To understand post-transplant Infection Management in Australia, Clinical utility and challenges of post-transplant Viral Load Monitoring, Roche Diagnostics spoke with Dr Adam Stewart, Consultant Infectious Disease physician at University of Queensland Centre for Clinician Research and Queensland Health.
Dr Stewart elaborated on the current state of post-transplant monitoring: “Australia performs many solid organ and hematopoietic stem cell transplants in both public and private hospital settings. We perform over 650 kidney transplants, more than 250 livers, almost 200 lungs and over 100 heart transplants per year, with a wide variety of both unique and common infectious agents affecting this cohort of patients. Typically, the incidence of infection relates both to the degree of immunosuppression, which may change depending on the time post-transplantation, and pathogen exposure. Infectious complications remain very common in this population, with a wide variety of surveillance and prophylaxis strategies being utilised to prevent infection, which really depends on both the pathogen and the risk.”
Measurement of viral load (DNAemia) has become an accepted element in the care of transplant patients, with results used to determine initiation of pre-emptive therapy, therapeutic responsiveness, and treatment endpoints. Such methods have existed for more than 20 years and since their inception have been plagued by variability of results both within and, particularly, between laboratories and assays. Such variability has undermined the development of consensus therapeutic breakpoints, has made it difficult to interpret literature across sites, and has reduced the portability of patient results.[1]
“The biggest challenge for post-transplant viral monitoring in Australia is that, in general, we still don’t know what the absolute values of viral load testing mean, as far as pathological correlation, and what should be regarded as a significant change in viral load”, Dr Stewart said. Dr Stewart mentioned that “There is a lack of consensus opinion on what constitutes a reasonable viral load to initiate something like pre-emptive therapy as a strategy to prevent infection such as CMV. Especially in the setting of highly sensitive assays which can detect very small amounts of viral DNA. So essentially, this still leaves some decision making for individual centers with determining their own thresholds, using their own assays and data”.
Among transplant viruses, development of international standards has been spread roughly over the past decade; those viruses for which standards have been available the longest show the highest degree of use among proficiency testing participants. One of the greatest drivers of adaptation is likely the availability of commercially produced, regulatory- approved, in- vitro diagnostic assays whose results are generated in International Units per millilitre (IU/ml). Unfortunately, such assays remain sparse. Among in-house IVD users, not only is the reporting of results in IU/mL far from universal, but the heterogeneity of such assays, trueness of secondary and tertiary standards, various means of mathematically normalising to IU, and other factors may diminish the efficacy of these materials in achieving harmonisation across assays and laboratories.[2]
Author: M.D, Medical Affairs Manager, Roche DiagnosticsAustralia
With over 17 years of experience spanning medical affairs, lab medicine, and team leadership, Dr Dawar joined Roche Diagnostics Australia in April 2022, focusing on Cardiac, Infectious Disease, and Sepsis. Her expertise encompasses pre-launch, launch, and post-launch activities, accreditation audits, and establishing labs from scratch.
Updated guidelines from the American Society of Transplantation Infectious Diseases Community of Practice review the diagnosis, management, and prevention of post‐transplant lymphoproliferative disorders (PTLD) and other Epstein‐Barr virus (EBV) syndromes after solid organ transplantation. It recommends that in settings where quantitative EBV viral load testing is warranted, it should be performed using assays calibrated to the WHO IS for EBV DNA. Because validation of the impact of the WHO EBV DNA IS calibration on result, harmonisation among assays is limited, it is recommended that patients should be monitored using the same sample type and the same assay in a single laboratory. If inter‐laboratory result comparison is required, formal cross‐referencing of results among the laboratories using clinical samples should be performed.[3]
Dr Stewart noted “Collaboration occurs both in the clinical context, as well as in the research context, both in a local setting as well as nationally and internationally. In addition to this, there are many institutional, national, and international guidelines, which provide clinicians tools in which to manage patients at risk of viral infection. At a clinician level, these patients are managed by a number of different specialists in the hospital and outpatient setting including transplant physicians, surgeons, nursing staff, transplant coordinators and so on. All will be involved in care of these patients, and often, there are institutional interdisciplinary meetings discussing difficult patients, as well as construction of local guidelines, which would indicate frequency of testing for monitoring of high-risk patients and for response to therapy, thresholds in terms of pre-emptive therapy on which to act on those with antiviral therapy, and so on.”
He further added “This feeds to a wider cohort of an Australian network of transplant infectious diseases clinicians, experts and people involved in managing transplant patients with infections where there are meetings and groups available to talk about tricky patients or access to specific testing or strategies for prevention and surveillance, and so on. And often we also have members of our Australian community sit on guideline committees which use our local data to inform a wider community in terms of determining things like frequency of testing and treatment strategies. So there is a lot going on in terms of improvement of clinical care and research, there are a number of ongoing research collaborations both in Australia and internationally.”
Viral load testing has contributed to contemporary principles for the diagnosis, prevention, and treatment of viral diseases such as CMV in the SOT population. CMV NAT assays are helpful clinically in assessing the risk of disease, ensuring sensitive and rapid diagnosis, and monitoring therapeutic responses. Despite the large amount of published research data, the interpretation of viral load results remains highly complex. This is due to the heterogeneity of the SOT population, variability of the risks within each SOT group, differing patient immune profiles and immunosuppressive regimens, and non-uniformity and lack of standardisation among the many molecular assays used for CMV DNA detection and quantification. Without standardised tests available across different laboratories, clinicians must establish assay- and institution-specific viral load thresholds, correlating to the test used, population tested, and disease characteristics present in any given medical center. The recently released WHO standard is a significant advance that will help to harmonise viral load reporting and assist the medical community in attaining the goal of standardised practice. However, there remain other variables that influence the viral load threshold. Reducing the variability of NAT assays will require a multifaceted approach to improving the performance and comparability of these tests. A better understanding of the variables involved should help us to better interpret the test results and, more importantly, better appreciate the complexity of our patients and the individuality that is needed for the management of every single transplant recipient.[2]
“The aim of viral load testing in post-transplant patients is to minimise complications and to support patients through their transplant, ultimately achieving a good quality of life”, said Dr. Stewart, noting that the best way to achieve this aim is by harnessing emerging evidence and supporting changes in practice. Educating Clinicians to Understand and encourage harmonisation and standardisation of Viral load monitoring in post-transplant patients, ensures equitable access to efficient diagnosis and treatment, and can facilitate optimal care in these patients.
References:
[1] Persistent Challenges of Interassay Variability in Transplant Viral Load Testing
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7512175/ (last accessed 4 June 2024)
[2] Clinical Utility of Viral Load in Management of Cytomegalovirus Infection after Solid Organ Transplantation
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3811235/ (last accessed 4 June 2024)
[3] Post‐transplant lymphoproliferative disorders, Epstein‐Barr virus infection, and disease in solid organ transplantation: Guidelines from the American Society of Transplantation Infectious Diseases Community of Practice
https://pubmed.ncbi.nlm.nih.gov/31230381/ (last accessed 4 June 2024)
