Transplant Capacity and Testing in the COVID-19 Era

April 28, 2020

The COVID-19 pandemic has resulted in a significant change in the US practice of transplantation. Deceased donation has declined, living donor transplants have been greatly curtailed, and multiple programs have been suspended. It is recognized that viral infection has not had the same impact upon the healthcare systems in different parts of the country, and the ASTS Strike Force thought it important to address salient issues necessary to stepwise (re)expand transplant care.

General considerations: Transplantation is intended to improve and extend people’s lives with organ failure. People cannot survive indefinitely with a diseased, failing organ, so it is imperative to offer transplant services when the risk/benefit analysis favors transplantation. However, the initial reports from U Wash, NYC and Wuhan suggest that the severity of COVID-19 disease mortality (10-30%) and morbidity (need for hospitalization and ventilatory support) is greater in transplant recipients than in the general population. While the exact risk factors are still unknown, this more virulent viral disease in the transplant population adds new variables to the decision calculus and challenges the provider to discern who would really benefit from transplantation and at what risk. There is no proven, effective treatment for severe COVID-19 disease, making disease acquisition by the transplant recipient quite risky. Additionally, centers should be aware that early in the Wuhan experience, general surgical procedures performed in 34 asymptomatic, COVID-19+ infected individuals was associated with 100% perioperative pneumonia, 44% ventilator requirement and 20% mortality (Lei S, Lancet 2020, https://doi.org/10.1016/j.eclinm.2020.100331). The risk to an infected (even asymptomatic) live donor is very significant. These issues and others must be considered when, how and to what degree centers increase transplant services.

COVID-19 Testing: The U Washington registry of COVID-19 infected organ transplant recipients reports that 14% of infections were suspected to have been acquired from hospitals. In addition, 10-20% of reported COVID-19 cases in the US are in healthcare workers. These two observations mean that centers must be concerned about bidirectional viral transmissions between patients and staff. Testing plays a major role in establishing “good” practice. Understanding the test results and knowing their limitations and meaning is key to rational policy development.

The COVID-19 PCR amplifies viral nucleic acids obtained from body fluids. As SARS-CoV-2 infection starts primarily as respiratory disease, bronchial lavage has been the most sensitive site for detection but is a risky method to detect the virus. The nasopharyngeal sample is most commonly obtained, as it has better detection than an oropharyngeal sample as a non-invasive sample of respiratory secretions. PCR is exceedingly specific for the viral nucleotides and detects individuals shedding the virus (very small false positive rate), but a single nasopharyngeal sample is thought to be positive in only about 70% of infected individuals. Any positive COVID-19 PCR should be treated as coming from an infected individual, irrespective of their symptoms. However, a negative test should not be presumed to “rule out” the presence of COVID-19, especially in the presence of clinical symptoms consistent with infection. Performance of this test is technically exacting and the availability and time for results of PCR can be highly variable. There is an increasing awareness that non-infectious viral fragments may be amplified, giving a positive test when the virus is not intact and presumably not contagious. This is likely true of the detection for viral nucleotides in feces and on many inanimate surfaces. However, as the consequence of disregarding active viral shedding can lead to spread of the disease and adverse outcomes, the Strike Force feels that individuals testing COVID-19 PCR positive should be treated as infectious to others, at least until there are reliable means to prove the contrary.

The COVID-19 antibody test detects immunoglobulins (IgG, IgM, or IgA) to viral capsular proteins. IgM is typically an early response, IgG the more established immunoglobulin, and IgA the dominant antibody in respiratory response. In test conditions, antibodies arose in >95% of patients with COVID-19 infections and appearance of IgG or IgM did not appear as in standard teaching (Clin Infect Dis. 2020 Apr 19. pii: ciaa461. doi: 10.1093/cid/ciaa461). Antibodies were identified early as 4 days after symptoms and as long as 40 days after onset, with three weeks after infection being typical for > 90% positive antibody detection. The test requires antibodies in the patient sera to bind with specific SARS-CoV-2 viral proteins in a test environment/kit. As coronaviruses are common in people with colds, it is crucial that the target antigen is specific for the SARS-CoV-2 proteins and not cross react with other respiratory viral proteins. The hurried development of diagnostic tests in the US has resulted in significant concerns about diagnostic uniformity and sensitivity of various manufacturers’ tests. Formal FDA approval for COVID-19 antibody test sensitivity and specificity of many manufacturers’ kits has yet to be obtained (see this link to review current status on serology testing kits by manufacturer: https://www.centerforhealthsecurity.org/resources/COVID-19/serology/Serology-based-tests-for-COVID-19.html#sec1). These concerns must temper transplant center decisions about positive or negative testing results.

A positive antibody test binding to specific SARS-CoV-2 proteins, in combination with a negative PCR, may be the best tool to identify healthcare workers who have cleared COVID-19 infection and may be resistant to subsequent infection. Caution of this conclusion, however, is necessary as the WHO has recently suggested. The transplant community has long known that antibody to viral proteins is not necessarily protective, but rather diagnostic, as observed with other RNA viruses (hepatitis C and HIV as examples). Additionally antibodies to respiratory viruses often decrease after an incident infection and people in the general population are often susceptible to recurrent bouts of upper respiratory infections over multiple seasons. While there are immunologic mechanisms in addition to antibody generation involved in viral clearance, the duration of purported resistance to infection must be ascertained. While we think antibody positive and PCR negative is optimal to identify those that have overcome viral infection, one must be cautious in extrapolating the meaning from these test results for either patients or healthcare workers.

It has long been known that immunosuppressed transplant recipients have diminished antibody response in quantity of antibody generated and time to detection (influenza, pneumococcal vaccine, and other antigens). Whether COVID-19 antibody generation has the same diagnostic specificity and sensitivity seen in the non-immunosuppressed population has not been reported. It is likely to be less so.

Healthcare system: The COVID-19 infection has depleted some systems of the ability to perform basic transplant care (NYC, northern Italy) with transplant personnel being redeployed into the care of infected patients. Each center must assess the prevalence of viral disease within the community and then discern whether sufficient resources exist (currently and the foreseeable future) to perform a transplant procedure and provide safe perioperative care (ICU beds, ventilators, blood products, operating rooms, skilled personnel including anesthesia, nursing, respiratory therapy, PT, OT, pharmacy, social services and others). System demands extend beyond any one person’s area of expertise. It is reasonable to seriously consider curtailing transplantation services when 20-25% of hospital resources are committed to COVID care or there is a very rapid increase in COVID population numbers. Assessment of PPE availability needs to be commensurate with the degree of risk, but must be considered for both staff and patient protection. Establishment of routine temperature screening, social distancing, respiratory barriers and COVID-free areas in the hospital should be commonplace. The overall degree of community penetrance of COVID-19 disease and adherence to social distancing should play into decisions about PPE needs.

It is easy to make the case in high prevalence areas of the country that universal testing of patients and healthcare workers be performed on a routine schedule. However, testing availability and reliability is not uniform, and penetration of the virus in the community/hospitals is erratic and changing. One will never know how to optimally care for the transplant population until there is sufficient information about rates of viral acquisition, the prevalence of infection, and the clinical consequences associated with immunosuppression and transplantation.

Patient testing and placement: As asymptomatic COVID-19 infection has been well described. In environments where viral penetrance is unknown or high, it is recommended that all transplant patients admitted to the hospital are PCR tested (at least once, but better is twice separated by at least 24 hours). The most logical system is creation of a screening area that allows for judicious placement of infected/uninfected patients. The goal of patient placement is to separate patients with COVID-19 shedding to an area geographically isolated from non-infected transplant patients. No specific guidance relating to retesting over time is possible without knowing risk and exposures. Respiratory barrier precautions and distancing as feasible should be commonplace in the hospital for patients and staff.

Staff: Staff shedding virus are a risk to uninfected transplant recipients. Antibody and PCR Covid-19 testing are probably the best way to assess HCW risk of disease transmission to patients. Community acquisition of viral infection can occur at any time, and only those staff who have demonstrated as antibody positive/PCR negative can likely be thought to be safe from viral shedding. This is still conjecture, but the best we can do at present. Actual staffing demands will sometimes trump rational structures, meaning that in areas with high prevalence, staff may be required to return to work after being asymptomatic for a period of time irrespective of testing. Depending upon penetrance into the community, temperature screening and repeat testing should be performed for HCW.

Live donors and caregivers: Transplant services often interact with non-immunosuppressed people. The safety of the donor must be paramount. The risk of a general surgical procedure in an asymptomatic COVID-19 infected/shedder or person within the incubation period is potentially life threatening. There is no foolproof means to ensure that any potential donor is not infected, but one should have an approach. After setting a date, it is probably prudent to perform a COVID-19 PCR and then request the donor self-quarantine for 5-7 days leading up to the surgical procedure. Within 48-72 hours of the donation, check the donor again. If both tests are negative, one is close to 95+% confident that the person is not shedding virus and proceed if the recipient is ready. Of course a thorough questioning of the donor for symptoms should also be performed. If the donor does not self-quarantine or “slips,” two tests done in the 72 hours prior to donation should be performed. Most likely both tests will be negative and the donor will need additional informed consent information of the risks of contracting the virus either within the hospital or the community. This discussion will certainly have to differ in the various regions of the country with differing rates of COVID-19 disease. If a potential donor is shown to have COVID-19 antibodies and a negative PCR, it is likely that the person cleared the virus in the past. It has been hoped that this testing combination is indicative of a person with increased resistance/immunity to recurrent infection.

Most live donor recipients need a caregiver to help during the immediate perioperative period. If the caregiver contracts or is exposed to COVID-19, that could be very deleterious to the recipient. Use of COVID-19 testing should be predicated upon community prevalence and symptoms, not necessarily upon their post care activity. It is recommended that caregivers self-quarantine for 7 days prior to the transplant to minimize community exposures and go past the normal incubation period. Additionally, it is recommended that there be a “plan B” in the event the primary caregiver becomes ill.

There are clearly many factors that will impact a center’s decision to expand capacity to perform organ transplants. At this time, even though these variables are ill-defined, it is our opinion that centers should continue transplanting patients as local community prevalence is generally low and hospital resources and capacity can support doing so. The ASTS feels strongly that in the absence of “good data” that prudent practice address the known risks for recipients and healthcare workers.