key: cord-0733959-dukgavfa
authors: Kose, A; Toplu, SA; Yalcinsoy, M; Yakupogullari, Y; Otlu, B; Otan, E; Aydin, C; Yilmaz, S; Bayindir, Y
title: Clinical Characteristics and Outcomes of Liver Transplantation Recipients with COVID-19 Pneumonia
date: 2021-06-19
journal: Transplant Proc
DOI: 10.1016/j.transproceed.2021.06.027
sha: 096db9aa4f62d24d22d142bd66b929b91ae6fabc
doc_id: 733959
cord_uid: dukgavfa

BACKGROUND: : We aimed to evaluate the clinical characteristics and outcomes of diagnosed with mild-severe COVID-19 pneumonia cases in liver transplantation (LT) recipients. MATERIAL AND METHODS: : Ten LT recipients diagnosed with COVID-19 pneumonia in six-month period in our transplantation center were included. Demographic and medical data of the recipients were retrospectively collected; clinical courses, treatment responses, and outcomes were evaluated. RESULTS: : Ten LT recipients were male, at median 57 years (min-max: 36-69; IQR: 13), and had right lobe, from living-donor LT performed in median eleven months (min-max: 1-72; IQR: 12). Five patients were diagnosed as severe, and the remaining were mild/moderate pneumonia. The most frequent symptoms were fever (90%) and cough (70%). Favipiravir, enoxaparin sodium and corticosteroid were initiated at the time of the diagnosis, immunosuppressive drug doses were reduced or discontinued in three cases. Lymphopenia median: 510/ml (min-max: 90-1400; IQR: 610), increased levels of CRP median: 4.72 (min-max:0.31-23.4; IQR: 8.5) and ferritin median: 641 (min-max:40-≥1650; IQR: 1108) were frequent. Four patients required antibacterial treatments due to emerging bacterial pneumonia and/or sepsis. All patients had a hospitalization for a median of ten days. One patient with sepsis died on the 26(th) day of intensive care unit (ICU) admission, and the remaining nine survived. No further complication was recorded for one-month follow-up. CONCLUSION: : The commencing of favipiravir, enoxaparin sodium and corticosteroid treatments, close follow-up of the developing complications, temporary reduction or cessation of immunosuppression, multidisciplinary approach, early awareness of the bacterial infections and the initiation appropriate antibiotic treatments can contribute to success.

In December 2019, a pneumonia outbreak caused by a novel coronavirus emerged in the Wuhan Region of China. The virus made a global spread within a few months. The virus is transmitted to humans due to contact with droplets and microdroplets in the respiratory secretions of infected individuals (1) . The World Health Organization (WHO) declared this outbreak as a "pandemic" on March 11 th , 2020. The International Virus Taxonomy Committee named this coronavirus as "Severe Acute Respiratory Distress Syndrome Coronavirus-2" (SARS-CoV-2), responsible for "Coronavirus Disease-19 (COVID-19) Disease". According to the WHO's data, by January 22 th , 2021, more than 98 million confirmed cases of COVID-19 were identified worldwide, and approximately 2.1 million people died (2) . It was observed that the mortality rate of the COVID-19 disease in general population was 2-3%, but, the risk of death was higher (>50%) in the elderlies, and the people with underlying diseases, such as chronic lung diseases, cardiovascular diseases, immunosuppression, diabetes, obesity, hypertension and cancer (3) . Among these, the patients with solid organ transplantations (SOT) are a particular concern. It has been reported that mild-severe respiratory failure findings developed at a rate of 39.6% and the mortality rate was 18% in LT recipients (4) .

LT is the second most frequent SOT worldwide following kidney transplantation and still the unique treatment choice for the patients with end-stage liver disease (ESLD) (5) . These patients are particularly susceptible to infections due to the ongoing immunosuppression and their backgrounds of major surgery and the possible systemic injuries that were potentially-developed due to long-standing illness and treatment courses (6) .

However, the clinical course, optimal treatment modalities and outcomes of COVID-19 in LT recipients are not yet known in all aspects (7) . Based on the experiences from two previous coronavirus outbreaks, it appeared that the risk of liver damage increased in SARS and MERS diseases (8) . In a recent international cohort, LT recipients hospitalized with a diagnosis of COVID-19 compared to the non-transplant patients had a higher incidence of severe disease (39 vs. 6.1%) and higher mortality rates (24 vs. 4 .3%) (9, 10) . Unfortunately, the current data are still very limited for a better understanding of the clinical characteristics and outcomes of the LT patients with COVID-19. As no effective drugs or therapies were available, countries have adopted different preventive and therapeutic strategies against COVID-19 (11) . The Turkish Health Ministry has recommended commencing hydroxychloroquine and/or favipiravir+enoxaparin sodium to all patients when the diagnosis of COVID-19 (12) . In this perspective, the outcomes of the LT recipients who received the treatment mentioned above have not been reported previously in our country.

In the current study, we aimed to evaluate that the clinical characteristics, treatment processes, and outcomes of LT recipients who were hospitalized in our medical center due to COVID-19 pneumonia. The results of this study may also contribute to coping with COVID-19 pneumonia both for the patients with SOT and for people who had no previous health problems.

This study was conducted in the Liver Transplantation Institute of Inonu University, which was a 130-bed organ transplantation center performing about 200 LT annually. Patients who underwent LT in our hospital, admitted to our center with the diagnosis of Covid-19 and following in ICU due to Covid-related pneumonia in between March-October 2020 were included in this study. However, patients who underwent LT in our center and were diagnosed with Covid-19 and followed up in other centers were excluded in the study. A retrospective data screening in the hospital registration system revealed that ten LT patients were diagnosed with COVID-19related pneumonia in the facility since the emerging of the SARS-CoV-2 pandemic. The information related to the medical status of these patients, including demographic characteristics, clinical data (onset symptoms, the treatments administered, results of the laboratory tests and radiological imaging, and clinical progressions), and the outcomes were collected.

The diagnosis of COVID-19 pneumonia was established according to the "COVID-19 Diagnosis and Treatment Guidelines of the Turkish Health Ministry" (12) . The criteria of mild/moderate pneumonia were as follows: respiratory rate <30/min and SpO 2 >90% in room air, and less than 50% lung involvement in the X-ray film of the chest or thoracic CT. Severe pneumonia criteria were as follows: respiratory rate ≥30/min or dyspnea, SpO 2 ≤90% or PaO 2 /FiO 2 ≤300 mmHg, respiratory failure requiring mechanical ventilation, shock or failure of other organs requiring ICU monitoring, new multi-lobular lesions on lung imaging or progression more than 50% in existing lesions within 48 hours, sequential organ failure assessment score (qSOFA) ≥2 and concomitant pneumothorax. Outcomes of the patients were assessed with recovery or 30-day all-cause mortality. The definition of the recovery from COVID-19 pneumoniae was based on the "SARS-CoV-2 Diagnosis and Treatment Guidelines of the Turkish Health Ministry" with minor modifications (12) . The cases were grouped as mild/moderate and severe pneumonia according to the "COVID-19 Severe Pneumonia, ARDS, Sepsis and Septic Shock Management Guideline" (13) . Briefly, resolutions of the clinical symptoms, normalization of blood and serum parameters, SpO2 ≥95% in normal breathing without any oxygen support, and two negative SARS-CoV-2 RT-PCR test results obtained at the interval of two consecutive days. Thirty-day all-cause mortality was defined as death due to any cause within 30 days of the COVID-19 symptoms onset.

The nasopharyngeal samples of the patients were collected with sterile swabs flocked with medical grade nylon microfibers and placed in vNAT Transfer Tube (Bioeksen R&D Technologies Ltd., Turkey) containing 2 ml vNAT solution, which was manufactured according to DNA/RNA shield technology. After RNA extraction, reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) was administered using Bio-Speedy SARS-CoV-2 RT-qPCR kit (Bioeksen R&D Technologies Ltd., Turkey) in the Rotor-Gene Q device (Qiagen, Germany). The RT-qPCR kit used in this study was targeting two genomic regions of SARS-CoV-2 encoding nucleocapsid (N) protein and ORF1ab.

Complete Blood Count (CBC; hemoglobin, total white blood cells (WBC), and the counts of neutrophils, lymphocytes, and platelets), coagulation parameters (INR and D-dimer), acute-phase reactants (CRP, PCT, IL-6, and ferritin) and serum biochemistry values (creatinine, albumin, total bilirubin, LDH, and liver enzymes) were measured initially on the day of COVID-19 diagnosis, as well as throughout the clinical course. In case of clinical suspicion for bacterial infection, sputum, tracheal aspirate, blood, and urine samples were collected for culture and gram staining.

The lung involvement of the LT recipients infected by SARS-CoV-2 was assessed using the chest X-ray film and non-contrast thoracic CT scanning. All imaging procedures were performed on a 16 slice multidetector CT device (Somatom-Scope, Siemens, Erlangen, Germany). Then, the obtained images were evaluated by author Yalcinsoy.

Categorical variables were expressed as frequency and percentage, and continuous variables of the patients were expressed as median, min-max, and Interquartile Range (IQR).

In this study, ten LT recipients at the median age of 57 years (min-max: 36-69; IQR: 13; year) were analyzed.

All patients were male and had right lobe living-donor LT in our transplantation center within a median of 11 months (min-max:1-72; IQR: 12; months). The patients had LT due to various reasons, such as chronic HBV infection, hepatocellular carcinoma (HCC) and sclerosing cholangitis. All patients were receiving immune suppressive treatment with tacrolimus and mycophenolate mofetil (MMF) (90%) or everolimus (10%). Diabetes mellitus was the most common co-morbidity.

At initial evaluation, four of the studied recipients were manifesting severe pneumonia, and a further one progressed to severe pneumonia during the hospitalization course. The representative CT images of the patients were shown in Figures 1, 2 and 3 .

The most frequent COVID-19 onset symptoms were fever (90%), cough (70%), fatigue (70%), and dyspnea (60%). Favipiravir (1600 mg daily twice on the first day, after then, 600 mg daily twice for minimum four days) for five to ten days, enoxaparin sodium (0.6 mg daily one), and metyl-prednisolone (40-250 mg per day) or dexamethasone (6-8 mg per day) were initiated as soon as possible to the patients. All recipients were hospitalized for a median of ten days (min-max: 5-32, IQR: 11; days). Three patients with severe pneumonia required ICU stay for a mean of 17 days and mechanical ventilation for a mean of eight days. According to the clinical courses, three patients received an IL-6 receptor blocker, tocilizumab (8 mg/kg max 800 mg, only once or twice). Four patients with severe pneumonia developed bacterial infections, including sepsis (n:3) and pneumonia (n:1). After antibacterial treatment, three of these patients recovered, but the remaining one patient died. No further progression was recorded in other patients studied. Overall, nine of the patients fully recovered from COVID-19 pneumonia (30-days all-cause mortality was 10%). General characteristics of the patients related to LT and COVID-19 pneumonia are shown in Table 1 .

At the initial evaluation, five patients presented with low blood leucocytes level (<2,65x10 3 /ml), five with low lymphocytes level (<600x10 3 /uL), seven with high CRP (>9 mg/dL) four with high IL-6 (>100 pg/mL) and four with high ferritin (>1000 ng/mL) levels. The INR and D-dimer results were also indicative of intravascular coagulation. During the clinical course, these parameters worsened further. The liver enzymes of nine out of the patients were detected in normal ranges. The blood and serum test results of the patients are shown in Table 2 .

In this study, we evaluated the clinical characteristics of COVID-19 pneumonia cases with LT, a group of patients having high risk for the serious health problems such as organ rejection or death due to a developing infection. To our knowledge, this is the first study involved such a group of patients from Turkey applying a particular antiviral and anticoagulant treatment policy all over the country. While one of our patients died, nine of our patients recovered. The patients were closely followed up with the specialists from infectious diseases, chest diseases, intensive care, and general surgery.

In an epidemiological study that included SARS-CoV-2 positive persons, it was reported that 29.2% of the patients showed neither any clinical symptom nor any positive radiological image in thoracic CT (14) . The high frequencies of severe pneumonia and mortality rate were reported from the patients of older ages, male sex, chronic obstructive pulmonary disease, cardiac failure, diabetes mellitus, renal disease, hematological malignancy, and SOT (15) . However, there are still many unknowns on why some persons with no co-morbidity die or have the severe pneumonia due to COVID-19 and why some persons with multiple known medical predisposing factors recover from this infection. Although it is varying by the countries and the territories, 2.2% of the infected patients lost their life due to SARS-CoV-2 virus all over the world, according to the WHO's database, by January 22 th , 2021 (16) . Therefore, investigation of the clinical features and outcomes of special patient groups can yield substantial outputs for enlightening the dynamics of COVID-19. Additionally, evaluating the patients' clinical characteristics who received different treatment regimens will also benefit determining the optimal management strategies (17) . In SOT recipients, due to increased angiotensin-converting enzyme-2 (ACE-2) protein expression and intense immunosuppression, COVID-19 is more likely to occur within the early period after LT (especially first six months) (18) . According to the current knowledge, it has been pointed out that COVID-19 that develops in LT recipients is more severe and has higher mortality rates compared to healthy individuals, but the data are still very limited (19) . In a multicenter study that included ten renal transplant patients who were found positive for SARS-CoV-2, Nair et al. (20) reported that seven (70%) of the patients developed pneumonia, three (30%) patients died, and half of the patients developed acute kidney injury. In a nationwide study from France that included 279 renal transplant patients diagnosed with COVID-19, 46% of the patients developed the severe pneumonia, and about 23% of all the studied patients died within 30 days (21) . In another multicenter study that included more than 480 SARS-CoV-2-positive patients with kidney, pancreas, liver, heart and lung transplantations, Kates et al. (22) reported that 31% of the patients required mechanical ventilation, and 20.5% of patients died. The immunosuppressive treatments of the patients in that study were modified after the diagnosis of COVID-19. The patients were administered different antiviral drugs, corticosteroids and immunomodulators such as anti-IL-6 drugs, and/or convalescent plasma and intravenous immunoglobulin (IVIG). Additionally, the authors underlined that specific predisposing factors, such as congestive heart failure, chronic lung disease, and obesity, were independently associated with mortality. Webb GJ et al. (23) conducted a cohort study in which 28 LT recipients and 167 the control group. According to this study, the mortality rate of LT recipient group (19%) is lower than control group (27%). No deaths were liverrelated in the transplant group. In this cohort study, six (75%) of the eight patients with non-liver cancer died, among whom the causes of death were COVID-19 lung disease four (67%), cardiac-related one (17%) and multiorgan failure one (17%).

We observed that the majority of our patients presented common COVID-19 lung involvement onset symptoms, such as fever, dry cough and dyspnea. Two patients were also presenting muscle and joint pains, and one with gastrointestinal symptoms. Fever was the most frequent symptom in our patients, generally mild-moderate (37.8-38.7 0 C). In a study conducted by Pereria et al. (18) , which included 90 SOT patients in two centers in the United States, the most common symptoms were fever, cough and dyspnea similar to the general population, and dyspnea was reported to be the most important finding for severe clinical course. Measurement of D-dimer, ferritin, PCT, CRP, IL-6, and high-sensitive troponin is initially valuable in hospitalized patients. Lymphopenia is a common laboratory finding. An increase in D-dimer, progressive lymphopenia and inflammation parameters are more likely in severe and critically ill patients (24) . In our LT recipients, all were presented with anemia that was one of the common findings in LT patients. On the other hand, we detected low blood leucocyte number, lymphopenia, high CRP levels, PCT and ferritin in our patients on the diagnosis day of COVID-19 and throughout its clinical course. These findings during the initial evaluation were similarly observed in a normal population. However, more care should be taken in LT recipients concerning nephrotoxic and hepatotoxic side effects of drugs used for the treatment of COVID-19 and their interactions with immunosuppressive drugs used.

Radiologically, the sensitivity of non-contrast thoracic CT to detect infiltrations in the lung parenchyma in the early period is higher than posterior-anterior X-ray chest radiography. When the diagnosis of COVID-19 pneumonia is made in the SOT patient group, it should be kept in mind that bacterial pneumonia may accompany both at the time of diagnosis and during follow-up (25) . We evaluated the clinical courses of ten LT recipients with mild/moderate to severe COVID-19 pneumonia. During our treatment courses of COVID-19 pneumonia, three patients in ICU (all sepsis) and one patient (severe pneumonia) in the clinic developed a bacterial infection.

Extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae grew in the blood samples of two patients with sepsis, but no pathogen was detected in the other two patients. Three of these patients responded well to the antibacterial treatment, but one patient who had LT recently could not be saved.

Confirmed COVID-19 Disease (as of November 3, 2020) states that no specific treatment is available (26) .

However, more than 300 active clinical therapy trials are going on. In these studies, chloroquinehydroxychloroquine, lopinavir/ritonavir, favipiravir, remdesivir, corticosteroids, adjunctive therapies (anticytokine or immunomodulatory agents and immunoglobulin therapy) have been administered to patients (27) .

No high-quality evidence exists for the efficacy of chloroquine/hydroxychloroquine therapies of SARS-MERS (28) . Monoclonal antibodies against IL-6. Tocilizumab, a monoclonal antibody IL-6 receptor antagonistic, has been used in a small series of severe COVID-19 cases (29) . Other potential adjunctive therapies are convalescent plasma or hyperimmune immunoglobulins that antibodies from recovered patients may help with both free virus and infected cell immune clearance for COVID-19 treatment (30) . The rationale for the use of corticosteroids is to decrease the host inflammatory responses in the lungs, which may lead to acute lung injury and acute respiratory distress syndrome (ARDS) (31) . It is likely that the beneficial effects of corticosteroids in severe viral respiratory infections are dependent on a selection of the right dose, at the right time, in the right patient.

However, this benefit may be outweighed by adverse effects, including delayed viral clearance and increased risk of secondary infection (32) . Therefore, successful and balanced supression of systemic anti-inflammatory response in COVID-19 pneumonia can be life-saving. All these data indicate that the clinical courses and the outcomes of COVID-19 in SOT recipients are influenced by a high number of factors belonging to the patients' medical characteristics; medical standards of the countries and the treatment regimens are administered (33) . Therefore, the need for data from this specific patient group sharing similar characteristics is going on for better planning the treatment modalities for COVID-19 in not only LT recipients but also in other patients (34). Upon the early period of the COVID-19 diagnosis, favipiravir, enoxaparin sodium as an anticoagulant drug, and metylprednisolone (40 to 250 mg/day) or dexamethasone (6 to 8 mg/day) were administered to all of our recipients.

Oxygen support given through nasal cannula improved blood oxygen saturation (above 90%) in nine patients, but a patient who had LT 25 days ago required endotracheal intubation in ICU. During the clinical follow, two more patients with severe COVID-19 pneumonia showed a progressive decrease in the blood oxygen saturation and required mechanical ventilation in ICU. However, that patient had a high number of co-morbidities; for example, he had major surgery (LT) in the last one month, still in the intensive immunosuppression and ICU stay. His medical condition and self-care were already rather poor at the pre-LT period due to the long-standing chronic alcoholism. Furthermore, he had additional immunosuppression due to COVID-19, such as high dose corticosteroid and tocilizumab; then he developed sepsis due to an ESBL (+) Klebsiella pneumoniae, which was a highly fatal complication even in non-transplant patients.

In briefly, to our knowledge, this is the first study reported in Turkey that the clinical characteristics of LT patients diagnosed with COVID-19 pneumonia. Although there was also a 10% mortality rate in our patients, we found that four patients with severe and five mild-moderate COVID-19 pneumonia survived. Although our patients had risk factors (such as major surgery, advanced age, immunosuppression, male gender, and DM) for high mortality in COVID-19 pneumonia, only one of our patients died. This mortality rate (10%) was lower than the rates previously reported.

Given that it has a lower mortality rate value than reported in previous studies, we speculate that the commencing of favipiravir, enoxaparin sodium and corticosteroid treatments, close follow-up of the developing complications, temporary reduction or cessation of immunosuppression, multidisciplinary approach, early awareness of the bacterial infections and the initiation appropriate antibiotic treatments contributed to this success. Since we observed a mortality rate in our LT patients as very close to normal population with COVID-19 pneumonia, we believe that some aspects of the data we present in this study have the potential to contribute to the ongoing battle against COVID-19 pneumonia in a normal population, too. However, comprehensive multicenter studies with large numbers of LT recipients are needed on COVID-19 pneumonia and to clarify the efficacy, side effect potential and drug-drug interactions of existing drugs in this patient group.

In this study, we evaluated total 10 LT patients with mild/moderate and severe pneumonia due to SARS-CoV-2 virus. This number was the sum of all the LT recipients determined for eight months in our facility. Though, it would be better to investigate higher numbers of the patients to analyze the clinical outcomes at the best level, no further patient could be determined throughout the study period. We thought that the awareness of the LT recipients about their critical health status, and obeying the public measurements such as masks, social distancing, etc. could prevent them from the spread of pandemic. 

☒ This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. 

A pneumonia outbreak associated with a new coronavirus of probable bat origin

World Health Organization Coronavirus disease (COVID-19) situation Dashboard

Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study

Epidemiological pattern, incidence, and outcomes of COVID-19 in liver transplant patients

Update on liver transplantation-newer aspects

COVID-19 in long-term liver transplant patients: preliminary experience from an Italian transplant centre in Lombardy

Management of COVID-19 in patients after liver transplantation: Beijing working party for liver transplantation

China Novel Coronavirus Investigating and Research Team. A Novel Coronavirus from Patients with Pneumonia in China

China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China

Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in Wuhan

Drug treatment options for the 2019-new coronavirus (2019-nCoV)

COVID-19 (SARS-CoV-2 INFECTION) (Study of Scientific Board). The Republic of Turkey Ministry of Health

COVID-19 Patient Management in Intensive Care

Clinical characteristics of 24 asymptomatic infections with COVID-19 screened among close contacts in Nanjing

Impact of hematologic malignancy and type of cancer therapy on COVID-19 severity and mortality: lessons from a large population-based registry study

WHO Coronavirus Disease (COVID-19) Dashboard. Available from

Individual risk management strategy and potential therapeutic options for the COVID-19 pandemic

COVID-19 in solid organ transplant recipients: Initial report from the US epicenter

COVID-19 pandemic: Its impact on liver disease and liver transplantation

COVID-19 in kidney transplant recipients

An initial report from the French SOT COVID Registry suggests high mortality due to COVID-19 in recipients of kidney transplants

UW COVID-19 SOT Study Team. COVID-19 in solid organ transplant: A multi-center cohort study

Outcomes following SARS-CoV-2 infection in liver transplant recipients: an international registry study

The role of biomarkers in diagnosis of COVID-19 -A systematic review

Imaging findings in COVID-19 pneumonia

COVID-19) clinical care

Pharmacologic Treatments for Coronavirus Disease 2019 (COVID-19) A Review

Effective treatment of severe COVID-19 patients with tocilizumab

Convalescent plasma as a potential therapy for COVID-19

Clinical evidence does not support corticosteroid treatment for 2019-nCoV lung injury

Dexamethasone in Hospitalized Patients with Covid-19 -Preliminary Report

The authors warmly thank all the nurses at the Inonu University Liver Transplant Institute for helping us access treatment records, all laboratory staff working in Molecular Microbiology, and the hospital pharmacy responsible for helping us access to daily drug outputs of pharmacy.