key: cord-0757176-fdpc6ym2 authors: Lauterio, Andrea; Valsecchi, Mila; Santambrogio, Sara; De Carlis, Riccardo; Merli, Marco; Calini, Angelo; Centonze, Leonardo; Buscemi, Vincenzo; Bottiroli, Maurizio; Puoti, Massimo; Fumagalli, Roberto; De Carlis, Luciano title: Successful recovery from severe COVID‐19 pneumonia after kidney transplantation: The interplay between immunosuppression and novel therapy including tocilizumab date: 2020-06-02 journal: Transpl Infect Dis DOI: 10.1111/tid.13334 sha: 235297ea9bb5c18917d273148a60189f6249107e doc_id: 757176 cord_uid: fdpc6ym2 Although immunosuppressed patients may be more prone to SARS‐CoV‐2 infection with atypical presentation, long‐term immunosuppression therapy may provide some sort of protection for severe clinical complications of COVID‐19. The interaction between immunosuppression and new antiviral drugs in the treatment of transplanted patients contracting COVID‐19 has not yet been fully investigated. Moreover, data regarding the optimal management of these patients are still very limited. We report a case of the successful recovery from severe COVID‐19 of a kidney‐transplanted patient treated with hydroxychloroquine, lopinavir/ritonavir, steroid, and tocilizumab. Previous medical history included Pneumocystis jirovecii pneumonia and cytomegalovirus infection 1 year after KT, arterial hypertension, hypothyroidism, and recurrent urinary tract infection (UTI). On March 10, 2020 (subsequently considered D0), she was admitted to the emergency room (ER) with fever (38.4°C), malaise, history of strangury, dry cough, and chest pain. Although the patient reported no clear contact with confirmed or suspected cases of COVID-19, as the clinical presentation was consistent with COVID-19 pneumonia, she underwent nasopharyngeal swab specimen and chest x-ray. Real-time reverse transcription-polymerase chain reaction (RT-PCR) assay for SARS-CoV-2 was positive. Her current immunosuppressive therapy consisted of cyclosporine (CSA) 35 mg BID, everolimus (EVL) 1 mg BID, and prednisone 5 mg once a day. She was also being treated with angiotensin receptor 1 blocker, levothyroxine, and fosfomycin as UTI prophylaxis. She had never been on hemodialysis, and her most recent serum creatinine (sCr) was 1.36 mg/dL. CSA level was in the range of 100-150 μg/L. On admittance to ER, the patient's physical examination was unremarkable. Blood pressure was 140/85 mm Hg, pulse 100 beats per minute, and oxygen saturation was 96% in ambient air. Initial laboratory tests revealed sCr 2.4 mg/dL, procalcitonin (PCT) 0.28 ng/mL, reactive C protein (RCP) 7.5 mg/dL, and D-dimer 0.67 μg/mL. A chest CT scan showed a single minor subpleural ground-glass opacification (GGO) in the lower lobe of the right lung ( Figure 1A ). The laboratory tests and main events are summarized in Figure 2 . The hospital protocol for COVID-19 was activated, and the patient was admitted to a dedicated COVID-19 pathway. On D1, treatment with lopinavir/ritonavir (400 mg/100 mg BID) and hydroxychloroquine (400 mg BID) was initiated and maintained for 7 and 10 days, respectively. CSA and EVL were withdrawn, while prednisolone was increased to 40 mg daily. Despite negative microbiological cultures, empirical broad-spectrum antibiotic therapy was initiated. Antithrombotic prophylaxis (low molecular weight heparin) was also introduced on D6. After 7 days of CNI withdrawal, CSA was reinstated and gradually increased to the initial dosage. Respiratory symptoms were absent until D6, when progressive hypoxia developed with progressive worsening of respiratory function. On D8, a second thoracic CT scan confirmed disease progression ( Figure 1B ). Laboratory tests revealed interleukin-6 (IL-6) serum levels of 147 pg/mL (normal value < 7 pg/mL); PCR rose to 4.2 mg/ dL; lymphocyte count fell to 0.34 × 10 9 /L. The patient was evaluated for treatment with tocilizumab, a recombinant humanized anti-human IL-6 receptor monoclonal antibody, and received a single dose of 8 mg/kg intravenously. Following the tocilizumab administration, the patient remained apyretic with substantially stable respiratory function in the subsequent 48 hours. As expected, on D10 IL-6 rose to 4830 pg/mL. On D10, the patient's respiratory symptoms worsened, and she was placed on non-invasive ventilation (NIV) and high-flow nasal oxygen therapy (HFNO) for 3 days, after which she required intubation for mechanical ventilation and was admitted to the intensive care unit (ICU) (D14). A new CT showed bilateral, multiple, and subpleural GGO consolidation, and thickening of intralobular septa (crazy-paving pattern) ( Figure 1C ). A CT scan performed on D25 showed pulmonary interstitial fibrosis with no active infection ( Figure 1D ). Two consecutive swab tests were negative on D38 and D40. The patient was discharged on D50 with normal kidney graft function, no fever, and peripheral oxygen saturation of 96% in ambient air. The patient we discuss presented overall clinical characteristics similar to those reported in non-transplanted COVID-19 patients. 14 Respiratory data on admission to the ICU were similar to non-immunosuppressed patients. Transplanted patients require careful consideration on account of their immunosuppressed status and the risk of graft loss during SARS-CoV-2 infection. We quickly withdrew CSA and EVL, and increased prednisolone to 40 mg/die. Given their anti-inflammatory effect, steroid adjustments seemed appropriate both to reduce the risk of acute rejection and to mitigate COVID-19 respiratory symptoms, although its use in COVID-19 pneumonia remains controversial. 15, 16 Nonetheless, balancing immunosuppression in COVID-19 is difficult due to the need to prevent graft rejection while trying to prevent excessive viral replication but also limit immune activation. Reduction or temporary withdrawal of immunosuppressive drugs has been recommended in kidney-transplanted patients during other viral pandemics. 17 The impact of long-term immunosuppression on the course of SARS-CoV-2 infection is not clear, and CNIs may play a positive role in mitigating the activation of the innate immune response and preventing the evolution of interstitial pneumonia. 18, 19 We are also aware of the additional risk of infection when increasing steroid therapy, and that the appropriate treatment is a careful balance between the risk of graft loss and the risk of worsening the infection. According to our ongoing (March 10, 2020) local indication to initiate antiviral treatment as soon as possible, lopinavir/ritonavir and hydroxychloroquine were administered early on for 7 and 10 days, respectively. 20 Similar to coronavirus-associated SARS, higher IL-6 levels have been reported in COVID-19 patients, and the severity of the clinical course-especially in terms of respiratory distress-would seem to be related and proportional to cytokine storm syndrome. 21 The patient received a single dose of tocilizumab in accordance with our local protocol. 20 There is no clear consensus on either the dose or number of administrations. 22 Given the patient's absence of fever, severe lymphopenia (absolute count 270 cells/ μcL), concomitant increased immunosuppressive treatment with methylprednisolone, and previous history of severe opportunistic infections, we decide not to administer a second dose in view of the high risk of bacterial infections related to further immunosuppression. Interestingly, the pneumonia worsened 3 days after tocilizumab administration, highlighting the lack of information regarding the F I G U R E 2 Patient's laboratory tests and main clinical events correct timing of administration, which should be possibly have been Successful recovery of COVID-19 pneumonia in a renal transplant recipient with long-term immunosuppression Case report of COVID-19 in a kidney transplant recipient: Does immunosuppression alter the clinical presentation? COVID-19 in kidney transplant recipients SARS Cov2 infection in a renal transplanted patients. 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