Aspergillus Infection in Lung Transplant Patients

(Edited for publication--R.S.)

Lung transplant recipients are at high risk of Aspergillus infection (15-27%). Infection may occur as early as 2 weeks or up to a year after transplantation. The transplanted lung is at risk of many infections having impaired antimicrobial defense mechanisms, a diminished cough reflex as it is denervated and is situated in an immunosuppressed patient. In addition Aspergillus may spill over from the other (diseased) native lung left in situ after single lung transplantation.

Aspergillus infection in lung transplant recipients is manifest in many ways including tracheobronchitis (ulcerative and psuedomembranous tracheobronchial aspergillosis), invasive pulmonary disease and disseminated disease (Kramer et al, 1991; Westney et al, 1996; Yeldandi et al, 1995; Kessler et al, 1997; Taillandier et al, 1997). For every lung transplant recipient with Aspergillus cultured from the airways there are as many patients with asymptomatic colonization and infection, but distinguishing the two is often difficult.

The relative risk of aspergillosis after lung transplantation is not uniform. Patients with cystic fibrosis and colonised with Aspergillus, virtually never develop invasive aspergillosis, despite high doses of corticosteroids. This low risk continues after transplantation (Flume et al, 1994; Yeldandi et al, 1995). However in those not colonised pre-transplant, the risks of invasive disease are considerable. This suggests that there is a protective immune response and is consistent with the observations of the development of Aspergillus antibody prior to disease in lung transplant recipients (Tomee et al, 1996).

Diagnosing disease is difficult as clinical symptoms may be absent or attributable to a concurrent clinical process (bacterial infection, rejection etc). Partly because of this, many lung transplant recipients with Aspergillus colonisation (defined as culture in the absence of clinical signs of illness) have been treated with aerosolized amphotericin B (5-15mg three times a day) or itraconazole (400-600 mg/day), and have not developed invasive infection (Westney et al,1996; Kanj et al, 1996). This strategy undoubtedly results in overtreatment of many patients because the positive predictive value of a positive culture for Aspergillus is low in lung transplant patients who frequently have respiratory tract cultures performed. However those patients may develop disease later and invasive aspergillosis carries a high mortality (Paradis et al, 1993; Denning, 1996). An alternative approach to immediate treatment of all those with positive cultures is to only treat the patient if there is a high risk of invasive Asperg infection; e.g. cytomegalovirus (CMV) infection, receipt of high-dose corticosteroids and liver or kidney failure (Paradowski et al, 1997). Itraconazole (400-600mg/d) is a reasonable choice in these cases, unless the patient has liver failure. It should be continued for as long as the patient remains at high risk. (Paradowski et al, 1997). As stated above, those with Aspergillus colonisation pre-transplant are at low risk and do not automatically require therapy (Yeldandi et al, 1995).

Tracheobronchial aspergillosis is a common form of aspergillosis in lung transplant recipients (Kramer et al, 1991). A spectrum of disease occurs varying from simple bronchitis to pseudomembramous tracheobronchial aspergillosis. The anastomotic site is often affected and can lead to disseminated disease. Treatment outcome has been described in a small number of patients. Kramer et al, (1991) treated six patients with itraconazole (200mg three times a day for four days as a loading dose, then 200mg twice a day) for 4-6 months with responses in all patients. Subsequently two of the six patients in this report died from invasive aspergillosis, one relapsed and failed amphotericin B, the other required artificial ventilation for a period and also failed amphotericin B. Other treatments which have been successfully used include combinations of intravenous amphotericin B and itraconazole (Yeldandi et al, 1995), aersolized amphotericin B and oral itraconazole (Westney et al, 1996) and amphotericin B alone (Bertocchi et al, 1995; Yeldandi et al, 1995). Liposomal amphotericin followed by itraconazole has been successfully used in at least 4 patients (Gavalda et al, 1996). A single patient was successfully treated with terbinafine (Harari, et al, 1997). Surgical resection and stent placement may be necessary in conjunction with antifungal therapy if dehiscence of the anastomosis occurs (Horvath et al, 1993; Biggs et al, 1994).

Allergic bronchopulmonary aspergillosis has been observed in two patients with cystic fibrosis who received lung transplants (Egan et al, 1995; Fitzsimmons et al, 1997). Combinations of corticosteroids and antifungal therapy were successful.

Invasive pulmonary aspergillosis and disseminated aspergillosis in lung transplant recipients are both associated with a poor prognosis even with antifungal therapy (Yeldandi et al, 1995; Westney et al, 1996; Denning, 1996). Amphotericin B and lipid-associated amphotericin have been successful in occasional cases (Westney et al, 1996; Yeldandi et al, 1995; End et al, 1995; Husni et al, 1996; Gavalda et al, 1996; Mannes et al, 1995), but mortality still exceeds 80%. Pneumonectomy combined with medical therapy was unsuccessful in one patient.

Primary prophylaxis against aspergillosis in lung transplant recipients is not recommended, although historically controlled studies suggest efficacy. (Gavalda et al, 1997; Reichenspurner et al, 1997). A more viable alternative to prophylaxis, is pre-emptive therapy based Aspergillus cultures (or positive microscopy) and or monitoring Aspergillus antibodies (Tomee et al, 1996). These approaches need further careful study and need to distinguish those with pre-existing positive cultures and antibodies from those who develop these post transplantation.

Prepared by D. Paterson and D.W. Denning, April 1998

NOTE: Reprinted without permission from the UK-based Aspergillus Site, http://www.aspergillus.org.uk/. If any copyrights are infringed, please notify me and I will remove it immediately. Roger Stevens.

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