key: cord-323787-9lq8rkih
authors: Bösch, Florian; Börner, Nikolaus; Kemmner, Stephan; Lampert, Christopher; Jacob, Sven; Koliogiannis, Dionysios; Stangl, Manfred; Michel, Sebastian; Kneidinger, Nikolaus; Schneider, Christian; Fischereder, Michael; Irlbeck, Michael; Denk, Gerald; Werner, Jens; Angele, Martin K.; Guba, Markus O.
title: Attenuated early inflammatory response in solid organ recipients with COVID‐19
date: 2020-06-26
journal: Clin Transplant
DOI: 10.1111/ctr.14027
sha: 
doc_id: 323787
cord_uid: 9lq8rkih

Immunosuppression leaves transplanted patients at particular risk for severe acute respiratory syndrome 2 (SARS‐CoV‐2) infection. The specific features of coronavirus disease 2019 (COVID‐19) in immunosuppressed patients are largely unknown and therapeutic experience is lacking. Seven transplanted patients (two liver, three kidneys, one double lung, one heart) admitted to the Ludwig‐Maximilians‐University Munich because of COVID‐19 and tested positive for SARS‐CoV‐2 were included. The clinical course and the clinical findings were extracted from the medical record. The two liver transplant patients and the heart transplant patient had an uncomplicated course and were discharged after 14, 18 and 12 days, respectively. Two kidney transplant recipients were intubated within 48 hours. One kidney and the lung transplant recipients were required to intubate after ten and 15 days, respectively. Immunosuppression was adapted in five patients, but continued in all patients. Compared to non‐transplanted patients at the ICU (n=19) the inflammatory response was attenuated in transplanted patients, which was proven by decreased IL‐6 blood values. This analysis might provide evidence that continuous immunosuppression is safe and probably beneficial since there was no hyperinflammation evident. Although transplanted patients might be more susceptible to an infection with SARS‐CoV‐2, their clinical course seems to be similar to immunocompetent patients.

On 7 January 2020, the new coronavirus severe acute respiratory syndrome 2 (SARS- was identified as the cause of coronavirus disease 2019 (COVID-19) 1, 2 . Although the majority of infections are asymptomatic or mild, there are patients who have severe courses that require hospitalization. Of these, approximately a fifth get oxygen and 17% are in need of invasive ventilation 2 . The case fatality rate varies and can be as high as 28.3%. However, case fatality rate is strongly related to the age of the patients and concomitant comorbidities of the patients such as heart disease, diabetes mellitus [1] [2] [3] .

Patients with a compromised immune system are more susceptible to viral infections than immunocompetent patients 4,5 . Thus, it can be assumed that transplant patients under immunosuppression and plagued with numerous comorbidities are at particular risk for an unfavorable course of COVID-19. However, data on COVID-19 in patients after solid organ transplantation is scarce. Profound information about the management of immunosuppression and the clinical course in solid organ recipients are still lacking 6-10 .

Here, we present comprehensive data about the clinical courses of solid organ recipients suffering of COVID-19. We aim to evaluate the clinical courses of these patients and provide a rationale for maintenance of immunosuppression.

This is a retrospective cohort study carried out at the University Hospital of the Ludwig-Maximilians-University Munich, Germany. Every patient hospitalized due to COVID-19 was screened for a history of solid organ transplantation. To securely diagnose a patient positive for SARS-CoV-2 a positive reverse real-time polymerase chain reaction (PCR) assay result of a respiratory specimen was demanded 1,2 . In total seven consecutive solid organ recipients (two liver, three kidneys, one double lung, one heart) were identified and included in the present analysis. Inflammatory response and early outcomes were compared to a cohort of nontransplanted, non-immunosuppressed COVID-19 patients treated at the same time on our ICU (n=19). Patients qualified for inclusion to the control collective if they were immunocompetent and stayed at least 19 days on the ICU such as the shortest ICU treatment of a transplanted patient.

The clinical course and the clinical findings recorded during treatment were extracted from the electronic medical record. The data collection within the CORKUM (COVID-19 Register des

This article is protected by copyright. All rights reserved LMU Klinikums) network was approved by the local ethics committee. Results are displayed as means with standard deviation and time frames (age and time since transplantation) as medians with IQ range. Univariate analysis was carried out by using Chi-squared test for categorical parameters (e.g., age, temperature); p-values lower than 0.05 were considered significant. Prism 8.0 for Mac (GraphPad Software, Inc., La Jolla, CA) was used for statistical analysis.

Here we describe the clinical presentation of the first seven transplanted patients hospitalized for COVID-19 in our institution ( 

On admission all, but one asymptomatic liver and the heart transplant patient, presented with cough and fever (Table 3) 

The clinical course differed significantly between the transplant patients. The two liver transplant recipients (LiTx 1 and 2) and the heart transplant (HTx) recipient could be managed on a regular ward. These patients had neither dyspnea nor oxygen demand. Initially, the heart transplant patient was admitted to an external clinic because of cholangitis and transferred to our institution due to

This article is protected by copyright. All rights reserved additional SARS-CoV-2 infection. The liver transplant recipients as well as the heart transplant recipient could be discharged after 14 (LiTx 1), 18 (LiTx 2) and 12 (HTx) days, respectively.

Two kidney transplant recipients (KiTx 1 and 2) had to be intubated within 48 hours after admission. The third kidney transplant recipient (KiTx 3) and the lung transplant recipient (LuTx) were initially managed with 4-6l oxygen flow. However, they showed a delayed progression requiring intubation ten (KiTx 3) and 15 (LuTx) days after admission, respectively. One of the kidney transplant patients (KiTx 3) was extubated after three days of mechanical ventilation.

Additionally, this patient was discharged in good health 17 days after admission. Weaning was 

This article is protected by copyright. All rights reserved In transplanted/immunosuppressed patients inflammatory response on admission was generally lower as compared to non-transplant patients. Moreover, during hospitalization IL-6 levels stayed significantly lower in transplanted patients as compared to non-transplanted patients. A similar observation was made for LDH, but not for CRP and ferritin. The inflammation markers of the transplanted patients not requiring intensive care treatment remained low throughout their stay ( Figure 1) . Apart from the heart transplant patient, who suffered cholangitis, liver enzymes, coagulation function, and blood count were not impaired during hospital stay (Supplementary Figure 1) .

There was no death of a transplanted patient within our institution.

The SARS-CoV-2 pandemic is spreading rapidly across the globe without any specific therapy or vaccination being available 13,14 . Risk factors for developing acute respiratory distress syndrome (ARDS), ICU admission and death have been published 1,2,15 . Nonetheless, these studies have been conducted in immunocompetent patients. Transplanted patients belong to a particularly vulnerable patient group, as they require life-long immunosuppression increasing their susceptibility for viral infections 4,5 .

It can be assumed that the clinical courses under immunosuppression differ from those of nonimmunosuppressed patients. The first assumption would be that immunosuppression is generally unfavorable for the course of the disease, but in the case of COVID-19 it could be different. One of the problems of COVID-19, apart from the direct damage caused by the virus, is a potentially excessive immune response, which in turn can lead to further damage to the lung parenchyma 16,17 .

Here, immunosuppressive drugs could even be advantageous by preventing what is often called a cytokine storm. Indeed, we observed significantly lower IL-6 levels in our patients than in the non-immunosuppressed reference cohort. Although no statistical significant difference was seen, a clear trend was obvious. The early inflammatory response in transplanted patients seems to be attenuated. In this context, it could be shown in our clinic that the level of IL-6 increase has a prognostic value for COVID-19 progression (in review) and pharmacological inhibition of IL-6 was proposed as a potential treatment strategy of COVID-19 18,19 . Since the follow-up period was relatively short, the results of the present study have to be interpreted with care. Nonetheless, no transplanted patient died due to SARS-CoV-2 infection. This finding is in

This article is protected by copyright. All rights reserved contrast to recently published reports with mortality rates of solid organ recipients of up to 28% It is interesting to speculate whether different transplants are varying with regard to their vulnerability to SARS-CoV-2 infection. In our cohort we noticed that the liver transplant and heart transplant patients took a relatively mild course. This could be due to the fact that successful liver and heart transplants have relatively little additional comorbidities. In contrast, kidney transplanted patients have more serious, mainly cardiovascular concomitant diseases due to the long dialysis treatment 33,34 . From theoretical considerations, as well as in our patients, it is to be assumed that lung transplantation is particularly prone to severe disease. In addition to the high level of immunosuppression required, the lung is the direct target of the virus and the transplant alters the lung physiology 35 .

What conclusions can be drawn from the experiences with this transplant collective? The first and perhaps the most important result of the present study is that there is no consistent pattern for COVID-19 illness under immunosuppression. There are very mild courses of the disease under

This article is protected by copyright. All rights reserved immunosuppression, but also severe ones, but overall the situation is not as bleak as first case reports suggest 7,20,36 . It seems advisable to maintain an adequate immunosuppression to avoid acute rejection and subsequent organ failure; there is currently no data basis for changing the immunosuppression at the time of infection. Our experience has been encouraging that with the appropriate allocation of intensive care resources, it is possible to successfully manage even severe courses of COVID-19 in transplanted patients. 

All authors declare no competing interests. 

This article is protected by copyright. All rights reserved 

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Clinical characteristics of non-critically ill patients with

This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved Accepted Article