key: cord-1041036-4gb2qbm1 authors: Maritati, Federica; Cerutti, Elisabetta; Zuccatosta, Lina; Fiorentini, Alessandro; Finale, Carolina; Ficosecco, Marta; Cristiano, Fabrizio; Capestro, Alessandro; Balestra, Emilio; Taruscia, Domenica; Vivarelli, Marco; Donati, Abele; Perna, Gian Piero; Giacometti, Andrea; Tavio, Marcello; Onesta, Maicol; Di Sante, Laura; Ranghino, Andrea title: SARS‐CoV‐2 infection in kidney transplant recipients: experience of the italian marche region date: 2020-06-23 journal: Transpl Infect Dis DOI: 10.1111/tid.13377 sha: 664b644cac01d4c6bde6468dd7f81757159e97d7 doc_id: 1041036 cord_uid: 4gb2qbm1 BACKGROUND: Infection related to Coronavirus‐19 (CoV‐2) is pandemic affecting more than 4 million people in 187 countries worldwide. By May, 10 2020 it caused more than 280.000 deaths all over the world. Preliminary data reported a high prevalence of CoV‐2 infection and mortality due to severe acute respiratory syndrome‐related to CoV‐2 (SARS‐CoV‐2) in kidney transplanted patients (KTRs). Nevertheless, the outcomes and the best treatments for SARS‐CoV‐2 affected KTRs remain unclear. METHODS: In this report we describe the clinical data, the treatments and the outcomes of 5 KTRs with SARS‐CoV‐2 admitted to our hospital in Ancona, Marche region, Italy, from March, 17 to present. Due to the severity of SARS‐CoV‐2, immunosuppression with calcineurin inhibitors, antimetabolites and mTOR‐inhibitors were stopped at the admission. All KTRs were treated with low‐dose steroids. 4/5 KTRs were treated with hydroxychloroquine. All KTRs received tocilizumab up to one dose. RESULTS: Overall, the incidence of SARS‐CoV‐2 in KTRs in the Marche region was 0.85%. 3/5 were admitted in ICU and intubated. One developed AKI with the need of CRRT with Cytosorb. At present 2 patients died, 2 patients were discharged and one is still inpatient in ICU. CONCLUSIONS: The critical evaluation of all cases suggests that the timing of the administration of tocilizumab, an interleukin‐6 receptor antagonist, could be associated with a better efficacy when administered in concomitance to the drop of the oxygen saturation. Thus, in SARS‐CoV‐2 affected KTRs a close biochemical and clinical monitoring should be set up to allow physicians to hit the virus in the right moment such as a sudden reduction of the oxygen saturation and/or a significant increase of the laboratory values such as D‐Dimer. Coronavirus disease 2019 (Covid-19) represents a major challenge for health system worldwide due to its pandemic spread and its associated mortality rate 1, 2 . By May, 10 2020 it caused more than 280.000 deaths all over the world. Italy is one of the countries with more infected patients (219.070) and deaths (30.560) 3 . Specifically, in the Marche region of Italy, the prevalence of Covid-19 infection in the general population is 0.41% 4 . The case fatality rate of infection varies between countries worldwide and it is about 13.4 % in general population in Italy 3 . Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the leading cause of death in patients affected by Covid-19 disease both in general population and in kidney transplanted recipients (KTRs) 2,5-8 . Several therapeutic approaches have been proposed starting from the first case of SARS-CoV-2 affected kidney transplant recipient described by Zhu et al in February 2020 9 . Briefly, the most used drugs were antivirals such as lopinavir/ritonavir, antibiotics such as azithromycin, anti-malaria drugs with anti-inflammatory properties such as hydroxychloroquine, high-doses glucocorticoids and tocilizumab, an interleukin-6 receptor antagonist 10- 15 . In addition, leronlimab (PRO 140, CytoDyn), a CCR5 inhibitor was used on a compassionate-use basis 5 . Some centers also used high doses intravenous immunoglobulin (IVIg) and interferon   . Recently, remdesivir, a nucleotide analogue that inhibits viral RNA polymerase has been proven to be effective in the 68% of 53 patients hospitalized for SARS-CoV-2 16 . However, the limitations of the published reports on SARS-CoV-2 affected KTRs such as i) the small sample size and ii) the heterogeneous association between the medications used along with their variable timing of drug administration, do not allow to evaluate their real efficacy. Herein, we describe the clinical course and the patient and graft outcomes of 5 KTRs admitted to our hospital with SARS-CoV-2. This article is protected by copyright. All rights reserved All KTRs resident in the Marche region, Central Italy, who developed SARS-CoV-2 admitted in the AOU Ospedali Riuniti of Ancona, by March 10, 2020 have been included. The presence of SARS-CoV-2 RNA in nasopharyngeal swab or bronchoalveolar lavage was assessed by RealTime RT-PCR using primers and probes covering two regions of the SARS-CoV-2 N gene as described in the CDC published protocols, the human RNaseP gene was also evaluated for swab cellularity check and sample validation, interstitial pneumonia was confirmed by chest-X-ray and CT scan. According to the severity of SARS-CoV-2, immunosuppression (IS) with calcineurin inhibitors (CNI) (tacrolimus, Tac and cyclosporine, CsA), antimetabolites (mycophenolic acid, MPA) and mTOR-inhibitors (sirolimus, SRL) were stopped at the admission. All KTRs were treated with low-dose steroids (methylprednisolone, MP) 16 mg/d. All KTRs with SARS-CoV-2 except one were treated with hydroxychloroquine adjusted for the GFR and antibiotics at the admission. QTc interval was strictly monitored in all patients. Antiviral therapy with lopinavir/ritonavir was adopted only for two KTRs with SARS-CoV-2 admitted on March 17 and 18, 2020 respectively and subsequently stopped after few days. The decision to stop earlier the therapy with lopinavir/ritonavir was made on the basis of the reported negative results 17 . For the same reasons, we decided not to adopt antiviral therapy in the subsequently admitted KTRs. All KTRs were treated with up to one dose of tocilizumab (8 mg/Kg of body weight, maximum dose per infusion 800 mg). High-dose immunoglobulin intravenously (IVIg) (0.4 g/Kg of body weight per day for 5 consecutive days, maximum cumulative dose 140 g) were administrated only in two KTRs. CMV infection was treated with ganciclovir according to the eGFR. All KTRs received antithrombotic prophylaxis with low molecular weight heparin (LMWH) with an anti-factor Xa target range of 0.6-1.0 IU/mL. Overall, the incidence of SARS-CoV-2 in KTRs resident in the Marche region, Italy, and admitted to our hospital was 0.85% (5/585). Median age was 72 years (range 51-73 years). 2/5 KTRs were women. 3/5 KTRs were admitted in intensive care unit (ICU) due to the need of intubation. One of 5 KTRs developed acute kidney injury (AKI) with the need of continuous renal replacement therapy (CRRT) along with hemoadsorption with Cytosorb. At present 2 patients died, 2 patients were discharged and one is still inpatient in ICU. Clinical characteristics, outcomes and laboratory values are summarized in Table 1 and 2. Herein, we reported a brief description of the cases. This article is protected by copyright. All rights reserved Due to a long QTc interval, hydroxychloroquine was not added to therapy. At admission, peripheral oxygen saturation was 98% with Venturi mask FiO2 0,6. On day 14 after admission peripheral oxygen saturation dropped to 94% with the same amount of oxygen delivery. On the same day the levels of D-dimer increased from 217 ng/ml to 5694 ng/ml. A CT scan of the chest revealed an increase of the patchy consolidation of the lungs and excluded a pulmonary embolism. Thus, a single dose of tocilizumab has been administrated. Two days after tocilizumab administration the patient fell well, peripheral oxygen saturation rose to 98% without oxygen support, D-Dimer returned to normal level and the patient was discharged on day 34 after admission. The patient was discharged after two consecutive nasopharyngeal swab resulted SARS-CoV-2 RNA not detected. Graft function remained stable. This article is protected by copyright. All rights reserved included Tac (trough levels: 6-8 ng/ml), MPA 180mg bid and Pred 5mg/d. She is affected by hypertension and ischemic cardiac disease. The chest X-ray revealed bilateral patchy consolidation that was confirmed with a CT scan. Since the admission, she was treated with a CPAP. On day 1 she developed an episode of atrial fibrillation associated to atrial flutter that were resolved with amiodarone and antithrombotic therapy with LMWH. Tac and MPA were stopped since day one after the admission MP 16 mg/d was started together with hydroxychloroquine and antibiotics. She was treated from day 8 to 12 with IVIg. On day 17 after admission the P/F ratio dropped to lower than 100 compared to values higher than 200 registered in the previous days. Tocilizumab was administered in the evening of the same day and a second dose of tocilizumab has been administrated the day after. Few days after tocilizumab therapy the patient fell very well. This article is protected by copyright. All rights reserved Her peripheral oxygen saturation rose to 98% without oxygen support and the pathological lesions of the lung were significant reduced compared to the basal as shown in Figure 1 . The patient was discharged on day 32 after two consecutive nasopharyngeal swab resulted SARS-CoV-2 RNA not detected. Graft function at the discharge was good with an eGFR of 63.4 ml/min per 1.73 m 2 . In this report we describe the clinical courses and the outcomes of the first five cases of kidney Based on the encouraging data on the efficacy of tocilizumab 15, 18 , an interleukin-6 receptor antagonist, we treated all KTRs with at least one infusion intravenously of tocilizumab. We found a dramatic improvement of the respiratory values and a significant reduction of the lung lesions demonstrated by CT scan in two patients few days after tocilizumab. The common denominator of the recovery of such patients is the timing of tocilizumab administration. In fact, the drug was administrated in concomitance to the drop of the oxygen saturation. In one of these two patients, besides the reduction of the oxygen saturation in the blood for the same amount of oxygen delivery, the concomitant dramatic increase of the D-Dimer was considered to decide tocilizumab This article is protected by copyright. All rights reserved administration. Thus, our feeling is that at least in part the efficacy of tocilizumab on SARS-CoV-2 infected patients is related to the timing of the administration. In two cases, as reported by other centers 8 , we administrated high doses of immunoglobulin for their proven immunomodulatory effect 21 . Consistently with the suggested pathogenesis of the lung damage induced by Covid-19 infection that at least in part could be related to a cytokine storm including IL-6 release 22 , we speculated that the removal of IL-6 by using an absorbed column namely Cytosorb could potentiate the effect of tocilizumab. Indeed, the hemofiltration with Cytosorb has been demonstrated to be efficacious in the removal of IL-6 in patients with septic shock [23] [24] [25] . Due to the absence of clear guidelines on the use of Cytosorb in SARS-CoV-2 affected KTRs and the fact that Cytosorb contemplates an extracorporeal treatment, as hemoadsorption alone or in combination with a continuous renal replacement therapy (CRRT), we decided to use it only in patients who developed AKI and very high levels of IL-6. Only one patient in our report was treated with hemoadsorption with Cytosorb associated to CRRT. The indication for CRRT in such patient was the reduction of the kidney graft function with oliguria due to renal hypoperfusion in the context of a sepsis caused by Enterococcus faecium. Serum level of IL-6 prior to Cytosorb were 11854 pg/ml. During CRRT treatment plus Cytosorb hemodynamic and hypoxemia ameliorated. The cytokine storm caused by Covid-19 infection has been suggested to be controlled also with high doses glucocorticoids but recent data did not support their use due to the associated increase of the viral load 26 . Moreover, a potential benefit of calcineurin inhibitor especially of cyclosporin in controlling the cytokine storm has been suggested at least in mild SARS-CoV-2 infected KTRs, therefore in these patients maintaining CNI at low dose rather than its withdrawal should be taken in consideration 27, 28 . In our cases we decided to stop any immunosuppressive medication except steroids because of the severity of the SARS-CoV2. Since it has been proven the role of angiotensin receptor (ATR) in the pathogenesis of Covid-19 infection by demonstrating the binding of the virus on ATR, it has been speculated that treatment with angiotensin converting enzyme inhibitors (ACEi) could be associated to an increased risk of Covid-19 infection 29, 30 . For the same reasons the angiotensin receptor antagonist (ARB) could be protective by blocking the binding of the virus to the ATR 31 . In our report none of the 5 SARS-CoV2 affected KTRs were treated with ACEi or ARB prior the infection. This article is protected by copyright. All rights reserved In conclusion, our report confirmed the high mortality rate of SARS-CoV2 as reported by other authors in kidney transplant recipients especially in those who are older and with comorbidities. Nevertheless, also patients younger than 60 years and with apparent no comorbidities could be severely affected by SARS-CoV2. Interestingly, in our opinion is the fact that SARS-CoV2 pneumonia gets worse even when the virus disappears as we demonstrated in the youngest KTR in which two consecutive SARS-CoV-2 RNA-PCR tests from bronchoalveolar lavage performed one month after infection failed to detect viral-RNA. Based on our experience we think that a close monitoring of the respiratory indices and biochemical blood tests such as D-Dimer could help physicians to take a decision on when it is the best moment to administrate tocilizumab. In addition, hemoadsorption with Cytosorb combined to tocilizumab might be considered at least in patients with severe SARS-CoV-2 who need extracorporeal renal replacement treatment. This article is protected by copyright. All rights reserved This article is protected by copyright. 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Managing COVID-19 in Renal Transplant Recipients: A Review of Recent Literature and Case Supporting Corticosteroid-sparing Immunosuppression SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor Structure analysis of the receptor binding of 2019-nCoV Should COVID-19 Concern Nephrologists? Why and to What Extent? The Emerging Impasse of Angiotensin Blockade The authors of these manuscript have no conflicts of interest to disclose. This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved This article is protected by copyright. All rights reserved