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Antifungal Prophylaxis During the Early Postoperative Period of Lung Transplantation^*

Víctor Calvo, MD; José M. Borro, MD; Pilar Morales, MD; Alfonso Morcillo, MD; Rosario Vicente, MD; Vicente Tarrazona, MD; Francisco París, MD and Valencia Lung Transplant Group

^* From the Hospital Universitario "La Fe," Valencia, Spain.

Correspondence to: Víctor Calvo, MD, Servicio de Cirugía Torácica, Hospital Universitario "La Fe," Avda Campanar, 21, 46009 Valencia, Spain; e-mail: vcalvo{at}separ.es

	Abstract

TOP Abstract Introduction Materials and Methods Results Discussion Appendix References

 
Introduction: Fungal infections occur frequently in lung transplant patients, with the highest risk being in the early postoperative period (the initial hospitalization after lung transplantation). Aspergillus is responsible for more than half of all fungal infections, and Aspergillus has even been considered a contraindication for lung transplantation because of its difficult therapy and frequently fatal outcome. The aim of this article is to evaluate the success of an antifungal prophylaxis protocol to prevent fungal infection in the immediate postoperative period in lung transplant recipients.

Material and methods: From March 1994 to March 1997, we performed 52 lung transplants in 31 men and 21 women who received antifungal prophylaxis with fluconazole, 400 mg/d, and aerosolized amphotericin B, 0.6 mg/kg/d, during the postoperative period.

Results: The mean (± SD) postoperative period duration was 49 ± 27.5 days. No fungal infections were observed during this period, and all patients provided negative cultures. We also found no toxicity related to antifungal drugs. The dose of cyclosporine was easily adjusted in every recipient according to blood levels so that effective immunosuppression was not compromised.

Discussion: In our study, the removal of the lungs and antifungal prophylaxis with fluconazole and aerosolized amphotericin B prevented fungal infection in the postoperative period in all 52 lung transplant recipients.

Key Words: amphotericin B • fluconazole • fungal disease • lung transplantation

	Introduction

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Infectious complications are frequent in lung transplant patients. Approximately 40% of all deaths occurring after transplantion are caused by infections; 60 to 80% of these infections are respiratory, and half of them are opportunistic.¹ Although bacterial infection occurs more frequently (65%), viral and fungal infections are more lethal.

The peak incidence of fungal infection occurs in the period from 10 days to 2 months after transplantion.^{2 3 4} Aspergillus is responsible for more than half of the fungal infections in lung transplant patients. These patients are more susceptible to Aspergillus because of heavy immunosuppression and the use of broad-spectrum antibiotics. Abnormal local defense mechanisms in the airways of lung transplant recipients also play a role in this high prevalence.³

Antifungal prophylaxis in lung transplant recipients receiving immunosuppressive treatment has been recommended but is not well established.^{3 5 6 7} There is controversy about which drug to use as an optimum prophylactic therapy that is most effective with minimal toxicity. Some physicians use fluconazole,⁷ whereas other physicians recommend itraconazole⁸ or topical or systemic amphotericin B.^{1 9}

The aim of this study is to assess the effectiveness and to present the results of an antifungal protocol designed to prevent fungal infection in lung transplant patients during the early high-risk postoperative period.

	Materials and Methods

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Patients
From February 1990 to March 1997, the Valencia Lung Transplant Group performed 65 lung transplantations. We selected the last 52 recipients of these 65 transplants (transplanted from March 1994 to March 1997) to receive antifungal prophylaxis in the early postoperative period. Of these 52 recipients, there were 31 men and 21 women with a mean age of 38 years old (range, 14 to 58 years old). Indications for transplantation included emphysema in 14 cases (27%), cystic fibrosis in 12 cases (23%), bronchiectasis in 10 cases (19%), pulmonary fibrosis in 9 cases (17%), primary pulmonary hypertension in 4 cases (8%), lymphangioleiomyomathosis in 2 cases (4%), and obliterative bronchiolitis in 1 case (2%). The mean follow-up time for our patients was 19 months (range, 1 to 35 months).

Selection Criteria
Potential transplantation candidates were screened for infection using chest radiographs, CT scans, cultures from sputum and blood samples, and gel diffusion for Aspergillus. Fungal disease was categorized either as a colonization (positive cultures without clinical signs of infection) or an infection (evidence of clinical or radiologic signs in the presence of positive cultures).¹⁰ The patients who presented with fungal infection were rejected for transplantation and received specific therapy for 3 months (fluconazole for Candida, and itraconazole and aerosolized amphotericin for Aspergillus). After treatment was completed, the patients were reevaluated for transplantation. The patients were listed for transplantation only when colonization was present with no clinical or radiologic signs, and the patients continued receiving specific therapy until transplantation.

Operative Technique
We performed 43 sequential double-lung transplants and 9 single-lung transplants. Bronchial anastomoses were always intussuscepted and wrapped with peribronchial tissue. Cardiopulmonary bypass was used in nine patients. The mean ischemic time was 200 min for the first lung and 310 min for the second lung.

Drug Therapy
Immunosuppression therapy consisted of methylprednisolone, cyclosporine, and azathioprine in all patients, but we also used antithymocyte -globulin in the first 20 patients. Maintenance immunosuppression consisted of prednisolone, azathioprine, and cyclosporine. Rejection episodes were treated by pulse methylprednisolone courses (1 g/d for 3 days). A protocol of prophylactic antibiotics was used as listed in Table 1 . We used an antifungal prophylaxis protocol for the postoperative period in all 52 recipients with fluconazole, 200 mg/12 h, and aerosolized amphotericin, 0.2 mg/kg/8 h. This antifungal prophylaxis was maintained during the first postoperative month and for a longer period if the patient was receiving broad-spectrum antibiotics for simultaneous bacterial infections, or if the patient had positive cultures for Aspergillus pretransplantation.

	Results

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Actuarial survival at 3 years for patients in our series is 59%, as shown in Figure 1 . The prevalence of infectious disease during the postoperative period was 71% for bacterial pneumonia and 10% for cytomegalovirus pneumonia. The mean number of rejection episodes per patient was 1.2 (range, 0 to 4), and all patients having rejection were treated with methylprednisolone pulses.

View larger version (8K): [in this window] [in a new window] [Download PPT slide]   Figure 1. A global actuarial survival at 3 years for lung transplant recipients who received antifungal prophylaxis (series from the Valencia Lung Transplant Group; n = 52).

Of the 52 patients who received antifungal prophylaxis during the first postoperative month, 22 patients had transplants performed because of septic lung disease (12 patients with cystic fibrosis and 10 patients with bronchiectasis). Four of these 52 patients died in the early postoperative period from complications not related to fungal disease. The mean duration for antifungal prophylaxis was 42 days (range, 30 to 92 days). Prophylaxis was maintained if bacterial infection was present (requiring broad-spectrum antibiotic therapy) or if the patient had positive Aspergillus cultures pretransplantion. Therapy was discontinued once the cultures became negative.

No fungal infections were observed in the postoperative period, and negative cultures were obtained from all patients. In addition, no suture complications by fungi were experienced during the prophylaxis period, nor were there complications or toxicity related to antifungal drugs. The cyclosporine dose was easily adjusted in every recipient according to blood levels so that effective immunosuppression was not compromised. After discontinuing prophylaxis, we did not observe a higher prevalence or severity of fungal infection. We had two episodes of Aspergillus infection in the context of obliterative bronchiolitis; both patients died despite treatment with liposomal IV and aerosolized amphotericin. We also had two episodes of Aspergillus in bronchial stenoses, one of which was related to a stent; these two patients did well with topical and systemic amphotericin therapy. We had three episodes of Aspergillus colonization with positive cultures in sputum several months after transplant but without clinical or radiologic signs of infection; these cultures all became sterile after therapy with aerosolized amphotericin.

	Discussion

TOP Abstract Introduction Materials and Methods Results Discussion Appendix References

 
The high morbidity and mortality rates of fungal infection in lung transplant patients during the postoperative period make it necessary to consider early preventive treatment; waiting for signs of clinical infection may be too late.

In immunodepressed patients, fungi require a prophylactic regimen as do bacteria and viruses. Because of the toxicity of immunosuppressive drugs and the interactions that take place between them, antifungal treatment in transplant recipients is slightly different than that in other immunocompromised patients. Antifungal drugs interact significantly with cyclosporine, resulting in an increased cyclosporine concentration in blood.^{11 12}

Following lung transplantation, a range of Aspergillus-related diseases has been described, including pneumonia, bronchitis, ulcerative tracheobronchitis, pseudomembranous bronchitis, bronchocentric granulomatosis, osteomyelitis, or allergic bronchopulmonary aspergillosis.^{13 14 15} Because of its activity and low frequency of serious toxicity, itraconazole is an elective therapy for Aspergillus infection in patients receiving cyclosporine therapy in whom nephrotoxicity is common.^{8 16} Fluconazole is also widely used in solid organ transplantation, mainly against Candida albicans and Cryptococcus neoformans; however, it is less effective in controlling Aspergillus infection.^{11 12} Both itraconazole and fluconazole interact significantly with cyclosporine, making it necessary to adjust the cyclosporine dose according to blood levels.¹⁰

Aerosol antibiotics have been widely used for the past decade.¹⁷ Topical therapy with aerosolized amphotericin has good effectiveness with few side effects. IV amphotericin B (mainly the liposomal form that appears to have fewer adverse effects at equivalent doses) remains the mainstay of treatment for deep fungal infection. Although this agent is effective, its interaction with cyclosporine can be associated with acute renal failure.¹¹

Combined therapy with systemic fluconazole and aerosolized amphotericin was effective in preventing fungal infection by the most frequent fungal pathogens in our lung transplant recipients in the postoperative period. Toxicity was absent, and there was little interaction with immunosuppressive therapy.

Systemic candidiasis develops most often in patients who are treated with prolonged courses of broad-spectrum antibiotics. As we had a high prevalence of septic lung disease and widely used broad-spectrum antibiotics in the postoperative period, we considered our patients to be at high risk for candidiasis. The colonization of the airway with Candida species is frequent, whereas invasive pneumonitis due to Candida is uncommon.⁴ The treatment of C albicans with fluconazole is usually successful. However, non-C albicans species may require treatment with amphotericin B.⁴ We treat patients with fluconazole if repeated positive cultures of sputum in the postoperative period contain Candida. Although infection of the vascular anastomosis is infrequent, it is highly lethal. One heart-lung transplant recipient died from aortic candidiasis at the beginning of our transplant program before we used antifungal prophylaxis.

Aspergillus is responsible for more than half of the fungal infections in lung transplant patients.³ Because of the difficulty of preoperative eradication, and the problems associated with therapy in immunocompromised patients having frequently fatal infections, Aspergillus has even been considered a contraindication for lung transplantation. An established diagnosis of aspergillosis in lung transplant recipients is often difficult because this fungus is saprophytic from the upper respiratory tract. The success rate of therapy for infection with Aspergillus in transplant recipients can be disappointing; however, an early diagnosis is helpful.¹ When there is only Aspergillus colonization of the airways in the postoperative period, observation or a prophylactic regimen is indicated. We recommend aerosolized amphotericin for this situation. When a clinical infection appears in a lung transplant recipient, the most effective treatment (itraconazole and liposomal amphotericin B) must be used, particularly if an invasive or progressive disease is present.^{4 18}

The decrease in the prevalence of fungal infections with our antifungal prophylaxis regimen may be due to the regimen, although it could be due to other causes. Our control group is a historical group, with all of its potential weakness. As a result of our experience, we conclude that Aspergillus colonization of the airways must not contraindicate lung transplantation. The resection of lungs (the main infective focus) together with the postoperative antifungal prophylaxis with fluconazole and aerosolized amphotericin B prevented fungal infection during the postoperative period in all of the lung transplant recipients in our series, even in those patients with pretransplant Aspergillus colonization. Prophylaxis is always less expensive than treating a proven invasive fungal infection.

	Appendix

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Eduardo Blasco, José M. Borro, Víctor Clavo, José M. Cafarena, Genaro Galán, Angel García, Alfonso Morcillo, José Padilla, Francisco París, Juan Pastor, and Vicente Tarrazona (Thoracic and Cardiac Surgery Team); Caridad Francia, Juan Porta, José L. Vicente, Rosario Vicente, and Fernando Ramos (Anesthesiology); Pilar Morales and Amparo Solé (Pneumology); César Lozano and Pilar Morant (Respiratory Rehabilitation).

	Footnotes

 
A complete list of participants is located in the Appendix.

Received for publication November 18, 1997. Accepted for publication January 12, 1999.

	References

TOP Abstract Introduction Materials and Methods Results Discussion Appendix References

 

1. Mannes, GPM, van der Bij, W, de Boer, WJ, et al (1995) Liposomal amphotericin B in three lung transplant recipients. J Heart Lung Transplant 14,781-784[ISI][Medline]
2. Flume, PA, Egan, TM, Paradowsky, LJ, et al (1994) Infectious complications of lung transplantation: impact of cystic fibrosis. Am J Respir Crit Care Med 149,1601-1607[Abstract]
3. Kramer, MR, Denning, DW, Marshall, SE, et al (1991) Ulcerative tracheobronchitis after lung transplantation: a new form of invasive aspergillosis. Am Rev Respir Dis 144,552-556[ISI][Medline]
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7. Horvath, J, Dummer, S, Loyd, J, et al (1993) Infection in the transplanted and native lung after single lung transplantation. Chest 104,681-685[Abstract/Free Full Text]
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10. Westney, GE, Kesten, S, De Hoyos, A, et al (1996) Aspergillus infection in single and double lung transplants recipients. Transplantation 61,915-919[CrossRef][ISI][Medline]
11. Paya, CV (1993) Fungal infections in solid-organ transplantation. Clin Infect Dis 16,677-688[ISI][Medline]
12. Como, JA, Dismukes, WE (1994) Oral azole drugs as systemic antifungal therapy. N Engl J Med 330,263-272[Free Full Text]
13. Egan, JJ, Yonan, N, Carroll, KB, et al (1996) Allergic bronchopulmonary aspergillosis in lung allograft recipients. Eur Respir J 9,169-171[Abstract]
14. Yeldandi, V, Laghi, F, McCabe, MA, et al (1995) Aspergillus and lung transplantation. J Heart Lung Transplant 14,883-890[ISI][Medline]
15. Taillandier, J, Alemani, M, Cerrina, J, et al (1997) Aspergillus osteomyelitis after heart-lung transplantation. J Heart Lung Transplant 16,436-438[ISI][Medline]
16. Kramer, MR, Marshall, SE, Denning, DW, et al (1990) Cyclosporine and itraconazole interaction in heart and lung transplant recipients. Ann Intern Med 113,327-329
17. Hodson, ME (1988) Antibiotic treatment: aerosol therapy. Chest 94(suppl),156S-162S[Abstract/Free Full Text]
18. End, A, Helbich, T, Wisser, W, et al (1995) The pulmonary nodule after lung transplantation: cause and outcome. Chest 107,1317-1322[Abstract/Free Full Text]

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