Independent report

SaBTO virology subcommittee recommendations on KSHV: executive summary

Published 31 May 2023

Introduction

Several cases of fatal primary Kaposi’s sarcoma-associated herpesvirus (KSHV), also known as human herpesvirus type 8 (HHV-8), infection have been observed in recent years in recipients of solid organ transplants in the UK.

Ten events were investigated between 2015 and 2019, triggered by a diagnosis of KSHV disease in recipients of solid organ transplants (SOTs). This led to the identification of 7 clusters involving 23 recipients, with 11 new infections consistent with donor-derived infection.

The observed transmission rate in this case series was 48% (11 of 23), with 64% fatality (7 of 11). Information from this period was used in the analysis presented in this report.

Since then and up to July 2021, 5 more cases were reported and investigated, with 2 donor-derived transmissions being identified, with an overall transmission rate of 52% (14 of 27) and 57% fatality (8 of 14).

A workstream was set up to look at the current scientific evidence and assess the size and impact of donor-related KSHV infection on recipient outcomes and the feasibility of implementing appropriate interventions.

A selection of possible initiatives were considered, ranging from promoting awareness about the infection to using virological testing strategies to identify risk to recipients.

Consideration was given to potential negative effects on the availability of safe organs for transplantation and on graft function and recipient survival resulting from inadvertent changes in recipients’ immunosuppression regimens.

Serological tests are required for the identification of asymptomatic, infected individuals. KSHV antibody testing is complex and restricted in availability, and its utility in the context of organ donor screening was carefully explored.

An economic analysis was performed, primarily to examine whether there were evident financial barriers that might render any specific intervention too costly to deliver in the setting of deceased organ donation.

With a focus on averting deaths due to donor-derived primary KSHV infections occurring within 12 months of transplantation, there was no indication that unfeasible costs would be incurred for the implementation of interventions that have the potential to improve patient outcomes and save lives.

This work primarily addresses the particular challenges of deceased organ donation and severe post-transplant primary KSHV infection in recipients, but also considers a risk-based assessment option for living donors and recipients. Further work is required to guide the KSHV testing of living solid organ donors.

Additionally, identification of donor and recipient infection status before disease development is the first step towards enabling the necessary studies into predictors of disease and effective therapeutic modalities for prophylaxis and treatment.

Working group recommendations

Main recommendation

We recommend the introduction of universal serological screening of deceased donors for KSHV infection. To begin with, such testing should be centralised. The programme should be monitored and reviewed to inform necessary changes.

The group is aware that SaBTO does not instruct on the operational aspects of recommendation delivery. The specific scope of this novel recommendation necessitates a detailed oversight of assay performance and interpretation, together with close liaison with transplant centres in order to maximise the benefit from such strategy, both in terms of clinical outcomes and in terms of accrual of knowledge to inform future strategy.

Additional recommendations

The working group also made the following additional recommendations:

• the organ procurement organisation with delegated function from the regulatory body shall co-ordinate the collection of information on recipient outcomes in collaboration with transplant centres and review the data on a regular basis, at least on an annual basis

• screening activity data shall be reported to SaBTO on an annual basis

• there should be a full review of screening policy at 3 years, or earlier in the event of significant findings and reported to SaBTO

• unintended negative effects from donor screening on the availability of safe organs for transplantation and recipient management shall be mitigated through communication of strategy and rationale across the transplant community

• UK healthcare professionals should familiarise themselves with the epidemiology and post-transplant clinical course of KSHV infection to enable early diagnosis. They should also report cases of post-transplant KSHV infection and disease to NHS Blood and Transplant (NHSBT) Organ and Tissue Donation and Transplantation (OTDT) to enable appropriate investigations and actions

• guidance on monitoring and management of recipients identified at risk of KSHV infection and disease should be incorporated into appropriate clinical practice guidelines

• guidelines should be developed to inform the need for screening of recipients and for living donors. This should be done with the appropriate professional bodies

• identification of recipient infection status before disease development is the first step towards closing gaps in knowledge, enabling the necessary studies into predictors of disease and effective therapeutic modalities for prophylaxis and treatment

Conclusion

The group has consulted and deliberated extensively on all aspects summarised in this report. Additionally, a detailed review of current knowledge on treatment options, use of antivirals, diagnostic strategies and virus pathogenesis was performed but not included in this report. This was necessary to inform the group during appraisal of the risk-benefits and feasibility of any potential intervention.

While the true incidence of donor-derived or newly acquired post-transplant KSHV infection is not known, the severity of disease observed in cases that have been described over the years indicates that action is necessary.

A clinical role for serological screening in organ transplantation has been proposed by many groups over the years, but there remain barriers, with progress yet to be made. The international literature indicates that there has been a gradual change in attitude, with utility of serological screening being explored in some settings.

Demand for commercially available assays which are suitable for the proposed use may act as a catalyst to promote more clinically applied developmental work in this field.

There is due acknowledgement that in the absence of a gold standard assay, current testing algorithms may misclassify individuals as infected or uninfected but assay performance is sufficiently good to identify those individuals who are likely to have the highest risk of transmitting the virus via a solid organ.

Members of this subgroup and stakeholders consulted were unanimous in acknowledging the limitations but also concluding that the added information provided through post-donation antibody testing would be welcome and an improvement from the current situation.

Early diagnosis with appropriate management according to disease phenotype is essential for improved outcomes; screening has the purpose of offering the opportunity for monitoring and early diagnosis. The therapeutic management challenges presented by severe, neoplastic and non-neoplastic forms of KSHV disease are recognised, emphasising the need to advance knowledge on pathogenesis and options for prophylaxis and treatment of the various forms of KSHV disease presentation.

Identification of infection status before disease development is the first step towards enabling the necessary studies into predictors of disease and effective therapeutic modalities for prophylaxis and treatment.

We strongly recommend the introduction of universal serological screening of deceased organ donors for KSHV infection.

Given the specific complexities of this proposal, testing should initially be centralised and performed as soon as practicable - with current technologies, this is likely to be done with the results available post-donation.

The organ procurement organisation with delegated function from the regulatory body shall co-ordinate collection of information on recipient outcomes in collaboration with transplant centres and review the data regularly, and at least on an annual basis. This is an essential activity which will guide future practice.

Updates on programme implementation and screening activity shall be reported to SaBTO on an annual basis, but as sufficient numbers of donors have to be screened and recipients of organs from seropositive donors have to be followed up for a minimum period after transplantation, a detailed review of the programme may give rise to misleading conclusions if undertaken too early.

On this basis, a first review of the new screening policy should be carried out at 3 years, or earlier in the event of significant findings or new developments.

Unintended adverse effects from donor screening on the acceptance of otherwise safe organs for transplantation as well as adverse effects on recipient management can be avoided by good communication of information across the transplant community.

UK healthcare professionals should familiarise themselves with the epidemiology and post-transplant clinical course of KSHV infection to enable early diagnosis. They should also report cases of post-transplant KSHV infection and disease to NHSBT OTDT to enable appropriate investigations and actions.

You can request a copy of the full report by emailing mbsabto@dhsc.gov.uk.