key: cord-0775765-x7xh8jwb
authors: Karruli, Arta; Spiezia, Serenella; Boccia, Filomena; Gagliardi, Massimo; Patauner, Fabian; Salemme, Anna; Maiello, Ciro; Zampino, Rosa; Durante‐Mangoni, Emanuele
title: Effect of immunosuppression maintenance in solid organ transplant recipients with COVID‐19: Systematic review and meta‐analysis
date: 2021-03-18
journal: Transpl Infect Dis
DOI: 10.1111/tid.13595
sha: e04e708a0fda548c6e666dfdce2b7debb40dc29c
doc_id: 775765
cord_uid: x7xh8jwb

BACKGROUND: The aim of this study was to assess the effect of continuing immune suppressive therapy in solid organ transplant recipients (SOTR) with coronavirus disease 2019 (COVID‐19). METHODS: Systematic review and meta‐analysis of data on 202 SOTR with COVID‐19, published as case reports or case series. We extracted clinical, hemato‐chemical, imaging, treatment, and outcome data. RESULTS: Most patients were kidney recipients (61.9%), males (68.8%), with median age of 57 years. The majority was on tacrolimus (73.5%) and mycophenolate (65.8%). Mortality was 18.8%, but an equal proportion was still hospitalized at last follow up. Immune suppressive therapy was withheld in 77.2% of patients, either partially or completely. Tacrolimus was continued in 50%. One third of survivors that continued immunosuppressants were on dual therapy plus steroids. None of those who continued immunosuppressants developed critical COVID‐19 disease. Age (OR 1.07, 95% CI 1‐1.11, P = .001) and lopinavir/ritonavir use (OR 3.3, 95%CI 1.2‐8.5, P = .013) were independent predictors of mortality while immunosuppression maintenance (OR 0.067, 95% CI 0.008‐0.558, P = .012) and tacrolimus continuation (OR 0.3, 95% CI 0.1‐0.7, P = .013) were independent predictors of survival. CONCLUSIONS: Our data suggest that maintaining immune suppression might be safe in SOTR with moderate and severe COVID‐19. Specifically, receiving tacrolimus could be beneficial for COVID‐19 SOTR. Because of the quality of the available evidence, no definitive guidance on how to manage SOTR with COVID‐19 can be derived from our data.

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China in 2019 and rapidly spread worldwide 1 causing the new disease named Coronavirus Disease 2019 . 2 Mechanisms of pathogenicity of SARS-CoV-2 have yet to be fully understood. In a review by Saddiqi and Mehra, 3 a three stage classification of COVID-19 clinical course, regardless of the baseline immune state, has been proposed. Stage 1 spans from inoculation to initial clinical symptoms. Following viral attachment to the ACE2 receptors, located in the lung, small intestine epithelium, and vascular endothelium, primary manifestations are respiratory, gastrointestinal and systemic. 4, 5 During this phase, lymphopenia may ensue. hyper-inflammation syndrome, with major increase of inflammatory cytokines and biomarkers such as C-reactive protein (CRP), IL6, IL2r, IL7, ferritin, and D-dimer. 6 High levels of inflammatory cytokines and biomarkers correlate with a higher score of lung involvement on CT scan. Lung CT scan score can be used to identify severe cases, and the inflammatory storm and hypercoagulability can indicate a higher risk of progressing to multiorgan failure and death. 7 Being a viral illness, COVID-19 could have a more complicated course in immunosuppressed hosts. However, the important role of the immune response in the late stages of the disease raises the question as to whether immune suppression could actually be protective in terms of disease progression. On the other hand, immune suppression could hamper or delay viral control generating a more prolonged immune stimulation, translating into a more severe clinical course and a higher chance of a negative outcome.

At present, COVID-19 clinical course and outcome in immune compromised patients, including solid organ transplant recipients (SOTR), seems to be grim, with mortality ranging between 20% and 30%. [8] [9] [10] Interestingly, most data published so far show the majority of SOTR with COVID-19 have either partially or completely withdrawn immune suppressive therapy. In an attempt to improve our understanding of the effects of ongoing immune suppressive therapy in COVID-19 SOTR, we performed a systematic literature review. We aimed to describe in better detail the clinical features and the outcome of COVID-19 in SOTR, with a specific focus on the effects of immune suppression changes.

This study is an individual patient data meta-analysis of SOTR with COVID-19. Publications in any form, including conference presentations, journal articles and non-peer-reviewed advance access publications, reporting data on SOTR with COVID-19, from January 1, 2020 to July 12 2020 were searched through PubMed, OVID, and Google Scholar. The search terms included "COVID-19," "transplant," "solid organ recipient," "SARS-CoV-2 infection."

Articles were included in our analysis if they provided information about every patient ≥18 years old and not presented in a collective manner but as single patient data. Thus, case reports and case series, regardless of the number of patients described, which provided information about each included case, were used. Articles were scrutinized for data retrieval and corresponding authors were contacted in order to obtain missing information if a specific information was not included in their article.

All relevant publications were used, irrespective of origin and type of article. While we searched for studies regardless of their language, only studies reported in English were included.

Two investigators selected articles, evaluated the quality of the studies selected and entered findings independently into a database using data provided in figures, tables, and text. In case of disagreement, each case was discussed and controversy resolved through debate and mutual consensus. We ensured no overlapping data were used by giving a unique ID to each case included in the dataset.

All SOTR patients ≥18 years old with confirmed SARS-CoV-2 infection through nasopharyngeal/oropharyngeal swab.

Non solid organ transplant recipients and patients younger than 18 years were excluded.

For each patient, we extracted general clinical data, hematochemical parameters, chest imaging results, treatments received and disease outcome. Among the clinical data we sought, there were: age, sex; organ transplanted; immune suppressive regimens used; symptoms at onset of COVID-19; timing of COVID-19 relative to transplant; interval from symptom onset to hospital admission; comorbidities. Hemato-chemical parameters considered were blood cell count and differential, lactate dehydrogenase, C-reactive protein, procalcitonin, creatinine, alanine/aspartate aminotransferases (ALT/AST), D-dimer, ferritin, interleukin-6, tacrolimus plasma levels.

Presence of chest CT abnormalities compatible with COVID-19 was noted. A detailed analysis of immune suppressing agents used at onset and their handling during the disease course was performed.

We also extracted and analyzed data on antiviral and/or immune modulating agent administration. Clinical classification was based on the worst clinical stage the patient progressed to. Accordingly, cases were classified in mild, moderate, severe and critical disease according to WHO guidelines. 11 Mild disease was defined as symptomatic patients meeting the case definition for COVID-19 without evidence of viral pneumonia or hypoxia; moderate disease as pneumonia without respiratory failure; severe disease as severe pneumonia with respiratory failure and oxygen saturation <90%; and critical disease as acute respiratory distress syndrome (ARDS). Predefined outcome considered was patient death.

Most analyses were performed on data obtained at the time of admission. Numerical variables were presented as median and interquartile range (IQR), while categorical variables as number and percentage. The statistical significance of differences was evaluated by chi-square or Fisher's exact test for categorical variables and by Mann-Whitney U test for numerical variables. Items associated to outcomes at univariate analysis (P <.05) were included in a multivariate logistic regression model to identify covariates independently associated with the outcome of interest. All analyses were carried out with the aid of SPSS 25 (IBM, Armonk, NY, USA) with the assumption of a P-value ≤.05 as indicative of statistical significance of the observed differences and using two-sided tests.

The literature search identified 790 articles. After exclusion of articles not regarding COVID-19 in SOTR, or articles regarding opinions, different protocols, or concerns about COVID-19 in SOTR, we identified 88 unique papers regarding COVID-19 in SOTR, including case reports, single-or multi-center studies irrespective of whether presenting information in a collective or single patient manner. Subsequently, after a full text review, we included in our analysis a total of 201 SOTR with COVID-19 from 67 articles 10, that met the inclusion criteria plus 1 case, a kidney transplant recipient admitted to our hospital. All articles except one (which was a preprint) were journal articles. The flow diagram of the literature search with exclusion criteria is presented in Figure 1 

The majority of patients were on a tacrolimus and mycophenolate regimen ( As shown in Table S1 , COVID-19 outcome was not different in recipients grouped according to transplant duration, although differences were observed. Recently transplanted patients were younger (P =.023). The proportion of patients receiving tacrolimus (P < .001),

and steroids (P =.032) was higher among those more recently transplanted and the opposite occurred for cyclosporin A (P =.001). There were no differences in terms of COVID-19 treatment between the two groups.

Definitive cure, defined as discharge to home after hospitalization and/or no need for further COVID-19 treatment for hospitalized or nonhospitalized patients, was reported in 61.4% of cases.

Reported mortality was 18.8%, while 18.8% patients were still in hospital at the latest follow up and in 1% outcome was not specified. After excluding patients who were still hospitalized at the time of the report and those with unspecified outcome, we performed an analysis of factors associated with hospital mortality in 162 SOTR with COVID-19 (Table 2 ). An older age (P < .001), higher

WBC, yet in the normal range (P =.035), higher LDH, IL-6, ferritin (P =.004, P =.002, P =.006) along with presence of respiratory symptoms (P =.016), presence of abnormal lung CT scan at hospitalization (P =.024), and treatment with lopinavir or darunavir regimens (P < .001, P =.038), invasive ventilation therapy (P =.000)

were associated with a higher risk of mortality, while maintenance of previous immune suppression (P < .001) and ongoing treatment with tacrolimus (P < .001) were protective in terms of mortality.

We then included in a multivariate analysis the four variables more strongly associated with mortality on the univariate analysis. Age (OR 1.07, 95% CI 1-1.11, P =.001) and treatment with a lopinavir-based regimen (OR 3.3, 95% CI 1.2-8.5, P =.013) were independent predictors of mortality while no change to the immune suppression therapy (OR 0.067, 95% CI 0.008-0.558, P =.012) and

continuation of tacrolimus (OR 0.3, 95% CI 0.1-0.7, P =.013) were independent predictors of survival ( Table 2) .

Comparison of patients who did not change their immune suppression therapy with those that changed their therapy either partially or completely is presented in Table 3 . The group that underwent changes to their immune suppression did not have more comorbidities but had a higher rate of hypertension (P =.001), a higher prevalence of mycophenolate (P =.001) and steroid treatment (P =.003), and had higher white blood cell count (P =.011), LDH (P =.028), and creatinine (P =.008). Also, these subjects had more often symptoms such as fever (P <.001) and pulmonary imaging positivity on diagnosis (P <.001), although lymphopenia was seen in both groups and respiratory symptoms, fever and abnormal pulmonary imaging were seen in more than 50% of cases continuing immune suppressive treatment. In the group that continued previous immune suppression, the worst COVID-19 disease stages observed were moderate and severe (33.3% and 35.8%). In contrast, most patients who underwent changes in their immune suppressive regimen progressed to severe and critical disease (45.4% and 35.6%) (P < .001 for comparison, Table 3 ).

In survivors who did not change regimen, 33.3% received dual therapy plus steroids, 12.8% dual therapy without steroids, 17.9% dual therapy including steroids and 35.8% received one drug (Table S2) . Only 1 patient on dual therapy plus steroid died.

Sparse data were available regarding bacterial coinfection during hospitalization. Also, no information was found regarding thromboembolic complications.

Comparing patients that continued tacrolimus with those who withdrew it or did not receive any tacrolimus (Table 4) , no differences were seen in terms of general comorbidities, although those who continued had more diabetes (P =.003), shorter transplant duration (P < .001), higher LDH (P =.015), lower CRP (P =.025),

and lower creatinine (P =.022). They also had lower rates of fever and abnormal pulmonary imaging at diagnosis (P =.014, P =.019),

although more than 70% of them were symptomatic and with positivity to imaging and 36% needed invasive ventilation. In the two In both groups the withdrawal of immune suppressive treatment and/or tacrolimus was associated with a greater use of steroids, lopinavir, and anti-interleukin-6 treatment.

Mycophenolate was continued in 34 patients (17%). Comparing patients that continued with those who withdrew or did not receive mycophenolate (Table 5 ), no differences were seen in terms of comorbidities and symptoms at diagnosis. However, patients treated with mycophenolate had lower LDH (P =.020), lower rates of hydroxychloroquine (P =.003), steroid (P =.016), and anti-IL-6 treatment (P =.050), and a better survival (P =.028). The rate of de novo steroid treatment was 7.8% in those who withdrew mycophenolate and 5.8% in those who did not (P = 1.000).

No differences in terms of outcome was seen between groups that continued only calcineurin inhibitors (CNI), only mycophenolate or both (Table S3 ). 

(Continues) data suggest that mortality was actually lower in SOTR who did not undergo changes to immune suppressive therapy. Up to 60% of patients who did not have their immune suppressive regimen changed were symptomatic and showed pulmonary imaging positive for COVID-19 pneumonia, suggesting that at baseline the disease could have progressed toward more severe stages also in these patients.

In a recent report, maintaining the immune suppressive therapy was recommended only for asymptomatic or milder cases, without high risk conditions (including comorbidities), and was not recommended in those receiving dual therapy plus steroids. 81 mycophenolate was shown to have antiviral activity against MERS-CoV by inhibiting Papain-like protease, a protein found to regulate viral spread for SARS-CoV-2 too. 96 Our data suggest that mycophenolate also exerted a protective effect in terms of COVID-19 mortality, although to a lower extent than tacrolimus.

Treatment with lopinavir was not associated with survival, in line with previous studies. 97, 98 In SOTR, many patients withdrew tacrolimus to start lopinavir/ritonavir because of their pharmacokinetic interaction, making it particularly difficult to give both drugs concurrently. 99 Our study has several limitations, mostly inherent to the type of analyzed data. For many patients follow up was not complete and many were still hospitalized at the time of reporting. However, we did not include this subset of patients in the analysis of outcome. We could not provide any data on mid-term follow up or other transplant related outcomes, including de novo donor specific antibody formation or subsequent graft loss. The beneficial effect of continuing immune suppression could have been the result of confounders that, based on available data, could not be accounted for in our analysis.

Also, we acknowledge that the therapeutic approach used in included patients may be outdated because of fast changing knowledge on this new disease. Finally, we could not provide definitive data on the timing of immune modification in relation to the time course of infection.

In conclusion, our study suggests that ongoing immune suppressive therapy may be safe in moderate and severe COVID-19 SOTR, and that treatment with tacrolimus and, possibly, mycophenolate, may be associated with survival. Further studies are needed to corroborate our results and to provide further answers to the question of how to optimally manage immune suppression in SOTR with COVID-19. Because of the quality of the available evidence, we could not provide more definitive guidance on how to manage SOTR with COVID-19.

The authors declare no conflicts of interest.

AK, RZ, EDM worked on concept of the study; SP, AS worked on data collection and data interpretation; FB, FP, MG worked on statistical analysis; AK, RZ and EDM drafted the manuscript; CM and all authors critically revised the manuscript.

The dataset generated for this study are available on request to the corresponding author. 

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Emerging coronaviruses: genome structure, replication, and pathogenesis

COVID-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal

Review of the clinical characteristics of coronavirus disease 2019 (COVID-19)

Epidemiology, causes, clinical manifestation and diagnosis, prevention and control of coronavirus disease (COVID-19) during the early outbreak period: a scoping review

Laboratory abnormalities in patients with COVID-2019 infection

Multiple enzyme release, inflammation storm and hypercoagulability are prominent indicators for disease progression in COVID-19: a multi-centered, correlation study with CT imaging score

Covid-19 and kidney transplantation

COVID-19 in solid organ transplant recipients: a single-center experience

A single center observational study of the clinical characteristics and short-term outcome of 20 kidney transplant patients admitted for SARS-CoV2 pneumonia

Clinical management of COVID-19

COVID-19 infection in kidney transplant recipients

Case report of COVID-19 in a kidney transplant recipient: does immunosuppression alter the clinical presentation?

Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression

COVID-19 in post-transplantation patients-report of two cases

Successful treatment of severe COVID-19 pneumonia in a liver transplant recipient

A familial cluster, including a kidney transplant recipient

SARS Cov2 infection in a renal transplanted patient. A case report

COVID-19 in kidney transplant recipients

Novel coronavirus infection and acute kidney injury in two renal transplant recipients: case report

Perioperative presentation of COVID-19 disease in a liver transplant recipient

First cases of COVID-19 in heart transplantation from China

Immunosuppressive therapy maintenance in a kidney transplant recipient SARS-CoV-2 pneumonia: a case report

Novel coronavirus (SARS-CoV-2) infection in a renal transplant recipient: case report

First case of COVID-19 in a kidney transplant recipient treated with belatacept

Fatal outcome in a liver transplant recipient with COVID-19

COVID-19 in solid organ transplant recipients: a single-center case series from Spain

COVID-19 in recent heart transplant recipients: clinicopathologic features and early outcomes

Successful treatment of severe COVID-19 pneumonia with clazakizumab in a heart transplant recipient: a case report

COVID-19 leading to acute encephalopathy in a patient with heart transplant

Early experience of COVID-19 in 2 heart transplant recipients: case reports and review of treatment options

Heart transplant recipient patient with COVID-19 treated with tocilizumab

COVID-19 in a high-risk dual heart and kidney transplant recipient

COVID-19 in a lung transplant recipient

Severe COVID-19 in a renal transplant recipient: a focus on pharmacokinetics

COVID-19 in kidney transplant recipients

Clinical outcomes and serologic response in solid organ transplant recipients with COVID-19: a case series from the United States

Low prevalence and disease severity of COVID-19 in post-liver transplant recipients-a single centre experience

Convalescent plasma therapy: helpful treatment of COVID-19 in a kidney transplant recipient presenting with severe clinical manifestation and complex complications

Withdrawing mycophenolate mofetil in treating a young kidney transplant recipient with COVID-19: a case report

Two distinct cases with COVID-19 in kidney transplant recipients

Renal infarct in a COVID-19-positive kidney-pancreas transplant

COVID-19 in an HIV-positive kidney transplant recipient

Earliest cases of coronavirus disease 2019 (COVID-19) identified in solid organ transplant recipients in the United States

COVID-19 in lung transplant recipients: a case series from

Early COVID-19 infection after lung transplantation

SARS-CoV-2 infection in two patients following recent lung transplantation

Clinical characteristics and immunosuppressant management of coronavirus disease 2019 in solid organ transplant recipients

Successful recovery from severe COVID-19 pneumonia after kidney transplantation: the interplay between immunosuppression and novel therapy including tocilizumab

COVID-19 in lung-transplanted and cystic fibrosis patients: be careful

COVID-19 pneumonia in a dual heart-kidney recipient

Case series of six kidney transplanted patients with COVID-19 pneumonia treated with tocilizumab

Viral shedding prolongation in a kidney transplant patient with COVID-19 pneumonia

COVID-19 pneumonia in a kidney transplant recipient successfully treated with tocilizumab and hydroxychloroquine

A case report of oligosymptomatic kidney transplant patients with COVID-19: do they pose a risk to other recipients

Threatening drug-drug interaction in a kidney transplant patient with coronavirus disease 2019 (COVID-19)

in an orthotopic liver transplant recipient living with human immunodeficiency virus

Virus C. pneumonia in a kidney transplant recipient

SARS-CoV-2 infection in kidney transplant recipients

Fatal SARS-CoV-2 infection in a renal transplant recipient

Tocilizumab therapy in five solid and composite tissue transplant recipients with early ARDS due to SARS-CoV-2

A case of SARS-CoV-2 pneumonia with successful antiviral therapy in a 77-year-old man with a heart transplant

Interleukin-6 receptor antagonist therapy to treat SARS-CoV-2 driven inflammatory syndrome in a kidney transplant recipient

Varied clinical presentation and outcome of SARS-CoV-2 infection in liver transplant recipients: initial experience at a single center

Failed antibody response in a renal transplant recipient with SARS-CoV-2 infected

Care of asymptomatic SARS-CoV-2 positive kidney transplant recipients

SARS-CoV-2 infection in kidney transplant recipients: experience of the Italian Marche region

Immunosuppressive therapy maintenance in a kidney transplant recipient with SARS-CoV-2 pneumonia: a case report

Clinical course of COVID-19 in a liver transplant recipient on hemodialysis and response to tocilizumab therapy: a case report

A case of successful treatment of severe COVID-19 pneumonia with favipiravir and tocilizumab in post-kidney transplant recipient

COVID-19 and liver transplantation: lessons learned from three reported cases

Coronavirus disease 2019 (COVID-19) in a renal transplant patient

COVID-19 infection in kidney transplant recipients: a single-center case series of 22 cases from

Incidental COVID-19 in a heart-kidney transplant recipient with malnutrition and recurrent infections: implications for the SARS-CoV-2 immune response

Case report: a kidney transplant patient with mild COVID-19

Clinical characteristics of coronavirus disease 2019 in China

Comorbidity and its impact on 1590 patients with Covid-19 in China: a Nationwide Analysis

Clinical characteristics of coronavirus disease 2019 (COVID-19) in China: a systematic review and metaanalysis

Case-fatality rate and characteristics of patients dying in relation to COVID-19 in Italy

Baseline characteristics and outcomes of 1591 patients infected with SARS-CoV-2 admitted to ICUs of the Lombardy Region

How should I manage immunosuppression in a kidney transplant patient with COVID-19? An ERA-EDTA DESCARTES expert opinion

Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China

On the alert for cytokine storm: immunopathology in COVID-19

COVID-19 and calcineurin inhibitors: should they get left out in the storm?

Associations between immunesuppressive and stimulating drugs and novel COVID-19-a systematic review of current evidence

Kidney allograft recipients diagnosed with coronavirus disease-2019: a single center

Should cyclosporine be useful in renal transplant recipients affected by SARS-CoV-2

Modulating immunosuppression in liver transplant patients with COVID-19

Association between administration of systemic corticosteroids and mortality among critically ill patients with COVID-19: a meta-analysis

Corticosteroids in COVID-19 ARDS: evidence and hope during the pandemic

European Renal Association-European Dialysis and Transplant Association

Purine metabolism and immunosuppressive effects of mycophenolate mofetil (MMF)

The impact of COVID-19 on kidney transplantation

Thiopurine analogs and mycophenolic acid synergistically inhibit the papain-like protease of Middle East respiratory syndrome coronavirus

Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity

A trial of lopinavir-ritonavir in adults hospitalized with severe Covid-19

Early administration of lopinavir/ritonavir plus hydroxychloroquine does not alter the clinical course of SARS-CoV-2 infection: a retrospective cohort study

Tacrolimus and lopinavir/ ritonavir interaction in liver transplantation

Effect of immunosuppression maintenance in solid organ transplant recipients with COVID-19: Systematic review and meta-analysis