Blood Transcriptomes of SARS-CoV-2–Infected Kidney Transplant Recipients Associated with Immune Insufficiency Proportionate to Severity
Authors: Sun Zeguo , Zhang Zhongyang , Banu Khadija , Azzi Yorg Al , Reghuvaran Anand , Fredericks Samuel , Planoutene Marina , Hartzell Susan , Kim Yesl , Pell John , Tietjen Gregory , Asch William , Kulkarni Sanjay , Formica Richard , Rana Meenakshi , Maltzman Jonathan S. , Zhang Weijia , Akalin Enver , Heeger Peter S. , Cravedi Paolo , Menon Madhav C. 
Published: August 2022

Significance Statement
Kidney transplant recipients are reported to have worse outcomes with COVID-19, and most centers have empirically reduced maintenance immunosuppression. Surprisingly, however, despite reduced immunosuppressant use, reported rates of acute rejection have been low among such patients. The authors evaluated the peripheral blood transcriptome of 64 kidney transplant recipients either during or after acute COVID-19. They identified transcriptomic signatures consistent with suppression of adaptive T cell responses that were significantly associated with disease severity during acute disease. These transcriptomic signatures also showed evidence of recovery after acute disease, even after adjustment for lymphocyte number. These transcriptomic findings of immune insufficiency during acute COVID-19 provide an explanation for the low rates of acute rejection among kidney transplant recipients despite reduced use of immunosuppressants.

Background
Among patients with COVID-19, kidney transplant recipients (KTRs) have poor outcomes compared with non-KTRs. To provide insight into management of immunosuppression during acute illness, we studied immune signatures from the peripheral blood during and after COVID-19 infection from a multicenter KTR cohort.

Methods
We ascertained clinical data by chart review. A single sample of blood was collected for transcriptome analysis. Total RNA was poly-A selected and RNA was sequenced to evaluate transcriptome changes. We also measured cytokines and chemokines of serum samples collected during acute infection.

Results
A total of 64 patients with COVID-19 in KTRs were enrolled, including 31 with acute COVID-19 (<4 weeks from diagnosis) and 33 with post-acute COVID-19 (>4 weeks postdiagnosis). In the blood transcriptome of acute cases, we identified genes in positive or negative association with COVID-19 severity scores. Functional enrichment analyses showed upregulation of neutrophil and innate immune pathways but downregulation of T cell and adaptive immune activation pathways. This finding was independent of lymphocyte count, despite reduced immunosuppressant use in most KTRs. Compared with acute cases, post-acute cases showed “normalization” of these enriched pathways after 4 weeks, suggesting recovery of adaptive immune system activation despite reinstitution of immunosuppression. Analysis of the non-KTR cohort with COVID-19 showed significant overlap with KTRs in these functions. Serum inflammatory cytokines followed an opposite trend (i.e., increased with disease severity), indicating that blood lymphocytes are not the primary source.

Conclusions
The blood transcriptome of KTRs affected by COVID-19 shows decreases in T cell and adaptive immune activation pathways during acute disease that, despite reduced immunosuppressant use, associate with severity. These pathways show recovery after acute illness.