key: cord-348786-25o7tam4 authors: Mella, Alberto; Mingozzi, Silvia; Gallo, Ester; Lavacca, Antonio; Rossetti, Maura; Clari, Roberta; Randone, Olga; Maffei, Stefano; Salomone, Mario; Imperiale, Daniele; Biancone, Luigi title: Case series of six kidney transplanted patients with COVID‐19 pneumonia treated with tocilizumab date: 2020-06-17 journal: Transpl Infect Dis DOI: 10.1111/tid.13348 sha: doc_id: 348786 cord_uid: 25o7tam4 Few reports described the outcome of kidney transplanted patients (KTs) affected by COVID‐19 treated with interleukin‐6 receptor inhibitor tocilizumab (TCZ). We report our case series of 6 KTs with COVID‐19 pneumonia who received TCZ: All were of male gender, with a mean age of 55.5 ± 8.4 years, a median time from transplantation of 3611 days (1465‐5757); 5/6 had cardiovascular comorbidities, 1/6 had diabetes, and 3/6 have one or more previous KTs. Four out of six patients died, at an average time of 9.75 ± 2.4 days after tocilizumab administration, 3/6 due to a coexistent septic shock. Two patients improved after TCZ and were discharged at 20 and 21 days, respectively; in both patient, a significant increase of total lymphocyte count was observed. In conclusion, KTs, where the role of peculiar factors such as chronic immunosuppression is still undetermined, represent a high‐risk group with significant COVID‐19‐associated mortality. The evaluation of the TCZ effect in COVID‐19 pneumonia requires controlled studies (ideally RCTs) in this specific population. Clinical characteristics and laboratory data are shown in Tables 1 and 2. Figure 1 reported the timeline of maintenance immunosuppression, COVID-19-specific treatments, and outcome. In all patients, diagnosis was performed by nasopharyngeal swab test (PCR) and chest radiography or high-resolution computed tomography (HRCT). TCZ was administered once daily for two consecutive days (dose 8 mg/kg) after a consultation with infectious disease specialist in patients with contemporary evidence of pulmonary involvement (oxygen saturation-Sa02-<93% if patients breath ambient air, or a ratio of the partial pressure of oxygen-PaO2-to the fraction of inspired oxygen-FiO2-of less than 300 mm Hg) and pro-inflammatory profile (C-reactive protein and/or IL-6 > × 10 normal values). All patients gave written informed consent for TCZ off-label use. 41-year-old patient. He received kidney transplant from deceased donor 15 years ago. Ongoing immunosuppressive therapy was composed by tacrolimus (TAC) and prednisone. After few days of fever and cough, patient was tested positive for COVID-19 on 03/25/2020. TAC was immediately discontinued while glucocorticoids (methylprednisolone 20 mg daily) were maintained. In the same day of the diagnosis, hydroxycloroquine and antiviral treatment (darunavir/ritonavir 800/100 mg) were started, in association with antibiotic therapy (cefepime). On day 7 after diagnosis, because of rapid worsening of respiratory status, TCZ was administered and repeated in day 8; concomitantly, according to progressive deterioration of kidney function and difficult management of fluid overload, continuous renal-replacement therapy (CRRT) was initiated. Despite the antibiotic therapy implementation with azithromycin, respiratory failure occurred needing mechanical ventilation from day 15; patient died two days after. 65-year-old patient. He received kidney transplant from a deceased donor on March 2020. A negative COVID-19 test was obtained before kidney transplant, and no positive contact with COVID-19 subjects was reported in the days before KT. Induction immunosuppressive therapy was composed by thymoglobulin (for three days) and methylprednisolone, and subsequent maintenance therapy included TAC (levels 10-12 ng/mL), mycophenolate mofetil (MMF) and prednisone. Patient also received ganciclovir for CMV prophylaxis (CMV IgG-/donor CMV IgG+). Eight days after KT patient experienced fever and cough; swab test was subsequently repeated and resulted positive. Immunosuppressive medications (TAC, MMF) were immediately stopped, except of glucocorticoids (methylprednisolone 20 mg/d). Patient started hydroxycloroquine (200 mg daily) and darunavir/ritonavir (800/100 mg daily) the day after and remained On day 6, arterial pO2 decreased and patient started non-invasive ventilation (NIV); after a further deterioration of pulmonary status, mechanical ventilation was needed from day 7. On day 8, blood and urinary cultures were both positive for multi-sensitive Klebsiella Pneumoniae (urinary culture was also positive for Enterococcus Faecalis), and antibiotic treatment was shifted from amoxicillin/clavulanic acid to cefepime. Despite progressive modifications on antibiotic therapy (with at least adoption of gentamicin, piperacillin/tazobactam, and daptomycin), fluid and medication support patient became oliguric (starting CRRT from day 12) and died on day 17. 54-year-old patient. He received his third kidney transplant in 2014. Ongoing immunosuppressive therapy was composed by TAC and TA B L E 2 Laboratory and pulmonary functional tests before and after TCZ adoption in our COVID-19-positive kidney transplant recipients COVID-19 is now considered as the most prominent health-care problem around the world. 13 Emerging data highlight the role of comorbid conditions (hypertension, diabetes, cardiovascular disease) and older age as major determinants of negative outcome. 10 Recently, kidney disease has also been associated with increased inhospital mortality. 14 Transplant patients, due to the combination of this frail profile associated with immunosuppressive medications, are considered a high-risk population 15 ; despite preventive strategies and medication protocols are urgently needed, definite guidelines for KT are not currently established and different and specular approaches have so far been reported. Some group suggest the immediately withdrawn of immunosuppressive drugs with only steroid maintenance, 1,16 despite steroid use is controversial and associated with reduced viral clearance. 17 Other authors report a possible antiviral effect of CNI inhibitors 2,4,6,10,18 suggesting per contrast their maintenance in solid organ transplanted patients, especially in liver transplants. This theory is also supported by the evidence that ARDS occurred in patients with important inflammatory activation (the so-called cytokine storm) and in this context immunosuppressive medications and anti-inflammatory drug (ie, TCZ) may mitigate the damage. All these data are partially questioned by a recent US report 19 were mortality in KT patients is extremely high compared to normal population, despite a recent Spanish case series detailed a more favorable picture 20. To date, few reports included TCZ-treated kidney transplanted patients with COVID-19 pneumonia 12,19-23 ( other Authors, the virus caused a profound immunosuppression 5, 11 and, in this context, the result of combined inhibition of IL-6 receptor in predisposing to bacterial infections is not well understood. We also pointed out that we treated with TCZ only kidney transplanted patients who required hospitalization with significant reduction of pulmonary function and increase of inflammatory markers. At the time we are writing, 20 patients who received KTs in our Center were tested positive for COVID-19, and 8/20 (including 4/8 who received TCZ) died. Because all patients with COVID-19 who do not need hospitalization were tested and remained at home, we do not have laboratory/pulmonary functional markers to compare this cohort to TCZ-treated patients. In conclusion, despite these data should be evaluated with extremely caution and have some limitations (selection bias, availability of IL-6 dosage in all patients, absence of CD4+/CD8 + count), our study confirmed that kidney transplanted patients are a high-risk group with significant COVID-19-associated mortality. The evaluation of the TCZ effect in COVID-19 pneumonia requires controlled studies (ideally RCTs) in this specific population. The authors of this manuscript have no conflicts of interest to disclose as described by the Transplant Infectious Disease Journal. 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