Pneumonia due to Blastomyces dermatitidis in a European renal transplant recipient

Nephrol Dial Transplant (1996) 11: 1376-1379

Nephrology Dialysis Transplantation

Case Report

Pneumonia due to Blastomyces dermatitidis in a European renal transplant recipient S. Winkler1-5, G. Stanek 2 , P. Hubsch 3 , B. Willinger2, S. Susani4, A. R. Rosenkranz 5 and E. Pohanka 5 'Department of Infectious Diseases, Internal Medicine I; 2Institute of Hygiene; 'Department of Radiology; 4Institute of Clinical Pathology; 5Department of Nephrology, Internal Medicine III, University of Vienna, Austria

Introduction

Case report A 41-year old man underwent cadaveric kidney transplantation in July 1995. Three years earlier he had developed end-stage renal disease due to focal segmental glomerular sclerosis and was maintained on peritoneal dialysis. The patient was born in Poland and had lived there until 1974. Since then he had worked as a long distance truck driver until 1989. His travel history included journeys to Kenya (1974), Spain (1981, 1982 and 1984), Cyprus (1983), Turkey (1985), the Dominican Republic and Haiti (1987), Poland (1988), the former Republic of Yugoslavia (1990, 1992, 1993, 1994) and Cuba (1991). Renal transplantation was performed without complications but due to insufficient postoperative function of the transplanted kidney the patient required haemoCorrespondeme and offprint requests to: Dr Stefan Winkler, Department of Infectious Diseases, Internal Medicine I, University of Vienna, Wahringer Gurtel 18-20. A-1090 Vienna, Austria.

^ 1996 European Dialysis and Transplant Association-European Renal Association

Downloaded from http://ndt.oxfordjournals.org/ by guest on January 26, 2016

Fungal pathogens can be the source of serious and sometimes fatal infections following organ transplantation [1]. Whereas Candida albicans and Aspergillus fumigatus are observed more frequently in immunocompromised patients, infection with the thermal dimorphic fungus Blastomyces (B.) dermatitidis is uncommon even in the endemic areas of North America. To our knowledge, only four cases of Blastomyces infection in renal recipients have been described, all of them within the USA, and further two cases, one each after heart and bone marrow transplantation respectively [2]. Outside North America occasional autochthonous cases within the normal population have been reported mainly from Africa, Central and South America, India, the Middle East and singularly from some European countries [3]. In this paper we present the first case of pulmonary blastomycosis in a kidney graft recipient outside the known endemic regions.

dialysis on four occasions with the last one on day 13 after grafting. Immunosuppressive therapy consisted initially of cyclosporin A (CsA) and steroids. Renal biopsy on day 7 confirmed the clinical diagnosis of rejection. The patient was consequently treated with a steroid pulse followed by a course of antithymocyte globulin (ATG, Thymoglobuline, Merieux, 175 mg/ day). For prophylaxis of cytomegalovirus (CMV) infection ganciclovir was coadministered during the period of antirejection therapy. Thereafter the immunosuppressive regimen was continued using triple therapy (CsA, prednisolone and azathioprine). During antithymocyte treatment diuresis improved and serum creatinine levels decreased subsequently, although fever spikes up to 39°C occurred on day 19 after transplantation, which could not be related to ATG therapy. Since the fever did not respond to a broad-spectrum antibiotic treatment with ceftazidime and netilmicin, fluconazole was added 4 days later. Total leukocyte counts were normal with a left shift, c-reactive protein increased to a maximum of 21 mg/dl, blood and urine cultures as well as virological tests were repeatedly negative and several chest roentgenograms were normal apart from moderate mediastinal widening (most probably due to haematoma caused by an unsuccessful attempt to place a central venous catheter) and small pleural effusions. The fever persisted even after termination of the ATG course and the patient continued to complain about night sweats and an intensifying mid-thoracic pain. Ceftazidime was replaced by imipenem and teicoplanin and the peritoneal catheter was removed as a possible source of infection. On day 26 computed tomography (CT) of the thorax was performed and, in addition to the mediastinal haematoma, a homogeneous consolidation (diameter of about 6 cm) in the medial portion of the anterior segment of the right upper lobe was described (Figure 1). The anterior segmental bronchus of the right upper lobe could be traced directly to the margin of infiltration; a central tumour with poststenotic inflammation or atelectasis could be ruled out. A control chest X-ray on day 28 showed a well-defined triangular opacification in the same region and pneu-

Blastomyces dermatitidis pneumonia in a European renal transplant recipient

1377

2,5

segment resection

needle aspiration biopsy ' en 1.5

To Q. O 0,5

0

1

2

3

4

5

6

7

8

9

10 11 12 16

weeks after transplantation Fig. 1. Computed tomography of the chest: Homogeneous lung consolidation (arrows) in the medial portion of the anterior segment of the right upper lobe.

Fig. 3. Serologic test results by EIA for antibody to B. dermatitidis during observation period and treatment with fluconazole ('•') amphotericin B and liposomal amphotericin B ( • ) , and itraconazole ( • ) .

Downloaded from http://ndt.oxfordjournals.org/ by guest on January 26, 2016

monic infiltration was suspected (Figure 2). The attempt to isolate organisms from bronchial washings On day 44 CT-guided, percutaneous needle aspiraand brushings was unsuccessful and fibreoptic brontion biopsy of the pulmonary infiltrate was performed. choscopy revealed a normal tracheobronchial tree. A small amount of turbid yellowish liquid was obtained Abdominal CT did not show any signs of a septic focus. and the material was sent for culture and also for Despite the persisting fever (subfebrile temperature, microscopic examinations, where yeasts were detected but spikes 3-6 times per week), serum creatinine had but could not clearly be related to a single definite decreased throughout this time slowly but continuously species. Attempts to culture the fungus failed; nevertheand finally reached levels of 1.7mg/dl. Overall, the less the patient was treated with 1 mg/kg amphotericin patient's condition was surprisingly good. Because of the poor response to previous broad-spectrum antibac- B daily. In addition, 1 litre of saline with 400 mg terial therapy all antibiotics includingfluconazolewere pentoxifyllin was given daily to minimize nephrotoxiccancelled on day 36. Since the patient had an unusual ity. Immunosuppressive treatment consisting of CsA, history of travelling, a possible exposure to unusual prednisolone and azathioprine was continued. After pathogens was considered and various serological administration of a total dose of more than 2 g amphoinvestigations were performed (Legionella pneumophila, tericin B, serum creatinine values increased to a maxMycobacteria, Toxoplasma gondii, Candida albicans, imum of 3.7 mg/dl, but after switch to liposomal Aspergillus spp., Cryptococcus neoformans, Histoplas-amphotericin B (5 mg/kg/day) kidney function ma capsulatum, Coccidioides immitis and B. derma- recovered. Clinical symptoms improved only temporarily titidis). All of them were negative with the exception that high antibody titres to B. dermatitidis were found during antifungal therapy and on day 63, control CT of the thorax revealed central hypodense areas within (Figure 3). the lung consolidation, probably due to partial liquefaction. Consequently the afflicted segment was removed surgically because of suspected abscess formation. Pathological and microbiological examinations revealed a chronic, partly organized pneumonia with abscess formation and chronic pleuritis, but without any identifiable pathogen. After this operation the patient recovered rapidly and was discharged on day 83 with a maintenance therapy of 400 mg itraconazole daily. Since then no further fever episodes have occurred and graft function remained stable (serum creatinine 1.6 mg/dl). The presence of IgG serum antibodies to Blastomyces dermatitidis was determined by ELISA, with the A-antigen of the dimorphic fungus adsorbed to microwells (Premier Blastomyces EIA, Meridian Diagnostics, Ohio). Tests were performed according to the manufacturers instructions. The results were anaFig. 2. Chest roentgenogram in p.a.-projection: There is a well lysed with a 400 AT photometer (SLT Laboratory defined homogenous opacification (arrows) projecting over the right Instruments) at a wavelength of 450 nm and a reference lower hilar region just lateral to the right heart border.

1378

manifestations after transplantation were clearly associated with a recent antirejection therapy (ATG, steroid pulse) [7,8]. The two other cases of blastomycosis occurring 2 years after transplantation at the earliest had no history of a recent rejection treatment and relied on maintenance treatment with azathioprine and prednisolone [5,6]. There is no clear explanation for the rare occurrence of blastomycosis in the immunocompromised host and, although T-cells undoubtedly play a role in the resistance to infection, underlined by overwhelming dissemination of the disease in AIDS patients with very low CD4 counts, other defence mechanisms may be equally important. Of interest in this context is the finding that therapeutic concentrations of hydrocortisone and CsA did not inhibit fungicidal macrophage activation by yinterferon [9]. All other cases previously reported were diagnosed by culturing the organism from lung or skin tissue [5-7], except one, which was a mixed infection of aspergillus and microscopically suspected blastomyces Discussion [8]. Our attempt to culture B. dermatitidis failed, obviously because of prior fluconazole administration, Pulmonary blastomycosis has been diagnosed most which was not efficacious in terms of eradication of frequently during epidemics but sporadic cases have the fungus, but might have hampered growth from also been described. Patients often present either with culture. Serological tests, which established the diaacute disease resembling bacterial pneumonia (usually gnosis in our case, have been valued differently bilateral and predominant involvement of the lower depending upon the method used. While complement lung fields) or with subacute illness (typically perihilar fixation and immunodiffusion tests have shown limited infiltrations, more common on the right side and usefulness in acute disease with antibody detection of eventually segmental or lobar consolidation) [4], The only 9 and 28% respectively when assessed during usual portal of entry for B. dermatitidis is the respirat- a large outbreak and with negative results in the ory tract by inhalation of infectious conidia, which few transplant recipients with blastomycosis, an then convert to the yeast form in the lungs at 37°C. EIA showed diagnostic utility in immunocompetent Manifestations at other body sites (e.g. the skin) sub- with detection of antibodies to the A antigen of B. dermatitidis in 77% of patients who also had other sequently result from dissemination. signs of infection [10]. Alltogether a sensitivity ranging Only four cases of infection due to B. dermatitidis [5-8], recently reviewed by Serody et al. [2], have been from 80 to 88% and a specificity ranging from 98 to reported in renal transplant recipients, emphasizing the 100% have been demonstrated using purified antigen rarity of this condition even in areas where blasto- A with indirect EIA titres of ^32 strongly supporting mycosis is endemic. Our case is the first one reported the diagnosis of blastomycosis [11]. The excellent outside the endemic regions of North America and correlation of titre changes of EIA with disease activity it still remains unclear where the infection has been and recovery of our patient suggests the usefulness of acquired. After detailed questioning the patient serological controls for disease surveillance and for the reported a 1-day stay in Miami, when he was on his prevention of relapses. Cross-reactivity with other trip to Central America, but Florida is not considered mycoses, particularly histoplasmosis, seemed to be very an endemic region. Contact with imported contamin- unlikely at the high antibody levels observed in our ated particles (e.g. ccttcn) frcrn endemic regions cannot naiipnt !inH was definitely excluded by appropriate be excluded, but more likely is direct exposure to the serological tests. fungus, which is sparse but widely distributed. The Amphotericin B is strongly recommended in the patient's profession as a long distance truck driver immunocompromised host, since ketoconazole treatmight have increased the risk of exposure to contamin- ment most often resulted in treatment failures or ated soil. Most African strains lack the A-antigen of relapses in AIDS patients [12]. Similar unsatisfactory blastomyces, but high levels of antibodies directed to results were seen in the two blastomyces-infected transthis particular antigen were found in the patient's plant recipients when treated with ketoconazole [2]. serum, thus making acquisition of the fungus in Kenya Experiences with the newer triazole antifungal agents unlikely. Hence, infection must have occurred either fluconazole and itraconazole are limited but itraconain Central America or in Europe. zole is probably more effective than fluconazole when In kidney-graft recipients occurrence of blasto- comparable doses are assessed [13]. Nevertheless, desmycosis was not associated with a particular immuno- pite successful therapy in terms of elimination of the suppressive regimen, but those cases with early fungus with a total dose of more than 2 g amp-

Downloaded from http://ndt.oxfordjournals.org/ by guest on January 26, 2016

wavelength of 620 nm. The results were considered positive if a serum sample in a dilution of 1:420 exceeded an absorbance of 0.150 OD (optical density). Blood samples were drawn on post-transplant days 40, 49, 56, 70, 80, 109 and, in addition, deep-frozen, stored sera from days 0, 14, and 28 were analysed retrospectively. The absorbance values (OD) are shown in Figure 3. To detect cross-reactivity, sera were again tested for the presence of antibodies to Coccidioides immitis (Premier Coccidioides EIA, Meridian Diagnostics, Ohio), Histoplasma capsulatum (Immunodiffusion, Meridian Diagnostics, Ohio), Aspergillus spp. (indirect haemagglutination test, LD Aspergillus IHA, Labor Diagnostica, Germany), Candida albicans (indirect haemagglutination, LD Aspergillus IHA, Labor Diagnostica, Germany) and Cryptococcus neoformans (Premier Cryptococcal Antigen EIA, Meridian, Ohio). All these tests yielded negative results.

S. Winkler et al.

Blastomyces dermatilidis pneumonia in a European renal transplant recipient

hotericin B and only temporary nephrotoxicity after having switched to liposomal amphotericin B, surgery was still necessary to remove necrotic and pneumonic changed lung tissue, which was followed by a rapid recovery of the patient. It seems unclear whether and when antifungal therapy can be terminated in the immunocompromised patient without risk for relapse. Serody et al. reported the case of a heart-transplant recipient with recurrence of the infection after amphotericin B and ketoconazole treatment and suggested lifelong antifungal therapy in this patient [2]. This case with the very rare and unexpected diagnosis of blastomycosis not only reflects the tremendous diversity of infections in transplant recipients but also emphasizes the utility of serological methods even in the immunosuppressed host.

1. Hibberd PL, Rubin RH. Clinical aspects of fungal infection in organ transplant recipients. Clin Infect Dis 1994; 19 [Suppl. 1]: 33-40 2. Serody JS, Mill MR, Detterbeck FC, Harris DT, Cohen MS. Blastomycosis in transplant recipients: report of a case and review. Clin Infect Dis 1993; 16: 54-58 3. Anonymous. Blastomycosis—one disease or two ? Lancet 1989; 7 Jan (8628): 25-26

Received for publication: 23.2.96 Accepted: 27.2.96

Downloaded from http://ndt.oxfordjournals.org/ by guest on January 26, 2016

References

1379

4. Johnson PC, Davies SF, Sarosi GA. Fungal diseases of the lung. In: Niederman MS, Sarosi GA, Glassroth J, eds. Respiratory infections: a scientific basis for management. Saunders, Philadelphia: 1994: 387-415 5. Bukta BJ, Bennett SR, Johnson AC. Disseminated inoculation blastomycosis in a renal transplant recipient. Am Rev Respir Dis 1984; 130: 1180-1183 6. Greene NB, Baughman RP, Kim CK, Roselle GA. Failure of ketoconazole in an immunosuppressed patient with pulmonary blastomycosis. Chest 1985; 88: 640-641 7. Hii JH, Legault L, DeVeber G, Vas SI. Successful treatment of systemic blastomycosis with high-dose ketoconazole in a renal transplant recipient. Am J Kidney Dis 1990; 14: 595-597 8. Pechan WB, Novick AC, Lalli A, Gephardt G. Pulmonary nodules in a renal transplant recipient. J Urol 1980; 124: 111-114 9. Brummer E, Hanson LH, Stevens DH. Kinetics and requirements for activation of macrophages for fungicidal activity: effect of protein synthesis inhibitors and immunosuppressants on activation and fungicidal mechanisms. Cell Immunol 1991; 132: 236-245 10. Klein BS, Vergeront JM, Kaufman L et al. Serological tests for blastomycosis: assessments during a large point-source outbreak in Wisconsin. J Infect Dis 1987; 155: 262-268 11. Kaufman L. Laboratory methods for the diagnosis and confirmation of systemic mycoses. Clin Infect Dis 1992; 14 [Suppl. 1]: 23-29 12. Pappas PG, Pottage JC, Powderly WG et al. Blastomycosis in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1992; 116: 847-853 13. Pappas PG, Bradsher RW, Chapman SW et al. Treatment of blastomycosis with fluconazole: a pilot study. Clin Infect Dis 1995; 20: 267-271