- Email: [email protected]
Concurrent Pulmonary Aspergillus fumigatus and Mucor Infection in a Cardiac Transplant Recipient: A Case Report
Concurrent Pulmonary Aspergillus fumigatus and Mucor Infection in a Cardiac Transplant Recipient: A Case Report B.J. Webb, J.E. Blair, S. Kusne, R.L. Scott, D.E. Steidley, F.A. Arabia, and H.R. Vikram ABSTRACT Invasive fungal infections are a significant complication of solid organ transplantation. Here we report the first case of concurrent invasive pulmonary fungal infection caused by Aspergillus fumigatus and Mucor species in a heart transplant recipient. Polymicrobial mold infection is rare but should be considered in solid organ transplant recipients who fail to respond to initial antifungal therapy targeting a single organism. It is also of interest that in addition to potent immunosuppression and prolonged voriconazole therapy, possible airway fungal colonization following hurricane Katrina cleaning efforts might have contributed to this dual invasive mold infection. ITH THE INTRODUCTION of potent immunosuppressive therapy, invasive fungal infections have become an increasingly recognized complication following solid organ transplantation; reported incidence range between 5% and 42%.1,2 In the last decade, an epidemiological shift has been observed with Aspergillus and other filamentous molds becoming increasingly prevalent.3– 6 Very few cases of dual invasive fungal infections have been reported; of these cases, involvement of two different organ sites was most common.7–10 Although rare, these cases may have important implications with respect to antifungal prophylaxis, immunosuppression, and environmental exposure. Herein, we present the first reported case of concurrent pulmonary aspergillosis and mucormycosis in a heart transplant recipient.
W
CASE REPORT A 52-year-old man with idiopathic dilated cardiomyopathy from New Orleans, Louisiana, initiated a cardiac transplantation evaluation but was interrupted by the devastation brought to the city by Hurricane Katrina in August 2005. After working with New Orleans city cleanup crews for several months following hurricane Katrina, the patient relocated to Arizona in April 2006 where he resumed cardiac transplant evaluation at our center. Pretransplant computed tomography (CT) in June 2006 showed a calcified granuloma in the left lower lobe. During his pretransplant evaluation, Coccidioides serology and cytomegalovirus (CMV) serology were negative. He underwent successful orthotopic heart transplantation in July 2006. Donor was CMV immunoglobulin G antibody positive (ie, CMV mismatch status). Immunosuppression consisted of prednisone, tacrolimus, and mycophenylate mofetil. The immediate postoperative period was complicated by insulinrequiring diabetes mellitus and acute renal failure necessitating 0041-1345/13/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.03.056 792
temporary hemodialysis. He was initiated on valgancyclovir and trimethoprim- sulfamethoxazole prophylaxis. Initial protocol-based posttransplant endomyocardial biopsies did not reveal evidence of rejection. Approximately 25 days posttransplantation, the patient developed a dry cough without fever or hemoptysis. A chest radiograph revealed a new infiltrate involving the right lower lobe. CT scan of the chest revealed nodular opacities in the basilar segments of the left lower lobe and a 6-cm opacity in the superior segment of the right lower lobe (Fig 1). CT-guided biopsy of the left lower lobe lesion was performed; tissue stains and cultures were negative for bacteria, fungi, nocardia, and acid-fast bacilli. Bilateral bronchioalveolar lavage was performed the next day; cytology of the lavage fluid revealed acute inflammation. Smears for Pneumocystis jerovecii and acid-fast bacilli were negative. Bacterial cultures grew normal respiratory flora; fungal, nocardial, and mycobacterial cultures remained negative. There was no evidence of concurrent CMV viremia by polymerase chain reaction. After empiric broadspectrum therapy, the patient was discharged on valgancyclovir and trimethoprim-sulfamethoxazole prophylaxis and a 10-day course of levofloxacin. Sixty days after transplantation, the patient was hospitalized for worsening cough. A chest CT revealed marked progression of the lung process, with multiple well-defined subcentimeter nodules in From the Department of Internal Medicine (B.J.W.), Mayo Clinic, Scottsdale, Arizona, USA; Division of Infectious Diseases (H.R.V., J.E.B., S.K.), Mayo Clinic, Phoenix, Arizona, USA; Division of Cardiovascular Diseases (R.L.S., D.E.S.), Mayo Clinic, Phoenix, Arizona, USA; and Division of Cardiothoracic Surgery (F.A.A.), Mayo Clinic, Phoenix, Arizona, USA. Address correspondence to Holenarasipur R. Vikram, MD, Division of Infectious Diseases, Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA. E-mail: [email protected] © 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 45, 792–797 (2013)
ASPERGILLUS FUMIGATUS AND MUCOR INFECTION
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Fig 1. Computed tomography of the chest from September 2006 demonstrating left lower lobe nodular opacities. the left upper lobe and lingula, large coalescent masses in the left lower lobe, and a 2.5-cm nodule in the right lower lobe (Fig 2). Ultrasound-guided biopsy of the posterior left lung mass revealed abundant branching septated hyphae (Fig 3); fungal culture grew Aspergillus fumigatus. Serum galactomanan index (GMI) was elevated at 3.3 (normal range ⱕ 0.5). Caspofungin and voriconazole were initiated and immunosuppression was reduced. A repeat chest CT after 4 weeks of combination antifungal therapy demonstrated reduction in size of the peripheral lung nodules and a modest improvement of the lingular mass. Caspofungin was discontinued. The patient continued voriconazole for an additional 15 weeks with a decreasing trend in serum galactomannan level. However, in January 2007, while still receiving voriconazole, he developed several episodes of hemoptysis requiring readmission to the hospital. Repeat chest CT scan demonstrated a persistent lobulated left lingular mass suggestive of aspergilloma (Fig 4). Urgent left lower lobectomy was performed. Intraoperatively, interlobar abscesses were noted between the left upper and lower lobes. Pathology demonstrated necrotizing pneumonia with abscess formation and fungal hyphae with different morphologies. Fungal cultures from multiple intraoperative specimens revealed growth of A fumigatus and Mucor species. Antifungal therapy was changed to posaconazole and liposomal amphotericin B and immunosuppression was decreased. Within weeks, however, the patient developed cardiogenic shock and despite maximal supportive
therapy he succumbed to multisystem organ failure. Autopsy demonstrated massive myocardial infarction, extensive pulmonary hemorrhage, and angioinvasive fungal infection but no evidence of cellular cardiac rejection.
DISCUSSION
Infectious complications represent the most common cause of late mortality following orthotopic heart transplantation.11 The incidence of invasive pulmonary aspergillosis (IPA) in heart transplant recipients is 3% to 14%12 and accounts for 15% of all-cause mortality in this population.13 Risk factors for IPA include concomitant CMV infection, perioperative hemodialysis, and reoperation (13). Similar to lung transplant recipients, lower airway Aspergillus colonization is highly predictive of invasive disease following heart transplantation.14 Infection with Aspergillus spp occurs at a median of 50 to 60 days posttransplant.15 Prognosis is poor, with mortality exceeding 70% in several case series.13 While less common than IPA, invasive mucormycosis is an increasingly important infection in solid organ transplantation, with an estimated prevalence between 1% and 9%.16 Previously known as zygomycosis, mucormycosis is caused by fungi of the order Mucorales (Rhizopus spp, Absidia spp,
794
WEBB, BLAIR, KUSNE ET AL
Fig 2. Computed tomography of the chest from October 2006 showing progression of nodular infiltrates in the left lower lobe.
Fig 3. (A) Gomori methanamine silver (1000⫻) and (B) hematoxylin and eosin stain (60⫻) of the left lower lung biopsy demonstrate branching septated hyphae consistent with Aspergillus.
ASPERGILLUS FUMIGATUS AND MUCOR INFECTION
795
Fig 4. Computed tomography of the chest from January 2007 revealed a persistent lobulated left lingular mass.
Cunninghamella spp, Rhizomucor spp, Mucor spp, and Apophysomyces spp) and manifests as a rapidly invasive infection with rhino-orbital, pulmonary, cutaneous, or disseminated disease in patients with diabetes mellitus, hematologic malignancy, recipients of hematopoietic stem cell transplant, or following iron chelation therapy.17–20 Pulmonary involvement is the most common presentation (53%) with mucormycosis in solid organ transplant recipients and manifests at a median of 5.5 months posttransplantation.21 A recent case control study identified renal failure and diabetes mellitus as independent risk factors for mucormy-
cosis in solid organ transplant recipients.22 Most case series report mortality rates between 40% and 70%.19,22 Studies in the past decade have attributed a rise in the incidence of invasive mucormycosis to the routine use of voriconazole for prophylaxis against invasive aspergillosis in the setting of immunosuppression following transplantation.23–26 Whether this increase can be attributed to voriconazole’s lack of activity against Mucorales or to the profoundly immunosuppressed state of transplant patients is not clear.23–26 In addition, inoculant Mucorales strains exposed to voriconazole have demonstrated selec-
796
tively enhanced virulence in Drosophilia and murine models.27 However, while a case control study in patients with hematologic malignancy identified an association between mucormycosis and voriconazole prophylaxis, studies in solid organ transplant recipients failed to reproduce similar results.22,28 Voriconazole is the antifungal agent of choice for the management of IPA.29 In addition, recent data suggest that combined therapy with voriconazole and caspofungin, as administered in the current report, may decrease mortality in solid organ transplant recipients, particularly in those with renal failure or A fumigatus infection.13 A polyenebased regimen remains the preferred therapy for mucormycosis, although limited data suggest that a combination of a lipid formulation amphotericin B and an echinocandin might confer additional benefit.30 Posaconazole has been utilized for salvage therapy in some patients with refractory mucormycosis.31,32 Concurrent dual mold infection remains a rare entity, even in profoundly immunosuppressed hosts6 – 8,10,33 and is exemplified by an accelerated progression and poor outcome.7,9 This case represents the first report of concomitant pulmonary aspergillosis and mucormycosis infection complicating orthotopic heart transplantation. While both Aspergillus spp and Mucorales are ubiquitous saprophytic organisms, specific environmental exposures are clearly associated with invasive mold infection.16 Such exposures include disruptive meteorological events, a fact recently highlighted by an outbreak of cutaneous mucormycosis in the aftermath of the tornado that struck Joplin, Missouri, in May 2011.34 Cutaneous mucormycosis has also been reported after the tsunami in Sri Lanka35 and a volcanic eruption.36 In the present case, it is possible that airway colonization with pathogenic molds occurred while the patient was involved in post– hurricane Katrina cleanup efforts. High levels of airborne molds such as Aspergillus spp and Mucorales spp were documented in that posthurricane environment.37,38 Subsequent heart transplantation with resulting immunosuppression may have resulted in the development of invasive pulmonary mold infection. In addition, pulmonary mucormycosis was identified only after incomplete response to an extended course of voriconazole for earlier biopsy-proven pulmonary aspergillosis. Selective pressure from prolonged voriconazole therapy and posttransplant diabetes mellitus may have led to subsequent invasive mucormycosis for the reasons cited above. Last, hospital building construction has been well documented as a source of nosocomial invasive fungal infection.39 Although construction at our institution was occurring at the time of this case and could have been a potential source of environmental mold exposure, measures to prevent construction-related nosocomial infection were in place according to established successful practices,40,41 including all transplant patients wearing face masks to prevent inhalation exposure.
WEBB, BLAIR, KUSNE ET AL
CONCLUSION
Our patient developed concurrent invasive pulmonary aspergillosis and mucormycosis following heart transplantation. Prior environmental exposure and airway colonization following hurricane Katrina, profound immunosuppression, posttransplant diabetes mellitus, and prolonged voriconazole therapy placed him at a higher risk for invasive fungal infection with both Mucor and Aspergillus. A coexistent pathogen should be considered early in the management of profoundly immunosuppressed hosts when there is lack of response to a previously documented infection.
REFERENCES 1. Marik PE: Fungal infections in solid organ transplantation. Expert Opin Pharmacother 7:297, 2006 2. Silveira FP, Husain S: Fungal infections in solid organ transplantation. Med Mycol 45:305, 2007 3. Husain S, Alexander BD, Munoz P, et al: Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin Infect Dis 37:221, 2003 4. Malani AN, Kauffman CA: Changing epidemiology of rare mould infections: implications for therapy. Drugs 67:1803, 2007 5. Singh N: Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices. Clin Infect Dis 33:1692, 2001 6. Stelzmueller I, Lass-Floerl C, Geltner C, et al: Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients. Transpl Int 21:534, 2008 7. Clauss H, Samuel R: Simultaneous mold infections in an orthotopic heart transplant recipient. Transpl Infect Dis 10:343, 2008 8. McLintock LA, Gibson BE, Jones BL: Mixed pulmonary fungal infection with Aspergillus fumigatus and Absidia corymbifera in a patient with relapsed acute myeloid leukaemia. Br J Haematol 128:737, 2005 9. Scheld WM, Royston D, Harding SA, et al: Simultaneous disseminated aspergillosis and zygomycosis in a leukemic patient. South Med J 72:1325, 1979 10. Viscoli C, Dodi F, Pellicci E, et al: Staphylococcus aureus bacteraemia, Absidia corymbifera infection and probable pulmonary aspergillosis in a recipient of orthotopic liver transplantation for end stage liver disease secondary to hepatitis C. J Infect 34:281, 1997 11. Montoya JG, Giraldo LF, Efron B, et al: Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 33:629, 2001 12. Singh N, Paterson DL: Aspergillus infections in transplant recipients. Clin Microbiol Rev 18:44, 2005 13. 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 81:320, 2006 14. Munoz P, Alcala L, Sanchez Conde M, et al: The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients is highly predictive of invasive aspergillosis. Transplantation 75:326, 2003 15. Munoz P, Singh N, Bouza E: Treatment of solid organ transplant patients with invasive fungal infections: should a combination of antifungal drugs be used? Curr Opin Infect Dis 19:365, 2006 16. Gabardi S, Kubiak DW, Chandraker AK, et al: Invasive fungal infections and antifungal therapies in solid organ transplant recipients. Transpl Int 20:993, 2007
ASPERGILLUS FUMIGATUS AND MUCOR INFECTION 17. Chayakulkeeree M, Ghannoum MA, Perfect JR: Zygomycosis: the re-emerging fungal infection. Eur J Clin Microbiol Infect Dis 25:215, 2006 18. Prabhu RM, Patel R: Mucormycosis and entomophthoramycosis: a review of the clinical manifestations, diagnosis and treatment. Clin Microbiol Infect 10(suppl 1):31, 2004 19. Roden MM, Zaoutis TE, Buchanan WL, et al: Epidemiology and outcome of zygomycosis: a review of 929 reported cases. Clin Infect Dis 41:634, 2005 20. Uckay I, Chalandon Y, Sartoretti P, et al: Invasive zygomycosis in transplant recipients. Clin Transplant 21:577, 2007 21. Sun HY, Aguado JM, Bonatti H, et al: Pulmonary zygomycosis in solid organ transplant recipients in the current era. Am J Transplant 9:2166, 2009 22. Singh N, Aguado JM, Bonatti H, et al: Zygomycosis in solid organ transplant recipients: a prospective, matched case-control study to assess risks for disease and outcome. J Infect Dis 200:1002, 2009 23. Imhof A, Balajee SA, Fredricks DN, et al: Breakthrough fungal infections in stem cell transplant recipients receiving voriconazole. Clin Infect Dis 39:743, 2004 24. Kontoyiannis DP, Lionakis MS, Lewis RE, et al: Zygomycosis in a tertiary-care cancer center in the era of Aspergillus-active antifungal therapy: a case-control observational study of 27 recent cases. J Infect Dis 191:1350, 2005 25. Marty FM, Cosimi LA, Baden LR: Breakthrough zygomycosis after voriconazole treatment in recipients of hematopoietic stem-cell transplants. N Engl J Med 350:950, 2004 26. Siwek GT, Dodgson KJ, de Magalhaes-Silverman M, et al: Invasive zygomycosis in hematopoietic stem cell transplant recipients receiving voriconazole prophylaxis. Clin Infect Dis 39:584, 2004 27. Lamaris GA, Ben-Ami R, Lewis RE, et al: Increased virulence of Zygomycetes organisms following exposure to voriconazole: a study involving fly and murine models of zygomycosis. J Infect Dis 199:1399, 2009 28. Linden P, Posey K, Johnson H: Stratified voriconazole prophylaxis for the prevention of aspergillosis in liver and multi-
797 visceral transplant recipients: comparison with a control cohort. Am J Transplant 8(suppl 2):564, 2008 29. Herbrecht R, Denning DW, Patterson TF, et al: Voriconazole versus amphotericin B for primary therapy of invasive aspergillosis. T N Engl J Med 347:408, 2002 30. Spellberg B, Walsh TJ, Kontoyiannis DP, et al: Recent advances in the management of mucormycosis: from bench to bedside. Clin Infect Dis 48:1743, 2009 31. Greenberg RN, Mullane K, van Burik JA, et al: Posaconazole as salvage therapy for zygomycosis. Antimicrob Agents Chemother 50:126, 2006 32. van Burik JA, Hare RS, Solomon HF, et al: Posaconazole is effective as salvage therapy in zygomycosis: a retrospective summary of 91 cases. Clin Infect Dis 42:e61, 2006 33. Molle M, Blaschke-Hellmessen R, Schuler U, et al: [Disseminated aspergillosis and mucormycosis. A case report]. Mycoses 39(suppl 1):59, 1996 34. CDC: Fatal Fungal Soft-Tissue Infections After a Tornado— Joplin, Missouri, 2011. MMWR Morb Mortal Wkly Rep 60:992, 2011 35. Andresen D, Donaldson A, Choo L, et al: Multifocal cutaneous mucormycosis complicating polymicrobial wound infections in a tsunami survivor from Sri Lanka. Lancet 365:876, 2005 36. Patino JF, Castro D, Valencia A, et al: Necrotizing soft tissue lesions after a volcanic cataclysm. World J Surg 15:240, 1991 37. Chew GL, Wilson J, Rabito FA, et al: Mold and endotoxin levels in the aftermath of Hurricane Katrina: a pilot project of homes in New Orleans undergoing renovation. Environ Health Perspect 114:1883, 2006 38. Rao CY, Riggs MA, Chew GL, et al: Characterization of airborne molds, endotoxins, and glucans in homes in New Orleans after Hurricanes Katrina and Rita. Appl Environ Microbiol 73: 1630, 2007 39. Vonberg RP, Gastmeier P: Nosocomial aspergillosis in outbreak settings. J Hosp Infect 63:246, 2006 40. Chang CC, Cheng AC, Devitt B, et al: Successful control of an outbreak of invasive aspergillosis in a regional haematology unit during hospital construction works. J Hosp Infect 69:33, 2008 41. Haiduven D: Nosocomial aspergillosis and building construction. Med Mycol 47(suppl 1):S210, 2009
W
CASE REPORT A 52-year-old man with idiopathic dilated cardiomyopathy from New Orleans, Louisiana, initiated a cardiac transplantation evaluation but was interrupted by the devastation brought to the city by Hurricane Katrina in August 2005. After working with New Orleans city cleanup crews for several months following hurricane Katrina, the patient relocated to Arizona in April 2006 where he resumed cardiac transplant evaluation at our center. Pretransplant computed tomography (CT) in June 2006 showed a calcified granuloma in the left lower lobe. During his pretransplant evaluation, Coccidioides serology and cytomegalovirus (CMV) serology were negative. He underwent successful orthotopic heart transplantation in July 2006. Donor was CMV immunoglobulin G antibody positive (ie, CMV mismatch status). Immunosuppression consisted of prednisone, tacrolimus, and mycophenylate mofetil. The immediate postoperative period was complicated by insulinrequiring diabetes mellitus and acute renal failure necessitating 0041-1345/13/$–see front matter http://dx.doi.org/10.1016/j.transproceed.2012.03.056 792
temporary hemodialysis. He was initiated on valgancyclovir and trimethoprim- sulfamethoxazole prophylaxis. Initial protocol-based posttransplant endomyocardial biopsies did not reveal evidence of rejection. Approximately 25 days posttransplantation, the patient developed a dry cough without fever or hemoptysis. A chest radiograph revealed a new infiltrate involving the right lower lobe. CT scan of the chest revealed nodular opacities in the basilar segments of the left lower lobe and a 6-cm opacity in the superior segment of the right lower lobe (Fig 1). CT-guided biopsy of the left lower lobe lesion was performed; tissue stains and cultures were negative for bacteria, fungi, nocardia, and acid-fast bacilli. Bilateral bronchioalveolar lavage was performed the next day; cytology of the lavage fluid revealed acute inflammation. Smears for Pneumocystis jerovecii and acid-fast bacilli were negative. Bacterial cultures grew normal respiratory flora; fungal, nocardial, and mycobacterial cultures remained negative. There was no evidence of concurrent CMV viremia by polymerase chain reaction. After empiric broadspectrum therapy, the patient was discharged on valgancyclovir and trimethoprim-sulfamethoxazole prophylaxis and a 10-day course of levofloxacin. Sixty days after transplantation, the patient was hospitalized for worsening cough. A chest CT revealed marked progression of the lung process, with multiple well-defined subcentimeter nodules in From the Department of Internal Medicine (B.J.W.), Mayo Clinic, Scottsdale, Arizona, USA; Division of Infectious Diseases (H.R.V., J.E.B., S.K.), Mayo Clinic, Phoenix, Arizona, USA; Division of Cardiovascular Diseases (R.L.S., D.E.S.), Mayo Clinic, Phoenix, Arizona, USA; and Division of Cardiothoracic Surgery (F.A.A.), Mayo Clinic, Phoenix, Arizona, USA. Address correspondence to Holenarasipur R. Vikram, MD, Division of Infectious Diseases, Mayo Clinic, 5777 E. Mayo Blvd, Phoenix, AZ 85054, USA. E-mail: [email protected] © 2013 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 45, 792–797 (2013)
ASPERGILLUS FUMIGATUS AND MUCOR INFECTION
793
Fig 1. Computed tomography of the chest from September 2006 demonstrating left lower lobe nodular opacities. the left upper lobe and lingula, large coalescent masses in the left lower lobe, and a 2.5-cm nodule in the right lower lobe (Fig 2). Ultrasound-guided biopsy of the posterior left lung mass revealed abundant branching septated hyphae (Fig 3); fungal culture grew Aspergillus fumigatus. Serum galactomanan index (GMI) was elevated at 3.3 (normal range ⱕ 0.5). Caspofungin and voriconazole were initiated and immunosuppression was reduced. A repeat chest CT after 4 weeks of combination antifungal therapy demonstrated reduction in size of the peripheral lung nodules and a modest improvement of the lingular mass. Caspofungin was discontinued. The patient continued voriconazole for an additional 15 weeks with a decreasing trend in serum galactomannan level. However, in January 2007, while still receiving voriconazole, he developed several episodes of hemoptysis requiring readmission to the hospital. Repeat chest CT scan demonstrated a persistent lobulated left lingular mass suggestive of aspergilloma (Fig 4). Urgent left lower lobectomy was performed. Intraoperatively, interlobar abscesses were noted between the left upper and lower lobes. Pathology demonstrated necrotizing pneumonia with abscess formation and fungal hyphae with different morphologies. Fungal cultures from multiple intraoperative specimens revealed growth of A fumigatus and Mucor species. Antifungal therapy was changed to posaconazole and liposomal amphotericin B and immunosuppression was decreased. Within weeks, however, the patient developed cardiogenic shock and despite maximal supportive
therapy he succumbed to multisystem organ failure. Autopsy demonstrated massive myocardial infarction, extensive pulmonary hemorrhage, and angioinvasive fungal infection but no evidence of cellular cardiac rejection.
DISCUSSION
Infectious complications represent the most common cause of late mortality following orthotopic heart transplantation.11 The incidence of invasive pulmonary aspergillosis (IPA) in heart transplant recipients is 3% to 14%12 and accounts for 15% of all-cause mortality in this population.13 Risk factors for IPA include concomitant CMV infection, perioperative hemodialysis, and reoperation (13). Similar to lung transplant recipients, lower airway Aspergillus colonization is highly predictive of invasive disease following heart transplantation.14 Infection with Aspergillus spp occurs at a median of 50 to 60 days posttransplant.15 Prognosis is poor, with mortality exceeding 70% in several case series.13 While less common than IPA, invasive mucormycosis is an increasingly important infection in solid organ transplantation, with an estimated prevalence between 1% and 9%.16 Previously known as zygomycosis, mucormycosis is caused by fungi of the order Mucorales (Rhizopus spp, Absidia spp,
794
WEBB, BLAIR, KUSNE ET AL
Fig 2. Computed tomography of the chest from October 2006 showing progression of nodular infiltrates in the left lower lobe.
Fig 3. (A) Gomori methanamine silver (1000⫻) and (B) hematoxylin and eosin stain (60⫻) of the left lower lung biopsy demonstrate branching septated hyphae consistent with Aspergillus.
ASPERGILLUS FUMIGATUS AND MUCOR INFECTION
795
Fig 4. Computed tomography of the chest from January 2007 revealed a persistent lobulated left lingular mass.
Cunninghamella spp, Rhizomucor spp, Mucor spp, and Apophysomyces spp) and manifests as a rapidly invasive infection with rhino-orbital, pulmonary, cutaneous, or disseminated disease in patients with diabetes mellitus, hematologic malignancy, recipients of hematopoietic stem cell transplant, or following iron chelation therapy.17–20 Pulmonary involvement is the most common presentation (53%) with mucormycosis in solid organ transplant recipients and manifests at a median of 5.5 months posttransplantation.21 A recent case control study identified renal failure and diabetes mellitus as independent risk factors for mucormy-
cosis in solid organ transplant recipients.22 Most case series report mortality rates between 40% and 70%.19,22 Studies in the past decade have attributed a rise in the incidence of invasive mucormycosis to the routine use of voriconazole for prophylaxis against invasive aspergillosis in the setting of immunosuppression following transplantation.23–26 Whether this increase can be attributed to voriconazole’s lack of activity against Mucorales or to the profoundly immunosuppressed state of transplant patients is not clear.23–26 In addition, inoculant Mucorales strains exposed to voriconazole have demonstrated selec-
796
tively enhanced virulence in Drosophilia and murine models.27 However, while a case control study in patients with hematologic malignancy identified an association between mucormycosis and voriconazole prophylaxis, studies in solid organ transplant recipients failed to reproduce similar results.22,28 Voriconazole is the antifungal agent of choice for the management of IPA.29 In addition, recent data suggest that combined therapy with voriconazole and caspofungin, as administered in the current report, may decrease mortality in solid organ transplant recipients, particularly in those with renal failure or A fumigatus infection.13 A polyenebased regimen remains the preferred therapy for mucormycosis, although limited data suggest that a combination of a lipid formulation amphotericin B and an echinocandin might confer additional benefit.30 Posaconazole has been utilized for salvage therapy in some patients with refractory mucormycosis.31,32 Concurrent dual mold infection remains a rare entity, even in profoundly immunosuppressed hosts6 – 8,10,33 and is exemplified by an accelerated progression and poor outcome.7,9 This case represents the first report of concomitant pulmonary aspergillosis and mucormycosis infection complicating orthotopic heart transplantation. While both Aspergillus spp and Mucorales are ubiquitous saprophytic organisms, specific environmental exposures are clearly associated with invasive mold infection.16 Such exposures include disruptive meteorological events, a fact recently highlighted by an outbreak of cutaneous mucormycosis in the aftermath of the tornado that struck Joplin, Missouri, in May 2011.34 Cutaneous mucormycosis has also been reported after the tsunami in Sri Lanka35 and a volcanic eruption.36 In the present case, it is possible that airway colonization with pathogenic molds occurred while the patient was involved in post– hurricane Katrina cleanup efforts. High levels of airborne molds such as Aspergillus spp and Mucorales spp were documented in that posthurricane environment.37,38 Subsequent heart transplantation with resulting immunosuppression may have resulted in the development of invasive pulmonary mold infection. In addition, pulmonary mucormycosis was identified only after incomplete response to an extended course of voriconazole for earlier biopsy-proven pulmonary aspergillosis. Selective pressure from prolonged voriconazole therapy and posttransplant diabetes mellitus may have led to subsequent invasive mucormycosis for the reasons cited above. Last, hospital building construction has been well documented as a source of nosocomial invasive fungal infection.39 Although construction at our institution was occurring at the time of this case and could have been a potential source of environmental mold exposure, measures to prevent construction-related nosocomial infection were in place according to established successful practices,40,41 including all transplant patients wearing face masks to prevent inhalation exposure.
WEBB, BLAIR, KUSNE ET AL
CONCLUSION
Our patient developed concurrent invasive pulmonary aspergillosis and mucormycosis following heart transplantation. Prior environmental exposure and airway colonization following hurricane Katrina, profound immunosuppression, posttransplant diabetes mellitus, and prolonged voriconazole therapy placed him at a higher risk for invasive fungal infection with both Mucor and Aspergillus. A coexistent pathogen should be considered early in the management of profoundly immunosuppressed hosts when there is lack of response to a previously documented infection.
REFERENCES 1. Marik PE: Fungal infections in solid organ transplantation. Expert Opin Pharmacother 7:297, 2006 2. Silveira FP, Husain S: Fungal infections in solid organ transplantation. Med Mycol 45:305, 2007 3. Husain S, Alexander BD, Munoz P, et al: Opportunistic mycelial fungal infections in organ transplant recipients: emerging importance of non-Aspergillus mycelial fungi. Clin Infect Dis 37:221, 2003 4. Malani AN, Kauffman CA: Changing epidemiology of rare mould infections: implications for therapy. Drugs 67:1803, 2007 5. Singh N: Trends in the epidemiology of opportunistic fungal infections: predisposing factors and the impact of antimicrobial use practices. Clin Infect Dis 33:1692, 2001 6. Stelzmueller I, Lass-Floerl C, Geltner C, et al: Zygomycosis and other rare filamentous fungal infections in solid organ transplant recipients. Transpl Int 21:534, 2008 7. Clauss H, Samuel R: Simultaneous mold infections in an orthotopic heart transplant recipient. Transpl Infect Dis 10:343, 2008 8. McLintock LA, Gibson BE, Jones BL: Mixed pulmonary fungal infection with Aspergillus fumigatus and Absidia corymbifera in a patient with relapsed acute myeloid leukaemia. Br J Haematol 128:737, 2005 9. Scheld WM, Royston D, Harding SA, et al: Simultaneous disseminated aspergillosis and zygomycosis in a leukemic patient. South Med J 72:1325, 1979 10. Viscoli C, Dodi F, Pellicci E, et al: Staphylococcus aureus bacteraemia, Absidia corymbifera infection and probable pulmonary aspergillosis in a recipient of orthotopic liver transplantation for end stage liver disease secondary to hepatitis C. J Infect 34:281, 1997 11. Montoya JG, Giraldo LF, Efron B, et al: Infectious complications among 620 consecutive heart transplant patients at Stanford University Medical Center. Clin Infect Dis 33:629, 2001 12. Singh N, Paterson DL: Aspergillus infections in transplant recipients. Clin Microbiol Rev 18:44, 2005 13. 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 81:320, 2006 14. Munoz P, Alcala L, Sanchez Conde M, et al: The isolation of Aspergillus fumigatus from respiratory tract specimens in heart transplant recipients is highly predictive of invasive aspergillosis. Transplantation 75:326, 2003 15. Munoz P, Singh N, Bouza E: Treatment of solid organ transplant patients with invasive fungal infections: should a combination of antifungal drugs be used? Curr Opin Infect Dis 19:365, 2006 16. Gabardi S, Kubiak DW, Chandraker AK, et al: Invasive fungal infections and antifungal therapies in solid organ transplant recipients. Transpl Int 20:993, 2007
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