COVID-19: A Year on

A YEAR IN AN ISSUE OF TRANSPLANTATION

A year into the SARS-CoV-2 pandemic, we have collated learnings of transplantation programs in this issue. The publication of data on the novel disease took a predictable course, with very early reports rushed through by both authors and journals, some of which may regret the short circuiting of peer review mechanisms. The urgency for getting data out to the world was driven for many by the frightening absence of data combined with reports of overwhelmed clinical services, first in Iran and then in countries unused to that concept in western Europe. The editors of Transplantation decided to separate out the early, almost anecdotal reports—which were of value to those yet to be impacted by the pandemic—by partnering with The Transplantation Society (TTS)—and publishing the reports initially on the TTS website and then formally, later in a collated document in the journal, mostly for historical value.^1,2 The website received >5000 readers in the first week, demonstrating the intense demand for information. In the year since then, we have received >170 submissions on COVID-19 and if we had published all of them you would, simply on the basis of single case reports, have been able to point to a single example to justify any response to the pandemic and management of transplantation. We chose not to do that and, so far, using expedited review, have accepted 35 submissions or about 20%, which is just a little over our usual acceptance rate.

The current issue of Transplantation combines both submitted and invited manuscripts to bring you data from around the world—United States, Iran, France, Spain, Italy, Sweden, Britain, Brazil, and from a number of specific environments.^3-7 We have data on the impact on both deceased and living donation and on the various transplanted organs, as well as on how HLA laboratories can assay for COVID antibodies.^8-10 Overviews include description of the disease in transplant patients and a reflection on therapeutic options from epicenters of disease.^11,12 We also present a summary report examining the various international expert consensus guidelines and recommendations on donation and transplantation practice under the impact of COVID-19.¹³ What we have tried to do, as others have in other journals, is to bring together more considered viewpoints and more data than was available in the earlier phases of the pandemic, hoping to facilitate evidence based decisions going forward.

There are facts that are no longer in dispute about the impact of COVID-19 on our patients. Moreover, there are consensus views on what actions are appropriate both for individual patients and for programs and nations.

We are now reasonably certain, based on confirmed infection rates between 0.5 and 2.0% in tested populations, that transplant patients are at significant risk of becoming symptomatically infected. Around 30% of hospital-admitted transplant patients, in the first waves, needed intensive care treatment and many died, with reported mortality rates ranging between a low of 3% and highs of nearly 60%, or worse in special populations, including pediatric patients, with most reporting around 15%–30% of admitted cases dying.

Reported in this issue are reviews of 85 infected transplant patients out of 7000 recipients in Iran, 53 from 4600 in Sweden, and 67 from 3000 in Saudi Arabia, as well as reports on specific populations such as the 35 lung recipients from 11 centers in France.^5-7,14 Risk factors for infection are still uncertain in the general population, and this is true in transplant patients too, with a low albumin a predictor in the Iranian series, while in a large study from Italy, DRB1*08 and Blood group A were more common in COVID-19 patients.¹⁵

Therapeutic approaches are as confused as in the general population in early data, but as the pandemic progressed and more trial data emerged, therapy for transplant patients has focused on use of heparin prophylaxis, remdesivir, and corticosteroids for the severely ill, avoiding the many unproven and proven useless remedies. Specific to our patients has, of course, been modification of immunosuppression doses because of drug-drug interactions and cessation because of a belief that some agents need to be removed during the severe phase of the illness. That we cannot provide clear advice is testament to our failure to test these alternatives in the chaos of the first year of COVID-19.

WHAT ARE THE 5 MOST IMPORTANT THINGS WE NEED TO KNOW AND COULD, BUT DO NOT

We have reasonable data on which to carefully continue organ transplantation in all organ types, and we have made assumptions, based on some case reports of poor outcomes, that we do not want to transplant from donors, or into recipients, with active COVID-19. What we do not know is how long we should wait after recovery from COVID-19 in either donors or recipients, either symptomatically or in terms of time with proven negative tests, to safely transplant. We call for these data to be collected internationally so that we can inch toward a clinically useful consensus that will maximize life-saving transplantation with minimal safety risks.

We need to be guided by general population data on therapeutic approaches, but in addition, we need to test modulation of preexisting immunosuppression in moderate and severely ill COVID-19 transplant recipients. We also need to test some of the treatments used in the general population, such as “hyperimmune immunoglobulin” from convalescent-phase plasma, monoclonal antibodies, and immune-modulatory therapies in our populations, knowing that these approaches might lead to different results in immunosuppressed patients.

We can provide general advice to our transplanted patients as to how best to protect themselves, and we can modify our clinical follow-up to increase intervals between clinics and hold most in a virtual mode. It would, however, be wise for us to monitor the impact of that approach. It might be, for example, that we will see an impact on patient and graft survival with even less adherence to immunosuppression and less attention to hypertension, cholesterol and glucose control, exercise, and weight control.

We do not yet know what the so called “long COVID” syndrome will look like in our patients, nor how to treat and advise those afflicted by it, although reports of lung transplants for COVID-19 lung disease and renal transplants for the half with Acute Kidney Injury who do not recover, may challenge us in the years ahead.¹⁶

The fifth proposal from this journal is that the field needs to consider how to safely provide protection for our patients when vaccines are finally available. Few of the current vaccine trials involve immunosuppressed patients, and we are in no position to predict which of the different vaccine types will work best for our patients given the preponderance of novel vectors and adjuvants being used. What will you tell your patients when a vaccine is available? What will you advise your government about vaccine policy for the transplant population?

WHAT HAS THE YEAR TAUGHT US ABOUT OURSELVES?

We need to ask ourselves how well we have responded in our field to protect the health of those under our care and whether we can do better next time? The conclusion of this journal is that we could have done better and as a result should prepare for next time. So, what might we concentrate on to achieve that improvement? We have 3 suggestions:

1. Standardize the collection of real time data, perhaps directly from patients themselves and certainly from clinical programs, using the impetus of virtual clinics that has driven a flight to Information Technology solutions in this pandemic. This will need to be combined with collaborative multicenter and multinational groups or clinical programs, together with a focus on investment in speed and utility of national registries.
2. Develop, with urgency, an investigator-driven clinical trials structure able to respond quickly to the need for testing treatment regimens, agents, or vaccines in transplant patients. Both collaborative structures and progressive trial designs are needed to test simple actions and complex novel agents or vaccines.
3. Learn to collect and share granular adverse event data with each other quickly to answer critical questions: for example, around donation protocols. We do not need to learn the same lesson in every jurisdiction or wait until every disaster is written up, accepted and published, or identified by regulatory authorities.

In the publishing environment, we also have our part to play, both by improving the speed of review and by not ignoring the critical importance of peer review. We could bring 6 reviewers’ and editors’ minds to bear on a single paper in a day, but we do not. We can put papers online and immediately advertise their presence in a day or 2, as we did in March 2020 using the website of TTS. The actual times taken for the individual actions in scientific publishing are measured in minutes, not weeks or months, yet the industry routinely allows 3 months to put out an issue of a major academic monthly journal.

Are we individually, locally, and internationally better prepared for the next waves of this pandemic? We would like to think so and the declining mortality rates for infected patients suggest that we are. Will we be better prepared for the next pandemic? The answer will be in our willingness to learn and adapt as a result of this one.