Successful implementation of preventive measures leads to low relevance of SARS‐CoV‐2 in liver transplant patients: Observations from a German outpatient department

Abstract Background Immunosuppressed liver transplant (LT) patients are considered to be at high risk for any kind of infection. What the outbreak of the novel severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) means for the transplant cohort is a question that, as of now, cannot easily be answered. Data on prevalence, relevance of the novel virus, and clinical course of the infection in stable LT patients are limited. Methods Nasopharyngeal swabs were performed in our outpatient department during the shutdown between March and April 2020 in Germany. Results The prevalence of SARS‐CoV‐2 was 3%. Three out of a cohort of 101 LT patients were asymptomatic for respiratory diseases. Respiratory complaints were common and not associated with SARS‐CoV‐2 infection. The overall monthly mortality rate was 0.22% and did not show alterations during the shutdown in Germany. Conclusions If preventive measures are applied, LT patients do not seem to be at a higher risk for SARS‐CoV‐2 infection. Telemedicine in the outpatient setting may help to maintain distance and to reduce direct patient contact. However, standard of care must be guaranteed for patients with relevant comorbidities in spite of pandemics, because complications may arise from preexisting conditions.

face the pandemic. 2,3 Most of them include social distancing, strict hygiene, imposition of quarantine in case of infection, and symptomatic treatment of ARDS ranging from oxygen application to extracorporal membrane oxygenation. Incidence and mortality of the viral infection differs largely among the countries, and clinical courses presented in the literature are more than alarming especially in highrisk groups such as older patients, patients with malignant diseases, diabetes, hypertension, and assumedly on immunosuppression. 4,5 As previously hypothesized, immunosuppressed patients may be protected via their therapeutic regimen by putative attenuation of an overwhelming inflammatory response, for example, "cytokine storm" in case of initial infection with SARS-CoV-2, as this immune reaction is thought to contribute to ARDS in a significant manner. [6][7][8] Overall affection of the liver in the COVID-19 (coronavirus disease) pandemic seems to be mild, even in severe cases. However, elevated liver enzymes and bilirubin have been reported. [9][10][11][12] Their relevance for the clinical course remains unclear, and liver damage may be secondary as part of multi-organ failure. A study of four deceased patients suffering from severe COVID-19 showed none or only mild inflammatory aspects of the liver in post-mortem biopsies. 13 Still, a case report describes bystander-hepatitis in a recently liver transplanted patient with a mild SARS-CoV-2 infection. 14 Liver transplant (LT) patients are formally considered a vulnerable population, prone to all kinds of infections, because of the immunosuppressive medication. There are not enough data on the role of SARS-CoV-2 in stable liver transplant recipients. Therefore, we attempted to deliver some real-world data from a high-volume liver transplant outpatient clinic at the Charité Universitätsmedizin-Berlin, Germany.

| ME THODS
Our LT outpatient clinic currently cares for about 1500 patients Figure 1. The routine activities comprise planed check-ups, routine blood test, and presentations for acute medical problems of any kind. As of March 2020, as the nationwide COVID-19 lockdown commenced, we reduced our routine activities by 50%-75%, in order to prevent a spread of infections among our immunocompromised patients. Still, regular care was provided for those in need of specialized treatment. Between the 23 of March and the 23 of April 2020, outpatients were specifically questioned for laryngopharyngeal or tracheobronchial symptoms, suggestive for COVID-19 (ie, cough, fever, sore throat, dyspnea, new/changed sputum, new fatigue, exhaustion, new onset of diarrhea) and examined accordingly. Nasopharyngeal swabs were performed in all liver transplant patients during this period to detect SARS-CoV-2 disregarding the reason for the appointment and the complaints of the patients.
Qualitative real-time PCR was used to detect RNA of SARS-CoV-2.
In this method, targeted RNA molecules are amplified and marked with fluorescence, thus assessing detectability, only, without quantitative analysis. The method proofed highly sensitive and specific if performed correctly. 15,16 The results were correlated with demographic and clinical data. The quarterly mortality between January  Patients that needed an urgent consultation in our transplant clinic were provided with a facemask upon arrival and immediately questioned for commonly known suggestive symptoms for COVID-19, that is, fever, cough, and contact to infected people. If nothing applied patients were instructed to disinfect their hands and con-

The second patient was a 77-year-old woman 21 years after LT
for primary biliary cholangitis. She was in a good shape and suffered from mild hypertension. Previously diagnosed bronchial carcinoma was treated by lung resection without chemotherapy 1 year before.
The immunosuppression was mTor-based (everolimus: trough level 5,6 ng/mL) in combination with low-dose tacrolimus (trough level 1,5 ng/mL). However, no symptoms were evident at the positive swap, and the patient stayed asymptomatic during the 14 days of quarantine.
The last asymptomatic patient, who tested positive for SARS-CoV-2 in our cohort, was a 70-year-old male who underwent LT 12 years ago for HCV cirrhosis. Recurrent HCV (genotype 1a) was successfully treated with intravenous silibinin 10 years ago. 17 There was no relevant report of comorbidities, and immunosuppression was stopped in an individual decision 2 months ago. The patient remained asymptomatic during the course of the 2-week quarantine.
All positive SARS-CoV-2-positive patients maintained a good and stable graft function without signs of inflammation assessed by laboratory (INR, bilirubin, and aminotransferases).

| D ISCUSS I ON
The results of the present study demonstrate that SARS-CoV-2 in- While death rate is stated to be 3.3% of all registered cases, median age of patients dying from COVID-19 was 82 years in Germany. 20 In Berlin, the prevalence of SARS-CoV-2 infection is reported to be 170/100 000 but the number of unrecorded cases is estimated to be 10-20 times higher, 20 thus resulting in an approximation of 1%-4%. Interestingly, exactly this prevalence was found in our study.
The reported mortality rate of the present analysis as demon-  Usual and frequent conditions such as acute rejection, cholangitis, ischemic-type biliary lesions should deserve the same amount of attention due to their significance after LT with the need for treatment persisting with an unaltered prevalence despite a pandemic.
These treatable pathologies should be first priority in endangered, high-risk patients, and optimal treatment is required to affect the overall prognosis in a positive manner.
Despite from that, countermeasures that took place in this pandemic including reduction in social activity ("social distancing"), basic hygiene, and overall reasonable actions may very well contribute to the favorable results. 22 However, even under these remarkable conditions, routine medical treatment practices and rationales of guidelines should be followed.

| CON CLUS ION
Respiratory complaints among stable liver transplant patients are common and were not associated with SARS-CoV-2 infection in the presented cohort. If preventive measures are consequently applied, LT patients do not seem to be at a higher risk for SARS-CoV-2 infection. The spectrum of mortality is normal in an institution with reduced activity during the shutdown in Germany. Therefore, telemedicine in the outpatient setting may help to keep patient contact to a minimum. However, standard care for patients who require immediate medical attention must be guaranteed.

CO N FLI C T O F I NTE R E S T
All authors declare no conflict of interest related to the presented work.