Multidrug antiviral “Rescue” therapy for severe cytomegalovirus infection after lung transplantation: a case report

Abstract

Introduction: Primary cytomegalovirus (CMV) infection or re-activation of prior latent CMV infection are common complications after lung transplant (LTX), associated with high morbidity and mortality [1]. Anti-CMV strategy usually includes antiviral drug prophylaxis and monitoring of CMV viral load after transplant [2]. Recently, CMV drug resistance is emerging as a severe postoperative complication with an incidence up to 4,7% [3]. Methods: A 32-year-old woman, affected by pulmonary veno-occlusive disease, was listed for bilateral LTX. She had a history of Sharp's syndrome, needing high dose of steroid. Both the patient and the donor anti-CMV IgG and CMV DNA were not detectable. Because of severe pulmonary hypertension (mean pulmonary arterial pressure >60mmHg), LTX was performed with pre-emptive VA-ECMO support that was prolonged until postoperative day (POD) 7. Since POD1, both induction immunosuppressive therapy (intravenous (iv) Methylprednisolone 0,5mg/kg/die, Mycophenolate-Mophetil 2g/die, and iv Cyclosporine 1mg/kg/die with plasmatic Cyclosporine concentration target of 200ng/mL) and CMV prophylaxis (iv CMV-hyperimmune-globulin 75IU/kg every 4 days) have been started. Results: On POD30 the patient developed abdominal pain, diarrhoea and lower gastrointestinal bleeding. Colonoscopy suggested an acute CMV colitis (Fig.1) and CMV-DNA was revealed in blood (>1million IU/mL) and feces. High dose Ganciclovir was promptly started, while Cyclosporine was stopped. However, the patient clinically deteriorated due to severe peritonitis. A CT scan showed diffuse pulmonary ground glass with tree-in-bud pattern (Fig.2A) and bowel distension with colon perforation (Fig.2B). A right hemicolectomy and ileostomy were immediately performed. Subsequently, the patient developed severe septic shock and acute respiratory failure (PaO2/FiO2 <50 during mechanical ventilation). CMV viremia continued to rise (>5milion IU/mL), despite high dose of Ganciclovir (10mg/kg/die). Because of a strong clinical suspicion of CMV drug resistance, specific molecular analysis was performed, but no relevant CMV DNA mutations potentially causing Ganciclovir resistance were found. However, iv Foscarnet (80mg/die, adjusted according to creatinine clearance) was empirically added and iv CMV-hyperimmune-globulin was potentiated (up to 75IU/kg/die). Six days later, CMV viral load started to decrease, until negativization on POD60 (Fig.3), with a significant improvement in patient clinical conditions. Unfortunately, the patient died on POD75 due to septic shock related to bronchial anastomosis dehiscence and Klebsiella Pneumoniae infection. Discussion: This case has several peculiarities: - early onset of CMV infection after LTX (reported median time of 253 days [1]) despite prophylaxis; - very high viremia peak (>5million IU/mL on POD33); - rapidly progressive CMV infection, with severe abdominal complication requiring surgery; - poor response to Ganciclovir, needing multidrug antiviral therapy, despite no molecular sign of drug resistance.