key: cord-260264-8fzlllde
authors: Kahan, Barry D.
title: COVID-19 Minisymposium: Toward a Strategic Roadmap
date: 2020-10-06
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2020.09.008
sha: 
doc_id: 260264
cord_uid: 8fzlllde

nan

A roadmap is defined as a strategic plan that defines a goal or desired outcome and includes the major steps or milestones needed to reach it. This communication tool usually includes a list of tasks to achieve a strategic initiative. In the clinical setting it may be considered to include a series of algorithms containing critical decision points for therapeutic interventions. Because of the wide variety of pre-existing and concomitant disease processes as well as the panoply of transplant procedures, it is easy to become mired in details during this enterprise. However, we must search for cohesive features in a strategic rationale to achieve successful outcomes.

The pandemic with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2; coronavirus disease 2019 ), an RNA virus, poses major challenges to the transplant enterprise from donation to operation and perioperative care to long-term follow-up, including treatment of afflicted cases.

SARS-CoV-2 hooks onto cells via the membrane protein angiotensin-converting enzyme 2 (ACE2) receptor, whose gene is encoded within the X chromosome. The protein is present on the surface of cells in the lung, endothelium, heart, kidney, and intestines. After the virus spike complex attaches and fuses to the cell membrane, it gains intracellular entry with ensuing infection. In a mouse experimental model, which has been created by insertion of the ACE2 receptor into the murine genome, the virus replicates in the nose, throat, pulmonary alveolae, trachea, and brain, and in higher doses, in the digestive tract, often as an asymptomatic infection.

Numerous transplantation societies have recommended against the use of organs from afflicted individuals as evidenced by viral testing, which can now be performed relatively rapidly. This opinion assumes the presence of transmittable virions in potentially transplantable organs. However, preliminary studies (with both COVID-19 and other common RNA respiratory viral infections) suggest that in the absence of severe infection, there is a low incidence of virions in nonrespiratory tissues or peripheral blood. Clearly, at the present state of knowledge, the use of COVID-19-positive donors must require negative results of tissue biopsies that have been subjected to real-time polymerase chain reactions for nucleic acid detection and/or immunochemistry or electron microscopic evaluations for virions, because the disease process may produce secondary effects, such as hepatocellular or renal injury, in noninfected, potentially transplantable organs.

By its very nature, the pandemic produces a variety of other considerations in the donation process. On the one hand, shelter-in-place regulations are likely to reduce the supply of donors from auto accidents or murder-related causes. On the other hand, in much of the country the intensive care resources necessary to effectuate organ donation may be preoccupied with the infected populations. The impact on donation among the centers in The Northern Italy Transplant Program is described in this issue by Cannavó et al [1] . To be assured of a COVID-19-negative organ, prolonged preservation may be necessary, as described in a liver transplant case by Bogensperger et al [2] Q2 .

The risk factors for an adverse outcome of COVID-19 infection (hypertension, diabetes and obesity) are not only conditions associated with upregulation of ACE2 but also common features of the transplant population as well as wellknown side effects of calcineurin antagonist/steroid regimens. Though these regimens might be expected to dampen host antiviral response, they may be at least partially protective against the cytokine storm response to infection.

Clinical roadmaps for transplant patients during the COVID-19 pandemic are described in this issue: Management of personnel as described by Thiessen et al [3] ; identification of potential recipients by Virmani et al [4] ; alterations of patterns of patient care as described by Binda et al [5] ; Niriella et al [6] , and Monaco et al [7] ; and detection of allograft injury by Garg et al [8] . Quite reassuring has been the physical and psychological resilience of transplant recipients, reported by Zgoura et al [9] and Lupi et al [10] . The emerging widespread applications of telemedicine in clinical practice as described by Abuzeineh et al [11] has been accompanied by the wider use of Zoom conferences to improve local and international physician interactions.

This issue also contains descriptions of patient outcomes. The low incidence and modest mortality rate among multiorgan recipients in The North Italy Program is described by Passamonti et al [12] and reviewed by Aziz et al [13] . Individual centers report their series Q3 of kidney (Lum et al [14] ; Kocak et al [15] ; Hasanoglu et al [16] ; Aziz et al [17] [14] , including 41 afflicted renal transplant recipients who most often presented with fever, dyspnea, and cough, revealed hospitalization to be necessary in 63.4% of subjects, with a 9.8% mortality rate and a 26.9% incidence of acute kidney injury.

Reviewing published experiences in liver transplantation, Fraser et al [19] note fever, dyspnea, and diarrhea as their most frequent symptoms at presentation. Among the 77% of recipients who required hospitalization, 40% experienced moderate and 36% experienced severe disease, with a 19.3% fatality rate at a median of 11.5 days.

Of great concern is the failure of some patients, particularly those requiring intensive care, to recover from the illness within 2 to 3 weeks. These individuals may display breathlessness, weakened cardiac output, neuropathic and autonomic dysfunction, and psychological "brain fog" symptoms as part of the chronic fatigue syndrome.

Though prophylaxis by vaccination seems to be rapidly approaching routine practice, current treatments that have been adapted from their clinical scenes are at best only moderately effective. Though vaccines are likely to protect the majority of the normal population, application to transplant patients may be more problematic, not only because of their blunted, iatrogenic dysfunctional immune responses but also because of the possibility of unintended autoimmune reactions to putatively benign viruses carrying the immunogen or their included adjuvants.

Our knowledge of protective immune responses in the general population has many gaps. Presumably the B cell response of neutralizing antibodies mediates resistance. The strongest evidence for a B cell response is the apparent benefit of treatment with convalescent plasma. However, there appears to be concern about the durability of this response. Though antibodies to SARS viruses are known to be detectable in blood for 2 years after infection, reports of re-infections with COVID-19 suggest that at least some patients' responses are more transient. Adding to this uncertainty, available antibody tests to detect neutralizing forms are not yet sufficiently reliable, arguing against application of "immunity passports."

For patients with moderate disease not requiring mechanical ventilation, a 5-to 10-day intravenous course of remdesivir has been given emergency use authorization by the United States Food and Drug Administration (FDA). This agent appears to be more efficacious than other antivirals such as lopinavir/ritonavir, the latter of which has an adverse interaction with calcineurin antagonists.

The FDA has also granted emergency use approval for convalescent plasma, which was successfully used in a lung transplant patient at the University of Chicago Q4 . However, one must bear in mind that donated plasma may contain alloantibodies. The participation of T cells in recovery is unclear.

Considerable progress has been achieved to counter the cytokine release syndrome associated with overwhelming host responses to infection. Dexamethasone has received FDA recognition for this use. Tocilizumab, a recombinant humanized monoclonal IgG 1 antibody directed against the interleukin 6 receptor, has been approved for treatment of severe rheumatoid arthritis and for life-threatening cytokine storm syndrome. Anecdotal reports suggest its beneficial effects in severe life-threatening cytokine storm responses to COVID-19. Similarly, addition of a 4 mg dose of the Janus kinase 1 and 2 inhibitor baricitinib to remdesivir further reduced the time to recovery compared with remdesivir alone.

The obvious option to prescribe available ACE2 receptor blockers is contraindicated because of their likely serious adverse effects on blood pressure and enhanced inflammation. Progress in pharmacotherapy of COVID-19 may be facilitated by the availability of the mouse strain with human ACE2 receptor insertion. One avenue for further investigation is decoy soluble ACE2 receptors, which have been shown to reduce the viral load in cell culture and to preserve respiratory function in animal models.

The Minisymposium presented in this issue includes early approaches to transplantation in the COVID-19 era. The enterprise to formulate robust roadmaps to deal with the pandemic will be facilitated by data from national and international registries of affected patients. As we progress in this challenging era, Transplantation Proceedings will continue to host Minisymposia that include article providing novel insights into the impact of the disease among this special patient population. 

The impact of COVID-19 on solid organ donation: the North Italy Transplantation program (NITp) experience

Dealing with liver transplantation in the SARS-CoV-2 pandemic: normothermic machine perfusion enables for donor, organ and recipient assessment-a case report

Rapid modification of workflows and fellow staffing at a single transplant center to address the COVID-19 crisis

Identifying a kidney transplant recipient COVID phenotype to aid test utilization in the setting of limited testing availability-does one exist?

Follow-up and management of kidney transplant recipients during the COVID-19 lockdown: the experience of an Italian transplant center, including two cases of COVID-19 pneumonia

Challenges for liver transplantation during recovery from the COVID-19 pandemic: insights and recommendations

Awareness and impact of non-pharmaceutical interventions during COVID-19 pandemic in renal transplant recipients

Use of donor-derived cellfree DNA for assessment of allograft injury in kidney transplant recipients during the time of the COVID-19 pandemic

Psychological responses to the COVID-19 pandemic in renal transplant recipients

Transplant patients' isolation and social distancing due to COVID-19: analysis of the resilient capacities of the transplant in the management of the coronavirus emergency

Telemedicine in the care of kidney transplant recipients with COVID-19: case reports

Solid organ transplantation in the coronavirus disease 2019 (COVID-19) era: "the great bet" in the North Italy Transplant program (NITp) area

Effects of COVID-19 on solid organ transplantation

Spectrum of COVID-19 outcomes in kidney transplant recipients-a single center experience

Oligosymptomatic kidney transplant patients with COVID-19: do they pose a risk to other recipients?

Do lifestyle changes of renal transplant recipients during the pandemic reduce the risk of COVID-19?

Early report on published outcomes in kidney transplant recipients compared to non-transplant patients infected with COVID-19

COVID-19 viremia, serologies and clinical course in a case series of transplant recipients

Clinical presentation, treatment and mortality rate in liver transplant recipients with COVID-19: a systematic review & quantitative analysis

Deceased donor liver transplantation in India in the COVID-19 era: current scenario and future perspectives

A kidney transplant recipient with COVID-19: utility of a prognostication score

A case report: minimal change disease with nephrotic syndrome associated with COVID-19 after APOL1 risk variant in kidney transplantation

COVID-19 in immunocompromised organ transplant recipients: a case report and review of the literature

Recovery of moderate COVID-19 in a liver transplant recipient on continued immunosuppression: a case report

Bilateral acute cardioembolic limb ischemia after COVID-19 pneumonia in a lung transplant recipient: a case report

Successful treatment of severe COVID-19 pneumonia with clazakizumab in a heart transplant recipient: case report