Impact of COVID-19 in Solid Organ Transplant Recipients

Lara Danziger-Isakov; Emily A. Blumberg; Oriol Manuel; Martina Sester


American Journal of Transplantation. 2021;21(3):925-937. 

In This Article

SARS-CoV-2 Infection, Immunity, and Pathogenesis

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19). While infection with SARS-CoV-2 is frequently asymptomatic or mild, clinical manifestations can also be serious. Risk factors for serious disease and mortality in the general population include older age, obesity, and comorbidities affecting the lung or the heart.[1,2] Disease severity may be influenced by the viral inoculum, dissemination, pre-existing immunity toward other coronaviruses, individual immunocompetence, and other host factors.[3–9]

In the general population, infection is followed by the induction of innate inflammatory responses and of SARS-CoV-2-specific humoral and cellular immunity including CD4 and CD8 T cells.[3–6,10] The magnitude of specific immunity may be directly related to viral load, dissemination to the lower respiratory tract, and/or disease severity.[6,10] In addition, SARS-CoV-2-specific T cells in patients with severe disease have a restricted functionality and higher expression levels of co-inhibitory receptors, which also extended to T cells in general.[6,11] Together this suggests that adaptive immunity is readily induced and contributes to viral control in the majority of infected individuals. However, in some patients, a cytokine storm is triggered that mediates severe lung inflammation and widespread systemic pathology.[12] High levels of specific adaptive immunity and the hyperinflammatory syndrome observed in severe disease emphasize the need for contraction processes to counteract excess immunopathology in the lungs.

In solid organ transplant (SOT) recipients, the extent of immunosuppression correlates with the severity of diverse infectious diseases,[13] which led to the initial prediction that SOT recipients may be more susceptible to severe COVID-19. Indeed, the risk of mortality in transplant recipients seems higher than in the general population.[14–17] However, this has not been universally noted. Early after infection, strong immunosuppression may adversely affect sufficient induction of specific immunity, which may account for insufficient control of viral load and frequently observed prolonged detection of viral RNA after disease onset.[18–21] In contrast, in later periods of the disease, immunosuppressive drugs may be beneficial in suppressing proinflammatory processes and supporting functional inactivation and contraction of cellular immunity. Thus, modulation of immunosuppression may be harmful or beneficial depending on the clinical stage of the infection in SOT. The time course for viral replication, infectivity, and induction of adaptive immunity in immunocompetent patients and potential alterations in SOT recipients, and implications for therapeutic management is outlined in Figure 1.

Figure 1.

Time course of SARS-CoV-2 infection and development of COVID-19. After infection with SARS-CoV-2, individuals may transmit the virus 1–2 days prior to and approximately 8 days after the onset of clinical symptoms (red curve). SARS-CoV-2 RNA as determined by PCR (orange curve) is detectable for longer periods of time. Infection is followed by the induction of SARS-CoV-2-specific CD4 and CD8 T cells (blue curve) that contribute to the control of viral replication. In addition, a hyperactive immune response contributes to immunopathology associated with COVID-19. As outlined by stippled curves, PCR positivity after infection may be prolonged in transplant recipients, with potential implications for prolonged infectivity. In addition, induction of specific immunity may be less pronounced given immunosuppressive drug therapy. Implications for therapeutic management are indicated. This includes antiviral drugs or convalescent plasma together with reduction in immunosuppression in the early period of infection to ensure control of viral replication, and immunomodulatory or anti-inflammatory treatment regimens associated with restoring or intensified immunosuppression in the later stages of infection to counteract immunopathology.