of July 2020, at 11 years and 3 months of age during a hospital admission. Rapid improvements were observed in oxygen saturation,exercise tolerance, spirometry results and nutritional status as well as her general wellbeing (Figure 1). After 5 weeks of Elexacaftor-Tezacaftor-Ivacaftor treatment FEV1 was 36% predicted and the insurer was persuaded to fund treatment until 12 years of age.After 2 months of treatment the National Israeli Transplantation Center informed the family and CF team that a matched donor for lung transplantation was identified and available for an immediate procedure, within hours.
The Dilemmas
As treating physicians, we were faced with a clinical dilemma. Should this child, with severe lung damage but difficult social background, undergo a complex, high risk procedure, that could potentially offer her years of healthy lungs. Alternatively, should conservative therapy with Elexacaftor-Tezacaftor-Ivacaftor be continued, despite the fact that it has not been studied in children and no long-term outcomes in patients with end stage lung disease were available?Furthermore, we were faced with ethical dilemmas as to our duty as clinicians towards the family and patient (who is a minor), in a clinical situation for which definitive data is lacking to support one treatment option over the other.
Considerations and Response
Given that a decision had to be reached within hours, the patient’s mother (sole legal guardian) was urgently called in for a discussion attended by herself, the treating physician and social workers. The mother requested the child not to be present for the discussion. As the child, had learning and cognitive difficulties. The staff, after consulting with the child’s therapist, agreed to the request especially since the patient suffered from significant anxiety following her prior life threatening acute deterioration. The discussion was initiated by a review of available data regarding the different options.
Data on Elexacaftor-tezacaftor-ivacaftor treatment in patients with end stage lung disease is scarce. Similar to results in our patient, available studies show that initiation of elexacaftor-tezacaftor-ivacaftor is associated with rapid improvement in multiple clinical aspects20,22,23, allowing for cessation of oxygen treatment or non-invasive ventilation and suspending lung transplantation listing in a significant number of patients23. However, improvement in FEV1 were shown to be more significant in patients not receiving oxygen and/or non-invasive ventilation at initiation, suggesting more modest efficacy in patients with more severe lung disease23. Furthermore, no data on long term follow up is currently available and it remains unknown whether elexacaftor-tezacaftor-ivacaftor treatment would provide survival benefits, over lung transplantation, in patients with end-stage lung disease.
Data on lung transplantation has a well demonstrated survival benefit for adult patients with cystic fibrosis24-26. In pediatric patients, reports demonstrate lower survival when compared with adults24,25,27,28 with a median survival of around 3.5 years for pediatric patients25,29. One notable study even questioned the validity of lung transplantation for pediatric patients, claiming that transplantation does not necessarily provide survival benefits in children29. However, these findings remain controversial30 and the International Society for Heart and Lung Transplantation (ISHLT) registry currently reports similar survival after bilateral lung transplant for children and adults with CF31,32. Still, transplantation centers appear to be conservative when assessing pediatric patients25 and a limited number of centers currently perform routine paediatric lung transplantation worldwide24.Following a long discussion, and consultation with other family members the mother decided to continue treatment with Elexacaftor-Tezacaftor-Ivacaftor and forego lung transplantation. Importantly, and in accordance with the mother’s requests, the child was not informed of the available donor lung.
Continued follow-up 9 months after Elexacaftor-Tezacaftor-Ivacaftor initiation showed continuous improvement in nutritional status, glycemic control (decreased insulin requirement) and decreased need for daytime oxygen supplementation (Figure 1). However, lung function did not further improve and a repeat polysomnography confirmed that non- invasive ventilation cannot be discontinued. Two hospital admissions, one for a pulmonary exacerbation and another for the eradication of new growth of methicillin-resistant staphylococcus aureus in sputum cultures, were evidence of persistent severe lung disease. The child remains formally listed with the national transplantation center, and her candidacy is subject to annual reviews.
We as treating staff were left with uncertainties:Was the right decision reached? What would other physicians and medical staff treating patients with CF recommend as the preferred course of action in this case? Should we provide a specific recommendation in such cases?
SURVEY IN CF CENTERS
For purpose of this manuscript, we conducted a post hoc email-invited online survey among CF-care teams in all CF centers in Israel (Institutional review board considered the survey exempt from a required approval). The survey briefly described the patient’s clinical course, early response to treatment with Elexacaftor-Tezacaftor-Ivacaftor and the option for lung transplantation. Only one multiple choice question was presented (alongside an image of her chest CT scan, Figure 1D):
What would be your recommendation to the child’s family, having presented the available data?
a. I would suggest referral for lung transplantation, and leave the final decision to the family.
b. I would suggest continued treatment with Elexacaftor-Tezacaftor-Ivacaftor, and leave the final decision to the family.
c. I would objectively inform the family of the pros and cons of each treatment option without favouring any option, and leave the final decision to the family.
Sixty-five survey responses of 109 online invitations (50 physicians and 59 other CF- care team members) were received (physicians n=43, nurse practitioners n=5, physiotherapists n=6, social workers n=4, dieticians n=3 and psychologist and clinical pharmacologists n=4). Results of this survey are presented in Figure 2. Overall, 53.85% preferred not to recommend a specific course of action but to present the data objectively and leave the decision to the family. Multivariate logistic regression analysis showed that a physician profession was the main factor associated with favouring a specific recommendation (either lung transplant or Elexacaftor-Tezacaftor-Ivacaftor vs. objectively presenting the information and letting the family decide; odds ratio (OR) (95% confidence interval (CI)) = 4.0 (1.2-12.8), p=0.021). When evaluating responses favouring a specific intervention, a physician profession (OR (95%CI) = 29.2 (1.7-492), p=0.019) and experience in treating patients with CF (OR (95%CI) = 2.9 (1.1-7.2), p=0.026) were factors independently associated with recommending treatment with Elexacaftor-Tezacaftor- Ivacaftor and not proceeding to lung transplantation (Figure 2).
Following this survey additional questions surfaced:Do we have a responsibility as clinicians to provide a recommendation even if data is lacking or is it wrong to provide a recommendation without supporting data? Were we wrong not to include the child in the clinical decision process? What are the ethical principles that can guide us in these situations?
ETHICAL CONSIDERATIONS
Ethics of clinical decision-making
Bioethics of medical decision-making has increasingly emphasized the need to respect and encourage patient and family autonomy by providing accurate and relevant information to allow informed decisions33,34. For children who lack the capacity for autonomy, clinical decision-making is often based on the best-interest of the child standard. The parents, as the primary stake-holders, are granted significant discretion in decision-making with the principal role of the physician being a facilitator or guide35. For children with decision- making capacity the process may become more complex as it would include both the pediatric patient and the parents with possibly different preferences, views and values.
Furthermore, as children mature their involvement in clinical decision making evolves and the physician must be flexible with regard to their participation36,37.The above case was particularly difficult in terms of clinical decision-making both because of the unknowns related to response to the different options, and the fact that neither of the options could be considered preferable based on the “best interest” standard. Even the physicians were divided as to the best choice.
Given this situation, we could have taken one of three different approaches. The first was to remain passive, only presenting the different interventions without making formal a recommendation. This option often puts the family in an uncomfortable position, as they may believe that they are ill-prepared to make such weighty and fateful decisions. A second option is to make recommendations based on established ethical principles such as non- maleficence even if there is a conservative bias in such an approach. The third option is for the treating physicians to insinuate themselves into the decision making process utilizing a shared-decision making model38.
The shared decision approach
Studies that have evaluated patients’ preferences in clinical decision-making have shown that most patients, but not all, prefer a shared decision-making approach39-43. This shared approach is based on continuity of care and the development of an ongoing clinician- patient relationship as is frequently the case with CF patients. This ongoing relationship allows for families and physicians to better understand each other in terms of the factors that inform the family’s decision-making processes. Importantly, it is advocated to empower and engage children in the decision-making process, since decisions related to complex or burdensome treatment regimens may not only affect outcome but also their quality of life36,44. This is particularly relevant in children with chronic disease in which treatment adherence significantly depends on their involvement and understanding44.
With this and other families under our care, we use a modified shared decision- making model based on guided autonomy. This model assumes heterogeneity among families related to their coping with disease, disease progression, and perception of the child’s quality of life. The initial stage in this model is for the physician, together with other members of the CF team, to initiate a dialogue with parents in order to identify the latter’s preferences in terms of how they view their child’s future, level of risk tolerance , and cultural and religious beliefs and values. The information obtained establishes the framework for evaluating which option best advances the interests of the family45. The team also deals with the uncertainty related to each option allowing the family to consider both the chances for an optimal or less favourable outcome.For this family, the discussion on whether to proceed to lung transplantation included relevant outcomes, long-term survival, potential complications following transplant and potentially improved quality of life. This was compared to the alternative of continued medical treatment which would include the likelihood of continued intensive medical interventions and the possibility that despite medical care, there would be a need for a future lung transplantation with the risk that an appropriate donor lung would not be available,46,47 or that a contraindication to lung transplant would develop (resistant organism, HLA sensitization etc.)48,49.At the end of such a discussion and according to this shared decision-making approach, a clinician, under moral obligation to recognize the preferences of patients and their families, volunteers to participate in the decision-making process by providing a recommendation reflecting these preferences45.
With our patient, the mother decided against lung transplantation. This decision may have been influenced by fear either related to the complex surgical procedure or coping with the long recovery. At the same time, the mother may have been more comfortable with the existing routine and hopeful that the new medication would improve her daughter’s condition. As clinicians, we were able to support the decision as it involved autonomous decision- making on the part of the family and represented their preferences and coping abilities. As mentioned above, the child was not part of this discussion and was not provided the opportunity to voice her opinion regarding the different treatment options.
Decisions on whether to include a minor in the clinical decision-making process are related to aspects of cognitive development and psychosocial maturity44. With our patient, it was agreed by all parties involved, that the child, at 11 years of age, lacked the required maturity to engage in the decision-making process. It is possible, that this was an unintentional paternalistic assessment on our part in order to simplify the already complex considerations for both the mother and the care team.
DISCUSSION
We present a case of an eleven-year-old child with CF and end stage lung disease awaiting lung transplantation who, having started treatment with Elexacaftor-Tezacaftor- Ivacaftor, received notification that a donor lung is available.This situation brought forth ethical issues that are at the core of our profession as clinicians, raising questions as to our ethical obligations towards patients’ welfare when supporting evidence of an optimal medical intervention is unavailable.
Studies evaluating patient preferences in clinical decision making have shown that most patients would appreciate the healthcare team to provide a recommendation even if medical data does not favour a specific approach39-43. Results of the survey we conducted among medical staff in CF centers showed that for this specific case, many CF-care team members (mainly non-physicians) refrain from providing a specific recommendation and prefer to support the family by providing objective information. Importantly, physicians were more inclined to provide a specific recommendation. This may reflect the perceived obligation that physicians, as leaders of the team, have towards patients in terms of providing them with information and guiding them through the decision-making process. Furthermore, results showed that more experienced medical staff preferred the treatment option with the least possible immediate harm, either reflecting a non-maleficence ‘first, do no harm’ approach or alternatively a hopeful trust in the novel modulator therapies. We presented our approach to this clinical dilemma using a shared decision-making process, reaching a decision which best reflects the family’s preferences, values and coping capabilities.
In summary, modulator therapy is changing the face of CF disease, and knowledge on treatment practices and outcome predictors needs to be re-evaluated50. In the near future, CF clinicians are bound to be faced with questions regarding treatment burden and related side effects of daily routine therapy. Until data is available, clinicians are obliged to provide an objective account to patients and families, respecting the patient’s and family’s autonomy and preferences while offering to participate in clinical decision-making.
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Figure captions
Figure 1. Timeline showing the patient’s clinical course according to specific outcomes and an axial chest computed tomography scan image showing irreversible structural lung disease.A. FEV1 (forced expiratory volume in 1 second). B. Oxygen saturation on room air C. BMI (body mass index). D. Axial chest computed tomography scan image.
Figure 2. Results of a survey conducted among CF center team members in Israel. A. All responders (n=65). B. CF center team members other than physicians (n=22). C. Only physicians (n=43). D. Physicians with more than 20 years of experience in CF (n=10).
ABBREVIATION LIST
BMI – Body Mass Index CF – Cystic fibrosis.
CFTR – Cystic Fibrosis Transmembrane Conductance Regulator CI – Confidence interval.
CT – Computed tomography.
FEV1 – Forced Expiratory Volume in 1 Second.
ISHLT – International Society for Heart and Lung Transplantation OR – Odds ratio.