Management of Coronavirus Disease 2019 Infection in a Small Bowel Transplant Recipient: A Case Report

Abstract

The coronavirus disease 2019 (COVID-19) pandemic has caused millions of people to become infected worldwide. Some patients may have disease progression and may need treatment with an anti-COVID-19 agent, hospitalization, and even intensive care. The risk factors for disease progression include old age, diabetes mellitus, pulmonary disease, cardiac disease, immunodeficiency, and immunosuppressant treatment. Therefore, the management of COVID-19 infection in transplant patients under immunosuppressant treatments needs specific consideration, especially the side effects of anti-COVID-19 agents and the interaction between immunosuppressants and anti-COVID-19 agents. In this report, we present the case of a small bowel transplant patient who had a COVID-19 infection. The patient was initially treated for paxlovid, and she developed bloody stools and dizziness. The treatment was then changed to molnupiravir without discontinuation of tacrolimus. The patient recovered smoothly after a 5-day treatment with molnupiravir. Here, we discuss the management experience of such patients and review the relevant literature.

Introduction

The coronavirus disease 2019 (COVID-19) pandemic has markedly influenced the world, with many people infected and dying. In Taiwan, more than 2 million people were infected during the COVID-19 outbreak in 2022, and the infection was predominantly caused by the Omicron severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant (B.1.1.529). Most patients infected by the Omicron variant had significantly reduced odds of severe disease than those infected with the Delta variant (B.1.617.2) [1]. However, some patients may have severe symptoms and need treatment with anti-COVID-19 agents, hospitalization, and even intensive care. Severe symptoms are often associated with risk factors such as old age, diabetes mellitus, pulmonary disease, cardiac disease, immunodeficiency, or immunosuppressant treatment [2,3].

Most transplant recipients take one or more immunosuppressants to prevent rejection or other possible adverse immunological events. However, these patients are at high risk of disease progression after COVID-19 infection [3], [4], [5]. The treatments for COVID-19 include anti-SARS-CoV2 monoclonal antibodies (mAbs) and direct-acting antiviral agents (DAA) [6,7], and the choice of treatment agents should be individualized. Awareness of the side effects of anti-COVID-19 agents and the interaction between immunosuppressants and anti-COVID-19 agents is important in the management of these patients. The American Society of Transplantation (AST) statement on oral antiviral therapy for COVID-19 for organ transplant recipients suggested the use of outpatient sotrovimab (anti-SARS-CoV2 mAbs) or intravenous remdesivir over nirmatrelvir/ritonavir, with molnupiravir being the less preferred option [6]. In addition, bamlanivimab/etesevimab and casirivimab/imdevimab have been found to have diminished efficacy against the Omicron variant [7]. In our country, the use of anti-SARS-CoV2 mAbs (such as sotrovimab and bebtelovimab) and remdesivir was limited to more severely hospitalized patients. In addition, the intravenous infusion of these drugs is difficult in patients quarantined at home. Therefore, it is more common to use oral form anti-COVID-19 agents in patients with mild symptoms.

In this report, we present the case of a small bowel transplant patient who had a COVID-19 infection. In addition, we discuss the management of such patients and review the relevant literature. Unfortunately, there are no reports on the management of COVID-19 infection in small bowel transplant patients; therefore, further studies are needed.

Case Report

A 33-year-old woman had progressive abdominal distension accompanied by vomiting when she was 25 years old. The patient was diagnosed with chronic intestinal pseudo-obstruction syndrome (CIPOS) after a series of examinations. The patient was then maintained on total parenteral nutrition. The patient had undergone cadaveric small bowel transplantation 5 years previously. The postoperative recovery was uneventful, and she was regularly treated with immunosuppressants, including prednisolone 5 mg every other day, mycophenolate mofetil 250 mg twice a day, and tacrolimus (Advagraf, 1 mg/cap) 3 mg per day, and the doses were adjusted according to the patient's clinical condition. The patient could eat and defecate smoothly after transplantation. The serum tacrolimus trough level was stable, and the last serum tacrolimus trough level was 2.9 ng/mL stationary 1 week before she got COVID-19 infection.

During the period of the COVID-19 outbreak, the patient received three doses of messenger ribonucleic acid (mRNA) COVID-19 vaccines, including two doses of Pfizer-BioNTech (Pfizer, Inc., and BioNTech) and 1/2 dose of Moderna COVID-19 vaccines (Moderna). One day later, the patient had a sore throat and dysphagia. The next day, the patient developed a fever of up to 38.2°C, rhinorrhea, cough, and a change in taste sensation. No dyspnea or muscle soreness was observed. The patient visited a nearby hospital, and the polymerase chain reaction test confirmed that she had a COVID-19 infection. Then, 300 mg nirmatrelvir/100 mg ritonavir (Paxlovid, Pfizer, New York, NY, USA) was administered twice a day at that hospital 2 days after the onset of symptoms. About 6 hours after taking the first dose of paxlovid, the patient also took immunosuppressants as usual. Approximately 12 hours after taking paxlovid, the patient presented with one episode of bloody stool and dizziness with a fainting sensation. There was no abdominal pain, diarrhea, worsening of fever, rhinorrhea, cough, or throat. The patient contacted our hospital via phone call. We suggested that she hold all drugs and contact the hospital that prescribed paxlovid. The treatment regimen was changed to 800 mg of molnupiravir twice daily for 5 days. In addition, immunosuppressants were re-started the next day. Subsequently, the patient had no more bloody stools, and the dizziness resolved gradually. After 1 day of molnupiravir treatment, the patient had no headache, fever, dizziness, diarrhea, nausea, vomiting, skin rash, or other major adverse effects. The upper respiratory tract symptoms resolved after 3-day molnupiravir therapy, and the patient recovered smoothly after 5-day molnupiravir treatment. The patient hemoglobin level was 11.7 g/dL, and the trough level of serum tacrolimus was 2.8 ng/mL 7 days after COVID-19 infection. The patient then returned to regular daily activities. During the 5 day-course of molnupiravir therapy, immunosuppressant regimens were maintained without dosage adjustments.

Discussion

Our patient was a small bowel transplant recipient under regular immunosuppressant treatment; therefore, she was considered to have a high risk of progression of COVID-19 infection [3,5]. The patient was treated with paxlovid initially; however, she developed bloody stool and dizziness approximately 12 hours after receiving the first dose of paxlovid. The cause of bloody stool is unclear; however, it may be related to rejection, COVID-19, or elevated tacrolimus levels induced by paxlovid. Rejection was less likely because the patient was treated with immunosuppressants regularly, and she had no abdominal pain, diarrhea, or any other symptoms of rejection. Although it is uncommon, gastrointestinal (GI) bleeding may be caused by COVID-19 infection [8]. A meta-analysis study revealed that the gastrointestinal (GI) bleeding rate is 0.6%, with 76.6% upper GI bleeding and 22.7% lower GI bleeding [8]. The mechanisms of GI bleeding in COVID-19 infection are unclear, but they may be related to the use of anticoagulants or non-steroidal anti-inflammatory drugs, inflammation-induced coagulopathy, thromboinflammation, and direct damage of the virus on the gastrointestinal mucosa [8]. However, our patient showed no evidence of disease progression of COVID-19 infection, except bloody stool and dizziness.

Since our patient also took immunosuppressants (including tacrolimus) 6 hours after the use of paxlovid, drug-drug interactions should be considered a possible cause of bloody stool. In addition, acute tacrolimus overdose has been found to be associated with a bleeding tendency [9]. Paxlovid, a combination of nirmatrelvir and ritonavir, has been shown to be safe and effective in the treatment of COVID-19 infection in non-transplant patients [10]. However, owing to the ritonavir component, paxlovid has significant interaction with multiple categories of medication such as calcineurin inhibitors (CNIs), mammalian target of rapamycin inhibitor, anti-hypertensive agents, and β-hydroxy β-methylglutaryl-coenzyme A reductase inhibitors [10], [11], [12], [13]. Ritonavir is a potent inhibitor of cytochrome P450 system CYP3A enzymes and P-glycoprotein (P-gp) [10,13]. The interaction between ritonavir and CYP3A-dependent drugs can result in increases in area under the curve blood concentrations of these latter drugs between 1.8- and 20-fold [10]. Tacrolimus is a calcineurin inhibitor metabolized by the cytochrome P450 3A4 enzyme system [7]. Coadministration of the ritonavir-containing direct-acting antiviral agents (DAAs) with tacrolimus reduced the tacrolimus clearance and resulted in an increased elimination half-life from 32 to 232 hours [11]. Healthy volunteers receiving a ritonavir-boosted DAA regimen coadministered with a calcineurin inhibitor (CNI) had a 57-fold increase in tacrolimus exposure and a 5.8-fold increase in cyclosporine exposure [11]. In a kidney transplant recipient receiving human immunodeficiency virus (HIV) salvage therapy and tacrolimus, the tacrolimus trough level was increased from 8.7 to 106 ng/mL (12.2 folds) after 3-day darunavir/ritonavir treatment, despite a 12% reduction in dose [14]. In another kidney transplant recipient with COVID-19 infection, after 2-day paxlovid treatment, the patient developed nausea and vomiting, and the serum tacrolimus level was increased to more than 30 ng/mL, above the goal range of 4–6 ng/dL [15]. The tacrolimus level was not checked in our patient because she was treated at another hospital. However, we thought that the paxlovid-induced elevation of tacrolimus level in our patient might not be as high as noted in previous studies [11,14,15]. Our patient took only one dose of paxlovid and tacrolimus approximately 6 hours after the intake of paxlovid. At that time, the ritonavir level was decreased because the circulating half-life of ritonavir was 3–6 hours, with its CYP3A effect lasting somewhat longer [10,16]. In addition, the patient serum tacrolimus trough level was maintained at a relatively low level (2.8 ng/mL) before COVID-19 infection. Therefore, we speculated that the interaction between these two drugs was not as strong as in previous reports [11,14,15].

Because of the probable interaction between paxlovid and tacrolimus, we suggested that the treatment for our patient be changed to molnupiravir. Molnupiravir is the prodrug of N⁴-hydroxycytidine (NHC), which has activity against SARS-CoV-2 and other ribonucleic acids (RNA) viruses [17], [18], [19]. After administration of molnupiravir, NHC circulates systemically and is phosphorylated intracellularly to NHC triphosphate [17], [18], [19]. The NHC triphosphate is incorporated into viral RNA by polymerase and then misleads the viral polymerase to incorporate either guanosine or adenosine during replication [17], [18], [19]. Eventually, the accumulation of errors throughout the viral genome renders the virus noninfectious and unable to replicate [17], [18], [19]. Molnupiravir has been found to be well tolerated, and the reported adverse events were mild, non-serious, and rapidly resolved [17], [18], [19]. Because it is a new drug with little safety data, molnupiravir is suggested to be used in non-severe patients with COVID-19 with a high risk of disease progressions, such as patients with old age, immunodeficiencies, chronic diseases, or those without vaccination [17,18,20]. One of the most important issues is that it has no significant interaction with other drugs [17], [18], [19], and immunosuppressants can be maintained without dose reduction or discontinuation. Therefore, in our patient, we suggested changing paxlovid to molnupiravir immediately, despite that molnupiravir is considered less preferred for transplant recipients [6]. During the 5-day molnupiravir treatment, the patient was well without discontinuation of immunosuppressants, including tacrolimus. The patient recovered smoothly, and the serum tacrolimus level was almost the same as before the COVID-19 infection.

From the experience of our patient and the data on solid organ transplants, we believe that awareness of drug-drug interactions is crucial because tacrolimus levels should be kept stable to avoid allograft rejection and intoxication. It is also advised to contact the transplant team during the management of transplant patients with COVID-19 infection. Consultation with the transplant team is important because members are more familiar with immunosuppressants and patients’ conditions. Patients under quarantine can be monitored using phone calls and mobile communication applications. It appears that molnupiravir can be used for the treatment of COVID-19 infection in small-bowel transplant patients with non-severe symptoms. This drug can be used without discontinuation of immunosuppressants such as tacrolimus. If paxlovid is the only available drug, reducing or withholding tacrolimus after initiation of paxlovid was suggested. The subsequent tacrolimus treatment should be based on the trough tacrolimus levels for at least as long as paxlovid treatment continues [10,15]. Once paxlovid treatment is completed, the original dose of tacrolimus may be resumed with trough level monitoring for 1 or 2 days [10]. In the literature, there is no report mentioning the management of COVID-19 infection in small bowel transplant recipients. Further studies are needed to investigate the feasibility and efficacy of variable anti-COVID-19 agents, including paxlovid and molnupiravir, in small-bowel transplant recipients and other solid-organ transplant recipients.

Funding

The authors declare no funding supports for this research.

Declaration of Competing Interest

The authors declare no conflicts of interest.