key: cord-356246-4p0ok1mc authors: Ammirati, Enrico; Travi, Giovanna; Orcese, Carloandrea; Sacco, Alice; Auricchio, Sara; Frigerio, Maria; Puoti, Massimo title: Heart-Kidney Transplanted patient affected by COVID-19 pneumonia treated with tocilizumab on top of immunosuppressive maintenance therapy date: 2020-07-17 journal: Int J Cardiol Heart Vasc DOI: 10.1016/j.ijcha.2020.100596 sha: doc_id: 356246 cord_uid: 4p0ok1mc nan A 61-year-old Caucasian man presented to the emergent department on April 1 st , 2020 due to breath shortening, after 15 days of fever and cough. The patient had received a heart transplantation (HT) in 2005 due to refractory heart failure in dilated cardiomyopathy and a subsequent living-related kidney transplantation in 2015 due to end-stage chronic renal failure on maintenance hemodialysis. Other medical history included hypertension on carvedilol 6.25 mg bid, and furosemide 12.5 mg qd, paroxysmal atrial fibrillation on warfarin and amiodarone 200 mg qd, hypothyroidism on levothyroxine 100 mcg qd. A recent echocardiogram showed preserved biventricular systolic function, and last coronary angiography revealed normal coronary arteries in March 2019. Immunosuppression was maintained with cyclosporine 50 mg bid; mycophenolic acid 720 mg bid and prednisone 2.5 mg qd. On admission day, temperature was 37.5°C, blood pressure 160/90 mm Hg, heart rate 68 beats per minute, sinus rhythm, respiratory rate (RR) of 24 breaths per minute, and oxygen saturation of 98% while the patient was receiving supplemental oxygen through a nasal cannula at a rate of 2 liters per minute. Initial arterial blood gas analysis revealed partial pressure of oxygen (PaO 2 ) of 71 mmHg with a ratio of the PaO 2 to fractional inspired oxygen (FiO 2 ) of 253. Before hospitalization he has been treated empirically with azithromycin for 3 days and amoxicillin/clavulanic acid 875/250 mg bid for 7 days. Nucleic acid testing of a nasopharyngeal swab for SARS-CoV-2 virus was positive. Chest computed tomography (CT) revealed diffuse bilateral glass ground opacities compatible with interstitial pneumonia (Supplemental Figure 1A) . Laboratory test in the emergency department revealed normal white blood count of 4.5*10 9 /L, with 0.27 lymphocytes*10 9 /L significantly increased C-reactive protein (CRP) of 7.8 mg/dL (upper reference limit [URL] of 0.5), without elevation of procalcitonin of 0.16 ng/mL (URL of 0.5). Creatinine value was mildly elevated (1.39 mg/dL) with an estimated glomerular filtration rate of 54 mL/min/1.73*m 2 . On admission day, cyclosporine was continued, while mycophenolic acid was reduced to 360 mg bid and prednisone was increased at 10 mg daily. HCQ 200 mg tds and intravenous (IV) ceftriaxone 2 g daily were started. On day 3 the patient developed an acute respiratory distress syndrome and needed supplemental oxygen through a nasal cannula at a rate of 15 liters per minute with a PaO 2 of 85 mmHg and a PaO 2 /FiO 2 of 94. The patient was tachypneic (RR of 28 breaths per minute) and a noninvasive ventilation with a FiO 2 of 70% was initiated, reaching an oxygen saturation of 100%. Due to clinical deterioration, the patient was referred to our hospital, a tertiary care center, where the patient had been transplanted. The day the patient was moved to our hospital, he received a dose of IV tocilizumab 600 mg (8 mg/kg based on actual body weight) for worsening respiratory failure, in the absence of signs of bacterial infections. After 12 hours a second dose of IV tocilizumab 600 mg was administered as per the off-label protocol adopted in our hospital. On day 1 after tocilizumab, the patient significantly improved, and was weaned off the noninvasive ventilation. Although increase of d-dimer was observed, CRP gradually decreased to 1.4 mg/dL and lymphocytes increased from 0.31 to the 0.59*10 9 /L in 5 days, while procalcitonin levels remained low. Respiratory function significantly improved in the following days after tocilizumab infusion: need for supplemental oxygen through a nasal cannula decreased from a rate of 10 to 2 liters per minute and the RR decreased from 30 to 16 breaths per minute after 7 days (TABLE) . Immunosuppressive regimen was maintained with a target cyclosporine trough level between 80 and 100 ng/mL, and HCQ was suspended on day 11. On day 15 after admission oxygen saturation decreased to 91% after a 6-minute walking test, while it was 96% on 2 liters per minute of supplemental oxygen. The SARS-CoV-2 nasal swab RT-PCR turned negative on day 15 and on day 16 when the assay was repeated for confirmation of negative result. A chest high-resolution CT scan was performed before discharge on day 17, revealing residual diffuse ground glass opacities mainly in the right lung (Supplemental Figure 1B) . Echocardiogram performed during the hospitalization confirmed preserved systolic ventricular function. The patient is alive on June 23 rd , with an oxygen saturation of 98% on room air and he did not develop any secondary infection after tocilizumab administration. Limited data on the use and efficacy of tocilizumab for the treatment of transplanted patients with COVID-19 exist [1, 2] . In a series from New York, 6 heart transplanted recipients were treated with tocilizumab, and one died, and two were still hospitalized at the time of the end of follow up [3] . Another report described two heart transplant recipients treated with tocilizumab, and one died and while the other survived [4] . This case report shows potential usefulness of tocilizumab administration at the onset of the respiratory failure, before tracheal intubation need, especially when clinical data and laboratory exams do not suggest latent or overt superimposed infections. In fact, the risk of severe infection can be a serious concern particularly in immunosuppressed patients as observed in another published case [4] . We observed a significant increase of d-dimer after administration of tocilizumab, supporting the need for monitoring d-dimer after administration of this drug, and suggesting the usefulness of anticoagulant agents such as enoxaparin. Our patient was on warfarin due to paroxysmal atrial fibrillation, thus enoxaparin was administered only when INR was below 2. Potential complications after the administration of tocilizumab in COVID-19 patients to be aware of include septic shock, and gastrointestinal perforation [5] . Several studies have showed the potential benefits of tocilizumab, but the results are mainly based on single-center non-randomized experiences with a maximum number of 100 treated patients [5] . In conclusion, this case summarizes the potential efficacy of tocilizumab to treat heart and heart and kidney transplanted recipients affected by COVID-19 severe pneumonia with a background of a maintenance immunosuppressive regimen. Nevertheless, only randomized trials will define the efficacy of tocilizumab and its place, timing and dosing in patients with COVID-19. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Covid-19 and Kidney Transplantation Characteristics and Outcomes of Recipients of Heart Transplant With Coronavirus Disease Early Experience of COVID-19 in Two Heart Transplant Recipients: Case Reports and Review of Treatment Options. American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons Tocilizumab for the treatment of severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure: A single center study of 100 patients in Brescia The authors of this manuscript have no conflicts of interest to disclose.