The present COVID-19 pandemic is a cause for concern among solid-organ transplant recipients, who are generally at high risk for infection and for whom infection with COVID-19 carries additional risks for complications and mortality that are higher than the COVID-19-associated risks for the general population. We report the case of a liver transplant recipient who presented with COVID-19 and multiple complications. A 39-year-old woman with a liver transplant was diagnosed with COVID-19 within the first week after transplant surgery. Mycophenolate was withheld, and interferon β was administered for management of COVID-19. She developed thrombotic thrombocytopenic purpura, acute antibody-mediated rejection, and posterior reversible leukoencephalopathy syndrome during hospitalization. All of these complications may be related to COVID-19 or its management modalities. We considered 3 possible causes for thrombotic thrombocytopenic purpura in this patient: the COVID-19 infection itself, immunosuppression treatment with cyclosporine, and treatment with interferon β. Immunosuppression reduction and interferon treatment may result in antibody-mediated rejection. COVID-19, thrombotic thrombocytopenic purpura, and cyclosporine may play a combined role in the development of posterior reversible leukoencephalopathy syndrome. In conclusion, thrombotic thrombocytopenic purpura, antibody-mediated rejection, and posterior reversible leukoencephalopathy syndrome may represent a continuum of 3 thrombotic microangiopathy conditions fostered by interplay between the COVID-19 infection and the treatment modalities for COVID-19 management in this patient.
Key words : Coronavirus disease 2019, Immunosuppression, Interferon, Liver transplantation, Thrombotic thrombocytopenic purpura
Solid-organ transplant recipients are typically treated with a posttransplant regimen of immunosuppression and therefore are at high risk for infections, including COVID-19. Additionally, these patients may experience higher rates of complications and mortality.1
Thrombotic thrombocytopenic purpura (TTP) is a thrombotic microangiopathy (TMA) that is generally characterized by occurrence of severe thrombocytopenia, microangiopathic hemolytic anemia, and ischemic organ damage in the brain, kidneys, and heart. Thrombotic thrombocytopenic purpura is classified as either acquired or hereditary. Acquired TTP is characterized by a deficiency in activity of ADAM metalloproteinase with thrombospondin type 1 motif 3 (ADAMTS13), which results in spontaneous aggregation of platelets and formation of platelet-rich clots in small blood vessels.2 Thrombotic microangiopathy is a critical complication that may occur after liver transplant, with poor prognosis and high mortality. Thrombotic microangiopathy occurs in deceased-donor liver transplant recipients less frequently than in living-donor liver transplant recipients.3 Viral infections and drugs such as calcineurin inhibitors (CNIs; eg, cyclosporine) are possible causes of TMA and TMA-like disorders after transplantation.2 Drug-induced TMA is usually not associated with ADAMTS13 deficiency.2
Posterior reversible leukoencephalopathy syndrome (PRES) is a neurologic syndrome with various etiologies, including hypertension, immunosuppression therapy (eg, CNIs), and autoimmune disorders. Posterior reversible leukoencephalopathy syndrome is a low-incidence, posttransplant complication. In liver transplant recipients, PRES typically appears within the first 2 months after transplant.4 Also, PRES has been reported as the most common neurologic finding in patients with severe TTP.5
Here, we report the case of a liver transplant recipient infected with the SARS-CoV-2 virus who experienced all of the complications mentioned here.
A 39-year-old woman with liver cirrhosis due to primary sclerosing cholangitis with a Model For End-Stage Liver Disease score of 35 underwent liver transplant from an ABO-compatible, negative crossmatch, deceased donor. Assessment of this patient for donor-specific antibodies was not conducted before transplant. According to the protocol at our center, COVID-19 polymerase chain reaction and chest computed tomography were performed before transplant, and results from both were negative for COVID-19. Maintenance immunosuppression therapy consisted of cyclosporine (75 mg twice daily), mycophenolate mofetil (1 g twice daily), and oral prednisolone tapered according to the center’s protocol.
Five days after transplant, she experienced a fever of 39 °C and dyspnea. Computed tomography scan of the chest showed ground-glass opacities in both lungs. The polymerase chain reaction test was positive for COVID-19. Mycophenolate mofetil was discontinued, and subcutaneous injection of 5 doses of interferon (IFN) β-1a (44 μg) was administered on alternate days. Her fever and other symptoms subsided after a few days. At day 14 after transplant, the control liver biopsy taken at the time of abdominal fascia closure revealed antibody-mediated rejection (AMR); the patient had normal liver function tests. Intravenous methylprednisolone pulse was given to treat acute rejection. Serum lactate dehydrogenase increased to 967 U/mL, and platelet count decreased rapidly to 4000 cells/μL. Serum creatinine increased from the baseline value of 0.5 to 1.3 mg/dL. Hemoglobin level was stable at around 8.5 g/dL. Prothrombin time, partial thromboplastin time, and international normalized ratio were normal. Schistocytes were detected in the peripheral blood smear. The ADAMTS13 activity was normal, and ADAMTS13 inhibitor activity was negative.
Sixteen days after transplant, she developed an alteration in mental status and an episode of seizure with transient loss of consciousness and a substantial increase in blood pressure. Intravenous nitroglycerin and levetiracetam were initiated. Brain magnetic resonance imaging results were compatible with PRES. Also, intraparenchymal hemorrhage was present at the left occipital lobe. Brain magnetic resonance venography results were normal. The trough level of cyclosporine in whole blood was 398 ng/mL on the same day (day 16). Thereafter, cyclosporine dose was reduced to 50 mg twice daily. We considered TTP as the probable diagnosis and initiated therapeutic plasmapheresis and intravenous immunoglobulin. Serum lactate dehydrogenase level decreased to 310 U/L and platelet count increased to 95 000/μL after 10 sessions of plasmapheresis, after which she regained consciousness (Figure 1). The patient was discharged to home about 2 months after transplant with sirolimus, mycophenolate, and prednisolone as maintenance immunosuppression treatment. One month later, on an outpatient visit, her liver function tests and platelet counts were normal.
Our patient was infected with COVID-19 a few days after receiving a liver transplant. She developed some complications, including AMR, TTP, and PRES, all of which could have been associated with COVID-19 or its management modalities. We considered 3 possible causes for TMA/TTP in this patient: the COVID-19 infection itself,6 treatment with cyclosporine,2 and treatment with IFN-β.7 The combination of immunosuppression reduction8 and IFN treatment for management of COVID-19 is a known risk factor for acute rejection.9-13 COVID-19 infection,14 TTP,5 and cyclosporine15 may have a combined role in PRES development (Figure 2).
Recent reports have shown that SARS-CoV-2 infection can cause diffuse endothelial inflammation, which may trigger acute TTP.6 Rapid-onset TTP with a reduction in ADAMTS13 activity and presence of an ADAMTS13 inhibitor in the first week after COVID-19 infection has been reported.6 Our patient also developed rapid-onset TTP after COVID-19 infection, but her ADAMTS13 activity was normal and no inhibitor was detected. In addition, TMA is a well-known complication of CNI treatment.2 In general, drug-induced TMA is not associated with ADAMTS13 deficiency.2 Our patient was under treatment with cyclosporine and did not show a reduction of ADAMTS13 activity. She also received IFN-β-1a for treatment of COVID-19, and TMA is a known adverse effect of IFN-β treatment, albeit uncommon.11 Generally, interferon-associated TMA is late onset and develops after months of well-tolerated treatment after a high cumulative dose of IFN is attained.7 In our case, we considered COVID-19 infection and its subsequent treatment (IFN-β) as well as cyclosporine immunosuppression therapy as possible causes of TTP in our patient. Normal ADAMTS13 activity may be in favor of drugs rather than COVID-19 infection as possible cause of TTP.2 Based on the time of TTP occurrence, the more likely offending drug was cyclosporine rather than IFN-β.
There are several factors that may have contributed to the AMR in this patient, including immunosuppression reduction8 or treatment with IFN-β,9,10 both of which were prescribed for management of her COVID-19 infection. Although the blood level of cyclosporine was maintained near the upper limit of the therapeutic range, the discontinuation of mycophenolate mofetil may have been the main causative factor of AMR in this patient. We also considered IFN-β treatment as another possible cause. There are several reports in the literature on the relationship between acute allograft rejection and IFN-α treatment in liver transplant recipients.9 Treatment with IFN-α can increase the expression of the HLA-DR antigens in donor hepatocytes, which may lead to severe immune response and organ rejection.10 Incidence of acute rejection has been reported to be about 21% after initiation of IFN therapy.9 Most IFN treatment studies have focused on IFN-α; however, IFN-β may cause similar effects. A recent perspective article expressed concern about the increased likelihood of acute rejection associated with IFN for treatment of COVID-19.12 Most patients who have experienced IFN-associated allograft rejection have shown cellular rejection, whereas cases of AMR have been limited. In one case report, a liver transplant recipient treated with pegylated IFN-α-2a for treatment of a chronic hepatitis E viral infection subsequently developed acute humoral rejection within 3 months of the IFN treatment.13 Our patient was diagnosed with AMR about 2 weeks after starting IFN-β, whereas a previous study reported this complication at 3 to 6 months after the start of IFN treatment.13
The interplay among several factors may have induced PRES in this patient. A possible cause of PRES could be TTP. In fact, PRES is the most common finding in the brain imaging of patients with TTP,5 and PRES may result from endothelial damage and leakage in the blood-brain barrier in these patients.5 In addition, the occurrence of PRES in patients with COVID-19 has been reported in several cases.14 It has been suggested that cytokine storm after COVID-19 increases vascular permeability and thereby implicates COVID-19 as a risk factor for PRES.14 These patients usually had acute kidney injury and elevated blood pressure, and PRES was managed by controlling blood pressure.14 Similarly, our patient showed elevated blood pressure at the time of TTP and PRES. She experienced a mild acute kidney injury (stage 1) that improved without any special management. Finally, cyclosporine-associated PRES was also a possibility in our patient. The incidence of CNI-associated PRES has been reported to be 0.13%. The average time to onset of PRES after transplant has been reported to be 17 days (1 day to 5 years).15 We identified PRES in our patient on day 16 after transplant. In previous studies most of the patients who developed PRES had CNI blood levels above the upper limit of the therapeutic range.15 Similar to the results in these reports, the trough level of cyclosporine was 398 ng/mL for our patient, which was above the desired therapeutic range. Our patient experienced hypertension concomitant with these complications, and high blood pressure has been reported in 69% of patients with CNI-associated PRES.15
In conclusion, after liver transplant and subsequent infection with COVID-19, our patient experienced TTP, AMR, and PRES. This interplay between several factors is difficult to assess for causality. Thrombotic thrombocytopenic purpura, AMR, and PRES may represent a continuum of TMA outcomes and, as such, may be the explanation for the details of this case. In addition to COVID-19 itself, drugs and treatment modalities for management of COVID-19 may have contributed to these complications. Specifically, IFN-β can trigger TTP and AMR, mycophenolate withdrawal may induce AMR, and cyclosporine may induce TTP and PRES.
Volume : 19
Issue : 9
Pages : 990 - 993
DOI : 10.6002/ect.2021.0020
From the 1Department of Pharmacotherapy, Liver Transplantation Research Center, Tehran University of Medical Sciences; the 2Department of Pharmacotherapy, Faculty of Pharmacy, Tehran University of Medical Sciences; the 3Department of Hepatopancreatobiliary and Liver Transplant Surgery; the 4Department of Infectious Disease; and the 5Department of Gastroenterology and Hepatology, Liver Transplantation Research Center, Tehran University of Medical Sciences, Tehran, Iran
Acknowledgements: We thank the nurses of the transplant ward of Imam-Khomeini Hospital Complex, Tehran, for their valuable role in the treatment of this patient. 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.
Corresponding author: Simin Dashti-Khavidaki, Liver Transplantation Research Center, Tehran University of Medical Sciences, PO Box 1417614411, Tehran, Iran
Figure 1. Laboratory Tests During Hospital Course After Transplant
Figure 2. Interplay Between Complications of the Patient and Probable Causes