Pediatr Transplantation 2014: 18: E169–E173

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12294

Successful lung transplant in a child with cystic fibrosis and persistent Blastobotrys rhaffinosifermentans infection Wong JY, Chambers AL, Fuller J, Lacson A, Mullen J, Lien D, Humar A. Successful lung transplant in a child with cystic fibrosis and persistent Blastobotrys rhaffinosifermentans infection.

J. Y. Wong1, A. L. Chambers1, J. Fuller1, A. Lacson1, J. Mullen1, D. Lien1 and A. Humar2 1

Abstract: Fungal respiratory infections in patients with CF are a significant concern both pre- and post-lung transplantation (LTx). Fungal infection is associated with increased mortality post-LTx, and in the past decade, the prevalence of fungal colonization in Canadian pediatric patients with CF has increased. The emergence of novel fungal pathogens is particularly challenging to the transplant community, as little is known regarding their virulence and optimal management. We present a case of a successful double-lung transplant in a pediatric patient with CF who was infected pretransplantation with a novel yeast, Blastobotrys rhaffinosifermentans. This patient was treated successfully with aggressive antifungal therapy posttransplantation, followed by extended fungal prophylaxis. The significance of fungal colonization and infection in children with CF pre- and post-LTx is reviewed.

In pediatrics, 75% of LTx are performed in children with CF (1). Fungal colonization is a significant concern both pre- and post-LTx, especially in the pediatric CF population (2, 3). However, the prevalence of filamentous fungi in respiratory secretions from patients with CF is increasing. From 2001 to 2011, in Canadian patients with CF, the prevalence of Aspergillus fumigatus almost tripled, to 22% (4). Although fungal colonization is not considered an absolute contraindication for LTx in the adult population, specific therapeutic regimens are required prior to transplant to minimize post-LTx complications (5). Post-LTx colonization with Aspergillus spp. is directly associated with both morbidity and the development of bronchiolitis obliterans syndrome (6). Invasive fungal disease in children is associated with increased mortality in the first year post-LTx (7); in adults, post-LTx invasive fungal disease is significantly associated with all-cause mortality (8). These complications are

Abbreviations: BAL, bronchoalveolar lavage; CF, cystic fibrosis; FDG, fludeoxyglucose; L-AmB, liposomal amphotericin B; LTx, lung transplantation; MIC, minimum inhibitory concentration; PET, positron emission tomography.

University of Alberta, Edmonton, AB, Canada, Multi-Organ Transplant Program, University Health Network, Toronto, ON, Canada

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Key words: pediatric lung transplantation – pediatric transplantation – lung transplantation – fungal infection – fungal infections - cystic fibrosis Jackson Y Wong, Department of Pediatrics, University of Alberta, 4-529 Edmonton Clinic Health Academy, 11405 - 87 Avenue, Edmonton, AB, Canada T6G 1C9 Tel.: 780 248 5650 Fax: 888 353 1323 E-mail: [email protected] Accepted for publication 24 April 2014

particularly significant in the CF population, because post-LTx, adult patients with CF have a higher incidence of both fungal colonization (42%) and invasive disease (11%) than patients with non-CF (9). Antifungal prophylaxis is frequently used in an attempt to limit fungal colonization and infection; despite this, the cumulative incidence of fungal infections post-LTx was reported to be 8.6% in a multicenter prospective study (10). Emerging fungal pathogens in immunosuppressed patients is a growing challenge to the transplant community (11). The Blastobotrys genus is composed of 18 species (12), but little else is known regarding its epidemiology. Our understanding of the ecology of Blastobotrys species is limited to brief descriptions within a few published reports, which describes environmental soil and reptile gastrointestinal tracts as sources (12). Human infection has been documented only once, in an adult who developed peritonitis while undergoing continuous ambulatory peritoneal dialysis (13). This report describes a case of successful double LTx in a child with CF and persistent airway infection with Blastobotrys rhaffinosifermentans pre-LTx and early on in the post-LTx period. E169

Wong et al. Case report Pretransplant

A nine-yr-old boy with CF and severe bilateral bronchiectasis aspirated soil particles, leading to a loss of 450 cc forced expiratory volume in one second (FEV1), to 31% predicted. An initial BAL culture isolated only yeast, Ustilago species. However, despite multiple courses of oral antibiotics, nebulized tobramycin, and DNase therapy, his pulmonary function failed to improve. His physician also attempted a six-week course of oral and nebulized steroids, with no effect. He was left requiring continuous nasal oxygen (2 L/ min). Two months later, a second bronchoscopy demonstrated purulent secretions in all airway lumens. Culture of the BAL fluid isolated yeast, which was ultimately identified as B. rhaffinosifermentans. Species identification was confirmed by DNA sequence analysis of the ribosomal large subunit variable domain and fermentation of raffinose. Over the subsequent 16 months, from 36 serial respiratory specimens, B. rhaffinosifermentans was cultured as the only fungal organism in 20 of 36 (55.6%) specimens. Antifungal susceptibility testing using broth microdilution showed low MIC values for amphotericin B, itraconazole, voriconazole, and caspofungin (14). Reduced susceptibility to fluconazole was observed (MIC >64 mg/mL). Pseudomonas aeruginosa was also isolated from 19 of the 36 (52.8%) serial specimens; however, it was not isolated in the initial purulent secretions. Sinus CT scan demonstrated severe sinus disease, but sinus aspirates were negative for both fungus and P. aeruginosa. The patient progressed to develop severe mucus plugging and permanent bilateral lower lobe collapse despite aggressive management with nebulized DNase, 7% hypertonic saline,

and chest physiotherapy. He had multiple episodes of febrile illnesses and acute type II respiratory failure, treated with both antibiotics with activity against P. aeruginosa and antifungals. Over the 13 months preceding the LTx, antifungal therapy included multiple courses of intravenous (IV) caspofungin, oral voriconazole, and nebulized L-AmB. Between acute illnesses, longterm therapy with oral voriconazole and L-AmB was provided for 13 and 7 months pre-LTx, respectively. Given his persistent disease, the patient received a CMV-mismatched (donor +/recipient ) double LTx 16 months after the initial clinical deterioration. Post-transplant

Intra-operatively, attention was given to avoid spillage of intrabronchial secretions, and the recipient’s trachea and bronchial stumps were irrigated with extensive amounts of povidone-iodine topical antiseptic. Tissue from the explanted lung (Fig. 1) yielded evidence of yeast on microscopy and B. rhaffinosifermentans on culture (Fig. 2). The airways had a heavy burden of neutrophils, but there was no evidence of angioinvasion on histopathology (Fig. 3). P. aeruginosa was not isolated from the explanted lung. Post-LTx, he received oral tacrolimus, mycophenolate mofetil, and prednisone, but no induction immunosuppression. B. rhaffinosifermentans was isolated twice postoperatively: from BAL on day 2 and from pleural fluid collected from a right-sided chest tube on day 4. He was extubated on day 3 post-LTx, and chest tubes were removed on day 9. He was transferred out of the intensive care unit on day 10 post-LTx and discharged home on day 36. Initially, the patient was treated with two-week IV meropenem and tobramycin, and three-week

Fig. 1. Cut surface of the right lung with consolidation and hyperemia of the lower and middle lobes. The darkened parenchyma demonstrates the plugging of the more distal bronchial and bronchiolar airways by whitish-yellow granular material. The perihilar areas are relatively preserved.

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Fig. 2. Grocott methenamine silver stain (4000 9 original magnification) of the intrabronchial granular material showing necrotic inflammatory cells, predominantly neutrophils and macrophages. Intracellular budding yeast-like organisms are shown.

once each on surveillance BAL. At 22 months post-LTx, voriconazole was discontinued due to development of severe and persistent photosensitivity in sun-exposed areas. At 24 months post-LTx, he was well with a FEV1 of 75% predicted; all antifungal therapy had been discontinued as of 22 months postLTx. However, at 28 months post-LTx, the patient developed a severe A. fumigatus airway infection, associated with a fall in FEV1 to 52% predicted. Following treatment with triple antifungal therapy, his FEV1 recovered to baseline. Antifungal prophylaxis with nebulized L-AmB was reinstated and continues indefinitely. He has remained free of rejection, and five subsequent transbronchial biopsies and/or BAL specimens have been culture negative for fungi. At the time of this report, 61 months post-LTx, he is clinically well with an FEV1 66% predicted. Discussion

Fig. 3. Grocott methenamine silver stain (250 9 original magnification) of the bronchovascular bundle in the lung demonstrating total occlusion by dark granular material, with silver deposits along the mucosal lining. Note the fibrous thickening around the bronchus. The blood vessels are unremarkable.

IV L-AmB; this regimen was discontinued due to a decline in renal function. Following this, antifungal therapy included a total of three-month nebulized L-AmB, nine-week IV caspofungin, and 22-month oral voriconazole. Voriconazole trough levels exceeded 1.0 mg/L by five months postLTx, after dose adjustment. Three PET/CT (positron emission tomography/computed tomography) scans between three and seven months post-LTx found non-progressive areas of pleural thickening in the right inferior hemithorax, with multiple FDG – avid areas in the pleura and right lower lobe. While on voriconazole, Penicillium and Scopulariopsis brumptii were isolated

Assessing suitability for LTx of a fungalcolonized patient is a common dilemma for transplant teams. Almost 30% of children with CF between the ages of 11 and 17 will have fungal colonization with A. fumigatus pre-LTx, and multiple other fungal genera are known to colonize pediatric CF patients, including Candida and Scedosporium (3, 4). The management of novel fungal pathogens is a particular challenge in LTx, as the understanding of their virulence and management strategies in the immunosuppressed host is limited. To our knowledge, there has only been one previous report of Blastobotrys spp. causing human disease, and it has never been reported in a patient with CF (13). However, many clinical laboratories do not routinely determine the genus and species of yeast in respiratory specimens; therefore, the true prevalence of B. rhaffinosifermentans may be underestimated. The significance of B. rhaffinosifermentans colonization in the immunocompromised patient is unknown. However, in our patient, repeated isolation of B. rhaffinosifermentans prior to LTx was associated with clinical deterioration and eventual respiratory failure. Although P. aeruginosa was also isolated pre-LTx, it was not isolated in the explanted lung or from the patient in the immediate post-LTx period. The presence of B. rhaffinosifermentans in the explanted lungs, with evidence of intracellular budding, strongly suggests B. rhaffinosifermentans contributed to airway inflammation. The heavy neutrophilia and severe mucus plugging of the airway lumen also support this hypothesis. In addition, E171

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isolation of B. rhaffinosifermentans from the pleural fluid, a normally sterile site, may suggest pathogenicity, although intra-operative spillage cannot be excluded. Finally, it is suspicious that three PET/CT scans between two to seven months post-LTx demonstrated abnormal activity at the chest tube site where B. rhaffinosifermentans was isolated. We feel it is likely that B. rhaffinosifermentans contributed to the patient’s clinical deterioration pre-LTx and to the persistent abnormal PET/CT findings post-LTx. The use of aggressive antifungal therapy in the perioperative period, in addition to removal of the infected organ at LTx, followed by an extended period of prophylaxis, likely attenuated the disease course in our patient. B. rhaffinosifermentans appeared to be pathologic in our patient, but there is no published literature to demonstrate whether B. rhaffinosifermentans can lead to invasive disease. Pre-LTx, decreased perfusion to collapsed lung may have limited delivery of antifungal therapy; this likely contributed to the need for LTx. The validity of MIC values for this organism is unknown, and their efficacy has not been established in this context. Our choice of antifungal agents was empirical based on the MIC result. This appeared to be adequate in preventing the diseased areas spread to other parts of the lung as repeated chest radiographs showed no deterioration over a prolonged period of time pre-LTx. Post-LTx, isolation of B. rhaffinosifermentans in the BAL and the pleural space in the first week was disconcerting. This could have reflected colonization of the recipient’s tracheobronchial tree proximal to the anastomosis or intra-operative contamination of the pleural space; regardless of the source, it emphasized the importance of antifungal therapy post-LTx. LTx recipients are at particularly high risk of invasive fungal infection early post-transplantation, when immunosuppression is most intense and airway anastomoses are vulnerable to ischemia and dehiscence (15). The risk of invasive fungal infections is increased by multiple factors unique to LTx, including direct exposure of the transplanted lung to inspired environmental fungal pathogens, suppressed cough reflex due to denervation of the transplanted lungs, depressed mucociliary clearance, disruption of lymphatic drainage of the allograft, ischemia of the bronchial anastomoses, and the use of aggressive immunosuppression to counteract high rejection rates (15, 16). Despite these risk factors for invasive fungal infection, clinically significant infection caused by B. rhaffinosifermentans was not observed beyond the first week post-LTx. Although abnormalities observed on PET/CT E172

scan were seen up to seven months post-LTx, activity was minimal. In addition, in the 60 months post-LTX, B. rhaffinosifermentans was not isolated on 15 transbronchial biopsies and/or BAL or on four sinus biopsies and/or washes. Two of the BAL and one sinus wash were performed, while the patient was on no antifungal therapy, between 22–28 months postLTx. This suggests that B. rhaffinosifermentans is a minimally virulent pathogen or that the choice of antifungal therapy was effective. We feel B. rhaffinosifermentans was likely eradicated, although this could not have been achieved without post-LTx antifungal treatment and subsequent prophylaxis. In the absence of antifungal treatment and prophylaxis, however, the behavior of B. rhaffinosifermentans remains undetermined. No guidelines are available regarding management of fungal colonization prior to pediatric LTx. However, a recent consensus guideline for the adult population did not consider fungal colonization a contraindication to LTx if specific therapeutic regimens are applied (5). In the pediatric population, the effects of pre-LTx fungal colonization and/or infection on postoperative outcomes have yet to be determined. In a multicenter, retrospective study of post-LTx children that spanned 17 yr (1988–2005), Danziger-Isakov et al. demonstrated that pre-LTx fungal colonization almost doubles the risk of pulmonary fungal infection in the first year post-LTx; several fungi were implicated in this study (7). Post-LTx, pulmonary fungal infection was found to be associated with a fourfold risk of decreased one-yr survival, despite the use of antifungal prophylaxis (7). Conversely, a more recent (2002–2007) single center, retrospective study of pediatric patients by Liu et al. did not demonstrate an association between pre- or post-LTx fungal colonization and pulmonary fungal infection (3). In addition, post-LTx pulmonary fungal infection was not associated with increased mortality (3). Interestingly, CF was not a risk factor for pulmonary fungal infection after transplantation in either study (3, 7). Both studies are limited due to their retrospective nature and heterogeneous groups of patients: fungal prophylaxis was not universal, and regimens varied among patients. In addition, in the patients studied by Liu et al., not all patients were evaluated for pre-LTx colonization, and the number of post-LTx pulmonary fungal infections was small (3, 7). To fully elucidate causal relationships between pre-LTx colonization and post-LTx colonization or infection in children, prospective studies of more homogenous cohorts are needed.

Blastobotrys rhaffinosifermentans infection

In our case, we feel antifungal therapy was warranted both pre- and post-LTx. Yeast susceptibility testing was used to guide treatment with the understanding that a clinical correlation of MIC values and treatment efficacy has not been established in this context. In addition to pharmcotherapy, the removal of the infected organ also helped to eradicate the B. rhaffinosifermentans. While maintained on fungal prophylaxis, our patient has not developed further fungal colonization or infection. Conclusion

B. rhaffinosifermentans caused significant airway inflammation pre-LTx and pleural space infection post-LTx in a young patient with CF. It did not appear to cause invasive lung disease and was likely eradicated with antifungal agents postLTx. Antifungal therapy was provided for an extended period post-LTx, until BAL cultures and imaging did not suggest fungal colonization or infection. Antifungal prophylaxis has been continued indefinitely due to the high risk of post-LTx fungal infections. The ideal agent and duration of antifungal prophylaxis in pediatric LTx patients infected with B. rhaffinosifermentans are speculative and should be assessed on a case-to-case basis. From our limited experience with B. rhaffinosifermentans, isolation of this fungus from airway secretions does not appear to be a contraindication to LTx. References 1. BENDEN C, EDWARDS LB, KUCHERYAVAYA AY, et al. The Registry of the International Society for Heart and Lung Transplantation: Fifteenth pediatric lung and heart-lung transplantation report–2012. J Heart Lung Transplant 2012: 31: 1087–1095. 2. SUDFELD CR, DASENBROOK EC, MERZ WG, CARROLL KC, BOYLE MP. Prevalence and risk factors for recovery of filamentous fungi in individuals with cystic fibrosis. J Cyst Fibros 2010: 9: 110–116. 3. LIU M, WORLEY S, MALLORY GB Jr, et al. Fungal infections in pediatric lung transplant recipients: Colonization and invasive disease. J Heart Lung Transplant 2009: 28: 1226–1230.

4. Canadian CF Registry Working Group. Canadian Cystic Fibrosis Registry - 2011 Annual Report. 2011. 5. ORENS JB, ESTENNE M, ARCASOY S, et al. International guidelines for the selection of lung transplant candidates: 2006 update–A consensus report from the Pulmonary Scientific Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2006: 25: 745–755. 6. WEIGT SS, ELASHOFF RM, HUANG C, et al. Aspergillus colonization of the lung allograft is a risk factor for bronchiolitis obliterans syndrome. Am J Transplant 2009: 9: 1903–1911. 7. DANZIGER-ISAKOV LA, WORLEY S, ARRIGAIN S, et al. Increased mortality after pulmonary fungal infection within the first year after pediatric lung transplantation. J Heart Lung Transplant 2008: 27: 655–661. 8. ARTHURS SK, EID AJ, DEZIEL PJ, et al. The impact of invasive fungal diseases on survival after lung transplantation. Clin Transplant 2010: 24: 341–348. 9. IVERSEN M, BURTON CM, VAND S, et al. Aspergillus infection in lung transplant patients: Incidence and prognosis. Eur J Clin Microbiol Infect Dis 2007: 26: 879–886. 10. PAPPAS PG, ALEXANDER BD, ANDES DR, et al. Invasive fungal infections among organ transplant recipients: Results of the transplant-associated infection surveillance network (TRANSNET). Clin Infect Dis 2010: 50: 1101–1111. 11. WALSH TJ, GROLL AH. Emerging fungal pathogens: Evolving challenges to immunocompromised patients for the twenty-first century. Transpl Infect Dis 1999: 1: 247–261. 12. KURTZMAN CP. Blastobotrys americana sp. nov., Blastobotrys illinoisensis sp. nov., Blastobotrys malaysiensis sp. nov., Blastobotrys muscicola sp. nov., Blastobotrys peoriensis sp. nov. and Blastobotrys raffinosifermentans sp. nov., novel anamorphic yeast species. Int J Syst Evol Microbiol 2007: 57(Pt 5): 1154–1162. 13. QUIRIN N, DESNOS-OLLIVIER M, CANTIN JF, et al. Peritonitis due to Blastobotrys proliferans in a patient undergoing continuous ambulatory peritoneal dialysis. J Clin Microbiol 2007: 45: 3453–3455. 14. Clinical and Laboratory Standards Institute (CLSI). Reference Method for Broth Dilution Antifungal Susceptibility Testing of Yeasts; Fourth Informational Supplement. Wayne, PA: Clinical and Laboratory Standards Institute, 2012. Report No.: CLSI document M27-S4. 15. SINGH NM, HUSAIN S. AST Infectious Diseases Community of Practice. Aspergillosis in solid organ transplantation. Am J Transplant 2013: 13(Suppl 4): 228–241. 16. HUSNI RN, GORDON SM, LONGWORTH DL, et al. Cytomegalovirus infection is a risk factor for invasive aspergillosis in lung transplant recipients. Clin Infect Dis 1998: 26: 753–755.

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Successful lung transplant in a child with cystic fibrosis and persistent Blastobotrys rhaffinosifermentans infection.

Fungal respiratory infections in patients with CF are a significant concern both pre- and post-lung transplantation (LTx). Fungal infection is associa...
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