Acute liver failure is a rare but life-threatening medical emergency. Despite advancements in medical management, mortality rates of acute liver failure remain high. Currently, liver transplant is the only definitive therapeutic option available. High-volume plasma exchange has been shown to increase transplant-free survival in patients with acute liver failure before liver transplant. However, the occurrence of infectious complications in patients who receive this treatment has not been well studied. We report 2 cases of severe opportunistic infections occurring within 30 days of transplant in patients who underwent high-volume plasma exchange before liver transplant.
Key words : Acute liver failure, Cytomegalovirus infection, Pulmonary aspergillosis
Acute liver failure (ALF) is a rare but life-threatening medical emergency that requires emergency liver transplant as a life-saving treatment. Because of the low incidence of spontaneous recovery after ALF, several supportive treatments have been evaluated as bridge treatments until a suitable donor liver becomes available.1-3 High-volume plasma exchange seems to be an effective and safe method for direct removal of pathogenic substances from the circulation of patients with ALF.4-9 Recent randomized controlled trials in Europe have demonstrated that high-volume plasma exchange in patients with ALF increased transplant-free survival.9,10 The guidelines from the American Society for Apheresis have been recently revised, in which high-volume plasma exchange, before recommended as a category III treatment, is now recommended as a category I treatment in 2016.9 However, the risks of infectious diseases are not well known in patients who receive high-volume plasma exchange, especially in those who undergo subsequent liver transplant.
At the Samsung Medical Center, a tertiary care hospital, 112 patients underwent liver transplant from March 2016 to February 2017. Of these, 4 patients with ALF had received high-volume plasma exchange. Three patients were diagnosed with cytomegalovirus (CMV) infection, and 1 patient was diagnosed with invasive pulmonary aspergillosis and CMV infection. We found that 2 of the 4 patients with opportunistic infections had been treated with high-volume plasma exchange before liver transplant. Here, we present our experiences with these 2 patients (Table 1).
A 21-year-old male patient with no history of liver disease presented with acute acetaminophen toxicity. He developed hepatic encephalopathy, coagulopathy, and lactic acidosis and was transferred to our hospital in June 2016. On admission to the intensive care unit (ICU), his vital signs were stable and the Glasgow coma scale (GCS) score was 4 (eye opening 2, verbal response 1, motor response 1).
Liver function tests revealed aspartate amino-transferase (AST) level of 15 586 IU/L, alanine transaminase (ALT) level of 12 707 IU/L, total amino bilirubin of 4 mg/dL, and albumin level of 3.2 g/dL. The prothrombin time international normalized ratio (INR) was 10.48. The Model for End-Stage Liver Disease (MELD) score, which validates chronic liver disease severity, was 40. He received mechanical ventilation and renal replacement therapy.
On day 2 of hospitalization, the patient received high-volume plasma exchange. On the basis of his weight and hematocrit level, approximately 8222 mL of plasma were removed at a rate of 1 to 2 L/hour with replacement with fresh frozen plasma in equivalent volume (49 units). After 1 session of high-volume plasma exchange, he underwent emergency deceased-donor liver transplant on day 4 of hospitalization. He was started on maintenance immunosuppression with tacrolimus, mycophenolate mofetil, and prednisolone on postoperative day (POD) 4 and was discharged on POD18. The patient did not receive antiviral prophylaxis because empirical mana-gement has been our strategy for cytomegalovirus (CMV) infection prevention in our hospital.
On POD28, CMV antigenemia was positive by 227/200 000 white blood cells without documented fever. Preemptive therapy with ganciclovir was missed in the outpatient clinic because the CMV antigenemia results were not available on the day of test (POD28). On POD37, he visited the emergency department with melena and bloody stools. Esophagogastroduodenoscopy was performed, and multiple variably sized ulcers were seen on the antrum, anterior wall, posterior wall, and lessor curvature of the stomach (Figure 1). Biopsy confirmed CMV gastric ulcer. He received intravenous ganciclovir for 5 weeks and was discharged with clinical improvement on POD70.
A 68-year-old female patient without chronic liver disease presented with ALF of unknown origin. She was transferred to our hospital for emergency liver transplant in August 2016. On admission to the ICU, her GCS score was 9 (eye opening 3, verbal response 2, motor response 4). Liver function tests revealed AST level of 551 IU/L, ALT level of 455 IU/L, total bilirubin of 47 mg/dL, and albumin of 3.4 g/dL. Her prothrombin time INR was 5.24 and MELD score was 40. She received mechanical ventilation and renal replacement therapy.
On the day after admission, the patient received high-volume plasma exchange. About 6684 mL of plasma were removed and replaced with fresh frozen plasma at equivalent volume (39 units). The day after high-volume plasma exchange, she underwent emergency living-donor liver transplant. On POD8, CMV antigenemia was detected, and the patient was treated with intravenous ganciclovir. In accordance with our protocol of postoperative routine manage-ment, the patient had a liver contrast-enhanced computed tomography scan on POD15. Both lungs showed multiple consolidations (Figure 2). She was transferred to the ICU for bronchoalveolar lavage procedure and was started on empirical antibiotics and liposomal amphotericin B.
Aspergillus galactomannan antigen titer in serum was 10.85. Bronchoalveolar lavage fluid culture and sputum culture identified mold-type fungi, confirmed as Aspergillus lentulus by 28S rDNA sequencing. Cytomegalovirus DNA polymerase chain reaction titer in bronchoalveolar lavage fluid was 612 237 IU/mL. Her brain computed tomog-raphy scan for evaluation of mood change showed 3 peripheral rim enhancing lesions with adjacent edema suspected of multiple abscesses, and funduscopic examination for evalu-ation of left eye visual loss was compatible with fungal endophthalmitis (Figure 3). She underwent left vitrectomy. Vitreous fluid culture grew Aspergillus species on POD69. During treatment with voriconazole for disseminated aspergillosis and with ganciclovir for suspected CMV pneumonitis, Aspergillus antigen titer decreased and CMV antigenemia turned to zero. She received ganciclovir for 6 weeks, which included maintenance treatment, and her medication plan included continuation of oral voriconazole. She was discharged on POD82.
Acute liver failure is defined as severe liver injury with onset of hepatic encephalopathy within 8 weeks of the first symptoms. It often results in hemo-dynamic instability, brain edema, renal and pulmo-nary failure, acid-base electrolyte imbalance, metabolic acidosis, coagulopathy, and development of multiorgan failure. The basic pathophysiology for development of multiorgan failure in ALF remains obscure. Several studies have suggested that patients with ALF have high concentrations of various metabolites (eg, ammonia, urea, and amino acids), endotoxins, and inflammatory mediators (eg, tumor necrosis factor, interleukin 1, and interleukin 6). Excessive production of these materials may cause many harmful effects and systemic inflammatory response syndrome.4,5,11
High-volume plasma exchange has been accepted as a bridge treatment for ALF until native liver cells regenerate spontaneously or until liver transplant. Several studies have demonstrated the efficacy of high-volume plasma exchange in reducing plasma levels of various metabolites, endotoxins, and inflammatory mediators and its ability to improve hepatic encephalopathy and coagulopathy.4-6,8,9,11 However, studies are not conclusive regarding the risks of infectious diseases in patients receiving high-volume plasma exchange. A recent randomized controlled trial in Europe demonstrated that treatment with high-volume plasma exchange improved outcomes with ALF by increasing liver transplant-free survival. That study showed that adverse events such as cardiac arrhythmia, pancreatitis, worsening gas exchange, acute respiratory distress syndrome, transfusion-related reaction, and culture-positive infections between those who received high-volume plasma exchange and those who did not were not statistically significantly different.9,10 That study also showed that the numbers of circulatory lymphocytes, including CD4 cell, CD8 cells, natural killer T cells, and regulatory T cells, did not change after 12 hours of high-volume plasma exchange.10
However, patients with ALF are at risk of developing opportunistic infection as a consequence of impairment of immune function by the disease itself. Plasma exchange may increase this risk, either as a direct result of the procedure or by virtue of its immunosuppressive effects.12,13 Opportunistic infec-tions after liver transplant are more frequent 1 to 6 months after transplant, when the net state of immunosuppression is the highest.14 In our study, 2 of 4 patients who underwent high-volume plasma exchange developed opportunistic infections related to dysfunction of cell-mediated immunity early and as severe disease, especially in patient 2. Among the patients who underwent total liver transplant, the incidence of opportunistic infection was only 3.6% (4/112), but 50% (2 of 4 patients) underwent plas-mapheresis. Although the effects of plasmapheresis on cell-mediated immunity are still unknown, the intensive alterations in immunoglobulin levels, complement levels, and other inflammatory mediators that follow overall incidence rate of other infections could be potent causes of both humoral and cell-mediated immune dysfunction.15 A study reported that life-threatening infections, including Pneumocystis jiroveci, CMV, and Aspergillus species, occur in a high number of patients with renal disease after plasmapheresis.15 That study and our report suggest that infectious complications might increase after high-volume plasma exchange because of additive immune defects associated with plasmapheresis.15 Further observations and investigations on occurrences of opportunistic infections in liver transplant patients who undergo high-volume plasma exchange are warranted.
DOI : 10.6002/ect.2018.0071
From the 1Division of Infectious Diseases, Department of Medicine; the
2Department of Surgery; the 3Department of Laboratory Medicine and Genetics; and
the 4Department of Medicine, Samsung Medical Center, Sungkyunkwan University
School of Medicine, Seoul, South Korea
Acknowledgements: The authors have no sources of funding for this study and have no conflicts of interest to declare. Present address of Ga Eun Park: Division of Infectious Diseases, Department of Internal Medicine, Konkuk University of Medical Center, Seoul, Korea.
Corresponding author: Kyong Ran Peck, Division of Infectious Diseases, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81, Irwon-ro, Gangnam-gu, Seoul 06351, Republic of Korea
Phone: +82 2 3410 032
Figure 1. Patient 1 Esophagogastroduodenoscopy Images Showing Diffuse Edematous Mucosa and Multiple Variably Sized Ulcers on Antrum, Anterior Wall, Posterior Wall, and Lessor Curvature of Stomach
Figure 3. Patient 2 Brain Contrast-Enhanced Computed Tomography Images Showing Peripheral Rim (arrows) Enhancing Lesions With Adjacent Edema Suggestive of Abscesses in Left Cerebral Hemisphere
Table 1. Clinical Characteristics and Laboratory Findings of 2 Patients Treated With High-Volume Plasma Exchange Before Transplant