Combination Antifungal Therapy for Invasive Pulmonary Aspergillosis in a Heart Transplant Recipient

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1 case report Combination Antifungal Therapy for Invasive Pulmonary Aspergillosis in a Heart Transplant Recipient Andres Beiras-Fernandez, 1 * Amir K. Bigdeli, 1 * Thomas Nickel, 2 Sebastian Michel, 1 Peter Ueberfuhr, 1 Bruno Reichart, 1 Ingo Kaczmarek 1 Abstract Invasive pulmonary aspergillosis is a severe complication after solid organ transplant, with a high mortality rate. We present a 45-year-old male heart transplant recipient who developed fever, progressive worsening of dyspnea, and productive cough without response to antibiotics. Diagnosis of invasive pulmonary aspergillosis was made based on clinical, laboratory, and radiographic findings. The patient was treated successfully with combined antifungal therapy (voriconazole and micafungin). This case report highlights the importance of a high degree of clinical suspicion to allow curative treatment of invasive aspergillosis and the efficiency of new antifungal drugs. Key words: Fungal infection, Echinocandins, Solid organ transplantation, Invasive pulmonary aspergillosis, Combination therapy Introduction Invasive aspergillosis is a common life-threatening infection in highly immunocompromised patients with mortality rates between 30% and 90%. 1 Concerning therapy of invasive aspergillosis, second-generation triazole voriconazole has replaced amphotericin B as a first-line therapy. 2 Owing to the suboptimal outcome with antifungal monotherapy, either with azoles or From the 1 Departments of Cardiac Surgery and 2 Cardiology, Klinikum Grosshadern, Ludwig- Maximilians-University, D Munich, Germany *Both authors contributed equally to this work. Acknowledgements: The authors present no conflicts of interest related to this manuscript. No external funding has been used. Address reprint requests to: Andres Beiras-Fernandez, MD, PhD, Department of Cardiac Surgery, Klinikum Grosshadern, Ludwig-Maximilians-University, Marchioninistr. 15, D München, Germany Phone: Fax: abeiras@med.uni-muenchen.de Experimental and Clinical Transplantation (2011) 4: amphotericin B, combination antifungal therapy has become a point of interest. However, there are only scant data from controlled studies regarding antifungal combination therapy for treatment of invasive aspergillosis. Conversely, some results of in vitro studies, animal models, and case reports suggest that antifungal combination therapy with azoles (eg, voriconazole, posaconazole, and ravuconazole) and echinocandins (eg, caspofungin, micafungin, and anidulafungin) may have additive activity against Aspergillus species. 3, 4 Here, we report the case of a 45-year-old man who developed fever, progressive worsening of dyspnea, and a mild productive cough without response to antibiotics 2 weeks after a heart transplant. The diagnosis of invasive pulmonary aspergillosis was made based on clinical, laboratory, and radiographic findings. The patient was treated successfully with a combined antifungal therapy consisting of voriconazole and micafungin. At 5- month follow-up, the patient remained well. Case Report With end-stage ischemic cardiomyopathy, a 45-year-old man underwent implantation of the Berlin Heart Excor biventricular assist device (Berlin Heart, Berlin, Germany) owing to acute cardiac decompensation with acute renal and liver failure as a bridge to transplant. The patient recovered well and an orthotopic heart transplant was performed 2 weeks after assist device implantation and 2 months after hospitalization. Posttransplant immuno - suppression consisted of tacrolimus (to maintain target trough levels of 10 to 15 ng/ml for the first 3 months), mycophenolate mofetil (to maintain target trough levels of 1.5 to 4 µg/ml), and prednisolone (initial dosage of 1 mg/kg/d, tapering to 0.1 mg/kg/d in the first month). Copyright Başkent University 2011 Printed in Turkey. All Rights Reserved.

2 280 Andres Beiras-Fernandez et al /Experimental and Clinical Transplantation (2011) 4: Exp Clin Transplant Ten days after transplant, cytomegalovirus viremia was documented, and the patient received cytomegalovirus preemptive therapy with ganciclovir orally (900 mg/d) for 14 days. Chest radiographs on postoperative days 1, 5, and 11 revealed no infectious pathologic findings (Figures 1 A-C). On postoperative day 18, the patient developed a high fever (> 39 C) and a mild productive cough. Laboratory tests revealed the following: C-reactive protein, 9.6 mg/dl (normal range, < 0.5 mg/dl); white blood cell count, /L (normal range, /L); hemoglobin, 125 g/l (normal range, g/l); platelets, /L (normal range, /L); creatinine, 110 µmol/l (normal range, µmol/l); and total bilirubin, 3.2 µmol/l (normal range, < 2.6 µmol/l). The results of cultures of blood, sputum, urine, stool, and throat swab were negative. A chest radiograph revealed an ill-defined infiltrate at the lower right lobe (Figure 2). Suspicion was raised for pneumonia, and empiric antibiotic therapy was initiated immediately with piperacillintazobactam (4.5 g 3 times daily IV) for 7 days. Results of a sputum culture showed no evidence of invasive aspergillosis. The infection parameters resolved, but the clinical condition of the patient did not improve substantially with the presence of weight loss (4 kg in 7 days), productive cough, and continuing subfebrile temperatures. Figure 2. A chest radiograph on postoperative day 18 revealed a diffuse infiltrate in the lower right lobe. Figure 1. A chest radiograph on postoperative day 1 (1-A), 5 (1-B), and 11 (1- C) revealed no infiltrates. A pleural effusion on the right side was evident on postoperative day 5 (arrow). On postoperative day 23, a thoracic computed tomogram confirmed a nodular infiltrate in the right upper lobe near the right hilum with a diameter of cm and another nodular infiltrate in the right lower lobe with a diameter of cm (Figure 3-A). The radiologist suspected a lung abscess. A bronchoscopy with bronchoalveolar lavage to obtain specimens for microbiologic examination was performed on postoperative day 24. Microbiologic examination revealed Aspergillus spp. A chest radiograph on postoperative day 26 revealed progressively enlarging of the opacities. At this late stage, clinical diagnosis of invasive pulmonary aspergillosis was made. Owing to the advanced stage, surgical resection of the pulmonary

3 Andres Beiras-Fernandez et al /Experimental and Clinical Transplantation (2011) 4: Figure 4. (A) A chest radiograph after 1 month follow-up revealed regression of the infiltrates. The same findings could be observed in a computed tomography. Figure 3. Serial thoracic computed tomography. (A) A nodular infiltrate in the right lower lobe with a diameter of cm can be observed. (B) A regression of the infiltrate can be observed 3 days after the initiation of antifungal therapy. aspergillomas was not recommended and antifungal therapy was initiated with voriconazole (400 mg/d initially IV and orally after 2 days) and micafungin (100 mg/d IV) 8 days after the onset of symptoms. Immunosuppression was reduced to a fixed dosage of mycophenolate mofetil (1000 mg/d) and tacrolimus to maintain target trough levels of 8 to 10 ng/ml. Prednisolone was paused. However, the patient s condition improved rapidly with resolving of fever and pulmonary symptoms, as well as infection parameters. Radiologic findings started to resolve, as shown on a chest radiograph, 7 days after the initiation of antifungal therapy. Three days after the initiation of antifungal therapy, thoracic computed tomography showed a significant decrease in the size of the pulmonary infiltrates (right upper lobe infiltrate diameter of cm and right lower lobe infiltrate diameter of cm (Figure 3-B). Eleven days after initiation of antifungal therapy, 1 day before discharge, thoracic computed tomography revealed further decreasing pulmonary infiltrates (right upper lobe infiltrate diameter cm and right lower lobe infiltrate diameter cm). Micafungin was discontinued after 12 days. The patient was discharged on postoperative day 38 with an antifungal maintenance therapy consisting of voriconazole (200 mg orally, twice daily) for the next 6 months. At the 1-month follow-up, the patient remained well with nearly resolved pulmonary findings on chest radiograph and computed tomography of the chest (Figure 4). Five months after the heart transplant and 4 months after the diagnosis of invasive pulmonary aspergillosis, the patient is doing well.

4 282 Andres Beiras-Fernandez et al /Experimental and Clinical Transplantation (2011) 4: Exp Clin Transplant Discussion Acute invasive aspergillosis in immuno - compromised patients is a rapidly progressive infection. Aspergillus infections have been reported in 1% to 15% of organ transplant recipients and invasive aspergillosis occurs in 3.3% to 14% of heart transplant recipients. The usual time of onset of invasive aspergillosis is 36 to 52 days posttransplant, with nearly 75% of the cases occurring within 90 days of the transplant. 5 Several factors including reoperation, cytomegalovirus disease, hemodialysis, and an episode of invasive aspergillosis in the heart transplant unit 2 months before or after the patient s transplant, have been shown to be independent risk factors for invasive aspergillosis in heart transplant recipients. 6 Owing to initial nonspecific signs and symptoms as well as lack of radiographic abnormalities, the diagnosis of invasive aspergillosis is usually delayed. 7 Our patient presented with high fever and a mild productive cough. Initially, a sputum culture showed no evidence of invasive aspergillosis. The results of a chest radiograph revealed an ill-defined infiltrate at the lower right lobe, and empiric antibiotic therapy was initiated immediately with suspicion of pneumonia. Though the infection was resolving, the clinical condition of the patient did not improve substantially, as there was the presence of weight loss, productive cough, and continuing subfebrile temperatures. Again, sputum culture showed no evidence of invasive aspergillosis. However, sputum cultures are neither sensitive nor specific for Aspergillus infection in the immunocompromised patient. Five days after the onset of symptoms, computed tomography confirmed 2 nodular infiltrates in the right lung. At this advanced stage, clinical diagnosis of invasive pulmonary aspergillosis was made. Bronchoscopy with bronchoalveolar lavage was performed and lastly microbiological examination revealed Aspergillus spp. In our patient, a previous concomitant cytomegalovirus infection may have increased his susceptibility for a fungal pneumonia. Tigen and associates recommend special vigilance in patients with infections that coexist with cytomegalovirus infection to ensure early diagnosis and timely treatment. 8 Antifungal therapy was initiated with voriconazole and micafungin 8 days after the onset of symptoms. Voriconazole has recently shown a clinical benefit and increased survival when compared with the standard approach with amphotericin B in the therapy of invasive aspergillosis in immunocompromised patients. 2 However, results of in vitro studies, animal models, and case reports suggest that antifungal combination therapy with azoles and echinocandins may have additive activity against Aspergillus species by targeting different cellular sites. 3, 4 According to the guidelines for aspergillosis treatment, primary combination therapy for invasive pulmonary aspergillosis is not routinely recommended, because of the lack of clinical data; instead, salvage therapy is recommended for refractory cases. 9 Furthermore, recent reports have shown excellent results of antifungal combination therapy with micafungin and amphotericin B or voriconazole. 10, 11 Several reports advocate combination therapy of echinocandins and azoles as primary treatment in invasive aspergillosis, 12, 13 as both drugs inhibit independent fungal targets and have been documented to have synergistic interactions; thus, concomitant application might be favorable. 4 Groetzner and associates documented the use of echinocandins as first-line therapy in an observational, noncontrolled trial, showing a high efficacy in the treatment of invasive aspergillosis in heart and lung transplant recipients. 14 Kontoyiannis and associates documented the safety and efficacy of micafungin alone, or in combination therapy for in hematopoietic stem cell transplant. 15 Denning and associates showed that primary therapy with micafungin was effective for the treatment of invasive aspergillosis. 16 In our patient, treatment with micafungin, a novel echinocandin, resulted in regression of the invasive aspergillosis, improvement of the clinical symptomatic and the radiologic investigations, resulting with a favorable outcome after 5 months follow-up. References 1. Paterson DL, Singh N. Invasive aspergillosis in transplant recipients. Medicine (Baltimore). 1999;78(2): Herbrecht R, Denning DW, Patterson TF, et al. Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. N Engl J Med. 2002;347(6): Perea S, Gonzalez G, Fothergill AW, Kirkpatrick WR, Rinaldi MG, Patterson TF. In vitro interaction of caspofungin acetate with voriconazole against clinical isolates of Aspergillus spp. Antimicrob Agents Chemother. 2002;46(9):

5 Andres Beiras-Fernandez et al /Experimental and Clinical Transplantation (2011) 4: Kirkpatrick WR, Perea S, Coco BJ, Patterson TF. Efficacy of caspofungin alone and in combination with voriconazole in a Guinea pig model of invasive aspergillosis. Antimicrob Agents Chemother. 2002;46(8): Singh N, Paterson DL. Aspergillus infections in transplant recipients. Clin Microbiol Rev. 2005;18(1): Muñoz P, Rodríguez C, Bouza E, et al. Risk factors of invasive aspergillosis after heart transplantation: protective role of oral itraconazole prophylaxis. Am J Transplant. 2004;4(4): Wieland T, Liebold A, Jagiello M, Retzl G, Birnbaum DE. Superiority of voriconazole over amphotericin B in the treatment of invasive aspergillosis after heart transplantation. J Heart Lung Transplant. 2005;24(1): Tigen E, Tigen K, Karaahmet T, Odabasi Z, Korten V. Concomitant Aspergillus and Cytomegalovirus infection in heart transplant: early diagnosis is the key to successful treatment. Exp Clin Transplant. 2009;7(3): Walsh TJ, Anaissie EJ, Denning DW, et al. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America. Clin Infect Dis. 2008;46(3): Aoki T, Miyamoto T, Mori Y, et al. Successful allogeneic stem cell transplantation in two patients with acute myelogenous leukaemia and invasive aspergillosis by antifungal combination therapy. Mycoses Mar 4. [Epub ahead of print] 11. Dockrell DH. Salvage therapy for invasive aspergillosis. J Antimicrob Chemother. 2008;61(suppl 1):i41-i Singh N, Limaye AP, Forrest G, et al. Combination of voriconazole and caspofungin as primary therapy for invasive aspergillosis in solid organ transplant recipients: a prospective, multicenter, observational study. Transplantation. 2006;81(3): Shlobin OA, Dropulic LK, Orens JB, et al. Mediastinal mass due to Aspergillus fumigatus after lung transplantation: a case report. J Heart Lung Transplant. 2005;24(11): Groetzner J, Kaczmarek I, Wittwer T, et al. Caspofungin as firstline therapy for the treatment of invasive aspergillosis after thoracic organ transplantation. J Heart Lung Transplant. 2008;27(1): Kontoyiannis DP, Ratanatharathorn V, Young JA, et al. Micafungin alone or in combination with other systemic antifungal therapies in hematopoietic stem cell transplant recipients with invasive aspergillosis. Transpl Infect Dis. 2009;11(1): Denning DW, Marr KA, Lau WM, et al. Micafungin (FK463), alone or in combination with other systemic antifungal agents, for the treatment of acute invasive aspergillosis. J Infect. 2006;53(5):