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ARTICLE
Management of COVID-19 in Liver Transplant Recipients With Immunosuppressant Therapy: Experiences of an Iranian Transplant Registry

Abstract

Objectives: With the declaration of the COVID-19 pandemic and the increased COVID-19 risk shown in transplant recipients, the prevalence, clinical course, and outcomes of COVID-19 infections among liver transplant recipients were assessed.
Materials and Methods: A questionnaire was designed and used to survey medical services for liver transplant recipients seen at our center in terms of COVID-19 infection.
Results: Twenty-five patients infected with COVID-19 were identified from 265 liver transplant recipients. Most patients were male and had COVID-19 despite quarantine at home. All patients received modified immunosuppressive drugs during infection with COVID-19 with minor changes in routine immunosup­pressive therapy. Among the identified patients, 21 recovered and 4 patients died. One of the dead patients, in addition to having a liver transplant, had brain cancer with metastasis to the lungs.
Conclusions: In liver transplant recipients infected with COVID-19, immunosuppressive drugs seemed to cause only mild to moderate illnesses or even helped them recover from the disease. However, more evidence
is needed to prove this hypothesis. It is also recommended that transplant recipients should be warned about personal hygiene and be monitored closely by organ transplant centers.


Key words : Novel coronavirus 2019, Pandemic, SARS-CoV-2, Solid-organ transplantation

Introduction

In late December 2019, COVID-19 spread as an emerging infectious disease in Wuhan, China, and quickly spread to other countries around the world.1 With the spread of the disease worldwide, Iran was the second country that reported COVID-19 cases in February 2019.2 Because patients with underlying diseases, including transplant recipients, are more prone to infection, they were expected to be at higher risk for COVID-19, experience different clinical signs and clinical courses, and possibly have higher mortality and morbidity.3

A review of published articles since the start of the COVID-19 pandemic in transplant patients has shown that, because of low immunity, especially cellular immunity, as well as fear of COVID-19 infection, home quarantine, hand hygiene, and social distance practices have been high in these patients, and patients who were infected with COVID-19 had a milder clinical course and recovered sooner.4-7

However, those who undergo liver transplant are expected to have high rates of infection and mortality due to reduced immunity because of the use of immunosuppressants after organ transplant.6,7 Despite these rates, recent reports have shown that these patients are not at increased risk for pulmonary infection compared with the general population. For example, some studies have shown that liver transplant recipients recovered from COVID-19, with few patient deaths reported.8,9 The studies have confusing results about the clinical course of COVID-19 disease, the use or stopping of immunosup­pressive drugs, and mortality rates.10,11

Care of liver transplant recipients during the SARS-CoV-2 epidemic has been challenging because of the urgent need to redistribute resources to other parts of the health care system. Existing guidelines have recommended that transplant care should be reorganized and that transplant centers should be prepared to prevent the spread of disease across the transplant community to reduce organ transplant mortality.12 However, scientific information related to the care of transplant patients during the SARS-CoV-2 epidemic is not yet sufficient.13

The low hospitalization statistics for these patients and the low number of reports from transplant centers have limited the knowledge on the prevalence, clinical course, and treatment of transplant patients infected with COVID-19.14,15 Therefore, it is hoped that by providing more studies from different countries we could achieve acceptable and definite results regarding the prevalence, clinical course, and necessary thera­peutic interventions for these patients. Here, we aimed to report the treatment process of patients within the Iranian Liver Transplant Registry with COVID-19 infection, in an effort to help health care teams to find the necessary protocol for care of these patients.

Materials and Methods

Research field
In April 2017, Tabriz University of Medical Sciences launched organ transplant centers for liver, kidney, heart, and bone marrow transplant procedures in northwestern Iran. The organ transplant centers were located in Imam Reza and Heart Shahid Madani Hospital as training and research centers of the Tabriz University of Medical Sciences. Correspondingly, the Iranian Transplant Registry was established for coherence of organ donation and transplantation and to upgrade therapeutic and educational services to patients. In 2019, this center obtained an identification number (64510) from the Deputy of Research and Technology of Tabriz University of Medical Sciences.

For our study, our liver transplant center examined 380 liver transplant recipients in terms of COVID-19, using a designed questionnaire, physical examination, and laboratory and paraclinical examinations.

Ethical approval
This study was approved by the Ethics Committee in Research of Tabriz/Iran University of Medical Sciences (number: TBZMED.REC.2020.423) and was performed in accordance with the ethical standards as stated in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. Patient examinations and data collection were performed after approval by the deputy of research of Tabriz University of Medical Sciences, with ethical approval and permission obtained from the head of Imam Reza Hospital, the individual patient, and the head of Transplant Registry (number 64510). Written informed consent was obtained from the patient or from legal guardians before start of study. Verbal informed consent of participants was obtained before interviews.

Questionnaire
A literature review, including health protocols from Iran’s Deputy Health Minister related to a COVID-19 pilot study,16 and brainstorming were used to design the questionnaire. The content validity of the questionnaire was verified through a survey of faculty members based on Waltz and Bausell methods17 to determine its content validity, and the Lawshe method was used to determine the content validity ratio. Expert knowledge on each item was judged based on 3 answers: 1 = item is required; 2 = item is useful but not required; 3 = item is not required. Answers with a content validity ratio of more than 0.62 were considered important based on the Lawshe table and the number of evaluators. A method effect was used to check the scores. Eventually, a semistructured questionnaire was provided with questions on demographic information and COVID-19 symptoms (Table 1).

The questionnaires were completed by telephone interviews and by face-to-face interviews with referred patients and their relatives at the centers and by using records of hospitalized patients and clinical examinations and paraclinical tests performed by a specialist.

Patients
Our study population included 380 liver transplant patients. Patients were surveyed by 2 members (ZS and LV) from the designed questionnaire between May 18 and November 9, 2020. Patients who were suspected to have COVID-19 were referred to Imam Reza General Hospital for definitive diagnosis by a medical team based on symptoms, clinical examination, laboratory tests, real-time polymerase chain reaction (PCR) test, and a chest computed tomography (CT) scan. Any person with at least 1 of the symptoms (listed in Table 1) was considered as suspected of having COVID-19.

Statistical analyses
We used descriptive statistics with SPSS version 21 (SPSS: An IBM Company), including frequency, percentage, mean, median, standard deviation, minimum and maximum, to describe.

Results

Sampling
Of 380 liver transplant patients, 265 patients participated in this study (Figure 1). According to the results of the investigation, 25 patients were identified after checking. The most common symptoms of COVID-19 in these patients were headache, anorexia, myalgia, fatigue, diarrhea, vomiting, and cough. The demographic characteristics and clinical courses of patients with COVID-19 are presented in Table 2 and Table 3.

Case presentation
Of the 25 participants identified with COVID-19, most were men with a median age of 58 years (range, 21-74 y). All patients were Muslim, Azeri-Turkish, married, and residents of Tabriz, Iran.All patients underwent liver transplant as a result of liver cirrhosis. The median time after liver transplant was 68 months (range, 10-156 mo). All patients had a history of diseases. In addition, all donors were deceased with diagnosis of brain death, and there was no relationship between donors and recipients.

The median time of diagnosis was 7 days (range, 2-14 d) for all patients. Two patients were initially diagnosed with a common cold due to runny nose, nasal congestion, and hoarseness; in both patients, COVID-19 was diagnosed late with mean time of COVID-19 diagnosis of 12 ± 8.2 days compared with 5 ± 3.3 days in other patients. It should be noted that, with the passage of time, people’s awareness of COVID-19 had increased, resulting in decreased time of referral and diagnosis.

Most patients were in quarantine since late February 2020, none had a history of hospitalization or travel, and none had outside contact except with first-degree relatives. Most patients had onset of symptoms that started with a dry cough, or myalgia, followed by anorexia, hair loss, septum cough, dyspnea, and loss of smell and taste. Respiratory problems were observed in almost all patients. All patients were alert at the time of admission; however, all hospitalized patients with COVID-19 had a low level of peripheral capillary oxygen saturation. A number of patients had preferred to be quarantined at home under the supervision of an infectious disease specialist. Chest CT scan was positive in all patients. Blood analyses of most patients showed increased levels of aspartate aminotransferase and alanine aminotransferase. Physical examination and laboratory results are shown in Table 3.

The median length of hospital stay was 8.5 days (range, 1-22 d). For the patients who died, they were first admitted to the general ward and then were transferred to the intensive care unit as a result of dyspnea and drop in peripheral capillary oxygen saturation. One of the patients who died also had brain cancer with lung metastasis. Hydroxychloroquine and azithromycin were administered to all patients along with immunosuppressant therapy with slightly changes in their dosage, especially for tab mycop­henolate mofetil. That is, all patients received immunosuppressive drugs at the same dosage as they received before their COVID-19 diagnosis. Only mycophenolate mofetil dosage was reduced to control liver enzyme levels. Because of the probability of organ rejection, we could not discontinue all of the immunosuppressive drugs.

Of the 25 patients, 4 patients (16%) died and 21 patients (84%) recovered. After discharge, patients were required to quarantine at home for 14 days.

Discussion

In this study, we surveyed liver transplant recipients in terms of COVID-19. Although a number of patients did not participate in this study because of fear of COVID-19, 25 patients were identified with COVID-19 among liver transplant recipients.

One of the most important findings of this study was the continuation of treatment with immunosup­pressive drugs at the same dosage or with as before COVID-19 diagnosis. Despite weakening of the immune systems by these drugs, patients were able to recover from COVID-19. Five patients were treated at home and recovered.

Therapeutic principles are unclear for transplant patients with COVID-19 who have increased cytokine production caused by acute respiratory failure. There is considerable variability in the use of immunosuppressive drugs. Some articles have recommended discontinuation or reduction in immunosuppressive drug dosage.13,18 Other studies have recommended continuing immunosuppressive therapy during COVID-19 infection.6,7 All of these studies reported recovered patients from COVID-19.

Most patients in our study were male, with a mean age of 56 years. In a systematic review study that was conducted by Lovato and de Filippis, 1556 patients with COVID-19 were examined for demographic characteristics and clinical signs where the number of men was higher than the number of women.15 In a study from Zeng and associates, mortality was higher in men than in women infected with COVID-19, which was associated with differences in levels of COVID-19 immunoglobulin G antibody between the 2 sexes.19 In a study from Niu and colleagues, older people with COVID-19 had greater susceptibility to infections and mortality than younger people. Another factor that influenced the mortality rate of COVID-19 was the underlying medical condition of patients that led to their hospitalization, intensive care, and mechanical ventilation necessity.18

In a 2020 study of 221 patients with COVID-19 at Wuhan University Hospital, older men showed a higher chance of contamination.4 Old age, male sex, and underlying diseases have emerged as risk factors for COVID-19. The results of our study were similar, with differences in the ratio of males to females and the mean age. In 2 of our patients, a definitive diagnosis was made later due to the similarity of the COVID-19 symptoms with common cold symptoms. In patients with COVID-19, clinical symptoms can range from relatively mild (similar to the common cold) to severe (bronchitis, pneumonia, and renal failure).5,6 These symptoms may be intensified by other diseases or by immunosuppressive agents, and patients can show atypical symptoms.

Because of similarities between COVID-19 and common cold symptoms, participants may not consider necessary precautions and may not be timely referred to a health care center. Delayed diagnosis can lead to complications in patients’ conditions and transfer of the disease to other family members. Therefore, it is necessary to explain all clinical symptoms to the general public and medical staff. Fortunately, referrals to medical centers and faster diagnosis have improved with increased awareness in medical staff and the public.

In our study, the mean time after transplant was 6 years and the mortality rate was 15.8%. In a systematic review conducted by Nacif and associates on 39 transplant patients, including 16 liver transplant patients, the mean time after transplant was 4 years for all patients and 5 years for liver transplant patients.20 In this study, the mortality rate for all transplant patients and patients with liver transplants was 26% and 38%, respectively. The mortality rate was 5% to 10% in other patients with underlying medical conditions.8,9 The presence of older patients and the underlying diseases in our study may have led to this difference. Muller and associates reported a mean length of hospital stay of 14 days,21 which was 9 days for our patients. Our survey on patient history showed that, despite staying at home, not traveling, and avoiding crowded places during quarantine, patients became infected with COVID-19. However, all had contact with first-degree relatives. Because of a lack of information on standardized principles of quarantine, patients may have disregarded maintaining distance, wearing masks, and observation of hygienic practices. It seems that quarantine principles may not yet be fully understood by many people. Many patients with COVID-19 infection may be asymptomatic or present cold-like symptoms, which could lead to virus transmission. Consequently, the global sharing and evaluation of quarantine principles are necessary.11,12

In our study, a chest CT scan showed lung involvement in all cases, even in patients with no signs of respiratory distress. A chest CT scan appears to achieve a definitive diagnosis, along with the use of laboratory tests and other radiological imaging, as well as taking an accurate history and clinical examination. Muller and associates also emphasized this issue and expressed satisfaction at the sensitivity of chest CT scans for the diagnosis of asymptomatic and symptomatic patients infected with COVID-19.21

Limitations
The main limitation of this study was the lack of access to all liver transplant patients and their evaluation for COVID-19, leading to a small sample size. Another limitation was the generalization of results for all liver transplant recipients due to the small sample size. In addition, we did not examine all transplant patients, including asymptomatic ones, due to financial constraints and patients not going to the hospital for fear of infection.

Conclusions

We found that the use of modified immunosup­pressants not only did not increase mortality but also seemed to have a positive effect on reducing the severity of the disease and clinical course. However, because we did not fully study the low mortality of these patients, it is not possible to have a definite opinion on the effects of immunosuppressants. We suggest further studies with a larger sample to allow definite opinions on our results to be made. To achieve a definitive diagnosis of COVID-19, the use of clinical signs and laboratory and paraclinical tests are essential.

Given that patients were in contact with their families at the time of home quarantine to prevent COVID-19, which also caused them to become infected, it seems that quarantine principles are not yet clear to all patients. As a result, these principles need to be fully explained, and patients should be advised to avoid contact with family members. Social distance practices, wearing masks, and observing health protocols should be emphasized. Education through mass media can play an important role in breaking the chain of disease transmission.


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DOI : 10.6002/ect.2020.0526


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From the 1Medical and Surgical Department; the 2Department of Surgery; the 3Physical Medicine and Rehabilitation Research Center, Aging Research Institute; and the 4Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
Acknowledgements: We thank the staff of the Liver Transplant Center of Tabriz University of Medical Sciences, the Organ Transplant Registry (ID: 64510), and the participants for taking part in the research process. Data are confidential and only available to the first and corresponding authors in the Liver and Gastrointestinal Diseases Research Center and Organ Transplant Registry of Tabriz University of Medical Sciences, Tabriz, Iran. The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Author contributions: Study design was provided by ZS, TAK, FK, and LV. Data collection was provided by ZS, FK, and LV. Statistical analyses were provided by LV and AFK. Writing and preparation of figures and tables were provided by ZS, TAK, AFK, and LV. All authors interpreted the data and provided final approval of the manuscript.
Corresponding author: Leila Vahedi, Medical Genetics, Liver and Gastrointestinal Diseases Research Center, Imam Reza Hospital, Gholghasht Street, Tabriz University of Medical Sciences, Tabriz, Iran
E-mail: vahedi.l49@gmail.com or vahedil@tbzmed.ac.ir

Experimental and Clinical Transplantation (2021)