Dropping Immunosuppression in COVID Didn't Up Transplant Rejection

Pam Harrison

September 01, 2022

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

Among kidney transplant recipients who had contracted COVID-19, rates of acute rejection were low despite reducing the patients' immunosuppressive regimens, new research shows.

"At the onset of the COVID pandemic, the whole kidney transplant community noted that kidney recipients had worse outcomes than nontransplant recipients, [so] a standard practice for any infection in organ recipients is to reduce the dose of immunosuppressive therapy, and this has remained the standard practice for COVID as well," the lead author of the work, Madhav Menon, MD, associate professor of nephrology, Yale School of Medicine, New Haven, Connecticut, told Medscape Medical News in an email.

"So we wanted to study the immunological landscape of COVID-19 in kidney recipients using the gene-expression of white cells in the peripheral blood of infected patients during acute infection (within 4 weeks) vs...recovery 4 weeks later, and we found that kidney transplant recipients with COVID-19 showed signatures of immune insufficiency in their peripheral blood that were...a temporary phenomenon during acute illness," he added.

The study was published online August 30 in the Journal of the American Society of Nephrology.

Asked to comment, Enver Akalin, MD, agreed that at the beginning of the pandemic, there was debate about what physicians should do regarding immunosuppressive treatment for kidney transplant recipients who had contracted COVID-19.

"While decreasing immunosuppressive treatment was important for patients to increase T- and B-cell activity to SARS-CoV-2 and mount an antibody response, it could have the potential to exacerbate inflammation and cytokine storm observed in patients with severe clinical picture of COVID-19," Akalin said in an email.

"[So] this study is very important, documenting that at the acute phase of COVID-19 in kidney transplant patients, T-cell and adaptive immune activation pathways are downregulated despite reduction in immunosuppressive treatment, and physicians should continue to minimize their patients' immunosuppression during early phase of COVID-19," added Akalin, medical director of the kidney transplant program at the Montefiore Medical Center and the Albert Einstein College of Medicine, New York.

Acute vs Post-Acute Phases of SARS-CoV-2 Infection

A total of 64 kidney transplant recipients who had been infected with SARS-CoV-2 were included in the analysis. Thirty-one had acute infection that lasted less than 4 weeks; the other 33 patients had been infected for longer than 4 weeks. Patients were enrolled from two hospitals in New York that were at the forefront of the pandemic in its early stages.

"We identified significant downregulation of T cell–mediated immune activation signatures in kidney transplant recipients with COVID-19 that were correlated with disease severity," the authors report.

These changes significantly resolved after the acute episode despite reinstitution of standard immunosuppressive regimens, they add. Interestingly, despite cytokine dysregulation during acute illness, there was no correlation between simultaneous mRNA expression in blood transcriptomes and corresponding protein levels for interleukin-6.

Indeed, the upregulation of neutrophils and innate immune pathways but the downregulation of T-cell and adaptive immune activation pathways were independent of the lymphocyte count despite a reduction in immunosuppressive regimens.

"This observation suggested that in spite of cytokine proinflammatory excess in severe COVID-19 infection among kidney recipients, adaptive immune cell activation responses appeared to be suppressed in the peripheral blood assessment," Menon noted.

The investigators also observed some overlap of these findings among SARS-CoV-2–infected nontransplant recipients from a previously reported dataset, suggesting that these peripheral blood findings are seen in SARS-CoV-2 infection overall.

COVID-19 Itself Induced Some Adaptive Immune Dysfunction

The fact that the authors also observed "recovery" of the peripheral blood immunosuppression signature 4 weeks post diagnosis — when antirejection medications had been resumed for the majority of patients — suggests that COVID-19 itself induced some adaptive immune dysfunction during the acute phase of the illness, Menon noted.

Akalin noted that this downregulation of adaptive immune pathways was associated with COVID disease severity and was independent of lymphopenia but improved after 4 weeks without an increase in the acute rejection rate among those patients.

This evidence of suppression of T-cell/adaptive immune responses in peripheral transciptomes accompanying COVID-19 and its association with disease severity has important therapeutic implications for kidney transplant recipients.

"Our findings may partly support the empiric practice of reducing transplant-specific T-cell directed IS (immunosuppressive) agents during severe COVID-19 in kidney transplant recipients when necessary for overall management," the authors conclude.

Menon has disclosed no relevant financial relationships. Akalin has received grant support from CareDx and Immuco and has served on the advisory boards for CareDx, Immucor, Eurofins, and Transplant Genomics.

J Am Soc Nephrol. Published online August 30, 2022. Full text

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