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 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.