Donor and Recipient management during SARS-CoV-2 pandemic

While we are gearing our health care systems to manage COVID-19 and looking for therapeutic strategies, several challenges exist in the field of lung transplantation. Assessment of an organ donor in the midst of the SARS-CoV-2 pandemic, potential impact on procuring teams and subsequently on the recipient are prominent among them. Donor derived infections such as West Nile virus, community -acquired viral pathogens including influenza, para-influenza, adenovirus and 1 respiratory syncytial virus are described. During these unprecedented times, wait list mortality remains an important concern. Limited donor pool due to sequestration, less travel along with stretched resources for performing transplantation including restricted travel, availability of operating rooms, intensive care units and health care work force have put a strain on the solid organ transplant programs. Donor testing a d excluding active infection with a single negative test if clinical phenotype is suspicious is insufficient since recent data is suggestive of

2 subsequent tests being positive especially from lower respiratory tract .

New recommendations from transplant societies include donor and recipient testing prior to implantation. If transplantation is performed, strict isolation procedures and vigilance for COVID-19 in recipient is mandatory. Organ from deceased donors that have epidemiological risk factors or have positive clinical criteria but test negative for SARS-CoV-2 should be used with caution due to possibilities of false negatives. Repeating or having two PCR tests is an option to confirm absence of COVID-19.

Antibody testing (serology) is in rapid evolution. At this time, antibody testing should be used as an adjunctive testing and not as primary testing for determining the acceptability of the donor. According to the American Society of Transplantation, strong recommendation exists for not performing lung transplantation if testing is not available. The process of organ procurement, transportation and implantation involves several personnel and exposure to SARS-CoV-2 could be a potential “super-spreader” event predominantly infecting health care workers.

In summary, deceased donor and recipient selection during COVID-19 pandemic Recommend P C R testing of S A R S - C o V- 2 u s i n g oropharyngeal/nasopharyngeal swab, sputum/tracheal aspirate of bronchoalveolar lavage (BAL) less than 72 hours prior to organ donation; latter two are reported to have high viral loads with higher sensitivity. However, BAL should only be performed if it is safe to do so within a closed ventilatory circuit with adequate personal protective equipment available Recommend PCR based testing for recipient prior to lung transplant surgery Thoracic CT scan is recommended for donor screening as imaging may show signs of COVID-19 pneumonia prior to symptoms Current guidelines do not recommend change in induction or immunosuppression

Post-transplant Surveillance

Allograft injury is most common in lung transplant recipients 3 compared to other solid organ transplant recipients . Chronic Lung Allograft Dysfunction (CLAD) is the most common limitation for long 4 term survival after lung transplantation . Early detection with active surveillance is essential in lung transplant recipients. Our practice had dramatically changed with current health crisis where telemedicine has replaced in-person visits. Spirometry is based on home compliance with measurements rather than standardized pulmonary function testing in clinics. However, phone and video conferencing are helping to triage patients early, for suspected SARS-CoV-2 testing to necessary locations. But, active surveillance for acute or chronic lung allograft injury is limited to telehealth visits since March of this year. Routine surveillance bronchoscopy and biopsies are postponed since early March especially with recipients who are greater than 3 months since transplantation with no recent history of rejection and those that are

not sensitized.

Key points summarized are

● Limiting clinic to essential patient visits and coordinating arrival to clinic and back to return to their own method of transportation without registration or waiting in clinic area is the current process. Regular screening procedures are mandatory

● Implementation of telemedicine/ WhatsApp technology for majority of patients and deferring routine surveillance for patients with stable lung function is now the current management strategy

Lung Transplant Recipients with COVID-19

It appears that there are two distinct features, one triggered by the virus itself and second, the host response. It is unclear if the infection risk is higher or the inflammatory response is milder due to immunosuppressed state. Structured approach to clinical phenotyping as mild, moderate and severe stages will help stratify therapeutic strategies. Two cases describing COVID-19 in lung transplant 5 recipients are described. Aigner C et al published as a mild case of COVID-19 in a 59-year-old female who recovered and was 6 discharged on day 21. Another mild case reported in a 53-year-old woman with chronic lung allograft dysfunction and multiple comorbidities also recovered with supportive care. Until recently lung transplant recipients were excluded from clinical trials with remdesevir or interleukin-6 monoclonal antibody Sarilumab. Alternatives in management include Tocilizumab and intravenous immunoglobulins (IVIG). Tocilizumab is described as treatment modality in desensitization and management of chronic antibody mediated 7,8. rejection in kidney transplant recipients Immunoglobulins are formulations of human IgG that demonstrate anti-inflammatory effects beyond just the viral infection such as prevention of graft rejection and 9-11 management of antibody mediated rejection.

Recent emergence of donor specific antibodies in a pediatric heart transplant recipient is described (COVID-19 in a pediatric heart transplant recipient: Emergence of Donor Specific Antibodies;jhltonline.org).

Limited data exists regarding post viral allograft injury in lung transplant recipients. Another major limitation in treatment of these patients whether immunosuppressed or not is the management of critical illness myopathy after recovering from initial intensive care unit admissions. Prolonged viral shedding with nasopharyngeal swabs being positive for several weeks after initial infection limits the ability of discharge disposition to unprepared inpatient rehabilitation units.

Key points are

● COVID-19 can present in mild, moderate and severe forms

● Steroids and other agents to address the cytokine storm are being used in various clinical programs

● Post viral rejection is not uncommon

● Prolonged viral shedding can occur in immunosuppressed lung transplant recipients

In summary, we are now facing unprecedented issues with SARS-CoV-2 pandemic. Several limitations exist for donor evaluation, wait list management, organ transplantation and post lung transplant care.

Modifying current regimens to mitigate the risk for viral transmission, early recognition and treatment are broad solutions for programs involved in lung transplantation

References:
1. Fishman JA. Infection in Organ Transplantation. Am J Transplant. 2017;17(4):856-879.
2. Wang W, Xu Y, Gao R, et al. Detection of SARS-CoV-2 in Different Types of Clinical Specimens. JAMA. 2020.
3. DerHovanessian A, Wallace WD, Lynch JP, 3rd, Belperio JA, Weigt SS. Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies. Semin Respir Crit Care Med. 2018;39(2):155-171.
4.DerHovanessian A, Todd JL, Zhang A, et al. Validation and Refinement of Chronic Lung Allograft Dysfunction Phenotypes in Bilateral and Single Lung Recipients. Ann Am Thorac Soc. 2016;13(5):627-635.
5.Aigner C, Dittmer U, Kamler M, Collaud S, Taube C. COVID-19 in a lung transplant recipient. J Heart Lung Transplant. 2020.
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8.Vo AA, Choi J, Kim I, et al. A Phase I/II Trial of the Interleukin-6 ReceptorSpecific Humanized Monoclonal (Tocilizumab) + Intravenous Immunoglobulin in Difficult to Desensitize Patients. Transplantation. 2015;99(11):2356-2363.
9.Hulbert AL, Pavlisko EN, Palmer SM. Current challenges and opportunities in the management of antibody-mediated rejection in lung transplantation. Curr Opin Organ Transplant. 2018;23(3):308-315.
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