EXPERIMENTAL AND CLINICAL TRANSPLANTATION

Objectives: The novel 2019 coronavirus (COVID-19) was first described in December 2019 in Wuhan, China and subsequently announced as a pandemic on March 12, 2020. In several studies, solid-organ transplant recipients were reported to have higher risk for COVID-19. Here, we aimed to determine the frequency of COVID-19 in our kidney and liver transplant patients.

Materials and Methods: Our study included 583 transplant patients who were admitted to our outpatient transplant clinics and emergency departments between March 1 and May 1, 2020. Seventy-four of them were liver transplant recipients (46 male, 28 female, of which 14 were pediatric and 60 were adult patients) and 509 of them were kidney transplant recipients (347 male, 162 female, of which 16 were pediatric and 493 were adult patients). We retrospectively evaluated demographic characteristics, currently used immunosuppressant treatment, present complaints, treatment and diagnosis of comorbid diseases, and results of COVID-19 tests.

Results: Of 583 transplant recipients, 538 were seen in our outpatient transplant clinics and 45 were seen in our emergency departments. Of these, 18 patients who had had cough and fever were evaluated by respiratory clinic doctors, and nasopharyngeal swab samples were taken. One kidney transplant recipient had a positive COVID-19 test; he was followed with home isolation.

He received treatment with hydroxychloroquine (400 mg/day). The other 17 patients had negative tests. There were no mortalities due to COVID-19.

Conclusions: Transplant patients also got affected during the COVID-19 pandemic. According to the data of our centers, this effect is not much more different from the normal population. We recommend that transplant recipients should be warned in terms of personal hygiene and should be closely monitored by organ transplant centers. If there is an indication for hospitalization, they should be followed in an isolated unit, with no aggressive changes made to immunosuppressive doses unless necessary.

Key words : Pandemic, SARS-CoV-2, Solid-organ transplantation

The novel 2019 coronavirus (COVID-19) was first described in December 2019 in Wuhan, China.¹ In our country, the first case was seen on March 11, 2020.² On March 12, 2020, the World Health Organization announced COVID-19 as a pandemic.¹ From the time that COVID-19 was first identified, it has been consistently suggested that patients with advanced age and systemic diseases have higher mortality rates.3 Recently, several studies on solid-organ transplant recipients have reported a higher risk for COVID-19 in this population.^4-6 Here, we aimed to determine the frequency of COVID-19 in our liver transplant (LT) and kidney transplant (KT) patients.

Materials and Methods

Since November 3, 1975, our 4 transplant centers (Ankara, Adana, Istanbul, and Konya) have performed 3104 KT procedures, with 656 LT procedures performed since December 1988. Transplant recipients receive periodic follow-up at our Division of Transplantation, Baskent University Hospitals outpatient clinics.

For this study, we included transplant recipients who had follow-up visits between March 1 and May 1, 2020. Our study included 583 transplant patients seen at outpatient clinics and emergency departments. Our patient cohort included 74 LT recipients (12.6%; 46 male, 28 female) and 509 KT recipients (87.4%; 347 male, 162 female). In the LT group, 14 (19%) were pediatric and 60 (81%) were adult patients. In the KT group, 16 (3.1%) were pediatric and 493 (96.9%) were adult patients.

We retrospectively evaluated demographic characteristics, currently used immunosuppressant treatment, present complaints, treatment and diagnosis of comorbid diseases, and results of COVID-19 tests. COVID-19 polymerase chain reaction (PCR) tests were conducted by the state institutions determined by our Ministry of Health in each province.

Between March 1 and May 1, 2020, 538 transplant patients were seen in our outpatient transplant clinics and 45 transplant patients were seen at emergency departments.

All transplant patients received routine immunosuppressive treatment (Table 1). According to our immunosuppressive protocol, LT recipients receive triple immunosuppression in the first year (tacrolimus/cyclosporine/mammalian target of rapamycin [mTOR] inhibitor + mycophenolate mofetil [MMF] + prednisolone), dual immunosuppression in the second year (tacrolimus/cyclosporine/mTOR inhibitor + MMF), and single immunosuppression in the third year (tacrolimus/cyclosporine/mTOR inhibitor). Recipients of KT receive lifetime triple immunosuppressive treatment (tacrolimus/cyclosporine/mTOR inhibitor + MMF + prednisolone).

Among LT patients, comorbid diseases were as follows: 11 (21.1%) with diabetes mellitus, 5 (9.6%) with hypertension, 6 (11.5%) with coronary artery diseases, and 1 with aplastic anemia. In KT patients, comorbid diseases included 47 (10.1%) with diabetes mellitus, 96 (20.8%) with hypertension, 23 (4.9%) with coronary artery diseases, 5 (1%) with chronic obstructive pulmonary disease, 2 with Kaposi sarcoma, and 1 with breast cancer.

From these LT and KT patients, 477 (88.6%) presented to outpatient clinics only for periodic follow-up, 15 (2.7%) had respiratory symptoms, 12 (2.3%) had urinary tract infection, 9 (1.7%) had dermatologic symptoms, 9 (1.7%) had gastrointestinal symptoms, 8 (1.5%) had gynecologic symptoms, and 8 (1.5%) had neurologic symptoms.

During the study period, 33 adult KT (73.3%) and 12 adult LT (26.7%) patients presented to the emergency departments of our hospitals. As comorbid diseases, 3 LT patients had coronary artery diseases, 1 LT patient had diabetes mellitus, 1 LT patient had chronic obstructive pulmonary disease, 8 KT patients had diabetes mellitus, 10 KT patients had hypertension, 2 KT patients had coronary artery diseases, and 1 KT patient had chronic obstructive pulmonary disease. Three transplant recipients (6.6%) were admitted to the emergency department with respiratory symptoms. The remaining patients (n = 42) were admitted for symptoms other than respiratory infection, such as urinary tract infection (n = 10), gastrointestinal symptoms (n = 9), hyperglycemia (n = 7), vertigo (n = 6), gynecologic symptoms (n = 5), and chest pain (n = 5). For COVID-19 treatment, our centers follow a standard protocol (Table 2). In accordance with the protocol, treatment is started for patients with suspected or definitive diagnosis.

In our study cohort, there were 18 KT and LT recipients with cough and fever who were evaluated by doctors in the respiratory clinic. All 18 patients provided nasopharyngeal swab samples at the respiratory clinic. Of these, only 1 KT recipient had positive COVID-19 PCR. This patient was followed with home isolation. He received treatment with hydroxychloroquine (400 mg/day) for 5 days and discontinuation of immunosuppressive treatment. After 14 days, his COVID-19 PCR test was negative. Immunosuppressive treatment was resumed at previous doses, and COVID-19 treatment was stopped.

Eight patients (44.4%) were hospitalized with positive clinical and radiological findings consistent with COVID-19, and the standard treatment was started, which included 400 mg/day hydroxychloroquine for 5 days and azithromycin (500 mg on day 1 and then 250 mg/day for 4 days). All immunosuppressive treatments (tacrolimus, cyclosporine, mTOR inhibitors, MMF) were discontinued until COVID-19 infection had resolved. All hospitalized patients were isolated and treated in the COVID-19 unit in our centers. Patients who were hospitalized were tested twice at different times, with COVID-19 PCR tests being negative in all cases. After tests for COVID-19 were shown to be negative, immunosuppressive treatment was resumed at the previous doses and COVID-19 treatment was stopped after resolution of symptoms.

Nine patients (50%) with mildly symptomatic suspected COVID-19 were followed with home isolation until symptoms had resolved. Patients were started on standard COVID-19 treatment (400 mg/day hydroxychloroquine for 5 days); all immunosuppressive treatments were stopped until tests for COVID-19 were shown to be negative. All COVID-19 PCR tests for these patients, which were performed twice, showed negative results. Immunosuppressive treatment was resumed at previous doses and COVID-19 treatment was stopped after symptoms had resolved.

Low-molecular-weight heparin was started in all 18 patients and continued until the COVID-19 tests were negative or until symptoms had resolved. We had no mortality due to COVID-19.

COVID-19 is a disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) , which was first identified in January 2020 as a result of research conducted in a group of patients who developed respiratory tract symptoms (fever, cough, shortness of breath) in Wuhan, China in December 2019. This disease rapidly spread across the world in a short period of time after it was first identified, and it was announced as a pandemic by the World Health Organization on March 12, 2020.¹ In Turkey, the first case was diagnosed on March 11, 2020.²

After the announcement of COVID-19 as a pandemic, investigators worked to identify risk factors and to create various diagnosis and treatment algorithms. Undoubtedly, as a portion of the world’s population, it is important to include chronic organ failure and solid-organ transplant patients in COVID-19 disease studies. Because of the immunosuppressive agents that they must use and the presence of comorbid diseases, these patients are at high risk for COVID-19.⁴

Studies have emphasized that the progression of disease in solid-organ transplant recipients infected with SAR-CoV-2 is generally worse than in the normal population.^5,6 Akalin and associates⁷ reported that the disease course for KT patients infected with SAR-CoV-2 was worse than shown in the normal population. Compared with the overall mortality rate in the United States of 1% to 5% (and up to 15% in patients over 70 years of age), the mortality rate in their centers was 28% in solid-organ transplant recipients.⁷ Similarly, Fishman and associates⁸ reported that mortality rate in infected transplant patients was approximately 21.4%. The group found that disease progression in transplant patients was fast and need for intensive care was higher than shown in the normal population. Fishman and associates also reported that kidney function was impaired at various rates.⁸ Another study from Italy reported 5 mortalities in 20 KT patients; the mortality rate was higher in transplant patients than the rate of overall mortality in the normal population.⁹

Infection rates of solid-organ transplant recipients versus the general population have been ignored in recent COVID-19 studies. We believe that is due to the limited number of SAR-CoV-2-infected LT and KT patients, and it is impossible to project these results to all organ transplant patients. In our study, of 583 LT and KT patients evaluated, only 1 KT patient (0.17%) had a positive COVID-19 test; 17 other patients, despite strong clinical suspicion, had negative COVID-19 tests. In addition, none of the patients in our study died from COVID-19.

During our study period, the number of cases in the general Turkish population, as provided by the Turkish Ministry of Health, was 0.15%.² Therefore, the infection rate among the normal population was similar to the rate for organ transplant patients seen at our centers between March 1 and May 1, 2020. Because only 1 patient was positive among our 583 patients and the treatment of this patient was adjusted and the patient was instructed to self-isolate from home, it is difficult to comment on the course of the disease in LT and KT patients. Despite the immunosuppressive state in transplant patients, their similar rate of infections versus the general population can be related to a number of reasons. We think that the most important reason is that LT and KT recipients have experience in social isolation and personal hygiene. Because these patients are immunosuppressant throughout the period of chronic kidney failure, chronic liver disease, and after transplant surgery, they have already been trained in terms of personal hygiene by our physicians.

Today, personal hygiene remains the most important way to protect against COVID-19. Furthermore, the Turkish Transplantation Society and The Turkic World Transplantation Society issued a review letter¹⁰ stating that solid-organ transplant recipients with suspected and diagnosed COVID-19 infections should not be hospitalized in organ transplant units to prevent the virus from transmitting to other organ transplant patients. In our series, 9 of 18 patients with suspected COVID-19 were followed with home isolation and 8 patients were hospitalized. Until COVID-19 infections had resolved, all hospitalized patients were isolated and treated in the COVID-19 unit in our centers. One patient who had been diagnosed for COVID-19 and had mild symptoms was followed up with home isolation until the test became negative in accordance with The Turkish Transplantation Society and The Turkic World Transplantation Society joint circular letter.¹⁰These personal and institutional precautions can be shown as the reason for infection rates in LT and KT patients to be the same as the normal population. In addition, in a study conducted in chronic kidney disease patients in our centers, among 2420 hemodialysis and 50 peritoneal dialysis patients, only 3 were diagnosed with COVID-19. In a sample of 227 patients randomly selected from 2470 chronic kidney disease patients, HAV antibodies were positive in 94.7% of them. As a result of this preliminary study, we think that the hepatitis A vaccine may be protective against COVID-19 infection via an adaptive cross-reaction.¹¹ We think that the same situation can also be applied to transplant patients considering that hepatitis A immunization was routinely performed in all patients before transplantation. The broad study on this subject is still being carried out by our Division of Transplantation team.

Treatment of COVID-19 in transplant patients remains unclear. From the first announcement of the pandemic to today, it has been said that one of the most important causes of development of acute respiratory distress syndrome is the cytokine storm.¹² Although, on this basis, research has indicated that immunosuppressive therapy can have protective effects,¹³ the common treatment principle recommended in the literature still calls for changing the immunosuppressive treatment protocol. Changes can differ according to the severity of the disease.¹⁴ The Turkish Transplantation Society and The Turkic World Transplantation Society review letter¹⁰ recommended for antiproliferative agents to be discontinued and the dose of calcineurin inhibitors to be reduced and discontinued in intubated patients. Immunosuppressive agents were reduced as recommended by this review letter in the 17 patients with suspected COVID-19. When COVID-19 tests for these patients were negative, the drugs were resumed at previous doses. In the 1 patient diagnosed with COVID-19, immunosuppressive treatment was reduced according to the review letter, with doses resumed when the test was negative. No rejection episodes were observed in patients during the period of reduced immunosuppressive treatments, and all patients were discharged with normal graft function.

Apart from these general precautions, hydroxychloroquine, azithromycin, and favipiravir were used safely in transplant patients for treatment of COVID-19 as recommended in the literature.¹⁴ It is also mentioned in the literature that low-molecular-weight heparin can be added safely to treatment.⁹ These treatments were started in our 17 patients with suspected COVID-19 and in our 1 patient with a definitive diagnosis, which continued until COVID-19 tests were negative.

COVID-19 is a life-threatening disease that spreads rapidly, resulting in its pandemic designation. Transplant patients have also been affected during this pandemic. However, according to data from our centers, this effect has not been much different from that shown in the normal population. On the other hand, COVID-19 pandemic rates may vary depending on case numbers, diagnosis, and treatment approaches of different centers and countries. Literature states that mortality rate in transplant patients is higher than in the normal population and therefore may lead to aggressive approaches in these patients, leading to discontinuation of immunosuppressive agents and graft loss in the early period of COVID-19. There was no mortality in our centers, and therefore we recommend that these patients should be warned in terms of personal hygiene and closely monitored by organ transplant centers. If there is an indication for hospitalization, they should be followed in an isolated unit, and no aggressive changes should be made to immunosuppressive doses unless necessary.

Volume: 18 Issue: 3 June 2020

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