Impaired immune responses and prolonged viral replication in lung allograft recipients infected with SARS-CoV-2 in the early phase after transplantation

Abstract

Purpose: Lung transplant recipients are at increased risk of severe disease following infection with severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) due to high-dose immunosuppressive drugs and the lung is the main organ affected by Coronavirus disease 2019 (COVID-19). Several studies have confirmed increased SARS-CoV-2-related mortality and morbidity in patients living with lung allografts; however, detailed immunological studies of patients with SARS-CoV-2 infection in the early phase following transplantation remain scarce.

Methods: We investigated patients who were infected with SARS-CoV-2 in the early phase (18-103 days) after receiving double-lung allografts (n = 4, LuTx) in comparison to immunocompetent patients who had not received solid organ transplants (n = 88, noTx). We analyzed SARS-CoV-2-specific antibody responses against the SARS-CoV-2 spike and nucleocapsid proteins using enzyme-linked immunosorbent assays (ELISA), chemiluminescence immunoassays (CLIA), and immunoblot assays. T cell responses were investigated using Elispot assays.

Results: One LuTx patient suffered from persistent infection with fatal outcome 122 days post-infection despite multiple interventions including remdesivir, convalescent plasma, and the monoclonal antibody bamlanivimab. Two patients experienced clinically mild disease with prolonged viral shedding (47 and 79 days), and one patient remained asymptomatic. Antibody and T cell responses were significantly reduced or undetectable in all LuTx patients compared to noTx patients.

Conclusion: Patients in the early phase following lung allograft transplantation are vulnerable to infection with SARS-CoV-2 due to impaired immune responses. This patient population should be vaccinated before LuTx, protected from infection post-LuTx, and in case of infection treated generously with currently available interventions.

Keywords: COVID-19; Immune responses; Immunosuppression; Lung transplant recipients; Solid organ transplantation.

Fig. 1

a Clinical course of SARS-CoV-2 infection of recent lung transplant recipients. The timeline indicates the order of events in relation to the date of the first positive SARS-CoV-2 PCR result (day 0, red arrow). The symbols indicate the time points of administration of remdesivir (pills), convalescent plasma (infusion bag), and bamlanivimab (monoclonal antibody), respectively. The first negative SARS-CoV-2 PCR result (black arrow) is indicated. Patient B passed away after 121 days of infection (cross). b SARS-CoV-2 viral load trajectories of recent lung transplant recipients. Viral load is indicated as copy numbers of the SARS-CoV-2 ORF1ab gene per ml of transport medium of nasopharyngeal swab samples. Values are plotted in relation to the first positive PCR result (days of infection) for each of the four transplant recipients

Fig. 2

Limited SARS-CoV-2-specific antibody responses in lung transplant recipients in comparison to non-immunocompromised patients. Serological results are shown for four commercially available assays for the detection of IgG antibodies against the SARS-CoV-2 spike S1 subunit (a), the receptor binding domain (RBD) (b) and nucleocapsid (c, d). Longitudinal results for the four lung transplant recipients (indicated in color) are shown in relation to the first positive SARS-CoV-2 PCR result. For comparison, longitudinal serological results of patients who have not received a solid organ transplant (noTx n = 88) are plotted as gray dots with locally estimated scatterplot smoothing (LOESS) shown as black curve with 95% confidence interval. Results are indicated as optical density for the chemiluminescence assay (a), or signal to cut-off ratio for immunoblot assays (b–d). The dotted horizontal line represents the cut-off considered for test result positivity as provided by the manufacturer

Fig. 3

Impaired T cell responses against SARS-CoV-2 in lung transplant recipients compared to non-immunocompromised controls. a PBMC samples of the four lung transplant recipients were stimulated with peptide pools covering the S1 and S2 subunits of the SARS-CoV-2 spike protein and the nucleocapsid protein (N). Results are shown as spots per million PBMCs for the time point closest to 30 days post-infection if multiple time points were available (patient A: 16, patient B: 28, patient C: 32 for S1 and 50 for S2 and N, patient D: 29 days post-infection). For comparison, non-immunocompromised donors were tested matched to 30 days post-infection for S1 (n = 10), S2 (n = 8) and N (n = 5) Elispot responses (blue). Bar graphs represent median values with interquartile range. Groupwise comparisons were performed using the Mann–Whitney test with * indicating p-values < 0.05. b Longitudinal T cell responses against S1 (blue), S2 (red), and N (green) peptide pools are shown for patient C and patient B in relation to viral load (black)