Fatal Scopulariopsis Infection in a Lung Transplant Recipient: A Case Report Wim A. Wuyts, MD, PhD,a Helmut Molzahn, MD,b Johan Maertens, MD, PhD,c Eric K. Verbeken, MD, PhD,d Katrien Lagrou, MD, PhD,e Lieven J. Dupont, MD, PhD,a and Geert M. Verleden, MD, PhDa A case of a fatal Scopulariopsis infection is reported in a 63-year-old lung transplantation patient with a 7-week history of dyspnea that presented initially with pericardial and pleural fluid. Because of a respiratory arrest, the patient was intubated and received positive pressure ventilation. Later, obstructive shock developed due to a pericardial tamponade requiring pericardectomy and then urgent extracorporal membrane oxygenation. The working hypothesis was of disseminated cytomegalovirus infection because cultures from bronchoalveolar lavage and transbronchial biopsy specimens were positive. The pericardial biopsy specimen showed fungal hyphae. After the patient died from the infection, the fungus was identified as Scopulariopsis acremonium. This case report describes the first case, to our knowledge, of an insidious Scopulariopsis acremonium infection in an immunocompromised lung transplant patient, underscoring the importance of a direct, invasive approach and early treatment with anti-fungal therapy in immunocompromised patients. J Heart Lung Transplant 2005;24: 2301– 4. Copyright © 2005 by the International Society for Heart and Lung Transplantation.
The advent of effective anti-bacterial and anti-viral strategies has led to the emergence of opportunistic mycoses such as Candida and Aspergillus as a major cause of infection-related mortality in solid organ transplant recipients. The risk even increases if these patients are admitted to a medical intensive care unit.1 Recent epidemiologic trends, however, have witnessed the emergence of mycelial fungi other than Aspergillus as increasingly important pathogens. To the best of our knowledge, we describe here the first case of an invasive Scopulariopsis infection in a lung transplant recipient. CASE REPORT A 63-year-old man underwent a single-lung transplantation (donor CMV–/receptor CMV⫹) for end-stage chronic obstructive pulmonary disease. The immunosuppressive regime consisted initially of rabbit antithymocyte globulin (rATG 3 mg/kg for 3 days), azathioprine (100 mg/day), cyclosporin A (trough level, 250 – 300 g/liter) and methylprednisolone (0.4 mg/kg).
From the aDepartments of Respiratory Disease, Lung Transplantation Unit, bMedical Intensive Care Unit, cHaematology, dPathology, and e Microbiology, University Hospital Gasthuisberg, Herestraat, Leuven, Belgium. Received April 4, 2005; revised June 9, 2005; accepted June 20, 2005. Reprint requests: G.M. Verleden, MD, PhD, University Hospital Gasthuisberg, Dept Respir Dis, Lung Transplantation Unit, 49, Herestraat B-3000 Leuven, Belgium. Telephone: ⫹32-16-346800. Fax: ⫹32-16-346803. E-mail:
[email protected] Copyright © 2005 by the International Society for Heart and Lung Transplantation. 1053-2498/05/$–see front matter. doi:10.1016/ j.healun.2005.06.015
After 3 weeks, cyclosporin A was switched to tacrolimus (trough level, 12–15 g/liter), and an intravenous methylprednisolone course was administered for a presumed acute rejection. Although there was a new pulmonary infiltrate, a transbronchial biopsy specimen demonstrated signs of alveolar damage with hyperplasia of type 2 pneumocytes. This infiltrate gradually disappeared, and further follow-up was uneventful. During hospitalization, he received aerosolized amphotericin (5 mg twice a day) and ganciclovir (5 mg/kg once a day); the latter was changed after discharge to acyclovir for 2 months. Seven months post-operatively, the patient presented with progressive dyspnea and fever. Biochemistry revealed an increased C-reactive protein concentration of 142 mg/liter (normal value, ⱕ5 mg/liter). Chest X-ray showed some pleural fluid at the left costodiaphragmatic sinus, which was unchanged. The presence of limited pericardial and pleural fluid was confirmed by a thoracic computed tomography (CT) scan. Therapy with ganciclovir (5 mg/kg twice a day) was started because of a presumed cytomegalovirus (CMV) infection. Viral DNA was detected by polymerase chain reaction (PCR) in blood and bronchoalveolar fluid (BAL) (⬎106copies/ml) and confirmed by a transbronchial biopsy specimen. Fungal pathogens were not isolated from BAL-fluid or sputum. No anti-fungal prophylaxis was administered at that time. After initial improvement, the patient’s condition gradually worsened. Chest X-ray revealed increasing pleural fluid (without pulmonary infiltrates) and cardiomegaly. Transthoracic echocardiography showed a pericardial effusion (1.8 cm) and an abnormal pericardial structure at the right ventricle that was confirmed 2301
2302
Wuyts et al.
The Journal of Heart and Lung Transplantation December 2005
by a transesophageal procedure. Additional cardiac magnetic resonance imaging (MRI) showed signs of an acute, exudative pleuropericarditis, but no evidence of a pericardial tumor. Two days later a new episode of high fever (38.8°C) developed, with decreased consciousness, and the C-reactive protein concentration was increased (205 mg/ liter). After the empirical start of meropenem, the patient recovered with normalization of his neurologic status. Pleural fluid was sampled; placing a chest tube showing granulocytes, 34%; lymphocytes, 61%; monocytes, 4%; glucose, 235 mg/dl; protein 12g/liter, and lactate dehydrogenase, 178 U/liter; culture and cytologic examination results were normal. A repeat chest CT scan showed no pulmonary nodules or infiltrates. One week later, the patient required endotracheal intubation and positive pressure ventilation due to respiratory failure; thereafter, the patient developed a hemodynamic collapse. A pulmonary artery catheter was placed, showing a picture of cardiogenic shock with low cardiac output (Table 1.) Acute renal failure developed. With the assumption of a recurrent CMV infection, ganciclovir was restarted at 5 mg/kg per day. One week later, the patient’s hemodynamic condition had further deteriorated. Repeat transesophageal echocardiography revealed tamponade with compression of the right ventricle. An urgent pericardiectomy was performed, and an extracorporal membrane oxygenation (ECMO) system was instituted. A few hours later, hypotension reoccurred and recurrence of tamponade was diagnosed by echocardiography. Bedside sternotomy and surgical drainage of the hemopericardium was performed. The biopsy specimen of the pericardium showed presence of fungal hyphae and a dense, mixed cellular infiltrate, suggestive of fungal pericarditis due to Aspergillus spp. (Fig 1). Intravenous voriconazole (200 mg twice a day) and caspofungin (70 mg loading dose, continued at 50 mg) was started. One day later however, the patient died from a cardiac arrest. Autopsy confirmed the diagnosis of an angioinvasive, necrotizing mycotic infection with involvement of the heart (pericardium, myocardium and epicardium), thyroid gland, stomach, kidneys, and both lungs; viral pneumonitis was not evident. One day after the patient Table 1. Swan Ganz Catheter Readings and Hemodynamic Parameters
Systemic vascular resistance Pulmonary vascular resistance: Cardiac index:
Measured 2908 dyne · sm2/cm5 444 dyne · sm2/cm5
Normal values (1970–2390) (255–285)
1.09 liters/min/m2
(2.5–4.0)
died, culture from the pericardial biopsy taken premortem showed macroscopically buff, powdery colonies (Figure 2A). Microscopic examination revealed penicillate conidiophores and smooth-walled ovoidal conidia, mostly with a pointed apex, which identified the fungus as Scopulariopsis acremonium (Figure 2B). DISCUSSION Aspergillus and Candida spp. are the most common fungal pathogens in immunocompromised lung transplant recipients. However, recent literature reports a growing number of emerging fungal pathogens that can cause serious infections in these hosts.2,3 We report here a dramatic case of disseminated Scopulariopsis acremonium infection in a lung transplant recipient. Scopulariopsis acremonium is a saprophytic mold occurring in soil that causes onychomycosis, skin lesions, or soft tissue infections after traumatic or surgical injuries, usually in immunocompetent patients. In immunocompromised patients, it can induce localized infections, invasive tissue infection, and/or disseminated disease, often associated with a dismal outcome.3,4 As with other invasive hyalohyphomycoses, the diagnosis is difficult, which often results in a dramatic delay of appropriate medical therapy. Physical examination is not helpful. In addition, clinical symptoms may be absent due to concomitant steroid treatment or attributable to a concurrent clinical process, such as bacterial or viral co-infections or rejection. Culture, including blood culture, is usually negative, and no serologic assay is available. Histopathologic examination, the gold standard to diagnose an invasive mycosis, reveals septated hyphae that are indistinguishable from species such as Aspergillus spp., Fusarium spp., Scedosporium proliferans, or Pseudallescheria boydii. It has been reported that Aspergillus infections most frequently occur early after transplantation,5 and although adequate prophylaxis with amphotericin B was started in the post-operative period as done in most centers,6 our patient was presumed to have invasive aspergillosis. He was treated as such until the species was identified. It is crucial to accurately distinguish between these species, especially given differences in anti-fungal susceptibility. While voriconazole may be the agent of choice for the treatment of Aspergillus infections,7 the activity against Scopulariopsis spp. is doubtful.8 Fungal pericarditis is usually a consequence of direct spread from adjacent infected lung tissue. Most cases of pericardial aspergillosis are rapidly fatal as described in hematologic patients.9 Moreover, 1% of the pericardial effusions in HIV patients are of fungal etiology.10 Unfortunately, in this case, fungal pneumonia was never suspected given the absence of respiratory symp-
The Journal of Heart and Lung Transplantation Volume 24, Number 12
Wuyts et al.
2303
Figure 1. (A) Macroscopic view of a biopsy specimen of the pericardium. (B–D) Microscopic views with hematoxylin and eosin staining at (B) ⫻50 original magnification, (C) ⫻400 original magnification; and with (D) Grocot staining at ⫻400 original magnification.
toms. Particularly discouraging was the lack of suggestive radiologic findings on standard X-ray and CT imaging, cardiac MRI findings, and even echocardiographic evaluations. Other diagnostic techniques such as PCR and enzyme-linked immunosorbent assay were used to rule out other causes of infection, as described in a protocol for the investigation of fungal infections,11 but their results were only positive for CMV. This case underscores the importance of a rapid and aggressive diagnostic approach for the exploration of unclear (clinical) findings in immunocompromised patients instead of relying on the use of non-invasive and time-consuming techniques. Earlier pericardial drainage or partial pericardiectomy would have provided an earlier diagnosis, allowing earlier treatment with broadspectrum anti-fungals. In a recent review of Scopulariopsis infections in immunocompromised patients, prolonged therapy with conventional amphotericin B deoxycholate or a lipidbased preparation, with or without additional surgery,
was often ineffective.12 However, with the development of broad-spectrum triazoles and echinocandins, physicians can now attempt newer regimens, including possible synergistic combinations.13 In the future, antifungal susceptibility data and in vivo animal studies could provide useful information to select the most appropriate therapy, although correlation between in vitro data and in vivo findings still needs to be established. As treatment of Scopulariopsis infections is very troublesome, another approach could be prophylaxis. This, however, has never been studied, but given the high minimum inhibitory concentration values for amphotericin B, voriconazole, and terbinafine described in literature,8 the use of current anti-fungal drugs as an effective prophylactic agent seems unlikely. Appropriate studies need to be done. Another interesting finding is that in this patient a proven CMV infection occurred in conjunction with Scopulariopsis infection. It is important to mention that
2304
Wuyts et al.
The Journal of Heart and Lung Transplantation December 2005
only way to demonstrate the extent of fungal dissemination.16 REFERENCES
Figure 2. Scopulariopsis acremonium was cultured from a premortem pericardial biopsy specimen. (A) Macroscopic view shows macroscopically buff, powdery colonies. (B) Direct microscopic view shows penicillate conidiophores and smooth-alled ovoidal conidia, mostly with a pointed apex.
some reports suggest that CMV can affect several components of the defense system and, therefore, could enhance the pathogenicity of other infectious agents.14 ECMO has been used as circulatory support in refractory cardiogenic shock post-cardiac surgery,15 started in the assumption of a disseminated CMV infection, which is potentially reversible. CONCLUSION We believe this is the first reported case of an insidious Scopulariopsis acremonium infection in an immunocompromised lung transplantation patient. Non-Aspergillus hyalohyphomycoses is an emerging threat to immunocompromised patients. Histologically, these mycoses cannot be distinguished from invasive aspergillosis. Scopulariopsis is a problem because of the high level of resistance to current anti-fungals. This case report specifically underscores the importance of a direct approach and early treatment with anti-fungal therapy in immunocompromised patients. It underscores the importance of an autopsy, since this often seems to be the
1. Meersseman W, Vandecasteele SJ, Wilmer A, Verbeken E, Peetermans WE, Van Wijngaerden E. Invasive aspergillosis in critically ill patients without malignancy. Am J Respir Crit Care Med 2004;170:621–5. 2. Groll AH, Walsh TJ. Uncommon opportunistic fungi: new nosocomial threats. Clin Microbiol Infect 2001;7 Suppl 2:8 –24. 3. Tomsikova A. Causative agents of nosocomial mycoses. Folia Microbiol (Praha) 2002;47:105–12. 4. Schinabeck MK, Ghannoum MA. Human hyalohyphomycoses: a review of human infections due to Acremonium spp., Paecilomyces spp., Penicillium spp., and Scopulariopsis spp. J Chemother 2003;15 Suppl 2:5–15. 5. Singh N, Husain S. Aspergillus infections after lung transplantation: clinical differences in type of transplant and implications for management. J Heart Lung Transplant 2003;22:258 – 66. 6. Dummer JS, Lazariashvilli N, Barnes J, Ninan M, Milstone AP. A survey of anti-fungal management in lung transplantation. J Heart Lung Transplant 2004;23:1376 – 81. 7. Maschmeyer G, Ruhnke M. Update on antifungal treatment of invasive Candida and Aspergillus infections. Mycoses 2004;47:263–76. 8. Cuenca-Estrella M, Gomez-Lopez A, Mellado E, Buitrago MJ, Monzon A, Rodriguez-Tudela JL. Scopulariopsis brevicaulis, a fungal pathogen resistant to broad-spectrum antifungal agents. Antimicrob Agents Chemother 2003; 47:2339 – 41. 9. Schwartz DA. Aspergillus pancarditis following bone marrow transplantation for chronic myelogenous leukemia. Chest 1989;95:1338 –9. 10. Chen Y, Brennessel D, Walters J, Johnson M, Rosner F, Raza M. Human immunodeficiency virus-associated pericardial effusion: report of 40 cases and review of the literature. Am Heart J 1999;137:516 –21. 11. Fishman JA. Overview: fungal infections in the transplant patient. Transpl Infect Dis 2002;4 Suppl 3:3–11. 12. Steinbach WJ, Schell WA, Miller JL, Perfect JR, Martin PL. Fatal Scopulariopsis brevicaulis infection in a paediatric stem-cell transplant patient treated with voriconazole and caspofungin and a review of Scopulariopsis infections in immunocompromised patients. J Infect 2004;48:112– 6. 13. Como JA, Dismukes WE. Oral azole drugs as systemic antifungal therapy. N Engl J Med 1994;330:263–72. 14. Singh N. Interactions between viruses in transplant recipients. Clin Infect Dis 2005;40:430 – 6. 15. Doll N, Fabricius A, Borger MA, et al. Temporary extracorporeal membrane oxygenation in patients with refractory postoperative cardiogenic shock—a single center experience. J Card Surg 2003;18:512– 8. 16. Roosen J, Frans E, Wilmer A, Knockaert DC, Bobbaers H. Comparison of premortem clinical diagnoses in critically ill patients and subsequent autopsy findings. Mayo Clin Proc 2000;75:562–7.
