Transplantation Issue: Volume 61(12), 27 June 1996, pp 1771-1774 Copyright: (C) Williams & Wilkins 1996. All Rights Reserved. Publication Type: [Brief Communications: Clinical Transplantation] ISSN: 0041-1337 Accession: 00007890-199606270-00018 [Brief Communications: Clinical Transplantation] SUCCESSFULLY TREATED INVASIVE PULMONARY ASPERGILLOSIS ASSOCIATED WITH SMOKING MARIJUANA IN A RENAL TRANSPLANT RECIPIENT Marks, William H.1,2; Florence, Lisa1; Lieberman, Joshua1; Chapman, Phillip1; Howard, Donald1,3; Roberts, Paul1,4; Perkinson, Diana1 Author Information Organ Transplant Program, Swedish Medical Center, Seattle, Washington 98104 1Organ Transplant Program, Swedish Medical Center, Seattle, WA. 2Address correspondence to: William H. Marks, MD, PhD, Organ Transplant Program, Swedish Medical Center, 1120 Cherry St, Ste 400, Seattle, WA 98104. 3Lab of Path/Dynacare, Seattle, WA. 4Department of Infectious Diseases, Swedish Medical Center, Seattle, WA. 5ABCD was kindly provided for compassionate use by the research pharmacy of the Fred Hutchinson Cancer Research Center, Seattle, WA. Received 18 October 1995. Accepted 22 January 1996. ---------------------------------------------- Outline Abstract REFERENCES Abstract Invasive pulmonary aspergillosis (IPA) is often a lethal entity in transplant recipients (up to 90%). We report the successful treatment of a case of IPA in a renal transplant recipient whose only risk for exposure was habitual marijuana smoking. Although marijuana smoking has been linked to the development of IPA in patients immunosuppressed for a variety of reasons, this case is the first report involving a solid organ transplant recipient. The patient's clinical course and treatment are described and the literature is reviewed with respect to environmental and patient risk factors. In this case, IPA was associated with the patient's heavy usage of marijuana during the immediate posttransplant period. Treatment was successful and included the experimental amphotericin product amphotericin B colloidal dispersion. Contemporaneous exposure to a large amount of inocula ofAspergillus within 30 days of receiving high doses of steroids appeared to be the most important factor that predisposed this patient to IPA. Transplant recipients should be specifically proscribed from marijuana use during periods of high steroid administration. ---------------------------------------------- We report the successful treatment of a case of IPA in a renal transplant recipient whose only risk factor for exposure was the habitual smoking of large quantities of marijuana. A correlation between the inhalation of marijuana contaminated with Aspergillus and the development of invasive pulmonary aspergillosis (IPA*) has been reported in patients with AIDS and chronic granulomatous disease, bone marrow transplant recipients, and patients receiving chemotherapy for small cell lung cancer (1-4). This is the first report involving a solid organ transplant recipient. The patient's clinical course and treatment are described and the literature is reviewed with respect to the risk factors associated with the development of invasive aspergillosis in this population. The patient is a 48-year-old biologic male, who underwent gender reassignment surgery at age 28 and developed end-stage renal disease secondary to chronic glomerulonephritis at age 34. She was maintained on hemodialysis for 14 years until pursuing renal transplantation in an attempt to stem the progression of metastatic calcifications and amyloid disease. The patient, who was CMV positive, underwent an uncomplicated cadaveric renal transplant from a CMV positive donor in December 1993. Her immunosuppressive therapy consisted of induction with anti-thymocyte globulin(ATGAM, 20 mg/kg/day for 10 days), methylprednisolone (500 mg/kg intraoperatively followed by a 10 day taper to 30 mg/day), and CsA (1 mg/kg/day as a continuous i.v. infusion followed by conversion to oral dosing on postoperative day (POD) 3). The CsA dose was increased to 10 mg/kg/day on POD 10 to maintain whole blood trough RIA levels of approximately 150 ng/ml. Azathioprine (1.5 mg/kg/d) was begun 48 hr before the last dose of ATGAM and the dose adjusted to maintain the white blood count greater than 3,500 cells/mm3 and the platelet count greater than 50,000 cells/dl. Antibiotic prophylaxis consisted of perioperative coverage with cefuroxime (1 g, i.v., every 8 hr for 24 hr), sulfamethoxazole/trimethoprim (SMTP, 1 single strength, daily) beginning on POD 3, and gancyclovir (5 mg/kg, i.v., twice a day during ATGAM administration) followed by acyclovir (800 mg by mouth, 4 times a day). The patient had an uncomplicated early postoperative course and was discharged on POD 6 with a serum creatinine level of 1.1 ng/ml and a leukocyte count of 6,500 cells/mm3. Four weeks after transplantation, the patient was readmitted with 24 hr of a nonproductive cough, fever to 100.2 [degrees]F, anorexia, and lethargy. On admission, the patient's temperature was 99.5 [degrees]F and the results of the rest of the physical examination were otherwise normal. Admission laboratory results were as follows: white blood cell count, 11,700 cells/mm3 (82% segs, 0.6% bands); serum creatinine, 1.1 mg/dl; blood urea nitrogen, 22 mg/dl. The initial chest x-ray film was unremarkable. A sputum gram stain demonstrated branching hyphae. All bacterial and viral cultures were subsequently negative. Initial treatment consisted of itraconazole (300 mg by mouth, 4 times a day) and reduction of prednisone (from 25 to 20 mg/day). Although she initially defervesced and had subjective improvement, a chest x-ray film 18 hr later demonstrated a subtle right perihilar upper lobe infiltrate (Fig. 1). Computed tomography of the chest demonstrated right perihilar nodules with necrosis (Fig. 2). Bronchoscopy revealed adherent mucopurulent plaques extending from the vocal cords distally into the right mainstem and right upper lobe bronchi. Septated hyphae characteristic of aspergillosis were identified on gram stains of bronchoalveolar washings, and biopsy specimens demonstrated invasion of the bronchial wall (Fig. 3). These findings prompted further dose reductions in prednisone (20 to 15 mg/day) and CsA (10 to 6 mg/day) and discontinuation of Imuran. SMTP was continued, and gancyclovir was substituted for oral acyclovir. Amphotericin B(1 mg/kg/day, i.v.) was begun, but, despite 3 days of therapy, the patient failed to improve and the condition seen on the chest x-ray film worsened so the patient was converted to the liposomal preparation amphotericin B colloidal dispersion (ABCD, 6 mg/kg/day, i.v.) (5). The patient's clinical condition improved. ABCD therapy was continued for a total of 6 weeks with the last 2 weeks of therapy administered on an outpatient basis. Upon completion of ABCD, objective improvement of the infiltrative process was documented by a normal chest x-ray film and computed tomography of the chest. Itraconazole (200 mg by mouth, 4 times a day) was administered for an additional 6 weeks. Although the patient's renal function deteriorated slightly during therapy as evidenced by a rise in serum creatinine level from 1.1 to 1.8 mg/dl, this returned to 1.0 mg/dl within 2 months after completion of ABCD. The patient continues to do well 1 year after transplantation. She has returned to an active life and is currently working as a stand-up commedienne. Her current immunosuppressive regimen includes prednisone (7.5 mg/day), Imuran(1 mg/kg/day), and CsA (3.5 mg/kg/day). Aspergillus risks were investigated. She specifically denied contact with construction sites, excavation or renovation sites, gardening, or potted house plants. On closer questioning, she revealed the habitual smoking of marijuana, which had been stored for an extended period of time in sealed plastic bags. She had resumed this practice on the day of discharge, POD 6. A small amount of marijuana, which was all that remained of her supply, was obtained and demonstrated mixed Aspergillus species on direct stains and culture. Invasive pulmonary aspergillosis, while infrequent, is a devastating complication in the immunocompromised patient; the mortality rate is as high as 90%. This high mortality has remained relatively unchanged over the past 20 years (5, 6). Risk groups include recipients of organ and bone marrow transplants, patients with hematologic malignancies and chronic granulomatous diseases, and patients with AIDS, diabetes, and severe burns (5-9). It has been speculated that the low overall incidence of IPA in these groups may be explained by the redundant nature of the body's defense mechanisms against this organism. It appears that for the fungus to be a pathogen, exposure must be accompanied by an additional risk factor(s) that compromises both cell mediated immunity and macrophage/polymorphoneutrophil function. Solid organ transplant recipients receive a combination of immunosuppressive agents including steroids. Although early investigators were unable to identify a direct relationship between steroid administration and invasive aspergillosis, others consider steroid use a significant risk factor (3, 9). Gustafson and colleagues (9) reported a direct relationship between steroid administration, exposure to Aspergillus conidia, and the subsequent development of IPA in a renal transplant population. In their report, Gustafson and colleagues at Vanderbilt University described an outbreak of invasive aspergillosis in 9 renal transplant patients occurring within a 31-month period from 1979-1981. This time period coincided with new construction and renovation activity at 1 of 2 facilities where renal transplants were performed. All 9 cases of invasive aspergillosis occurred at the facility under construction, while no cases were documented at the other facility, confirming exposure to high levels of inocula of the fungus as an important mode of transmission. Multivariate analysis found that only high dose corticosteroid therapy represented a significant co-risk factor. High dose steroids were defined as doses greater than or equal to 1.25 mg/kg/day administered during the 30 days preceding exposure to A. conidia. The patient described in this report shares similar features with the aspergillosis population described by Gustafson and colleagues: She inhaled high levels of inocula of the Aspergillus species while smoking multiple stored marijuana cigarettes during the early posttransplant period when her cellmediated immunity was maximally compromised from her immunosuppressive medications including prednisone. Marijuana appears to have been her source of inocula as no other risk factors for exposure could be identified (10). Specifically, no construction or renovation activity occurred either at the hospital where her transplant was performed or in her home environment. She did not garden or have exposure to soils or potted plants in her home. It has been well documented that marijuana is a highly contaminated source of Aspergillus. Whereas the recreational use of marijuana remains high in our society, the incidence of invasive infection remains low even in immunocompromised populations. As noted previously, this finding may be caused by the redundant natural protection we enjoy against this fungus. That marijuana associated IPA has not been described previously in solid organ transplant recipients does not mean that it has not occurred, but that perhaps it has not been recognized. Our case demonstrates that solid organ transplant recipients, during critical periods of immunosuppression (e.g., during the immediate posttransplant period or after treatment for acute allograft rejection), are at risk to develop IPA from the use of marijuana. Because current clinical practice often allows hospital discharge to the home environment within the first postoperative week, patients must be strongly cautioned regarding the recreational use of marijuana because it is an infectious risk factor during the first few posttransplant months and when they receive high dose steroids for the treatment of rejection. The treatment course in our patient was expedited by a high degree of suspicion for opportunistic infection. Despite standard therapy with amphotericin B and reduction in the patient's immunosuppressive medication, the infection progressed. Clinical improvement did not occur until therapy with high dose ABCD was begun. This lipophilic delivery system allowed administration of 6 times the dose of amphotericin B normally given for the treatment of systemic fungal infections, without major nephrotoxicity. Our experience supports the findings of others documenting the efficacy and safety of this preparation. (11, 12) Renal transplant recipients are not uniquely at risk for marijuana associated aspergillosis. Similar immunosuppressive therapies are employed for all solid organ transplant recipients. Therefore, it seems prudent to proscribe the use of marijuana for all transplant recipients during periods of high dose steroid administration. In summary, this report documents a case of IPA acquired by a renal transplant recipient through the use of marijuana. The risk for exposure toAspergillus may increase as clinical practice dictates earlier hospital discharge. ABCD was highly effective in treating this aggressive infection with minimal renal toxicity. 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J Infect Dis 1983; 148: 230. Full text via Find It Bibliographic Links 10. Kagen SL. Aspergillus: an inhalable contaminant of marihuana. N Engl J Med 1981; 304: 483. 11. Hay RJ. Liposomal amphotericin B, AmBisome. J Infect 1994; 28 (suppl 1): 35. Full text via Find It Bibliographic Links 12. Lopez-Berestein G. Liposomal Amphotericin B in the treatment of fungal infections. Ann Int Med 1986; 105: 130. Full text via Find It Bibliographic Links ----------------------------------------------