key: cord-0908539-b7sosrc7 authors: Iacovoni, Attilio; Boffini, Massimo; Pidello, Stefano; Simonato, Erika; Barbero, Cristina; Sebastiani, Roberta; Vittori, Claudia; Fontana, Alessandra; Terzi, Amedeo; De Ferrari, Gaetano Maria; Rinaldi, Mauro title: A case series of Novel-Coronavirus infection in heart transplantation from two centers in the pandemic area in the North of Italy date: 2020-06-26 journal: J Heart Lung Transplant DOI: 10.1016/j.healun.2020.06.016 sha: ec200f8d772909871e77c67337cc96d8de6a1e3a doc_id: 908539 cord_uid: b7sosrc7 BACKGROUND Little is known about the coronavirus SARS-CoV-2 disease (COVID-19) in solid organ transplanted patients. We here report a series of heart transplanted patients with COVID-19 from two centers of Italy. METHODS All heart transplanted patients of Transplant Centers of Bergamo and Torino with a microbiologically confirmed SARS-CoV-2 infection were enrolled. Data collection included clinical presentation, laboratory and radiological findings, treatment and outcome. Follow-up was performed by visit or phone. RESULTS From February to March 2020 twenty-six heart transplanted patients (age 62±12 years; 77% males; time from transplant 10±10 years; 69% with comorbidities) had a microbiologically confirmed COVID-19. The most frequent symptom was fever, followed by cough. Seventeen patients had a pneumonia, 8 of them severe pneumonia. Seven patients died (27%) and 17 (65%) were hospitalized. Discontinuation of immunosuppression was associated with death (71 vs 21%, p=0.02). Conversely, all patients receiving steroids survived (p<0.001). Patients who received heart transplantation during COVID-19 outbreak survived and no acute graft rejection occurred. Patients who died were older than survivors, had a longer time from transplant and a worse clinical presentation at diagnosis. The current regimen enabled the prolonged survival and function of orthotopic cardiac xenografts in altogether 6 of 8 baboons, of which 4 were now added. These results exceed the threshold set by the Advisory Board of the International Society for Heart and Lung Transplantation. CONCLUSIONS COVID-19 has a significant impact on long term heart transplanted patients. Conversely, SARS-CoV-2 infection seems to have a limited influence on more recent transplants. Our experience may suggest that heart transplantation programs can be maintained even during the pandemic phase if specific and tailored paths to prevent and to limit virus transmission are provided. Emerging reports suggest that case fatality rate ranges from 2 to 15% according to regions. (2,3) In 6 addition, SARS-CoV-2 infection has a higher incidence and case fatality rate among the elderly and 7 those with chronic comorbidities. (4) 8 Immunosuppressed patients may have a different epidemiology. In fact, it is questioned whether 9 immunosuppression may play a role in SARS-CoV-2 infection. (5) It has been speculated that 10 SARS-CoV-2 damages the host through two overlapping mechanisms, the first is the direct damage 11 of the virus itself, the second is an abnormal host response that may lead to a cytokine storm Aim of this study is to report a series of heart transplanted patients with SARS-CoV-2 infection 3 from two Heart Transplant Centers in the North of Italy describing clinical characteristics, 4 prognosis and the impact of COVID-19 on heart transplant programs. All patients were evaluated by a heart transplant specialist in conjunction with an infectious disease 8 specialist. Data collection included anamnestic and demographic data, pharmacological treatment 9 and immunosuppressive therapy, physical evaluation and clinical data at first medical contact, all 10 laboratory and radiological findings performed after diagnosis, treatment and follow-up. Follow-up 11 was performed by direct or phone clinical examination. Fever was defined as an axillary temperature of 37.5°C or higher. Leukopenia and lymphocytopenia 13 were defined as a count of less than 4000 and 1500 cells per cubic millimetre, respectively. Severe Heart transplant programs in the COVID era 18 Since the outbreak of COVID-19 in Italy, specific protocols of infection restraint were applied and 19 COVID-19-free paths were identified inside our hospitals. In particular, history of contacts with 20 confirmed or suspected cases of COVID-19 was carefully investigated in both donors and 21 recipients. RT-PCR on bronchoalveolar lavage was performed in all donors and only negative 22 donors were considered. Before transplant, all recipients were tested with a nasopharyngeal swab 23 and only negative patients were accepted for surgery. During surgery, before admission to a 24 dedicated COVID-free intensive care unit, a second test on the bronchoalveolar lavage was performed to confirm the absence of virus. Induction and maintenance immunosuppressive therapy 1 did not change. After ICU discharge, patients were followed in a COVID-19-free ward. Different 2 paths for outpatients were also identified. The outpatient follow-up was regularly performed 3 without changes in the scheduled program for the most recent transplanted patients. The follow-up 4 of patients transplanted from more than one year was performed by phone and only urgent visits 5 were carried out. Anyway, before entering the transplant centre, all patients were routinely tested. If 6 SARS-CoV-2 positive, they were followed in dedicated rooms, in dedicated catheterization and 7 echo-Doppler laboratories. From the beginning of February to the end of March 2020, twenty-six heart transplanted recipients 2 had a microbiologically confirmed SARS-CoV-2 infection, among a total of seven hundred and 3 forty patients followed in two Heart Transplant Centres (incidence of SARS-CoV-2 infection of 4 3.5%, at least). The median follow-up was 21 days (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) (21) (22) (23) (24) (25) (26) . During the follow-up, 7 deaths (27%) 5 occurred and 17 patients were hospitalized (65%). Fifteen patients had a hospitalization or a 6 scheduled in-hospital visit, while 4 patients had a close contact with a confirmed case of COVID-19 7 in the two weeks before SARS-CoV-2 testing. Testing was performed in all symptomatic patients 8 and in patients (regardless symptoms) requiring outpatient clinic admission. We tested a total of 62 9 patients. Positive patients were older (62 ± 12 vs 46 ± 18 years, p <0.001), more recently Table 1 . Eighteen patients (69%) had at least one comorbidity. The most frequent ones 17 were arterial hypertension and chronic kidney disease. Seven patients (27%) received heart 18 transplantation after the begin of COVID-19 outbreak in China. Immunosuppressive treatment is 19 shown in Table 1 . Cyclosporin was the most frequent calcineurin inhibitor (85%) and 8 patients 20 (31%) received three immunosuppressive drugs including oral steroids. Patients who died were older than those who survived (71 ± 6 vs. 59 ± 12 years, respectively, 22 p<0.01), had a higher incidence of chronic kidney disease and diabetes (57% vs 37%, p 0.02 and 23 43% vs 5%, p 0.04, respectively). All patients who received heart transplantation after the begin of 24 COVID-19 outbreak survived (100 vs 63% in other patients, p=0.04), such did all patients receiving oral steroids (100 vs 42% in patients not on steroids, p=0.02). No association between calcineurin 1 inhibitors trough levels and adverse events was found. Clinical presentation is described in Table 2 . The most frequent symptom was fever (81%), 5 followed by cough (62%), dyspnea and gastrointestinal symptoms were less frequent (31% e 23%, 6 respectively). Cough or fever were present in all but two patients (88%). At presentation, the first 7 symptom was fever (80%) or cough (52%). Gastrointestinal symptoms occurred only in patients 8 taking mycophenolate. At the first clinical evaluation, 11 patients (42%) had low oxygen saturation on room air, while 3 10 had oxygen desaturation at walk test. A respiratory rate higher than 14 breaths per minute was 11 recorded in 10 patients (38%) and 5 patients (19%) had a partial pressure of oxygen lower than 65 12 mmHg. Patients who died had a higher respiratory rate and lower oxygen saturation at the first 13 clinical evaluation (p<0.01 for both). 14 15 In all patients a chest X-ray was performed, 16 patients (62%) presented signs of pneumonia. A CT 17 scan was performed in 6 patients showing interstitial involvement with diffuse bilateral ground-18 glass opacities in all patients. Laboratory tests are detailed in Table 2 . Leukopenia was found in 13 patients (50%) and 20 lymphopenia in 16 (62%). Elevated C-reactive protein was found in 15 patients (58%). Among variables at first clinical contact, the best predictors of mortality were age higher than 65 17 years, procalcitonin higher than 0.5 ng/ml and oxygen saturation on room air lower than 95% with 18 an area under the curve of 0.78, 0.94 and 0.89, respectively (Table 4) . This is a cohort from two centers in the North of Italy. The two centers are located in the epicenter 9 of the Italian epidemic. Testing has been performed only in patients with symptoms or requiring 10 outpatient clinic admission. Therefore, the real incidence in our cohort is probably underestimated. 11 However, our data show that the incidence of SARS-CoV-2 infection in transplanted patients was 12 higher than in the overall Italian population (19). The higher incidence may be related to the Moreover, the mortality rate of this cohort was higher than expected. In fact, in Italy, in the general 22 population over 60 years, the mortality rate for COVID-19, the overall hospitalization rate and the 23 ICU hospitalization rate are 12.6%, 20.4% and 4.5%, respectively. Our cohort showed alarming 24 high rates of both mortality, hospitalization and ICU admission (27, 65 and 19%, respectively). 1 Interestingly, both the case fatality rate and baseline characteristics were similar to those recently 2 reported by Latif et al. The high case fatality rate observed in heart transplanted patients may be due 3 to the characteristics of the cohort evaluated in the analysis. The majority of our cohort is 4 represented by long-term heart transplanted survivors. These patients are chronically exposed to a 5 long immunosuppressive therapy and at high risk to develop side-effects. Although they show a 6 good heart function, this population must be considered very fragile due to the presence of different 7 comorbidities (i.e. chronic kidney disease) related to a long exposure to immunosuppressive drugs. 8 In a transplanted cohort the association of advanced age with time-dependent comorbidities, such as 9 calcineurin inhibitor nephrotoxicity and other common complications of immunosuppressive 10 therapy may be detrimental. Also, this conditions often require frequent in-hospital visits, 11 increasing the risk of exposure to SARS-CoV-2. These characteristics may therefore explain the 12 higher incidence SARS-CoV-2 infection, the more severe clinical presentation and the higher 13 mortality rate in transplanted patients. The incidence of infection appeared to be unrelated with time 14 from transplant. However, all the recently transplanted patients survived and seemed less prone to 15 develop severe COVID-19 than those transplanted from a longer period. 16 Clinical presentation was similar to non-transplanted patients. The incidence of fever and cough 17 was in line with previous reports. At least one of the two was present in almost all patients. Interestingly, dyspnea at onset was less frequent and was not associated with adverse outcome. Gastrointestinal symptoms were significantly more frequent than in the overall COVID-19 20 population (23 vs 4-6%). It is difficult to explain this finding, however all these patients were 21 receiving mycophenolate that may have gastro-intestinal side-effects. Physical evaluation and 22 radiological examination suggesting severe pneumonia at onset were the most accurate predictors of 23 worse outcome. The diagnostic and prognostic utility of laboratory findings may be challenged 24 since immunosuppressive drugs may reduce the inflammatory response in transplanted patients. 1 However, both C-reactive protein and procalcitonin were higher in patients who died, while 2 leukopenia and lymphopenia were not. During the COVID-19 outbreak the management of immunosuppression is challenging. In our 4 experience, reduction of immunosuppression could not provide a significant benefit and on the 5 contrary this strategy was associated with a worse outcome. It must be recognized that it is not 6 possible to discriminate if deterioration was related with this strategy or it was the result of an 7 independent progression of the disease and immunosuppression reduction only a marker of more 8 severely ill patients. In our series, patients on oral steroids (required for the age of transplant, i.e. 9 recent transplants, or because of recurrent acute rejection) did not have severe pneumonia nor died. 10 Moreover, all patients that received heart transplantation within three months had a higher grade of 11 immunosuppression (i.e. three immunosuppressive drugs) and did not develop a severe disease. However, it must be recognized that these results should be interpreted with caution owing to 15 potential bias and residual confounders in this observational study with a small sample size and a 16 more robust evidence is required. It should be also considered that patients who received heart 17 transplantation in the last three months were younger, had less comorbidities and followed a strict 18 protocol of mitigation strategies such as quarantine or social distancing. These characteristics may 19 adequately explain the better observed outcome. No differences were found between the incidence 20 of COVID-19 and the type of immunosuppressive agent, nor their concentration was associated 21 with severity of COVID-19. Once some evidence on the beneficial effect of methylprednisolone has emerged in the literature, World Health Organization: Coronavirus Disease (COVID-19) Clinical features of patients infected with 2019 novel 5 coronavirus in Wuhan, China Defining the epidemiology of covid-19 -studies needed Clinical course and mortality risk of severe COVID-19 Coronaviruses and Immunosuppressed Patients: The Facts During the Third Epidemic COVID-19: consider cytokine storm syndromes and 13 immunosuppression Clinical evidence does not support corticosteroid treatment for 2019-nCoV 16 lung injury. The Lancet ISHLT: Guidance for Cardiothoracic Transplant and Ventricular Assist Device Centers regarding the SARS 18 CoV-2 pandemic Case report of COVID-19 in a kidney transplant recipient: Does 21 immunosuppression alter the clinical presentation? Successful recovery of COVID-19 pneumonia 24 in a renal transplant recipient with long-term immunosuppression First cases of COVID-19 in heart transplantation from China Characteristics and Outcomes of Recipients of Heart Transplant With 29 Early experience of COVID-19 in two 31 heart transplant recipients: Case reports and review of treatment options Epidemiological and clinical characteristics of heart transplant recipients 34 during the 2019 coronavirus outbreak in Wuhan, China: a descriptive survey report World Health Organization. Global surveillance for COVID-19 caused by human infection with COVID-19 Coronavirus disease (COVID-19) technical guidance: laboratory testing for 4 2019-nCoV in humans Diagnosis and treatment of adults with community-acquired 7 pneumonia: an official clinical practice guideline of the A Trial of Lopinavir-Ritonavir in Adults Hospitalized with Severe Covid-19 19 Task force COVID-19 del Dipartimento Malattie Infettive e Servizio di Informatica Clinical Characteristics of Coronavirus Disease 2019 in China Clinical, laboratory and imaging 16 features of COVID-19: A systematic review and meta-analysis. Travel Medicine and Infectious Disease for the International Society for Heart and Lung Transplantation. 19 ISHLT 36th Adult Heart Transplantation Report COVID-19 illness in native and immunosuppressed states: A clinical-therapeutic 22 staging proposal Risk Factors Associated With Acute Respiratory Distress Syndrome and Death 24 in Patients With Coronavirus Disease