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Infections are leading causes of morbidity/mortality following solid organ transplantation (SOT) and cytomegalovirus (CMV) is among the most frequent pathogens, causing a considerable threat to SOT recipients. A survey was conducted 19 July–31 October 2019 to capture clinical practices about CMV in SOT recipients (e.g., how practices aligned with guidelines, how adequately treatments met patients’ needs, and respondents’ expectations for future developments). Transplant professionals completed a ∼30-minute online questionnaire: 224 responses were included, representing 160 hospitals and 197 SOT programs (41 countries; 167[83%] European programs). Findings revealed a heterogenous approach to CMV diagnosis and management and, sometimes, significant divergence from international guidelines. Valganciclovir prophylaxis (of variable duration) was administered by 201/224 (90%) respondents in D+/R− SOT and by 40% in R+ cases, with pre-emptive strategies generally reserved for R+ cases: DNA thresholds to initiate treatment ranged across 10–10,000 copies/ml. Ganciclovir-resistant CMV strains were still perceived as major challenges, and tailored treatment was one of the most important unmet needs for CMV management. These findings may help to design studies to evaluate safety and efficacy of new strategies to prevent CMV disease in SOT recipients, and target specific educational activities to harmonize CMV management in this challenging population.
Cytomegalovirus (CMV) is one of the most important opportunistic viral pathogens in the solid organ transplant (SOT) setting (
Pre-transplant CMV immunoglobulin (Ig)G serological testing is generally undertaken in both donor and recipient to establish CMV disease risk and guide infection prevention strategies (
Two approaches that reduce risk of CMV infection and disease following SOT are universal prophylactic therapy for all “at-risk” patients (excluding D−/R−), and pre-emptive antiviral treatment (PET) for those with evidence of infection but no overt disease (
The CMV-DNA polymerase inhibitors ganciclovir and valganciclovir are first-line agents for CMV prevention and treatment; foscarnet and cidofovir are reserved for refractory/resistant infections. Although these therapies are generally efficacious in SOT recipients, their clinical value is limited by their toxicity profiles: adverse events observed include myelosuppression (ganciclovir and valganciclovir), nephrotoxicity (foscarnet and cidofovir), and electrolyte imbalances (foscarnet) (
Regular post-transplant monitoring of viral replication helps to predict CMV disease risk and guide decisions relating to treatment duration and efficacy (
Despite these apparently successful approaches for managing risk of CMV disease in SOT recipients, a retrospective analysis of French data from 2007 to 2011 involving 20,473 SOT recipients demonstrated that ∼12% developed CMV disease within 24 months post transplantation (
To better understand current international practices within transplant professionals, the European Society for Organ Transplantation (ESOT) conducted a survey that aimed to characterize strategies used to prevent, diagnose, and treat CMV infection in SOT recipients. The survey also sought to analyze variations in clinical practice by organ type and donor/recipient match, and to investigate drivers for variations in the use of immunosuppressive therapy regimens. Monitoring CMV-specific T cell immunity was also investigated. It was anticipated that the survey findings might influence the design of prospective multicenter studies, and identify educational needs of the transplant professional community, to help improve CMV management in SOT recipients.
This was a questionnaire-based, cross-sectional online study, devised by ESOT and undertaken among the ESOT transplant professional’s community. A Working Group was established in May 2019 to develop, refine, conduct, interpret, and publish this survey: group members were selected by the ESOT executive council, based on specific expertise in the management of CMV in SOT rather than by geographic location or nationality. A key objective was to involve experts from the field of infectious diseases and those with organ-specific expertise, including multiorgan transplantation.
The Working Group developed the questionnaire via several rounds of in-person and virtual discussion/revision, and the content was ratified in a virtual meeting in June 2019. The final survey consisted of 57 questions, including structured (multiple-choice) and open-ended questions (
The survey was promoted via a targeted online newsletter to all persons in the ESOT contact database via the congress app during the ESOT 2019 congress in Copenhagen, Denmark (September 2019), and via ESOT social media postings. European scientific organizations with an infectious disease focus [e.g., ESCMID (European Society of Clinical Microbiology and Infectious Diseases)] and European national transplant societies were also asked to promote the survey among their members.
The survey could be completed by any respondent, provided they had direct experience with managing CMV infection. Because the focus of the survey was the practice, knowledge, and opinions of the single transplant professional, responses from multiple personnel from the same institute were permitted. Questions 1–4, which focused on the respondent’s specialty area and length of active clinical practice, were included to eliminate practitioners who did not declare appropriate experience.
Participants were provided with information outlining the survey objectives prior to their involvement. Those who answered all questions were offered 1 year’s free access to the ESOT e-learning platform,
Request for authorization by the ethics committee at each center was deemed unnecessary: the survey was only intended to collect the personal perceptions/opinions of transplant professionals and neither directly involved patients nor sought patient-specific data.
All fully completed surveys were included in the analysis. Summary statistics were generated from SurveyMonkey®. Raw data were downloaded onto an Excel® (Microsoft Office, Redmond, WA, United States) spreadsheet, for subsequent analysis. Continuous variables are reported as mean ± SD or median; categorical variables are reported as %. Most of the questions returned categorical answers, therefore for the scope of this manuscript, between-group differences were analyzed using the χ2 test (PRISM 7; GraphPad Software Inc., San Diego, CA, United States).
For several questions, respondents were asked to grade their opinions regarding specific statements by using a 1–7 ranking, where 1 indicated maximum disagreement and 7 indicated highest agreement. Responses were analyzed by calculating the weighted average for each item: if the weighted average was >5, we assumed consensus for that statement; if it was <3, we assumed consensus against; scores between 3 and 5 were interpreted as no consensus.
Disposition of study respondents is shown in
Disposition of study respondents according to medical specialty, and geographic distribution of respective transplant programs
Of 224 responses, 197 (88%) were completed by individuals from different transplant programs, and when analyzing responses by the few individuals from the same center we often found differences in some of the practice areas, with most variability in behaviors such as pre-emptive treatment threshold. The majority of respondents (213; 95%) were involved in adult transplantations. In addition, the majority of clinicians were physicians rather than surgeons (
When considering European representation, the 128 European hospitals represented in this survey are 40% of the total (316) transplant hospitals active in the 27 European countries included in the survey.
The majority of respondents (217/224; 97%) indicated blood CMV-DNA PCR as the tool used to diagnose CMV infection: only 7 (3%) centers used antigenemia. However, the types of assay and units of measurement utilized revealed substantial variability: 124 (57%) used whole-blood PCR and 92 (42%) used plasma PCR. Of note, while 162 respondents (72%) declared that their laboratory used World Health Organization (WHO) standard units to measure DNAemia, only 66 (40%) reported using them for clinical decision making (e.g. threshold for PET initiation) instead of the non-standardized DNA copies/ml. In seven institutions, the WHO standard was not used, and 55 respondents (24%) were unaware as to whether their laboratory used the measurement unit.
In total, 193/224 (86%) respondents reported having an established protocol for CMV prevention in SOT recipients, modulated according to organ type in 135 (70%), D/R serostatus in 182 (94%), and use of antithymocyte globulin (ATG) in 114 (59%) of centers. In this context, 31 (13%) of respondents never used PET, and only 10 (5%) never used prophylaxis.
Antiviral prophylaxis was administered in D+/R− transplantations by 201 (90%) of respondents (
Duration of prophylactic antiviral therapy for cytomegalovirus infection in
Prophylaxis use was reported by 99 (44%) of respondents in D+/R+ and 87 (39%) in D−/R+ transplantations. However, 18% and 26% of respondents used neither prophylaxis nor PET in D+/R+ and D−/R+ transplantations, respectively. Conversely, despite D−/R− having the lowest risk of CMV infection, 16% of respondents used prophylaxis in these patients. In this relatively low-risk group, prophylaxis was significantly more commonly utilized in thoracic organ recipients and least utilized in liver transplant recipients (
Prophylaxis duration in R+ recipients was significantly shorter than in D+/R− recipients (
While antiviral prophylaxis was evenly distributed across SOT types, duration varied significantly (
Valganciclovir was the drug most frequently utilized in prophylaxis regimens. Respondents reported that ∼90% of patients received valganciclovir, while ∼10% of patients might also require intravenous ganciclovir because they were unable to take the oral formulation in the early postoperative period. According to 183 (80%) of respondents, prophylaxis commenced within the first week after transplantation, and 18 (8%) reported the addition of CMVIg for D+/R− patients or those receiving ATG.
Despite its widespread use, myelotoxicity was considered to have substantial negative impact on valganciclovir administration by 174 (78%) of respondents (leading to drug discontinuation in 10%–20% of SOT recipients, according to 98 [43%] of respondents) (
Conditions impacting use of currently approved anti-CMV agents in solid organ transplant recipients. Scores 1–2 do not impact use; score 3 has moderate impact on use; scores 4–5 substantially impact use.
Responses regarding PET management provided a snapshot of the extreme variability and lack of standardization in assay and criteria for treatment initiation. Of 201 respondents indicating DNA thresholds for PET initiation, 58% were based on whole-blood assays; only 66 responses gave thresholds in WHO units. Thresholds were dispersed over a wide range of plasma and whole-blood DNAemia values across all SOT recipients. The median reported plasma DNA threshold value for PET initiation was 1,000 copies/ml (range, 10–10,000 copies/ml), and the median reported whole-blood threshold DNA value was 1,000 copies/ml (range, 5–20,000 copies/ml).
Reported thresholds for pre-emptive antiviral therapy initiation in different organ recipients from respondents using whole-blood polymerase chain reaction assays.
Most respondents (185; 83%) monitored patients after cessation of prophylaxis or PET, with a wide variability of schedules used within 3–6 months after cessation. Values ranged from testing once- or twice-weekly to every 2–3 weeks, depending on time since transplantation and level of infection risk.
PET was widely used, especially in liver recipients: 48% of centers used PET in R+ patients and 12% in D+/R− transplantations. Valganciclovir was the most common first-line PET strategy (reported by 195 [87%] of respondents), followed by intravenous ganciclovir, which was often administered in inpatient settings. In 6% of centers, CMVIg was added to valganciclovir or ganciclovir.
Treatment of CMV disease was assessed by a question allowing multiple responses. Most respondents (172/224; 77%) indicated intravenous ganciclovir as treatment of choice for CMV disease, but 140 (63%) also administered valganciclovir, supporting an initial uptake of the evidence deriving from the VICTOR trial (
Molecular diagnostic approaches for detecting CMV resistance were employed by 102/224 (46%) of respondents, while 80 (36%) said that resistance testing was unavailable and 34 (15%) did not know whether testing was available in their institution. Ganciclovir resistance was quite rare, with annual incidence rates of <1% reported by 180 (80%), rates of 1%–5% reported by 39 (17%), and rates of 6%–10% reported by 5 (2%) of respondents.
Infections caused by ganciclovir-resistant CMV strains were treated with high-dose ganciclovir by 109 (49%) of respondents; most of these (157; 70%) used foscarnet, which was usually given following high-dose ganciclovir. A smaller rate of respondents used cidofovir (22%). CMVIg was administered by 69 (31%) of respondents, in combination with antivirals, and 69 (31%) respondents switched patients with infections resultant from ganciclovir-resistant CMV strains to mTOR inhibitors.
Ganciclovir resistance was considered a relevant issue in current CMV management by only 57% of respondents (128 scored ≥5 on a 7-point scale; mean score 4.75). Conversely, when asked about relevant issues for future research, 169 (75%) respondents said that improvement of strategies to manage CMV resistance would be relevant (mean score, 5.29).
Most respondents (183/224; 82%) said that monitoring of CMV-specific T cell responses was not routinely performed. Centers that offered this facility generally utilized QuantiFERON (26/49; 53%) and/or ELISpot (21/49; 43%). Only 2/49 (4%) utilized other techniques, such as intracellular cytokine staining, MHC multimer, or Viracor. Questions 51 and 52 (
Perception among respondents regarding the importance of CMV-specific T cell response
When addressing opinions regarding the major open issues for CMV management, we recorded consensus for “drug toxicities” (5.15), late CMV infection (5.09), and “ease of administration” (5.07). The relevance of “management of CMV resistance” (4.74), “drug cost” (4.57), and “drug interactions” reached lower levels of consensus.
Respondents were asked to indicate what would be relevant for future research and development of CMV in SOT populations (Question 57;
This article presents the key findings of an international survey designed to investigate current practices in the management and prevention of CMV infection among members of the ESOT community. Our aims were to assess the distance between current practice and established guidelines, identify educational gaps, explore the unmet needs of currently available treatments, and anticipate the developments in this field.
The findings provide a real-world snapshot, covering a large proportion of the transplant units in Europe, with a glimpse of extra-European practice. As opposed to another recent survey (
Prevention and management of CMV infection had a center-specific approach, with some divergence from current guidelines (
Major discrepancies between guideline recommendations and survey-reported practices.
Guideline recommendation | Survey-reported practice | |
---|---|---|
CMV-DNA assay | • WHO units for DNAemia are recommended | • Only 40% of respondents use them for decision making |
• 28% don’t know what WHO units are | ||
CMV prophylaxis prescription | • Prophylaxis is NOT recommended in D−/R− patients | • 15% of respondents claim to use prophylaxis in D−/R− patients |
CMV prophylaxis duration in D+/R− | • 6 months for KTx | • Most respondents are in line with recommendations, but HTx usually seem to receive longer-term prophylaxis than KTx |
• 3–6 months for HTx and LTx | ||
• 6–12 months for LuTx | ||
Post-prophylaxis DNAemia surveillance | • Suggested only in high-risk patients with high immunosuppression burden | • 12%–16% of respondents perform post-prophylaxis monitoring, but with frequencies between 1 and 3 months |
• Weekly/biweekly frequency is preferred | ||
CMV resistance | • CMV genotyping is recommended if viral load persists over 6 weeks of adequate GCV administration | • CMV genotyping is unavailable or unknown to 54% of respondents |
HTx, heart transplant; KTx, kidney transplant; LTx, liver transplant; LuTx lung transplant.
Regarding diagnostic strategies, CMV-DNA was widely used, with a preference for whole blood as a matrix. Antigenemia was still used by a small minority of centers represented. A previous survey of CMV management in European transplant recipients showed an almost identical proportion of centers using whole blood and plasma (42% vs. 41%, respectively) (
Current guidelines/recommendations are apparently clear in terms of diagnosis, duration of prophylaxis, and CMV-DNA monitoring, followed by pre-emptive strategies and treatment of CMV disease (
Preventive strategies in high-risk (D+/R−) transplantations appeared to rely heavily on valganciclovir prophylaxis. Prophylaxis was used more widely in thoracic organ transplantations than in other SOT procedures, perhaps due to the higher risk of direct and indirect effects of CMV infection in lung recipients, and the fear of indirect CMV effects in heart transplant patients (
The observed low rate of prophylaxis in R+ liver transplant recipients is consistent with the perceived lower risk of CMV disease and the reports of lower activity of valganciclovir in these patients (
Although expected, between-center variations in PET cut-off values and sampling schedules were striking. However, most relied on whole-blood (frequently) or plasma (occasionally) CMV-DNA threshold levels in the range of 500–5,000 copies/ml. More than the CMV-DNA value disparity, it is noteworthy that the two matrices were used as synonymous specimens, while it is known that whole blood overall contains 1 log10 more CMV-DNA than plasma. Furthermore, ∼40% of centers (those using plasma) were indeed starting PET at a 1 log10 higher CMV-DNA level than those using whole blood. These findings reinforce the need for prospective studies to determine the optimum cut-off, sampling schedule, and standardized assay and units of measurement before recommendations for using PET can be decisively made.
Most respondents reported no ganciclovir resistance in their centers, despite extensive use of prophylaxis and the availability of resistance testing. It is unclear whether this reflects the wider real-world situation or represents underestimation specific to this survey. Although a few participants reported using CMVIg in cases of resistance, it is unclear whether this reflects actual documented resistance or merely refractory or recurrent CMV infection. We believe that these uncertainties highlight another educational gap that should be specifically addressed.
Although monitoring the CMV-specific T cell response was not considered crucial, respondents felt it would soon become more important. There is a strong scientific rationale for monitoring the CMV-specific immune response (
The current study had several potential limitations. The survey was advertised to the broad ESOT community, targeting individual healthcare professionals rather than institutions. This approach may have introduced some degree of interest bias by collecting responses from people interested and educated in CMV, while missing data on practices from institutions where CMV infection in SOT is not considered relevant or is not addressed properly. Consequently, we could have missed some education gaps that need to be addressed specifically. Another potential limitation is that some answers were ambiguous. Finally, this survey was conducted in the pre-COVID-19 era, which might have had an impact on the policies within centers, particularly in those using pre-emptive strategies to prevent CMV disease in order to avoid frequent access to the hospital for CMV testing. Nevertheless, this survey highlights a very wide variability in clinical practice, often in discordance with current evidence, thus prompting us to encourage specific education activities to favor a more homogeneous management approach for CMV infection in SOT patients.
Although the burden of CMV in SOT has been alleviated through advances in diagnosis, prevention, and treatment, this viral infection continues to have substantial impact in this patient population. The present survey adds to the body of evidence demonstrating a heterogenous approach to CMV infection management and a divergence from international guidelines. Myelotoxicity is perceived as the major drawback with current agents, underlying the need for novel therapies for prophylaxis, to facilitate a safer and more effective strategy to prevent CMV infection. In this setting, the potential availability of letermovir in SOT may represent a relevant step forward (
Managing ganciclovir-resistant CMV strains was perceived as a major challenge for most centers. Results of a phase II and III trial with maribavir in refractory/treatment-resistant CMV infection may contribute to improved management of resistance (
In conclusion, this study highlights several education gaps and unmet needs in the context of management of CMV infection in SOT. Toxicities of current first-line therapies are a major drawback in clinical practice, while improving the knowledge of WHO standard units for CMV-DNA assays may help to design studies targeted to identify the most appropriate threshold to initiate PET. In this context, further development of assays for CMV-specific immunity could represent a key asset to tailor both PET and prophylaxis approaches (
The raw data supporting the conclusion of this article will be made available by the authors, without undue reservation.
PG, NK, FS, JA, and LP were part of the Working Group and contributed to the development of the survey. All authors helped to analyze the data and reviewed/provided input into the entire manuscript, attending meetings/telephone calls to aid its development; PG, NK, FB, and LP wrote specified sections of the manuscript. PG was also Chair of the Working Group and facilitated development of the manuscript with the medical writer. The first full draft of the article was reviewed by PG and LP; the revised draft was reviewed, finalized, and approved by all co-authors before submission for publication.
Unrestricted financial support for the survey and the development of this publication was provided by MSD. MSD had no influence on study design, analysis or reporting and had no contact with the working group components.
PG has been a consultant or member of an advisory committee for Angelini, Becton Dickinson, Biotest, Correvio, Gilead Sciences, Merck Sharpe & Dohme, Nordic Pharma, Paratek Pharmaceuticals, AlloVir, and Shire; and a speakers’ bureau member for Becton Dickinson, Biotest, Gilead Sciences, Merck Sharpe & Dohme, Pfizer, Atara, and Vertex. NK has been a speaker or an advisory board member for AbbVie, Amgen, Astellas, Biotest, Chiesi, CSL Behring, Gilead, Fresenius Medical Care, Merck Sharpe & Dohme, Neovii, Novartis Pharma, Sandoz, Sanofi, and Shire. FS has received speaker’s honoraria and/or research grants from Novartis, Astellas, Chiesi, Gilead, Merck Sharp & Dohme, Neovii, Sandoz, Pfizer, Biotest, Takeda, and Baxter. FB has received grants/research support from AB Analitica, DiaSorin, ELITechGroup, NTP, and Qiagen; he has also received honoraria or consultation fees from Biotest, DiaSorin, HUMABS, Merck Sharpe & Dohme, Qiagen, and Shire. JA has been a consultant and speakers’ bureau member for Astellas Pharma, Biotoscana, Gilead, Merck Sharpe & Dohme, Pfizer, Roche, and United Medical. LP has been a consultant for Novartis and Biotest and received speaker fees from AstraZeneca, Boehringer Ingelheim, Abbott, and Paragonix.
The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Writing assistance was provided by Tina Morley Medical Writing Services and Linda Edmondson Medical Communications. Administrative supervision/data collation was provided by Justyna Klimek (ESOT).
The Supplementary Material for this article can be found online at: