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ORIGINAL ARTICLE
Year : 2022  |  Volume : 16  |  Issue : 2  |  Page : 180-183

Clinical characteristics and immunosuppression management in kidney transplant recipients infected with severe acute respiratory syndrome coronavirus 2 infection - An observational study


Department of Nephrology, Kilpauk Medical College Hospital, Chennai, Tamil Nadu, India

Date of Submission02-Jul-2021
Date of Acceptance05-Apr-2022
Date of Web Publication30-Jun-2022

Correspondence Address:
Dr. Kiruthika Somasundaram
Department of Nephrology, Kilpauk Medical College and Hospital, Chennai - 600 010, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijot.ijot_68_21

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  Abstract 


Background: COVID-19 infected kidney transplant patients need specialist care in tailoring their immunosuppression drugs alongside routine care. Methods and Materials: This is an observational data from a single center of 12 kidney transplant recipients (KTR) who were hospitalized with COVID-19 from April 2020 to November 2020. The demographics, COVID treatment including immunosuppressive drug regimen were reviewed. Their graft function during the stay, at the time of discharge, and 30 days after discharge was also reviewed. Results: Of 12 patients included, 83% were male patients. The median age was 37 years and the median time since transplant was 42 months. Common comorbidities were diabetes (50%), hypertension (50%), and cardiovascular disease (8%). Ninety-two percent had triple immunosuppressive regimen whereas 8% were in steroid-free protocol. Fifty percent had mild COVID, 8% had moderate disease, and 41% has severe COVID which was managed with institution-specified protocol. Steroids dose was increased in all patients. Antimetabolite was uniformly withdrawn in all patients irrespective of disease severity. Acute kidney injury was noted in 50% of patients which recovered to baseline at discharge. Graft function at 2 weeks and 30 days after discharge was stabilized close to their baseline value. Mortality was 8%. Conclusion: Reduction of immunosuppression, especially the withdrawal of antimetabolites, was found to be safe without graft rejection in KTRs.

Keywords: COVID-19, graft rejection, immunosuppression, kidney transplant recipients


How to cite this article:
Somasundaram K, Thoppalan B, Chellaiah V, Kumar R P, Murugesan V, Thirumavalavan S. Clinical characteristics and immunosuppression management in kidney transplant recipients infected with severe acute respiratory syndrome coronavirus 2 infection - An observational study. Indian J Transplant 2022;16:180-3

How to cite this URL:
Somasundaram K, Thoppalan B, Chellaiah V, Kumar R P, Murugesan V, Thirumavalavan S. Clinical characteristics and immunosuppression management in kidney transplant recipients infected with severe acute respiratory syndrome coronavirus 2 infection - An observational study. Indian J Transplant [serial online] 2022 [cited 2022 Aug 15];16:180-3. Available from: https://www.ijtonline.in/text.asp?2022/16/2/180/349350




  Introduction Top


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first reported in December 2019 from Wuhan, China, which was then reported as pandemic by WHO in March 2020. As on December 2020, about were affected worldwide with percentage mortality. Immunosuppressed organ transplant recipients have high risk of viral and bacterial infections. The presentation and progression of infections in organ transplant recipients differ from immunocompetent hosts.[1] An earlier study reported kidney transplant recipients (KTR) with COVID-19 had lower CD3, CD4, and CD8 cell counts and more rapid clinical progression than persons with COVID-19 in the general population. The low CD3, CD4, and CD8 cell counts indirectly support the need to decrease doses of immunosuppressive agents in patients with COVID-19.[2] Their results were very high early mortality of 28% at 3 weeks as compared with the reported 1%–5% mortality among patients with COVID-19 (3 nejm).

When T-helper cells are key to successful control of SARS-CoV and the Middle East respiratory syndrome-related coronavirus, it may be probably true for SARS-CoV-2 as well, continuation of immunosuppression such as calcineurin inhibitors (CNI) and antimetabolites may exert harm in the management of this potentially fatal viral pneumonia.[3] Earlier management of immunosuppression was left to clinical judgment until the European Renal Association–European Dialysis and Transplant Association (ERA-EDTA) and DESCARTES Working Group formulated a consensus opinion which suggests reduction on immunosuppression based on the severity of COVID.[4] As treatment of COVID is evolving, currently practice of care includes antiviral therapies, steroids,[5] anticoagulants, and reduction of immunosuppressive drugs to allow specific immunity against virus.[5]

Herein, we report the impact of reduction of immunosuppression on graft function in 12 KTR.


  Methods and Materials Top


This study is an observational data of 12 KTR from a single center in South India. All hospitalized KTRs with COVID-19 during the period April 2020–December 2020 were included. They were diagnosed either by reverse transcriptase–polymerase chain reaction in throat and/or nasal swab or imaging.

Baseline characteristics such as age, sex, time since transplant, baseline kidney function, and comorbidities such as diabetes, hypertension, cardiovascular disease, and drug chart before admission were reviewed. Their disease severity was stratified and managed for COVID-19 according to the institutional protocol. The clinical features, vital parameters, and management protocol including oxygen requirement, antiviral therapy, steroids, and immunosuppression modification were reviewed and the outcome was analyzed. Their graft function during the hospital stay, at the time of discharge, and 30 days after discharge was also reviewed.

  • Mild: flu-like illness, Spo2 >94%
  • Moderate: symptoms + spo2 90%–93%
  • Severe: altered sensorium, chest tightness, shock, and spo2 <90%.


Statistical analysis

All the data collected were coded and entered in Microsoft Excel sheet which was rechecked and analyzed using IBM SPSS version statistics 20; Chicago, IL, USA. Quantitative variables were summarized using mean, median, and standard deviation. Categorical variables were represented using frequency and percentage.

Declaration of patient consent

The patient consent has been taken for participation in the study and for publication of clinical details and images. Patients understand that the names and initials would not be published, and all standard protocols will be followed to conceal their identity.

Ethics statement

The study was approved by Institutional Ethics committee. All guidelines of Declaration of Helsinki were followed. The study was performed according to the guidelines in Declaration of Helsinki.


  Results Top


We included 12 KTRs of whom the majority were males (83%). The median age of the study population was 37 years. The median time since transplant was 42 months. The comorbidities observed were diabetes in 50%, hypertension in 50%, and cardiovascular disease in 8% of patients. Thirty-three percent of patients had no comorbid condition. Fifty percent of them had underlying graft dysfunction. Ninety-two percent were in triple immunosuppression regimen including CNIs, mycophenolate, and steroids. One patient (8%) was receiving dual immunosuppression with tacrolimus and mycophenolate [Table 1].
Table 1: Demographics of the study population

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The presenting clinical features were fever, cough, myalgia, loose stools, shortness of breath, and loss of smell and taste. One patient was aymptomatic. Out of 12 patients, 5 (42%) had severe disease and 6 (50%) developed graft dysfunction. One patient (8%) died due to severe disease [Table 2].
Table 2: Clinical features

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Immunosuppression management

Eleven patients were taking CNI-based triple immuno suppressive therapy before admission. One was on steroid withdrawal protocol. After admission, antimetabolite was stopped irrespective of disease severity. In all patients, oral prednisolone was changed to parenteral dexamethasone 6 mg daily for 5–10 days based on clinical symptoms. After clinical recovery, prednisolone was restarted at 10 mg/day. One patient who was on steroid-free protocol also received dexamethasone 6 mg parenterally for 7 days. Both CNI and mycophenolate mofetil (MMF) were withheld in only one patient due to progressive disease.

After recovery, CNI was continued as before, antimetabolites were restarted after 2 weeks of clinical recovery, and dexamethasone was changed to oral prednisolone 10 mg after 5–10 days of treatment based on clinical status. For patient who was on steroid-free protocol, oral prednisolone was stopped and mycophenolate was restarted 1 week after discharge and safely continued on dual immunosuppression-like before.

Graft function recovered to baseline in five out of six patients at the time of discharge. We could follow up 10 patients after discharge and graft function remained close to baseline at 2 weeks and 4 weeks after discharge [Table 3].
Table 3: Outcome of the patients

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  Discussion Top


T-helper cells may play a major role in controlling SARS-CoV-2 infection-like other viral infections. In severe COVID infection, dysregulation and exhaustion of T-lymphocytes, namely decrease in the number and functionality of T-helper cells, have been described.[6],[7] Hence, continuation of drugs such as T-cell depleting agents, CNIs, and antimetabolites may exert harm in these patients. However, reducing them might cost the graft due to rejection. Since steroids are now routinely used in moderate-to-severe diseases, reducing other immunosuppressive agents may help to avoid complications of over immunosuppression.

Initially, when pandemic started, these drugs were tailored based on local hospital practice considering the clinical factors until Maggiore et al., on behalf of the DESCARTES Working Group of the ERA-EDTA, proposed a progressive approach of immunosuppression withdrawal for patients beyond 3–6 months of transplantation depending on the severity of SARS-CoV-2 infection.[4] It is actually expert opinion based on previously published results and no previous study has analyzed the impact of such strategy. According to ERA-EDTA, reducing or stopping antimetabolites and proliferation signal inhibitors to be considered even for asymptomatic high-risk transplant recipients. In case of severe disease, they suggest stopping both CNI and antimetabolites with increasing steroid dose.

Various studies published across countries had reduction of immunosuppressants in some form mostly reduction of antimetabolites.[2],[8],[9],[10],[11] In a study done from multicenters of India by Kute et al., antimetabolites (mycophenolate/azathioprine) were discontinued in the majority of patients (75%) and in other patients (23%), the dosage was reduced. CNIs were not changed in most patients (66%) but 20% of patients underwent a dose reduction. The dose of prednisolone was increased in 40% of cases, whereas no changes were made in the remaining 60%.[12]

We withdrew mycophenolate in all patients (100%) irrespective of disease severity on admission. CNI was stopped in one patient only (8%). Steroid dose was increased in all patients (100%). This is similar to a study done by Paula et al. from Spain, which included 47 patients where at least one drug was reduced in 80% of cases and MMF was the most discontinued drug.[13]

We restarted the original drug regimen a week after discharge. We found that reducing immunosuppressants did not result in graft dysfunction at 15- and 30-day follow-up. In Paula et al. study, despite reducing immunosuppressants, none of their patients developed de novo donor-specific antibodies (DSA) or rejection at 4-month follow-up.[13]

Limitations

It is a single-center observational study with small sample size. Modification of drugs based on the severity of disease may tell us more about adjusting drugs. Monitoring of DSA was not performed. Graft biopsy postrecovery could have told about subclinical inflammation and rejection.


  Conclusion Top


Reduction of immunosuppression, especially the withdrawal of antimetabolites, was found to be safe without graft rejection in KTRs.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Fishman JA. Infection in organ transplantation. Am J Transplant 2017;17:856-79.  Back to cited text no. 1
    
2.
Akalin E, Azzi Y, Bartash R, Seethamraju H, Parides M, Hemmige V, et al. COVID-19 and kidney transplantation. N Engl J Med 2020;382:2475-7.  Back to cited text no. 2
    
3.
Prompetchara E, Ketloy C, Palaga T. Immune responses in COVID-19 and potential vaccines: Lessons learned from SARS and MERS epidemic. Asian Pac J Allergy Immunol 2020;38:1-9.  Back to cited text no. 3
    
4.
Maggiore U, Abramowicz D, Crespo M, Mariat C, Mjoen G, Peruzzi L, et al. How should I manage immunosuppression in a kidney transplant patient with COVID-19? An ERA-EDTA DESCARTES expert opinion. Nephrol Dial Transplant 2020;35:899-904.  Back to cited text no. 4
    
5.
Alberici F, Delbarba E, Manenti C, Econimo L, Valerio F, Pola A, et al. A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia. Kidney Int 2020;97:1083-8.  Back to cited text no. 5
    
6.
Razonable RR. Management of viral infections in solid organ transplant recipients. Expert Rev AntiInfect Ther 2011;9:685-700.  Back to cited text no. 6
    
7.
Qin C, Zhou L, Hu Z, Zhang S, Yang S, Tao Y, et al. Dysregulation of immune response in patients with coronavirus 2019 (COVID-19) in Wuhan, China. Clin Infect Dis 2020;71:762-8.  Back to cited text no. 7
    
8.
Pereira MR, Mohan S, Cohen DJ, Husain SA, Dube GK, Ratner LE, et al. COVID-19 in solid organ transplant recipients: Initial report from the US epicenter. Am J Transplant 2020;20:1800-8.  Back to cited text no. 8
    
9.
Bossini N, Alberici F, Delbarba E, Valerio F, Manenti C, Possenti S, et al.; Brescia Renal COVID Task Force. Kidney transplant patients with SARS-CoV-2 infection: The Brescia Renal COVID task force experience. Am J Transplant 2020;20:3019-29.  Back to cited text no. 9
    
10.
Caillard S, Anglicheau D, Matignon M, Durrbach A, Greze C, Frimat L, et al.; French SOT COVID Registry. An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants. Kidney Int. 2020;98:1549-58.  Back to cited text no. 10
    
11.
Kates OS, Haydel BM, Florman SS, Rana MM, Chaudhry ZS, Ramesh MS, et al. Coronavirus disease 2019 in solid organ transplant: A multicenter cohort study. Clin Infect Dis 2021;73:e4090-9. [Epub ahead of print. August 7, 2020].   Back to cited text no. 11
    
12.
Kute VB, Bhalla AK, Guleria S, Ray DS, Bahadur MM, Shingare A, et al. Clinical profile and outcome of COVID-19 in 250 kidney transplant recipients: A multicenter cohort study from India. Transplantation 2021;105:851-60.  Back to cited text no. 12
    
13.
Paula AP, Trujillo H, Melilli E, Urban B, Sandino J, Favá A, et al. Immunosuppression minimization in kidney transplant recipients hospitalized for COVID-19. Clin Kidney J 2021;14:1229-35.  Back to cited text no. 13
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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