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Report of the Standardized Outcomes in Nephrology-transplant Consensus Workshop on Establishing a Core Outcome Measure for Infection in Kidney Transplant Recipients

2024; Wolters Kluwer; Volume: 108; Issue: 3 Linguagem: Inglês

10.1097/tp.0000000000004839

1534-6080

Samuel Chan, Rosanna Cazzolli, Allison Jauré, David W. Johnson, Carmel M. Hawley, Jonathan C. Craig, Bénédicte Sautenet, Anita van Zwieten, Christopher Cao, Ellen Dobrijevic, Greg Wilson, Nicole Scholes‐Robertson, Simon Carter, Tom Vastani, Yeoungjee Cho, Emily A. Blumberg, Daniel C. Brennan, Brooke M. Huuskes, Greg Knoll, Camille N. Kotton, Nizam Mamode, Elmi Muller, Hai An Phan Ha, Hélio Tedesco‐Silva, David M. White, Andrea K. Viecelli,

Cytomegalovirus and herpesvirus research

Infection is inconsistently measured and reported across kidney transplant trials. There is no standardized definition, in part because it is unclear which infection outcome measures are important to patients and clinicians. In a systematic review of randomized trials in kidney transplant recipients published between 2010 and 2019, infections were reported in only 38% of 397 trials, with 113 different outcome measures reported.1 The need to standardize reporting of critically important outcomes has been advocated to improve interpretation of trial-based evidence to inform care.2-4 The international Standardized Outcomes in Nephrology (SONG) initiative aims to establish a set of core outcome measures across the kidney disease spectrum based on shared priorities of patients, caregivers, clinicians, researchers, policy makers, and industry.5 Infection was identified as a core outcome domain in kidney transplantation based on consensus among 1200 patients, caregivers, and health professionals from >70 countries.6-8 CONTEXT AND SCOPE The international SONG kidney transplant infection consensus workshop was convened virtually in November 2021. Stakeholders discussed the implementation of an infection core outcome measure to be reported in all kidney transplant trials. The proposed core outcome for discussion was infection-related hospitalization.9,10 PARTICIPANTS AND CONTRIBUTORS Patients, caregivers, and health professionals with current or previous kidney transplantation experience were invited to the workshop. Invitations were also extended to representatives of professional societies, regulatory agencies, nephrology journals, registries, funding organizations, industry, and guideline organizations. In total, 59 participants (12 patients, 3 caregivers, and 44 health professionals) from 12 countries attended, and 16 contributors provided feedback on the workshop materials (Table S1, SDC, https://links.lww.com/TP/C905). WORKSHOP PROGRAM AND MATERIALS The workshop program, background material, and interim survey results were sent to participants 2 wk in advance of the workshop. Participants were allocated to 1 of 6 breakout discussion groups. Each group had 8 to 12 members, including 2 to 4 patients/caregivers. Participants discussed interim survey results, including potential core outcome measures.10 Group facilitators (E.M., A.V., S.C., Y.C., G.W., and S.Ca.) received training and a question guide (Table S2, SDC, https://links.lww.com/TP/C905). All breakout and plenary discussions were audiotaped and transcribed; transcripts were entered into HyperRESEARCH (ResearchWare Inc; version 3.0.) to facilitate coding and data analysis. SUMMARY OF THE WORKSHOP DISCUSSION We identified 3 themes from the discussion (Table 1). The breakout groups that contributed to these themes are shown in Table S3 (SDC, https://links.lww.com/TP/C905). TABLE 1. - Selected quotations from the workshop discussions on the identification and implementation of a core infection outcome measure in kidney transplantation Hospitalization capturing the burden of infection An indicator for severe infection "Admission to hospital reflects something about the severity of infection."—H4"The advantage of sticking with the hospitalisation is that it captures the severity of problem."—H4"Admission to hospital is a very clean and helpful endpoint as it is indicating severity."—H5"Burden on the patient is captured in hospitalisation."—H6"The advantage of sticking with the hospitalization is that it captures the severity of problem or real complications rather than more preventative monitoring."—H6"We know there is a lot of infection around and admission to hospital would be an important outcome measure for trials."—P1"Going into hospital is a marker of severity."—P4"I see hospitalisation as a key lifeline to me for treatment as it is a marker the severity of my underlying infection."—P6"Going into hospital reflects the vulnerability of the patient and how easy it is for them to tip over."—C2 Limiting life participation "It takes away a lot of quality of life, the career was always long on dialysis already and they had so multiple hospitalisations, they don't want to come anymore."—H1"It is all about the wellbeing. When you go back to work or you go back to school or you, you can go out and do all the things we normally do. When do you feel able to get on with life again."—P2"Being in hospital with an infection means that I have been unable to go shopping … gardening … going to the movies … playing with my grandchildren."—P3"You actually get back to doing the shopping or whatever it is you do day-to-day your day-to-day life. That should be your end point and how long ever it takes to get there is the physical outcome."—H4"The UTI that requires intravenous treatment can make you not being able to go to work, having to cancel a trip, not participate in the daughter's wedding."—H6 Accounting for practice patterns and resource availability Variability in treatment of infection across health systems "And it's quite easy in some regions to do the diagnostics in a clinic, for example, if they are not, of course, in sepsis or something. In other places, they are hospitalised for very, let's say trivial infections, which really not always need hospitalisation. So, there is a huge variability. And I think that is important to consider (with) hospitalisation."—H2"We may measure different practices rather than the different severities of an infection that pragmatic measure."—H4"This is the heterogeneity in how a hospitalization is managed, how hospitalization stays could represent in different patient profile, how does this health system deal with different things and different ways because of flow, availability of bed, resources, and so on."—H4"Hospitalisation varies quite a lot depending on your health system."—H5"In Australia, once acute care is finished, we may be transitioning to an ambulatory outpatient care with more frequent visits."—P3"Even milder infection will need to admit the patient for one, two or four weeks of intravenous infusions."—C4 Use of composite outcomes for granularity and efficiency "The length of follow-up may be inadequate to characterize the safety profile of a therapy and the treatment effect may be driven by components of lesser importance."—H3"Composite outcomes for infection may help understand the severity … for example, we can break it down into things like outpatient management, inpatient stuff like going into hospital, or intensive care setting or measure it like infection-associated death."—H4"You collecting data on hospitalisation in clinical trials will help us understand why patients are being admitted and look at preventative strategies to reduce admissions."—H4"Composite outcomes help detect an increased event rate."—H5"You have to have a composite outcome in order to have a statistical significant with a smaller sample size."—H5 Enhancing feasibility for implementation Minimizing completion burden "Hospitalisation is useful from a trialist perspective in terms of it occurred with a reasonable number of events, so you could get adequate power from a not too large trial."—H2"Infections requiring hospitalisations would be a sensible outcome measure to use as this would be practically easy for a clinical nurse, clinical trialist, and so on to record data."—H3"It could be easily practically implemented particularly as SAEs (severe adverse events) are recorded anyway and it is simply just using the information that has been recorded."—H3"It needed to be easy to measure, readily implemented in everyday practice. It also needs to minimise the burden on study investigators and to be measured easily in a clinical trial."—H5"Hospital admissions fulfil the definition of Serious Adverse Event which warrants exhaustive declaration by investigators and this information is already captured."—H6"Acknowledged the limitations by keeping it simple is a real strength."—C4 Avoiding ambiguity in the data "The number of days spent in hospital may reflect the economic burden and severity of the illness."—H1"The number of admissions to hospital is easy to collect because you simply count the number of admissions that the patient is admitted whereas the number of days admitted can cause confusion because you are curious to know whether the days spent in hospital is for infection related or not."—H5"You may go into hospital with a pneumonia and get better in a few days but stay in hospital because you develop diverticulitis and somehow end up getting a colonoscopy and end up staying in hospital for 3 months which does not have much to do with the infection."—H6"It is very clear. Hospitalization is important because that sort of gives me a guideline. And in mind, it tells me how bad infection is and in a year, if I've been hospitalised three or four times, then I am in a really bad state and that would affect my graft function. Hospitalisation is definitely a good measure for and the duration as well."—P4"It is very clear about the number of admissions. You generally don't go into hospital unless you need to and that reflects severity, and it is easy to count."—P5"There's so many factors that impact on how long it takes, and it is not just the system, it is also how you respond to the treatment and how quickly."—P6"Hospitalization is definitely a good measure for and the number of times admitted per year is important because there is no confusion regarding whether the patient went into hospital or not."—C4 C, caregiver; H, health professional; P, patient; UTI, urinary tract infection. The number indicated (eg, H1) refers to the Group ID (1–6). HOSPITALIZATION CAPTURING THE OVERALL BURDEN OF INFECTION Indicating Severe Infection Participants suggested that hospitalization for infection was meaningful because it indicated severe infection. Health professionals remarked, "the advantage of sticking with the hospitalization is that it captures the severity of problems or real complications." Patients suggested that it was not possible to prioritize a specific type of infection, such as cytomegalovirus and BK virus, and capturing infection severity and impact was more important. For caregivers, hospitalization also indicated "vulnerability of the patient and how easy it is for them to tip over." Although some suggested that infection-related death or infection-related intensive care unit admission may also capture infection severity, these outcomes were considered less suitable Limiting Life Participation Participants supported infection-related hospitalization as a core outcome measure because it captured the detrimental impact of posttransplant infections on quality of life. Patients reported that hospitalization for transplant-related infections meant losing the ability to participate in activities of daily living, which was reinforced by health professionals. ACCOUNTING FOR VARIABILITY IN PRACTICE PATTERNS AND RESOURCING Variability in Infection Management Across Health Systems Participants asserted that the core outcome measure had to reflect international differences in infection management: "We may measure different practices rather than the different severities of an infection." Participants noted that the threshold for hospital admission for infection depended on factors including resources, hospital accessibility, and patient factors (eg, independence and comorbid profile), in addition to infection type and severity. International variability in hospital-based and general infection management was exemplified by health professionals: "in Australia, once acute care is finished, we may be transitioning to an ambulatory outpatient care with more frequent visits," and in South America, "even for milder infection, we will need to admit the patient for one, two, or four weeks of intravenous infusions." Use of Composite Outcomes for Granularity and Efficiency Consideration was given to using a composite outcome for infections to account for the full spectrum of infection severity and management. Components included outpatient treatment, infection-related hospitalization, infection-related intensive care unit admission, and infection-related death. Proponents of composite outcomes suggested trial cost savings by increasing event rates, thereby reducing study sample size. In contrast, disadvantages of composite outcomes raised by participants included "the length of follow-up may be inadequate to characterize the safety profile of a therapy." ENHANCING FEASIBILITY OF IMPLEMENTATION Minimizing Completion Burden For a core outcome measure to be reported across all kidney transplant trials, participants suggested that "it needed to be readily implemented in everyday practice … needed to minimize burden on study investigators and to be measured easily in a clinical trial." They also supported a simple definition that was easy to understand and commonly collected. Participants reported that hospitalization is considered a serious adverse event, and "this information is readily captured" in trials, which facilitated implementation. Avoiding Data Ambiguity Most participants asserted that defining the metric for the core outcome measure was important to avoid ambiguity. The metrics discussed were rate and duration of infection-related hospital admissions. Both metrics captured severity, but hospital admission rate was preferred over hospital duration because the latter may be confounded by intercurrent illnesses that prolong hospital stay. One patient summarized the views of many participants: "There's so many factors that impact on how long it takes and it is not just the system, it is also how you respond to the treatment and how quickly." SUMMARY AND DISCUSSION Infection-related hospitalization was identified as the most appropriate core outcome measure for kidney transplantation trials. It captured infection severity and quality of life impact irrespective of infection type and location. It was deemed feasible and implementable across different settings, given that hospital admissions are routinely collected as hospital administrative data and reported as a safety outcome in clinical trials. Limitations to the proposed core outcome measure were considered, including global variations in clinical practices and available resources, different thresholds for hospitalization due to infection, and inability to account for the full spectrum of infection severity. The use of a composite infection outcome consisting of infection-related death, hospital- and intensive care unit admission, or outpatient management was considered but deemed less suitable. Participants, including patients and caregivers, were from many countries, including high- and low-income countries, suggesting that the workshop's findings are readily transferable (Table 2). Notably, this workshop was conducted in English and, therefore, was not generalizable to non–English-speaking populations. Although only 2 participants were infectious disease specialists, 13 transplant infection experts attended the workshop. TABLE 2. - Proposed outcome measure for infections Proposed outcome measure Advantages Disadvantages Infection-related death Simple to collect as part of routine practice Captured already in SONG-Tx mortality core outcome, thereby duplicating data collection Infection requiring intensive care unit admission Captures the most severe infections Outcome measure not applicable to all settings due to lack of intensive care units in some hospitals Infection in the community or outpatient setting Able to assess infections that do not require inpatient admission Difficult to capture as part of a clinical trial Infection requiring hospitalization Easy to administer; simple to collect as part of routine practice Differences in clinical practices worldwide; inability to effectively capture the specifics of the infection SONG-Tx, Standardized Outcomes in Nephrology-Transplant. The themes derived from the discussion will contribute to outcome measure content validity. The measure will need to be assessed on the basis of Core Outcome Measures in Effectiveness Trials criteria, including content and structural validity, responsiveness, and measurement error.11 Establishing a valid, relevant, pragmatic, and readily available infection outcome measure is expected to improve the consistency and reliability of how infection is assessed and reported, reduce research waste, improve the certainty of evidence, and better inform decision-making in kidney transplantation. ACKNOWLEDGMENTS The authors thank the SONG Steering Committee and SONG Coordinating Committee for advice and comments. They thank the following organizations for their support: International: Cochrane Kidney and Transplant, Dialysis Outcomes and Practice Patterns Study, International Society of Nephrology, Kidney Disease | Improving Global Outcomes, PKD International, The Transplantation Society, and World Transplant Games Federation; Australia/New Zealand: Australian and New Zealand Society of Nephrology, Australian Kidney Trials Network, Christchurch Kidney Society, Kidney Health Australia, Caring for Australasians with Renal Impairment Kidney Health New Zealand, PKD Foundation of Australia, Renal Society of Australasia, and Transplant Australia; Canada: The Kidney Foundation of Canada, Canadian Society of Nephrology, and Canadian Society of Transplantation; Europe: British Kidney Patient Association, British Renal Society, European Kidney Patients Federation, European Kidney Transplant Association, European Society of Transplantation, European Renal Best Practice, UK National Kidney Federation, PKD Charity, Société Francophone de Transplantation, and The Renal Association; and America: American Association of Kidney Patients, Home Dialysis Central, National Kidney Foundation Southern California, and Sociedad Latinoamericana de Nefrología e Hipertensión. The following people attended the SONG-Tx Infection Consensus Workshop on ZOOM 2021: Adam Martin, Allison Tong, Andrea Matus Gonzalez, Andrea Viecelli, Andrew Demaine, Angela Wang, Anita van Zwieten, Ann Demaine, Anthony Preston, Benedicte Sautenet, Brenda De Coninck, Brooke Huuskes, Camille Kotton, Carmel Hawley, Chandana Guha, Christoph Wanner, Daniel Gossett, David Johnson, Deb Purdy, Dorcas Tarumbwa, Ellen Dobrijevic, Elmi Muller, Fritz Diekmann, Gene Tyson, Germaine Wong, Gillian Mundy, Greg Wilson, Helio Tesdesco-Silva, Jonathan Craig, Karine Manera, Kevin Abbott, Krista Lentine, Lorna Marson, Lucrezia Frurian, Luuk Hilbrands, Maarten Naesens, Maria Irene Bellini, Matty Hempstalk, Nicole Isbel, Nicole Scholes-Robertson, Paolo Ferrari, Patrick Rossignol, Paul Henman, Peter Reese, Rainer Oberbauer, Roberto Pecoits-Filho, Rosanna Cazzolli, Samuel Chan, Shyamsundar Muthuramalingam, Simon Carter, Tamara Al-Jabary, Tess Harris, Tom Vastani, Watanyu Parapiboon, Wim van Biesen, and Yeoungjee Cho.