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COVID-19 in Heart Transplant Recipients

Objectives The aim of this study was to assess the clinical course and outcomes of all heart transplant recipients affected by coronavirus disease-2019 (COVID-19) who were followed at the leading heart transplant centers of Northern Italy. Background The worldwide severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has created unprecedented challenges for public health, demanding exceptional efforts for the successful management and treatment of affected patients. Heart transplant patients represent a unique cohort of chronically immunosuppressed subjects in which SARS-CoV-2 may stimulate an unpredictable clinical course of infection. Methods Since February 2020, we enrolled all 47 cases (79% male) in a first cohort of patients, with a mean age of 61.8 ± 14.5 years, who tested positive for SARS-CoV-2, out of 2,676 heart transplant recipients alive before the onset of the COVID-19 pandemic at 7 heart transplant centers in Northern Italy. Results To date, 38 patients required hospitalization while 9 remained self-home quarantined and 14 died. Compared to the general population, prevalence (18 vs. 7 cases per 1,000) and related case fatality rate (29.7% vs. 15.4%) in heart transplant recipients were doubled. Univariable analysis showed older age (p = 0.002), diabetes mellitus (p = 0.040), extracardiac arteriopathy (p = 0.040), previous PCI (p = 0.040), CAV score (p = 0.039), lower GFR (p = 0.004), and higher NYHA functional classes (p = 0.023) were all significantly associated with in-hospital mortality. During the follow-up two patients died and a third patient has prolonged viral-shedding alternating positive and negative swabs. Since July 1st, 2020, we had 6 new patients who tested positive for SARS-CoV-2, 5 patients asymptomatic were self-quarantined, while 1 is still hospitalized for pneumonia. A standard therapy was maintained for all, except for the hospitalized patient. Conclusions The prevalence and mortality of SARS-CoV-2 should spur clinicians to immediately refer heart transplant recipients suspected as having SARS-CoV2 infection to centers specializing in the care of this vulnerable population.

T he worldwide severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) pandemic has created unprecedented challenges for public health, demanding exceptional efforts for the successful management and treatment of affected patients. Northern Italy was the first region in Western Europe to experience a large outbreak of coronavirus disease 2019 (COVID-19), which has since rapidly spread throughout the world. As of the end of June 2020, more than 70% of the total number of positive patients nationally and almost 80% of deaths occurred in this area (1).
In this context, information on the incidence and clinical characteristics of COVID-19 in heart transplant recipients is still limited (2,3). Challenges Scientific published reports is still lacking organized and multi-institutional reports on this especially vulnerable population (2,3,5).
To date, this study provides the most comprehensive data on SARS-CoV-2 infection prevalence and clinical characteristics in heart transplant recipients.
Here, we sought to identify clinical variables and therapeutic strategies associated with a worse outcome, focusing on immunosuppressive therapy modulation and its possible interactions with anti-inflammatory medication and antiviral drugs.

METHODS
STUDY OVERSIGHT. It is declared that every reasonable effort was made to obtain informed consent to participate in this study.
Notably, the use of data for scientific and research purposes is already included in the informed consent agreements used at the participating centers. The local ethics committees approved of the study design, consent process, and review and analysis of the data.
We also guarantee the respect of anonymity and professional secrecy and use the collected data and the statistical analysis solely for the scientific purposes granted in accordance with the law in force (GDPR). STUDY POPULATION. We designed a retrospective, observational, multicenter study across 7 leading heart transplant centers of Northern Italy: Milan, Padua, Bergamo, Bologna, Turin, Verona, Udine. All heart transplant recipients with positive nasopharyngeal reverse transcriptase-polymerase chain reaction tests for SARS-CoV-2 at these centers were included in this study.
DATA SOURCES. We obtained medical records and compiled data for hospitalized patients and outpatients with laboratory-proven COVID-19 infection.
We extracted data on recent exposure history, clinical symptoms or signs, and laboratory findings on admission from electronic medical records. All laboratory testing and radiological assessments were performed according to standard of care. Pertinent information was compiled into a unique dataset and forwarded to the data-processing coordination center Data are updated to July 1, 2020.

RESULTS
Of 2,676 heart transplant recipients alive before the onset of the COVID-19 pandemic at the end of February 2020, 47 patients were included in this analysis as part of a first cohort of patients. Among them, 2 patients had received combined heart-kidney transplants and 1 patient had undergone retransplantation. This preliminary series reports baseline patient characteristics, features of COVID-19 onset and hospital course, laboratory results, and outcomes ( Table 1). COHORT 1 ANALYSIS. B a s e l i n e a n d r i s k f a c t o r s . All collected data are presented in Table 1  for SARS-CoV-2, with 93% of being symptomatic. The most frequent symptom was fever (87%), followed by cough (70%) and shortness of breath (70%). Mean duration of symptoms was 9.80 AE 7.31 days. In febrile patients, the mean fever peak was 38.2 AE 0.6 C and fever lasted for a mean of 7.5 AE 3.8 days. In 72% of cases, radiographic signs of pneumonia were present.
These data are summarized in Table 2.  Table 2). For this analysis, we report the lowest echocardiographic left ventricular ejection fraction (LVEF) and the peak troponin I levels. Mean LVEF during hospitalization was 59.1% AE 6.7% and comparable to that measured in the last pre-  Table 3.
t r a n s p l a n t r e c i p i e n t s . Nine patients in our cohort were either asymptomatic or had mild symptoms.
These patients did not require hospitalization, but were instructed to self-quarantine at home according to a protocol that included frequent telephone monitoring by the corresponding heart transplant team. Compared with remainder of the population, the nonhospitalized patients exhibited significant differences in mean age (p ¼ 0.002), eGFR (p < 0.001), and prednisone use (p ¼ 0.033) ( Table 1). Cyclosporine and mycophenolate mofetil were the most common immunosuppression regimen, and 67% of patients in this group also received corticosteroids. At COVID-19 onset, 5 (71%) recipients were symptomatic, presenting mostly with fever (78%) and cough (67%); median oxygen saturation at onset was 98 AE 1%.

DISCUSSION
We present the largest retrospective and first Italian multicenter case series of heart transplant recipients with COVID-19. We enrolled a total of 53 patients with smokers. Comorbidities such as hypertension, diabetes, and cardiovascular and respiratory disease also can influence prognosis (6). Our findings confirm these observations. According to our univariable analysis, age, higher NYHA functional class, diabetes, chronic kidney disease, peripheral vascular disease, cardiac allograft vasculopathy, and lower oxygen saturation at admission (related to severe pulmonary involvement and delay in hospital referral), may account for the observed higher case-fatality rate.
In the nonsurviving population, diabetes-related     As for the new infections we registered, in 5 cases, being asymptomatic, as in the previous cases described, we did not modify the immunosuppressive therapy, we did not add antiviral drugs, and we treated the patients with careful home monitoring. In 1 patient, in whom pulmonary involvement was more important, the patient was hospitalized and treated as discussed previously by reducing immunosuppressive therapy and adding antibiotics to avoid opportunistic infections. The clinical characteristics of the patients self-quarantined were comparable regardless the cohort considered.
The data presented here highlight that heart trans- The high mortality we observed seems to be unrelated to allograft dysfunction or rejection. The reduction of immunosuppression in severe forms of disease is crucial for 2 fundamental aspects: first, promoting the immune response against viral infection, and second, reducing the risk of superinfections related to hospitalization. For future hospitalized heart transplant recipients with COVID-19, our strategy will consist of reduction of immunosuppression and antibiotic prophylaxis, along with the best supportive care available. We believe that in the asymptomatic forms, immunosuppressive therapy may remain unchanged until the first symptoms emerge. One of the main findings, in light of this experience, is that there is always a careful monitoring of the patient, because at any moment the patient can take different paths.
Furthermore, availability of targeted SARS-CoV-2 antiviral drugs seems to be closer; hopefully they will soon be available for the physician.