Invasive pulmonary aspergillosis is typically caused by a single Aspergillus
species, most frequently Aspergillus fumigatus. Here we report that a lung
transplant recipient developed invasive aspergillosis due to a mixed infection
caused by Aspergillus flavus and A. fumigatus. The implications for this
unusual finding are discussed.La aspergilosis pulmonar invasora es producida típicamente por una única especie de Aspergillus, siendo habitualmente Aspergillus fumigatus. Se presenta el caso clínico de un receptor de trasplante de pulmón que desarrolló aspergilosis invasora por una infección mixta causada por Aspergillus flavus y A. fumigatus. Se discuten las implicaciones de la rareza
de este caso

Camargo, José Jesus Peixoto

Pasqualotto, Alessandro Comarú

Sales, Maria da Penha Uchoa

Severo, Cecília Bittencourt

Severo, Luiz Carlos

Xavier, Melissa Orzechowski

English

Repositório Institucional  Universidade Federal do Rio Grande

Invasive pulmonary aspergillosis dueto a mixed infection caused byAspergillus flavus and AspergillusfumigatusMelissa Orzechowski Xavier1, Alessandro Comarú Pasqualotto1,2,Maria Da Penha Uchoa Sales3, Cecília Bittencourt Severo1,4,José J. Peixoto Camargo4, Luiz Carlos Severo4,51Programa de Pós-graduação em Ciências Pneumológicas, Universidade Federal do Rio Grande do Sul(UFRGS), Brazil; 2School of Medicine, The University of Manchester, UK; 3Faculdade Integrada do Ceará,Brazil; 4Santa Casa-Complexo Hospitalar, Porto Alegre, Brazil; 5Pesquisador 1B do CNPq, Faculdade deMedicina da UFRGS, BrazilInvasive pulmonary aspergillosis is typically caused by a single Aspergillusspecies, most frequently Aspergillus fumigatus. Here we report that a lungtransplant recipient developed invasive aspergillosis due to a mixed infectioncaused by Aspergillus flavus and A. fumigatus. The implications for thisunusual finding are discussed.Aspergillosis, Aspergillus fumigatus, Aspergillus flavus, Lung transplantationAspergilosis pulmonar invasora causada porinfección mixta de Aspergillus flavus y AspergillusfumigatusLa aspergilosis pulmonar invasora es producida típicamente por una únicaespecie de Aspergillus, siendo habitualmente Aspergillus fumigatus. Se presenta el caso clínico de un receptor de trasplante de pulmón quedesarrolló aspergilosis invasora por una infección mixta causada porAspergillus flavus y A. fumigatus. Se discuten las implicaciones de la rareza de este caso.Aspergilosis, Aspergillus fumigatus, Aspergillus flavus, Trasplante de pulmón176 Rev Iberoam Micol 2008; 25: 176-178A 33 year-old man with primary pulmonary hyper-tension underwent a single right lung transplantation pro-cedure in 1990. His immunosuppressive regimen consistedof azathioprine, cyclosporine and prednisone. Four monthsafter transplantation, the patient was diagnosed with cyto-megalovirus (CMV) pneumonia based on the histopatho-logical findings obtained by transbronchial biopsy, and treated with intravenous gancyclovir. Six weeks later hepresented with productive cough and severe dyspnea, re-porting very limited tolerance to exercises. At admission tothe hospital, chest radiograph showed bilateral pulmonaryinfiltration with areas of pneumonic-type consolidation.Bronchoscopy and transbronchial biopsy were performed.Address for correspondence:Dr. Alessandro C. PasqualottoPrograma de Pós-graduação em Ciências PneumológicasUniversidade Federal do Rio Grande do Sul (UFRGS)BrazilTel.: +44 161 291 5818Fax: +44 161 291 5806E-mail: acpasqualotto@hotmail.comAceptado para publicación el 31 de marzo de 2008©2008 Revista Iberoamericana de MicologíaApdo. 699, E-48080 Bilbao (Spain)1130-1406/01/10.00 €Hyaline septate branched hyphae were seen in thebronchoalveolar lavage fluid after preparation with potas-sium hydroxide (KOH 10%). Histopathological studies(haematoxylin and eosin, and Gomori-Grocott methana-mine-silver nitrate stain) revealed acute suppurative bron-chial inflammation. In addition, there was evidence of tissue invasion by hyphae consistent with Aspergillus spe-cies. Amphotericin B deoxycholate treatment (1.5 mg/kgdaily) was commenced, and Aspergillus flavus was recove-red in culture (Sabouraud dextrose agar with chloramphe-nicol, and Mycosel agar at 25 ºC and 35 ºC).The patient died 15 days later despite antifungaltherapy in association with broad spectrum antimicrobialdrugs. Two courses of steroids were also attempted,without success. At autopsy, the right lung revealed vis-ceral pleura congestion with extensive adhesion. Therewere multiple yellowish nodules irregularly distributedthroughout the lungs, 0.1-1.0 cm in diameter. Some ofthese nodules had coalesced to form a large reddish mass.Yellowish nodules were observed also in the heart andright kidney (Figure 1) with histopathological evidence oftissue invasion by Aspergillus hyphae. In the mycologylaboratory, the lung fragment was processed in the laminarflow hood and cut using sterile technique. Three pieceswere removed from a deep pulmonary nodule, and cultureshowed growth of both A. flavus and Aspergillus fumiga-tus in triplicate (Figure 2).SummaryKey wordsResumenPalabras claveNoteDiscussionMixed invasive fungal infections are reported in-frequently in the literature [1,6]. Previous reports haveusually been associated with states of marked immunosup-pression, or with the presence of infected medical devices,such as central venous catheters. However, the isolation oftwo different fungal species belonging to the same genusfrom clinical specimens is particularly rare. Fungaemiasprobably represent an exception to this general rule [17].For instance, 2-9% of cases of candidemia have beenshown to be mixed [2,8], caused by more than one Can-dida species. Interestingly, both the clinical presentationand the severity of mixed fungaemias seem to be similar tothat seen with monomicrobial fungaemias [8]. In cases ofmixed infections, the existance of a drug-resistant isolatemight complicate patient management.Cimerman et al. seem to be the first to report theoccurrence of aspergillosis caused by two Aspergillus spe-cies [5] in a report of osteomyelitis due to A. flavus and A. fumigatus. Chalara ellisii was also recovered in culture.This case was that of a healthy young man who suffered a closed transverse fracture of the femur as a result of atraffic accident. In a review of the literature up to the year2000, Singh and Husain [15] found that 5% (two of 40) ofaspergillosis cases following lung transplantation wereassociated to mixed infections due to two Aspergillus spe-cies. However, no details were given about these cases.In contrast to the invasive forms of aspergillosis,cases of chronic pulmonary aspergillosis are commonlyassociated with infection by multiple genotypes, particu-larly in the presence of fungal balls [3,4]. Mycological studies in patients with chronic cavitary aspergillosis andfungal balls usually show the presence of various morpho-logies and considerable antigenic variability among isola-tes [4,9-11], which is probably part of a dynamic processconsequent to the continual growth and death of fungalelements [14]. Neuvéglise et al. also showed by moleculartyping techniques that cystic fibrosis patients can harbourseveral strains of Aspergillus fumigatus over time [12].The recovery of two isolates belonging to different Asper-gillus species is, however, rare.The precise mechanisms leading to a mixed infec-tion as seen for our patient are unknown. Also unknown isthe reason why mixed Aspergillus infections are so rare.Our patient had been infected by CMV, an immunomo-dulatory virus that impairs cellular immunity, thereforeincreasing susceptibility to opportunistic fungal infections[13,16]. He was also potentially exposed to a high infec-tious load of Aspergillus species, since renovations werebeing undertaken in the hospital area. However, thisassumption is only speculative since we do not routinelymeasure spores in the hospital air, and this case was notpart of an outbreak.Although invasive pulmonary aspergillosis isusually acquired by inhalation of Aspergillus conidia, thediameter and surface characteristics of the conidia seem tobe important factors in the pathogenesis of aspergillosis.Accordingly, the bigger size of A. flavus conidia favourstheir deposition in the upper respiratory tract, and this spe-cies is the main aetiology of Aspergillus sinusitis [7]. Therarity of mixed Aspergillus infections in cases of invasivepulmonary aspergillosis probably results from the diffi-culty imposed for the conidia (mainly to A. flavus) to reachthe pulmonary alveoli during this acute condition. Howe-ver, the importance of this and other factors remain to beelucidated.In conclusion, we report in this study a rare case ofmixed Aspergillus infection causing invasive pulmonaryaspergillosis. The incidence of this condition is unknownand might be underestimated, considering the low yield ofmicrobiological methods in the diagnosis of invasiveaspergillosis. Theoretically, the association of differentspecies in mixed fungal infection could be a cause of treat-ment failure as, for example, one of the isolates showingresistance to any particular antifungal drug. The impor-tance of multiple sampling to promote greater overall sen-sitivity to the microbiological methods also deserves fur-ther investigation.177Invasive pulmonary aspergillosis due to a mixed infectionOrzechowski M, et al.Figure 1. Lesions found at autopsy. Nodular lesions were present in the lungs (A), heart (B), and right kidney (C).Figure 2. Cultures in triplicate of lung fragments removed after autopsy.The mixed pattern is evident by the repeated growth of both A. fumigatus(green to fairly blue colonies) and A. flavus (yellow-greenish colonies).1. Binder C, Rüschel R. Case Report. Mixedsystemic mycoses with fatal outcome in apatient with acute myeloblastic leukaemia.Mycoses 2000; 43: 59-63.2. Boktour MR, Kontoyiannis DP, Hanna HA,Hachem RY, Girgawy E, Bodey GP, Raad II. Multiple-species candidemia inpatients with cancer. Cancer 2004; 101:1860-1865.3. Burnie JP, Coke A, Matthews RC.Restriction endonuclease analysis ofAspergillus fumigatus DNA. J Clin Pathol1992; 45: 324-327.4. Burnie JP, Matthews RC, Clark I, Milne LJ.Immunoblot fingerprinting Aspergillusfumigatus. J Immunol Methods 1989; 118:179-186.5. Cimerman M, Gunde-Cimerman N, Zalar P,Perkovic T. Femur osteomyelitis due to amixed fungal infection in a previouslyhealthy man. J Clin Microbiol 1999; 37:1532-1535.6. Guarro J, Nucci M, Akiti T, Gené J. Mixedinfection caused by two species ofFusarium in a human immunodeficiencyvirus-positive patient. J Clin Microbiol2000; 38: 3460-3462.7. Hedayati MT, Pasqualotto AC, Warn PA,Bowyer P, Denning DW. Aspergillus flavus:human pathogen, allergen and mycotoxinproducer. Microbiology 2007; 153: 1677-1692.8. Jensen J, Muñoz P, Guinea J, Rodríguez-Créixems M, Peláez T, Bouza E. Mixed fungemia: incidence, riskfactors, and mortality in a general hospital. Clin Infect Dis 2007; 44: 109-114.9. Leslie CE, Flannigan B, Milne LJ.Morphological studies on clinical isolatesof Aspergillus fumigatus. J Med VetMycol 1988; 26: 335-341.10. Mishra SK. Antigenic profile of sometypical and septate phialide-strains ofAspergillus fumigatus. Sabouraudia 1984;22: 91-100.11. Mishra SK, Staib F, Rajendran C, Folkens U. Serodiagnostic value ofculture filtrate antigens from aspergilliwith septate phialides. Sabouraudia 1982;20: 63-74.12. Neuvéglise C, Sarfati J, Debeaupuis JP,Vu Thien H, Just J, Tournier G, Latgé JP.Longitudinal study of Aspergillusfumigatus strains isolated from cysticfibrosis patients. Eur J Clin MicrobiolInfect Dis 1997; 16: 747-750.13. Schröeder R, Michelon T, Wurdig J,Fagundes I, Schio S, Sanchez L,Camargo JJ, Sukkienik TC, Pasqualotto AC, Neumann J. Theincidence of cytomegalovirus infection inlung transplant recipients under universalprophylaxis with intravenous ganciclovir.Braz J Infect Dis 2007; 11: 212-214.14. Severo LC, Geyer GR, Porto NS.Pulmonary Aspergillus intracavitarycolonization (PAIC). Mycopathologia1990; 112: 93-104.15. Singh N, Husain S. Aspergillus infectionsafter lung transplantation: clinicaldifferences in type of transplant andimplications for management. J HeartLung Transplant 2003; 21: 258-266.16. Westney GE, Kesten S, Hoyos AD,Chapparro C, Winton T, Maurer JR.Aspergillus infection in single and doublelung transplant recipients. Transplantation1996; 61: 915-919.17. Wong SS, Woo PC, Yuen KY. Candidatropicalis and Penicillium marneffei mixedfungaemia in a patient withWaldenström’s macroglobulinaemia. Eur J Clin Microbiol Infect Dis 2001; 20:132-135.178ReferencesRev Iberoam Micol 2008; 25: 176-178

Aspergilosis pulmonar invasora causada por infección mixta de Aspergillus flavus y Aspergillus fumigatus

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Aspergilosis pulmonar invasora causada por infección mixta de Aspergillus flavus y Aspergillus fumigatus

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Repositório Institucional Universidade Federal do Rio Grande