Endobronchial Fungal Disease: An Under-Recognized Entity

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Interventional Pulmonology – Review

Respiration 2007;74:88–104 DOI: 10.1159/000094708

Endobronchial Fungal Disease:An Under-Recognized Entity

Demet Karnak

a Robin K. Avery

b Thomas R. Gildea

c Debasis Sahoo

d

Atul C. Mehta

c

a Department of Chest Diseases, Ankara University School of Medicine, Ankara , Turkey; b

Department of Infectious Disease and c

Pulmonary Diseases and Critical Care Medicine, Cleveland Clinic Foundation, Cleveland, Ohio , USA; d

Department of Chest Medicine, KEM Hospital, Mumbai , India

Introduction

Reports of endobronchial fungal infections (EBFI) are infrequent; however, their existence is undeniable. Re-viewing the English literature, we recognized that the most common agents causing EBFI are Aspergillus spp. [1–45] , Coccidioides immitis [46] , agents of zygomycosis [6, 47–73] , Candida spp. [6, 34, 74–76] , Cryptococcus neo-formans [77–88] , and Histoplasma capsulatum [89–92] . We have also encountered a single case of endobronchial (EB) Pseudallescheria boydii in a lung transplant recipient that has not been reported previously. With the increas-ing popularity of flexible bronchoscopy, this entity is also being recognized with increasing frequency.

Colonization with these organisms seems to be the ini-tial event in patients on mechanical ventilation [93] or those receiving steroid therapy, eventually leading to air-way involvement [94] . Lung transplantation is another major risk factor leading to EBFI.

We believe that EBFI is under-recognized and under-reported. The purpose of this report is to highlight its presentation and suggested management.

Literature Review

The English literature was searched using the http://www.ncbi.nlm.nih.gov/entrez/query.fcgi website of the MEDLINE database from the beginning to the end of July

Key Words Endobronchial fungal infections � Aspergillosis � Coccidioidomycosis � Cryptococcosis � Histoplasmosis � Zygomycosis (mucormycosis) � Candidiasis

Abstract Most fungi enter the human body via inhalation; however, endobronchial fungal infection (EBFI) seems to be a rare manifestation compared to pulmonary or systemic disease. This presentation seems to be related to environmental fac-tors as well as to the host status. With the increasing popu-larity of flexible bronchoscopy, it is being recognized with a higher frequency. Bronchoscopic findings in EBFI vary from mild mucosal inflammation to central airway obstruction. We searched English literature related to the topic and found 228 total cases of EBFI: Aspergillus species (121), Coccidioides immitis (38), Zygomycetes (31), Candida species (14) Crypto-coccus neoformans (13), and Histoplasma capsulatum (11). We have also included a single case of endobronchial Pseu-dallescheria boydii infection in a lung transplant recipient that has not been reported previously. Most patients were immunocompromised, exhibited systemic manifestations of the primary infection, and responded to appropriate ther-apy. EBFI should be included in the differential diagnosis of any form of airway lesions in immunocompromised patients, especially among residents from the endemic areas.

Copyright © 2007 S. Karger AG, Basel

Received: February 4, 2006 Accepted after revision: April 13, 2006 Published online: July 20, 2006

Atul C. Mehta, MD, FCCP, FACP Vice Chairman, Pulmonary and Critical Care Medicine Head Section of Bronchology, Lung Transplant Team/A90, 9500 Euclid Avenue Cleveland, OH 44195 (USA) Tel. +1 216 444 2911, Fax +1 216 445 8160, E-Mail [email protected]

© 2007 S. Karger AG, Basel

Accessible online at: www.karger.com/res

http://dx.doi.org/10.1159%2F000094708

Endobronchial Fungal Disease Respiration 2007;74:88–104 89

2005 without any limitation. PaperChase search based on databases of the National Library of Medicine and the National Cancer Institute was performed using these terms ‘aspergillosis’, ‘histoplasmosis’, ‘mucormycosis’, ‘mycoses’, ‘endobronchial’, ‘tracheobronchial’, and ‘anas-tomotic’. We also searched all issues of the Journal of Bronchology for any article related with EBFI. Informa-tion was collected on patients’ age, gender, type of immu-nosuppression, and location and characteristics of EB le-sions ( table 1 ). Whenever available, information on treat-ment and outcomes was collected.

Numbers. A total of 228 cases were encountered: as-pergillosis (121), coccidioidomycosis (38), zygomycosis (31), candidiasis (14), cryptococcosis (13), and histoplas-mosis (11). Although information about age was not available in 72 patients, coccidioidomycosis was reported more frequently in younger patients, with a mean age of 25.9 8 30.5 (median: 30.5) years. Most EBFI seemed to occur among males, with male/female ratios (M/F) for aspergillosis, coccidioidomycosis, zygomycosis, candidi-asis and cryptococcosis being 43/25, 23/6, 18/7, 8/4 and 7/2, respectively. Histoplasmosis (M/F: 3/8) was reported more frequently in female patients, though numbers were small ( table 1 ).

Percentages. A hundred and twenty-three (54%) pa-tients were immunocompromised hosts, 51 (22%) were immunocompetent, 26 (11%) had diabetes mellitus and no information on the immune status was available in 29 patients (13%; table 1 ).

Lesions predominantly involved the lobar and seg-mental bronchi unilaterally (n = 160, 70%), while bilat-eral (n = 34, 15%) and tracheal involvement (n = 20, 9%) were uncommon. The characteristics of the lesions in-cluded yellowish-white necrotic plaques, irregular-sessile nodules, granulomatous lesions, EB masses (hemorrhag-ic or non-hemorrhagic), hyperemic mucosa and bronchi-al stenosis and anastomotic infection, especially in trans-plant patients ( table 1 ).

Bronchial washings and/or brushings provided a diag-nosis in 82 patients (36%). Bronchoalveolar lavage (BAL) culture was positive in 56 cases (25%). Endobronchial bi-opsy of the lesion was diagnostic in 104 patients (46%). Diagnosis was established by necropsy in 27 cases (12%). Serology was positive in 44 (19%) cases among all patients with coccidioidomycosis (28/38, 74%), aspergillosis (6/121, 5%) and cryptococcosis (10/13, 77%), in respective categories ( table 2 ). However, the true utility of serology in this situation cannot be assessed since full information is not available on how many of these patients had sero-logic tests obtained.

Intravenous amphotericin B (AmB) alone was the most common initial treatment in 80 patients (35%). In-travenous AmB in combination with another aerosolized or inhaled liposomal form of AmB preparations or to-gether with other antifungals were used in 36 patients (16%). Oral azoles were used as a primary and/or second-ary treatment in 63 (27%) patients. Duration of therapy varied between 3 and 48 months depending upon the se-verity of EB disease and clinical condition. Therapeutic bronchoscopy was required in 65 (29%) patients to excise or vaporize the mass lesions (n = 12, 5%), to stop hemop-tysis (n =14, 6%) and to place a stent or perform balloon dilatation through stenotic airways (n = 19, 8%, and n = 20, 9%), respectively. Surgery in combination with medi-cal therapy was required in aspergillosis (4/121, 3%), coc-cidioidomycosis (1/38, 3%), zygomycosis (13/29, 4%), cryptococcosis (7/13, 5%), and histoplasmosis (8/11, 7%) in totally 33 cases (14%).

Complete cure was reported as 36% for aspergillosis, 11% for coccidioidomycosis, 35% for zygomycosis, 78% for candidiasis, 62% for cryptococcosis, and 100% for histoplasmosis, for an overall total of 89 cases (38%; table 2 ).

Although extended follow-up was not available for all patients, 58 with aspergillosis (48%), 3 with coccidioido-mycosis (8%), 16 with zygomycosis (52%), 3 with candi-diasis (21%) and 4 with cryptococcosis (31%) died despite appropriate therapy ( table 2 ). In the discussion, sections are given in this order: incidence, predisposing factors, clinical presentation, radiological and endoscopic find-ings, diagnosis and therapy and outcome for each com-mon fungus causing EB disease. Each section can also have numbers and percentages relevant to literature knowledge, if it is available.

Discussion

Aspergillus Species Incidence Aspergillus species are ubiquitous molds that grow in

decaying vegetation, soil and water with no geographic predilections. They are common colonizers of the air-ways in immunocompromised hosts and the primary cause of invasive mycosis. They have been isolated from up to 57% of patients with cystic fibrosis [1, 10, 17, 26, 33, 35] . In lung transplant recipients, the incidence of infec-tion ranges from 3 to 22%, and the incidence of isolated tracheobronchitis is 5% [29, 44] . Invasive pulmonary as-pergillosis constitutes about 90% of all the clinical pre-

Karnak /Avery /Gildea /Sahoo /Mehta

Respiration 2007;74:88–104 90

Table 1. Demographic, immune, bronchoscopic and pathological features of patients with endobronchial fungal disease

Type of fungaldisease

Age-rangeyearsmean/median

M/F ratio(sex NA)

Immune status(NA)

Locationtrachea/bronchi/both (NA)

Bronchoscopic/pathological description

Aspergillosis 6477 43/25 ICH: 90 5/95/21 bronchial stenosis: 25(n = 121) 43.0816.1 (53) ICT: 16 yellowish-white necrotic material-plaques: 22b

44 (10) pseudomembranous plaques: 19DM: 5 yellowish exudative material: 5

white-colored nodules: 14broken sutures: 8edematous irregular mucosa: 8ulcerative appearance: 7grayish mucous plaque: 6friable brownish material: 5dehiscence: 5dark-black pigmentation: 4c

mucosal irregularity: 4

Coccidioidomycosis 0.4454 23/6 ICT: 14 6/17/5 irregular nodules: 6(n = 38) 25.9830.5 (9) ICH: 10a (10) sessile nodules: 6

30.5 (14) submucosal nodules: 5granular lesions: 4mass-like lesion: 3friable mass: 1polypoid mass: 1hyperemic patches: 1papillary excrescences: 1cobble-stoned view: 1white nodular raised lesions: 1

Zygomycosis 0.4483 18/7 DM: 20 5/24/1 mass-like lesion: 10(n = 31) 50.4819.0 (6) ICH: 7 (1) gray white fibrinous plug: 8

56 ICT: 1 inflammation: 3(3) granular lesion: 2

slough of mucosa: 2ulcer: 2stenosis: 2green pseudomembrane: 1

Candida 19482 8/4 ICT: 1 3/12/0 anastomotic site infection: 10(n = 14) 51.5816.9 ICH: 13 pseudomembrane: 2

49.5 (malignancy: 1, multiple, large, firmly adherent plaques: 1AIDS: 2) hemorrhage: 1

Cryptococcosis 19472 7/2 ICT: 8 1/4/4 hemorrhagic mass: 3(n = 13) 47.6819.2 (4) ICH: 2 (4) white mass-like lesion: 3

45.5 DM: 1 infiltrative mucosal lesion: 2(2) gelatinous mass: 1

soft, reddish, broad-based nodule: 1ulcerative lesion: 1pseudomembranous appearance: 1white mucous plaque: 1

Histoplasmosis 29482 3/8 ICT: 11 0/8/3 hyperemic mucosa: 3(n = 11) 53.3815.2 bronchoesophageal fistula: 3

52 friable mass: 2hemorrhage: 1mass: 1broncholithiasis: 1

NA = Not available; ICT = immunocompetent host; ICH = immunocompromised host; DM = diabetes mellitus.a Ten patients were HIV positive.b Aspergillus nidulans infection (n:2) [8, 20], Aspergillus flavus infection (n:4) [5, 15, 21, 28].c Aspergillus niger infections (n:4) [1, 9, 12, 28].


sentations. About 7–20% of pulmonary invasions simul-taneously manifest tracheobronchial involvement [16] . In a study among transplant recipients, tracheobronchitis and anastomotic infections were seen in 37 and 20% of the patients, respectively [39] . Among 121 patients (both transplant recipients and other cases) retrieved from the literature, 1 patient had A. fumigatus and A. flavus [25] , 2 had A. nidulans [8, 20] , 4 had A. niger [1, 9, 12, 28] and 4 had A. flavus [5, 15, 21, 28] . In 34 patients no species were identified [2, 5–7, 16, 17, 27, 31, 34, 42] while the rest (63%) had A. fumigatus.

Predisposing Factors Depending upon the patient’s local and systemic im-

mune status and alterations in host tissues, Aspergillus spp. can cause a wide variety of tracheobronchial and pulmonary manifestations [95] . Alveolar macrophages are normally capable of killing the conidia, however, if the former are low in number or defective, conidia will begin to germinate, forming hyphae. During hyphal growth, the fungus produces various metabolites such as complement inhibitor, various proteases, and several my-cotoxins which help to evade host defenses [95–97] . Im-munosuppressive drugs, radiation therapy, antilympho-cytic therapy, hematopoietic malignancy, granulocyto-penia, uremia, diabetes mellitus, aplastic anemia and miliary tuberculosis are other predisposing factors [98] . Lung transplant recipients have a unique predilection for aspergillosis. Direct exposure of the transplanted organ to the environment, impairment in local host defenses (i.e. mucociliary clearance and cough reflex), disruption of lymphatic drainage, ischemic airway injury, altered al-veolar phagocytic function and overall greater require-ment of immunosuppression can cause airway disease and colonization by Aspergillus [12, 28, 29, 34] . Patients treated with resectional surgery could also develop bron-chial stump aspergillosis, resulting from the colonization of the suture material. It has been suggested that this risk can be reduced by using an unbraided nylon monofila-ment rather than silk sutures [13, 36] . In the literature reviewed, 90 patients (74%) with EB aspergillosis were immunocompromised, and 83 (68%) had undergone lung transplantation (n = 80) or surgery for bronchogen-ic carcinoma (n = 3). Among transplant patients, 32 (40%) had anastomotic infection.

Clinical Presentation Tracheobronchial aspergillosis can present in various

forms such as invasive tracheobronchitis, ulcerative tra-cheobronchitis and pseudomembranous tracheobron-

chitis. These three entities are distinguished from each other only by histopathological examination. Fever is not a common symptom as the patients are usually immuno-compromised. Cough and dyspnea are nonspecific symp-toms. Most patients presented with progressing dyspnea or hemoptysis. The latter was because of blood vessel in-vasion. Patients occasionally expectorated fungal casts. Shortness of breath and hypoxia were the signs of airway dehiscence related to aspergillosis in lung transplant pa-tients ( fig. 1 ). Some cases in lung transplant patients are discovered on routine surveillance bronchoscopies.

The pseudomembranous form is the most severe con-dition and is usually fatal despite treatment with antifun-gal agents. Another presentation of tracheobronchial as-pergillosis, obstructive bronchial aspergillosis, is in real-ity a separate saprophytic form of the infection such as aspergilloma, due to its non- or less invasive features. Pa-tients with obstructive bronchial aspergillosis can expec-torate fungal casts in the shape of the bronchial tree.

Aspergillosis is often found in EB mucosa in associa-tion with other presentations of Aspergillus infection and hence its nature (primary or secondary) is difficult to es-tablish [95–97] .

In our review, tracheobronchial aspergillosis without defining its subtype was described in 20 patients (16%). Tracheobronchial aspergillosis subtypes, invasive tra-cheobronchitis, ulcerative tracheobronchitis and pseudo-membranous tracheobronchitis were reported in 9 (7%), 12 (10%) and 9 patients (7%), respectively. Obstructive bronchial aspergillosis was seen in 6 (5%) patients. Paren-chymal invasion was seen with tracheobronchial and pseudomembranous forms in 8 (7%) and 7 (6%) patients, respectively. Combined forms of tracheobronchial and allergic bronchopulmonary aspergillosis together and obstructive bronchial aspergillosis and organizing pneu-monia were found each in 1 person in the literature search. Aspergilloma with EB involvement was the least common combination (4%, n = 5) [2, 6, 13, 27] .

Radiological Findings Although radiographic findings vary in different

forms of pulmonary aspergillosis, in the appropriate clin-ical setting, the presence of the ‘air crescent sign’ of as-pergilloma or the ‘halo sign’ of invasive aspergillosis on computed tomography of the chest may support clinical suspicion of EB aspergillosis [95, 99] . Tracheal or bron-chial wall thickening, proximal bronchiectasis, airway plaques and patchy centrilobular nodules or branching linear-nodular areas having a ‘tree-in-bud’ appearance may be other direct or indirect signs of tracheobronchial


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Symptoms, n Diagnostictechnique, n

Diagnosis, n Therapy, n (NA) Outcome(NA)

Aspergillosis hemoptysis: 11 Br wash&brush: 49 Anast Inf: 32 IVAmB: 36 58 died(n = 121) dyspnea: 11 EB bx: 42 TBA: 20 IVAmB+Itc: 14 44 alive

fever: 10 BAL: 34 UT: 12 Itc: 9 (19)cough: 5 necropsy: 17 PT: 9 aAmB+LAmB: 7stridor: 4 serology: 6 IAT: 9 aAmB+Itc: 6wheezing: 4 sputum: 3 TBA+Parench: 8 aAmB+LAmB+Itc: 5sputum: 2 TBBX: 4 PT+Parench: 7 LAmB: 3low-back pain: 1 open lung bx: 2 aspergilloma: 5 Csp: 2pleuritic pain: 1 lobectomy: 2 OBA: 6 Vrc: 1nausea-vomiting: 1 Br-art Fist: 3 Flc: 1

BSA: 3 IVAmB+LAmB+Flcy: 1pulmonary Art thrombus: 2 IVAmB+Flc: 1Tr: Br Fist: 1 LAmB+Terb: 1OBA+OP: 1 IVAmB+Csp+Itc: 1TBA+ABPA: 1 IVAmB+Csp: 1Semi: Inv Asp: 1 Vrc+Itc: 1BrSG: 1 (19)

balloon dil: 18stent: 16debridement: 8tracheostomy: 2Br removal: 2surgery: 4laser: 9electrosurgery: 1

Coccidioidomycosis stridor: 9 serology: 28b disseminated: 20 IVAmB: 18 4 alive(n = 38) dyspnea: 8 EB bx: 25 parenchymal: 14 IVAmB+Flc: 4 3 died

chronic cough: 15 BAL: 12a hilar: med LAP: 12 Flc: 2 (31)wheezing: 5 surgical bx: 1 IVAmB+Itc: 2hoarseness: 12 Laryn bx: 1 IVAmB+Ktc+Flc: 1

Br wash&brush: 1 IVAmB+Ktc+Flc+Itc: 1skin bx: 1 surgery: 1Parav mass bx: 1 tracheostomy: 3

stent: 1(4)

Zygomycosis dyspnea: 15 Br wash&brush: 16 Br mucor: 24 IVAmpB: 24 16 died(n = 31) hemoptysis: 9 EB bx: 14 Tr mucor: 5 surgery: 13 11 alive

fever: 10 necropsy: 8 Bro-art Fist: 6 Br removal: 1 (4)thrombosis: 3 (5)renal disse: 2

Candida stridor: 1 Br wash&brush: 10 primary tracheal IVAmB+aAmB: 8 3 died(n = 14) nausea: 2 BAL: 8 candidiasis: 2 Flc: 5 11 alive

fever: 2 (fungus ball: 1) Itc: 2EB bx: 5 Tr bronchitis: 1 balloon dil: 2necropsy: 2 Anast Inf: 10 Br removal: 1

stent: 2

Cryptococcosis dyspnea: 4 serology: 10 cryptococcoma: 6d surgery: 7 8 alive(n = 13) hemoptysis: 4 EB bx: 9 Pri pulm cryp: 4 Flc: 4 4 died

stridor: 1 Br wash&brush: 6 disseminated: 2c IVAmB: 2 (1)fever: 1 BAL: 2 Cryp abscess: 1 IVAmB+Flcy+Flc: 1hemoptysis: 1 IVAmB+Flcy+Itc: 1

IVAmB+Flc: 1(4)

Table 2. Symptoms, diagnostic workups, diagnoses, therapy types and outcomes of patients with EBFI


aspergillosis on a high-resolution CT. Obstructive bron-chial aspergillosis can cause lobar or segmental lung col-lapse due to obstructive fungal casts [22, 31] .

Endoscopic Findings Obstructive bronchial aspergillosis can be described

when thick mucous plugs loaded with Aspergillus are found in the airways, with little mucosal inflammation or invasion ( fig. 2 ). In invasive tracheobronchitis, necrot-ic white mucosa can be seen [11, 16, 21] . In the ulcerative form, there is focal fungal invasion ulcer of the tracheo-bronchial mucosa and/or cartilage [2, 7] . The pseudo-membranous form is characterized by extensive inflam-mation and invasion of the bronchial mucosa with a pseudomembrane composed of necrotic debris and hy-phae [1, 5, 12] . In patients with A. niger , black pigmenta-tion can also be seen. In addition, white masses of calci-um oxalate crystals are also seen. The fungus produces oxalic acid with an affinity to bind tissue calcium form-ing these crystals ( fig. 3 ).

Diagnosis A high degree of suspicion is required to make the di-

agnosis of EBFI. The fungus is known as a common colo-nizer of the respiratory tract, thus sputum cultures are

not reliable. A tissue diagnosis is most definitive; how-ever, when this is not available, multiple positive cultures may suggest the diagnosis. Serological diagnosis for the presence of galactomannan antigen has been utilized, with some authors reporting sensitivity as high as 81% and 89% specificity [100] . However, far lower sensitivity (30%) has been reported in lung transplant recipients with invasive aspergillosis [101] . Polymerase chain reac-tion and nucleic acid sequence-based amplification are other advanced methods for establishing the diagnosis of aspergillosis and may support EB involvement [102–105] . Histopathological examination and culture of EB biop-sies in 42 (35%), bronchial washing and brushing mate-rial in 49 (40%) and BAL in 34 (28) were the main con-firmatory tests for EB aspergillosis reported in the litera-ture.

Therapy and Outcome Suggested treatment for EB aspergillosis is similar to

that for invasive aspergillosis, which includes intrave-nous AmB (1–1.5 mg/kg/day), liposomal AmB (5 mg/kg/day), and/or 400 mg/day of oral itraconazole. Voricon-azole, a new triazole, is also being used with increasing frequency with the loading dose of 6 mg/kg every 12 h; followed by maintenance dose of 4 mg/kg every 12 h

Table 2 (continued)


Symptoms, n Diagnostictechnique, n

Diagnosis, n Therapy, n (NA) Outcome(NA)

Histoplasmosis hemoptysis: 8 EB bx: 9 Med fibrosis: 6 surgery: 8 11 alive(n = 11) dyspnea: 1 Gr med: 2 laser: 1

BrSG: 1 argon: 1Gr lymph: 1 Itc: 1B. lith+Gr med: 1 Flc: 1

Art embolization: 3

NA = Not available; bx = biopsy; Parav mass = paravertebral mass; hilar-med LAP = hilar or mediastinal lymphadenopathy; Laryn = laryngoscopic; Br wash&brush = bronchial washing and brushing; Cryp abscess = cryptococcal abscess; TBBX = trans-bronchial biopsy; TBA = tracheobronchial aspergillosis; Anast Inf = anastomotic infection; UT = ulcerative tracheobronchitis; PT = pseudomembranous tracheobronchits; IAT = invasive Aspergillus tracheobronchitis; OBA = obstructive bronchial as-pergillosis; ABPA = Allergic bronchopulmonary aspergillosis; Semi-Inv Asp = invasive aspergillosis; BSA = bronchial stump aspergillosis; BrSG = bronchocentric granulomatosis; OP = orga-nizing pneumonia; Br Mucor = bronchial mucormycosis; Tr mucor = tracheal mucormycosis; Pri pulm cryp = primary pulmonary cryptococcosis; Parench = parenchymal; Bro-artFist = bronchoarterial fistula; renal disse = renal dissemination;

B. lith = broncholithiasis; Gr med = granulomatous mediastinitis; Med fibrosis = mediastinal fibrosis; Gr lymph = granulomatous lymphadenitis; Art = arterial; IVAmB = intravenous AmB; aAamB = aerosolized AmB; LAmB = liposomal AmB; Ktc = ke-toconazole; Itc = itraconazole; Flc = fluconazole; Csp = caspofun-gin; Vrc = voricanozole; Flcy = flucytosine; Br removal = bron-choscopic removal; balloon dil = balloon dilatation.

a BAL was the sole leading to diagnosis in 5 patients. b Complement fixing antibody was the sole leading to diagno-

sis in 1 patient.c 1 meningeal and 1 systemic dissemination. d One mediastinal cryptococcoma with trachea, and right

main bronchus (RMB) &left main bronchus (LMB) infiltration; 5 endobronchial cryptococcoma.


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(400 mg b.i.d. ! 2 doses then 200 mg b.i.d. for oral vori-conazole). Duration of therapy is guided by clinical re-sponse. It may be extend to several weeks to a year. The ultimate response of these patients to antifungal therapy is largely related to host factors, such as correction of neu-tropenia and neutrophil function and reduction of im-munosuppression [106, 107] .

Other possible therapies include caspofungin alone (though some experts have raised concerns about its ef-ficacy in severe disease) or in combination with voricon-azole, intravenous AmB, or liposomal AmB. The role of aerosolized AmB in therapy remains controversial, al-though authors have reported it to be effective [19, 21, 32, 106] . Further studies are needed to determine optimal therapy. Liposomal and standard AmB inhaled formula-tions have been studied more extensively in the context of prophylaxis in lung transplantation [108, 109] . Post-transplant antifungal prophylactic or preemptive thera-pies are used in many transplant centers, especially in patients with cystic fibrosis where Aspergillus is a com-mon colonizer [110] . If the suture material from prior surgery is present in the EB tree, it should be removed with scissors or burned with a neodymium:yttrium alu-minum garnet (Nd-YAG) laser [35] . In this literature re-view, 54 (45%) of the lung transplant recipients with EB aspergillosis, required bronchoplasty for stenosis.

EB involvement with Aspergillus may indicate a poor prognosis [1, 2, 6, 45] . Eleven cases of EB aspergillosis (9%) with invasive disease and concomitant massive he-moptysis died immediately after the diagnosis. Overall reported mortality from EB aspergillosis was 48%.

Coccidioidomycosis Incidence Coccidioidomycosis is an endemic fungal infection

occurring after inhalation of its arthroconidia and can be seen in any age group. Approximately 100,000 new cases of coccidioidomycosis are reported each year, especially from the southwestern part of the United States; 0.5% of which progress to disseminated disease [111] . It is report-ed in 1–8% of all cases of solid organ transplantation [112] in endemic areas. However, incidence of EB involvement from this organism is unknown.

Predisposing Factors Depending upon the size (3–5 � m) of the spores, the

organism can reach the terminal airways or even the al-veoli. Once an arthroconidium is inhaled it transforms to a spherical structure of 70 � m or larger with internal septations. Within each of the subcompartments of

spherical structures, individual cells (endospores) evolve. After several days, mature spherules rupture, releasing endospores which are potentially capable of producing more spherules. Cell-mediated or humoral immunity of normal individuals can block the last step of dissemina-tion using macrophages and complement activation [46, 113] . Immunocompromised hosts, especially those with human immunodeficiency virus infection, infants, preg-nant females, diabetics and non-Caucasians are consid-ered at increased risk of developing the disease [111] . Of the 38 cases in this review, 10 (26%) in whom virus test-ing had been performed were found to be positive. One patient had jejuno-ileal bypass and 1 patient was preg-nant. Eight were Caucasian, 9 were either African-Amer-ican or Hispanic, Asian, Native American, or from the Indian subcontinent. Race was not reported in 21.

Clinical Presentation Dyspnea and stridor were the most common symp-

toms due to either the parenchymal disease or extrinsic compression of the airway by the enlarged lymph nodes.

Radiological Findings Coccidioidomycosis produces a wide variety of pul-

monary infiltrates including pneumonia and nodules with cavities or miliary pattern [46] . In our review, 6 pa-tients (16%) had disease confined to trachea and/or main-stem bronchus without evidence of parenchymal disease but 14 (37%) had infiltrates. One patient later developed cavitary lesion and 12 (31%) had hilar or mediastinal lymphadenopathy.

Endoscopic Findings Proliferation of organisms accounts for the inflamma-

tory appearance of the bronchi. Bronchitis and bronchi-olitis have been reported in association with parenchy-mal lesions, and are occasionally accompanied by in-flammatory debris filling the lumen, or mucosal ulceration [46] . Other reported EB abnormalities were mainly sessile-irregular and submucosal nodules (n = 17, 45%). In patients with mediastinal or hilar lymphade-nopathy, extrinsic compression of the airways was also reported.

Diagnosis Diagnosis of EB coccidioidomycosis was established

by demonstration of the spherules on a wet preparation of the EB specimen in the majority of the patients. Potas-sium hydroxide solution, calcofluor staining or Papani-colaou staining were used for this purpose [112, 113] . The


Fig. 1. Tracheobronchial aspergillosis in a 56-year-old male, sta-tus post (S/P) left single lung transplantation with fever, hypoten-sion, bilateral infiltrates and hypoxemia requiring mechanical ventilation. Necropsy specimen of the trachea showing whitish-tan confluent flat plaques (by permission: Cleve Clin J Med [30] ).

Fig. 2. Obstructive pulmonary aspergillosis in an 18-year-old male with bilateral lobar (living related donor) lung transplanta-tion [unpubl. case].

Fig. 3. 37-year-old female with bilateral lung transplantation with shortness of breath, cough, wheezing and recurrent fever. Bron-choscopic image shows exophytic pale necrotic yellow mass with dark black pigmentation (by permission: J Heart Lung Transplant [44] ).

Fig. 4. Mucormycosis involving hard palate in an elderly diabetic male.


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diagnosis of coccidioidomycosis was made by surgical, laryngoscopic, or EB biopsy of an airway lesion in 1 (3%), 2 (5%) and 25 (66%) of the patients, respectively. A bronchial brush of a lesion provided the diagnosis in 1 patient. Skin and paravertebral mass biopsy also led to diagnosis, each in 1 case. Culture of BAL was reported to be positive in 12 (32%) cases and exclusively diagnos-tic in 5 (13%).

Although serology was available in 28 (74%) patients, it was helpful for presumptive diagnosis in only 1 (3%) patient. It is not recommended as a diagnostic test due to impaired serologic responses among immunocompro-mised hosts [46] .

Therapy and Outcome Therapies utilized in reported cases have generally fol-

lowed the Infectious Diseases Society of America (IDSA) guidelines for pulmonary coccidioidomycosis. These in-clude intravenous AmB (0.5–0.7 mg/kg/day), oral keto-conazole (400 mg/day), oral or intravenous fluconazole (400–800 mg/day), or oral itraconazole (200 mg b.i.d.) either singly or in combination. According to these guide-lines, a total intravenous AmB dose of 1.5–3.0 g is fol-lowed by oral azole therapy lasting from 3 to 24 months depending on the response. Among immunocompro-mised hosts, lifelong suppressive therapy may be required. Surgical resection may also be required for localized re-fractory lesions or those associated with significant he-moptysis [114] .

In 38 EB coccidioidomycosis cases, 26 (68%) patients received a course of intravenous AmB 10 (26%), 2 cases oral ketoconazole, 8 oral fluconazole and 3 itraconazole before or after the course of AmB. Two patients received multiple azoles and another 2 received fluconazole ther-apy alone. Therapy duration was at least 12 months. Air-way disease required stent, tracheostomy, and surgical management to prevent complete obstruction of the air-way, each in 1 cases. Even if AmB was used, 3 patients died, 4 were alive and the survival status of 31 patients was unknown.

Zygomycosis (Mucormycosis) Incidence Zygomycosis (mucormycosis) is an opportunistic in-

fection from fungi of the class Zygomycetes. Mucor, Rhi-zopus, Absidia and Chlamydoconidia are the most fre-quent species affecting the human population, with Mu-cor being the most common. It is a ubiquitous organism and abundantly present in the soil and decaying matter. It enters the body by inhalation of aerosolized spores [6,

47–73] . In over 90 case reports of pulmonary mucormy-cosis, 31 (34%) had EB involvement. Mucor was isolated in 20 (64%), Rhizopus in 4 (13%) and Chlamydoconidia in 1 (3%) of these cases.

Predisposing Factors These organisms have an enzyme, ketone reductase,

that allows them to thrive in a high glucose environment. Serum from individuals with normal blood sugar inhib-its the growth of the fungus, whereas that with diabetic ketoacidosis stimulates growth. Iron overload and defer-oxamine also increase the risk of mucormycosis [115] . The deferoxamine-iron chelate, called feroxamine, is a siderophore for the Zygomycetes; increased iron uptake by the fungus stimulates fungal growth and may lead to clinical infection. Diabetic individuals have increased se-rum iron because of impaired transferrin binding, which may contribute to their increased risk of infection ( fig. 4 ). Consistent with this, the most common underlying con-dition was diabetes mellitus (n = 20, 65%) in EB mucor-mycosis. Hematologic malignancies, prolonged neutro-penia, treatment with corticosteroids or deferoxamine, bronchogenic cancer, renal transplantation and acquired immunodeficiency syndrome were other reported risk factors [6, 47–73] . Consistent with this, 7 patients (23%) were reported to be immunocompromised hosts; includ-ing diabetic patients, the number increased to 25 (81%), reflecting the opportunistic behavior of this organism.

Clinical Presentation The pace of mucormycosis is usually rapid, yet there

are a few descriptions of an indolent course. Most healthy individuals with low-inoculum exposure remain asymp-tomatic for a considerable period of time. However, pa-tients who inhale a large inoculum often develop a severe and potentially fatal diffuse pulmonary infection [67–71] . Lungs are the most common site of Mucor infection, which may then spread to contiguous structures such as the mediastinum and heart. As it is an angioinvasive or-ganism, infarction is its hallmark and hemoptysis is a common clinical symptom as well as cause of death. If EB involvement occurs, it mainly affects large bronchi and is also associated with high mortality [62, 67] . Patients with EB disease mainly present with dyspnea and hemoptysis; the latter can sometimes be massive due to angioinvasion leading to bronchoarterial fistulas (n = 6, 19%).

Radiological Findings In patients with EB disease, radiographic findings are

usually nonspecific and can vary from focal consolida-


tion to mass effect [62, 67, 116] . Specific radiological signs of infarction, or cavitary lesions including air crescent sign, have seldom been reported.

Endoscopic Findings EB zygomycosis presented as a mass lesion in 10 pa-

tients (32%) or a grayish-white fibrinous plug obstructing the bronchus in 8 (26%). It also caused sloughing of mu-cosa, granular lesions, ulcer, stenosis and pseudomem-brane formation in 12 individuals (39%).

Diagnosis The EB biopsy reveals characteristic broad, nonseptate

hyphae with right-angle branching on calcofluor white or methenamine silver stains. However, the absence of hy-phae does not rule out the diagnosis in a proper clinical setting. Sputum or BAL specimens may also show the characteristic hyphae [117] . In published cases of EB mu-cormycosis, bronchial washing and brushings in 16 cases (52%) and EB biopsy in 14 patients (45%) were useful tools in reaching the diagnosis. However, in 8 patients (26%) the diagnosis was established at necropsy.

Therapy and Outcome If disease is not detected early enough, mortality is

very high. The recommended therapy is high-dose intra-venous AmB or liposomal AmB, as well as surgical or EB resection, in appropriate clinical settings [52] . Mucormy-cetes are resistant to azoles and echinocandins. Of the 31 reports, 24 (77%) were treated with intravenous AmB (1 mg/kg/day), 13 (42%) patients underwent surgery and 1 (3%) had endoscopic removal of a plug with rigid bron-choscope. Reported mortality was 52%.

As Mucor is angioinvasive and a rapidly growing fun-gus, surgical intervention should be early and aggressive. Concomitant systemic treatment is also required [118, 119] . Eleven (85%) out of 13 patients who were reported to undergo surgical treatment survived their disease.

Candidiasis Incidence Candidiasis is caused by saprophytic yeasts that are

normal commensals of the human skin and gastrointes-tinal tract, which occasionally become pathogenic. Four-teen cases of EB involvement exist in the literature [6, 34, 74–76] . Eight subjects (57%) were lung transplant recipi-ents. Although esophageal candidiasis is far more fre-quently reported, EB candidiasis seems to be uncommon. Laryngeal candidiasis is also a familiar entity to otolar-yngologists ( fig. 5 ). Most EB infections are caused by

Candida albicans and produce unilateral bronchial in-volvement except for 2 patients with unspecified type. Tracheal involvement with C. albicans has been reported in 2 cases while there is a single case report of Candida parapsilosis with fungus ball formation.

Predisposing Factors Numerous conditions predispose an individual to de-

velopment of candidiasis, including age, endocrine disor-ders, malignant neoplasms, alteration of immunologic status, antibiotic therapy, neutropenia, and aplastic ane-mia. In immunocompromised cases, Candida infection can occur in association with other fungi such as Asper-gillus and Mucor [120] .

Clinical Presentation The clinical manifestations of EB infection with Can-

dida species range from those related to local mucosal infections to widespread dissemination with multisys-tem organ failure [74–76] .

Radiological Findings There are no specific findings mentioned in the litera-

ture for EB candidiasis [113] . Almost every case reported in the literature had a normal chest X-ray.

Endoscopic Findings Multiple white plaques are a characteristic feature of

mucosal invasion on EB examination [74–76] . Pseudo-membrane formation and hemorrhagic bronchitis are other common presentations.

Diagnosis To establish the diagnosis of primary pulmonary

candidiasis, the following criteria have been proposed: (1) Candida cultured from bronchoscopic material; (2) negative mycobacterial culture; (3) no other etiology for pulmonary disease, and (4) Candida demonstrated on the biopsy specimen [120] . However, there are no estab-lished criteria to confirm airway candidiasis. Primary pulmonary candidiasis may be associated with EB in-volvement. However, ruling out of other organisms caus-ing airway involvement is essential.

Therapy and Outcome Management of EB candidiasis is similar to systemic

infection. Systemic therapy for primary candidiasis con-sists of either intravenous AmB or liposomal AmB in se-verely ill patients or oral fluconazole in milder presenta-tions [97] . Caspofungin is a more recent alternative, par-


Respiration 2007;74:88–104 98

ticularly for azole-resistant yeasts. In our literature search 8 patients (57%) received intravenous AmB and/or aero-solized AmB, 5 fluconazole (36%) and 2 itraconazole (14%). Reported mortality was 21%.

Cryptococcosis Incidence Cryptococcosis is caused by the yeast-like fungus

Cryptococcus neoformans, found worldwide, with a high-er prevalence in the United States and Australia [121] . Humans become infected with inhalation of basidio-spores having small polysaccharide capsules, thus facili-tating deposition in the alveoli and terminal bronchioles [77–88] . The reported incidence of new cases of crypto-coccosis is 1.9 in males and 0.26 in females per 100,000 population in an endemic region such as California, and 0.02–0.03 in other parts of the USA [121] . The incidence of direct airway involvement is unknown. In patients with acquired immunodeficiency syndrome and dissem-inated disease, 8.3% were reported to have EB involve-ment [122] .

Predisposing Factors Predisposing conditions for systemic infection include

human immunodeficiency virus infection, malignancy, cirrhosis, renal failure, chronic lung diseases, diabetes mellitus, sarcoidosis, stem cell and solid organ transplan-tation, sickle cell disease and steroid therapy [77–88] . However, among 13 cases of EB Cryptococcus , only 3 (23%) were immunocompromised with the underlying diseases of myocarditis, diabetes mellitus and acquired immunodeficiency syndrome. In these cases, there was no evidence of disseminated disease. Conversely, 2 (17%) immunocompetent cases had dissemination to the cen-tral nervous system besides the EB involvement suggest-ing high virulence of the organism.

Clinical Presentation Dyspnea and hemoptysis were the most common

symptoms with EB cryptococcosis. If systemic infection exists, fever, cough, and headache can also be seen in ad-dition to these. Some patients may develop acute respira-tory distress syndrome. In most cases of EB involvement, the disease was identified incidentally on abnormal chest radiographs, biopsy of lung masses or cultures of lung specimens obtained for other reasons [77–88] .

Radiological Findings The radiographic findings of pulmonary cryptococ-

cosis vary from well-defined, small, non-calcified nod-

ules (with or without cavitation) to lobar infiltrates and hilar or mediastinal adenopathy. Pleural effusions have also been occasionally reported [121–124] . In EB crypto-coccosis, ‘fungus ball’ has been reported in 6 (46%) cases. Abscess with an air-fluid level was also seen in 2 (15%) patients with EB involvement.

Endoscopic Findings The most common presentation of EB cryptococcosis

is a white or hemorrhagic mass. Intense mucosal inflam-mation, gelatinous mass, nodules, plaques, pseudomem-branes, and/or ulcerative lesions have also been reported ( fig. 6 ).

Diagnosis Cryptococcus species are rare pathogens colonizing

the airways. Encapsulated yeast forms in sputum, BAL and tissue establish the diagnosis of cryptococcosis. The serum antigen titer is also indicative of infection and sug-gests extrapulmonary spread [124–125] . Cryptococcal antigen testing has been reported to be of more utility in the immunocompromised host since its presence does not require immune response by the host. Examination of the cerebrospinal fluid is a standard part of the evalu-ation in immunocompromised hosts with pulmonary cryptococcosis [78–83, 87, 126] . In EB cryptococcosis, se-rology in 10 patients (77%), EB biopsy in 9 (69%), other bronchoscopic material in 6 (46%) and BAL culture in 2 (15%) were helpful in making the diagnosis.

Therapy and Outcome In pulmonary cryptococcosis, recommended therapy

is intravenous AmB (0.7 mg/kg/day) plus flucytosine (100 mg/kg/day) for induction therapy for 3–4 weeks, and later fluconazole alone [119] . The optimal duration of maintenance therapy with fluconazole is unclear. In im-munocompromised hosts, at least a 6- to 12-month course of therapy should be considered. It is recommended that all human immunodeficiency virus-infected individuals continue maintenance therapy for life. Itraconazole is an acceptable prophylactic alternative [127] . There are no specific recommendations for the treatment of EB dis-ease. Hence, a regimen similar to that for systemic infec-tion should be acceptable.

In our review of 13 patients, 2 patients (15%) were treated with AmB alone, 3 (23%) received a combination of AmB with oral azoles or with flucytosine, and 4 (31%) received oral fluconazole alone. Therapy duration varied from 3 to 18 months. With appropriate therapy, 62% of patients were alive at the time of reporting.


Fig. 6. 66-year-old female on high-dose steroids for suspected We-gener’s disease with shortness of breath and noise breathing. Bronchoscopic view of the carina with flat yellow ulcerative lesion (by permission: J Bronchol [88] ).

Fig. 5. Laryngoscopic view of candidal plaques in a 68-year-old male with single lung transplantation complaining of hoarse-ness.

Fig. 7. Spider-like microvasculature involving the right main bronchus in a patient with fibrosing mediastinitis (by permission: Respir Care [91] ).

Fig. 8. Pseudallescheria boydii infection in a lung transplant re-cipient with cystic fibrosis [unpubl. case].


Respiration 2007;74:88–104 100

Histoplasmosis Incidence Histoplasmosis is the most common endemic respira-

tory mycosis in central United States and Latin America. In the United States, it is encountered in the midwestern states located in the Ohio, Missouri and Mississippi Riv-er valleys. Individuals are infected by inhalation of the aerosolized microconidia form of the fungus. Up to 50 million people in the United States have been infected by Histoplasma capsulatum , and up to 500,000 new infec-tions occur each year. Infection is mostly self-limited; only 1% of the affected individuals develop chronic dis-ease [89–92, 116] . Airway involvement from histoplas-mosis can be direct or indirect. Direct invasion of the airways by the fungus is relatively uncommon. In most instances, airways are indirectly involved by either en-larged or calcified lymph nodes or fibrosing mediastini-tis. Eleven cases of EB histoplasmosis have been reported in the literature.

Predisposing Factors Residence in endemic areas, the organism load and

depressed immune status positively correlate with sever-ity of disease [89–92, 116] . Consistent with this, of pa-tients with EB disease due to histoplasmosis in this re-view, 9 (81%) were from endemic areas, yet surprisingly, all were immunocompetent.

Clinical Presentation Most people infected by this fungus remain asymp-

tomatic, yet around 10–40% can develop self-limiting in-fluenza-like illness. The duration of symptoms depends upon the extent of exposure, underlying lung disease, general immune status and specific immunity to H. cap-sulatum. Mediastinal lymph nodes are the most common site of involvement while EB involvement is rare [128] . In this review, patients presented mainly with hemoptysis (72%) probably related to fibrosing mediastinitis. Expec-toration of broncholiths is also a rare manifestation of EB histoplasmosis.

Radiographic Findings Radiographic findings of pulmonary histoplasmosis

are nonspecific and varied. They can vary from a solitary nodule to fibrocystic disease. There are no radiological markers of EB involvement except for those related to fi-brosing mediastinitis. Interstitial markings and lymph node enlargement are the most prominent features [89–92] . A nonspecific infiltrative pattern (72%), lymph node enlargement (63%) and calcification (36%), all have been

stated. The presence of splenic calcifications may also suggest prior histoplasmosis. In 2 patients (18%), chest X-rays were reported to be normal.

Endoscopic Findings EB histoplasmosis can present as mild-severe stenosis

of the trachea, carina or main bronchi from the enlarged or calcified lymph nodes. EB disease can be due to com-pression caused by a calcified lymph node between the bronchus and a vessel or esophagus. Chronic compres-sion between calcified lymph nodes, the airways and the esophagus can cause disruption of the bronchial and esophageal wall leading to the development of a broncho-esophageal fistula. Fibrosing mediastinitis can cause hy-peremia, or mucosal edema with diffuse spider-like mi-crovasculature in the airways due to distal obstruction of the bronchial blood vessels ( fig. 7 ). Direct EB involve-ment may mimic tumor [89–92] .

The most prominent finding of EB histoplasmosis in this review was hyperemic mucosa in 3 (27%). Three other patients also developed bronchoesophageal fistulas (27%) and recurrent aspiration pneumonias. Masses, mucosal hemorrhage and broncholiths were other EB findings.

Diagnosis In the appropriate clinical setting, detection of the or-

ganism on a bronchoscopy specimen culture or glycopro-tein antigen detection in urine or serum by complement fixation help establish the diagnosis. Low-level positive antibody titers, however, may relate to past rather than active infection. Involvement of the airways is confirmed by bronchoscopy or by verifying the lesion by biopsy via appropriate specimen recovery [129] . In 9 (82%) patients diagnosis was established by the EB biopsy.

Therapy and Outcome According to the Infectious Diseases Society of Amer-

ica guidelines for pulmonary histoplasmosis, if the pa-tient is critically ill, intravenous AmB (0.7–1.0 mg/kg/day) is considered, with the total AmB treatment amount-ing less than 35 mg/kg. After stabilization of symptoms, the patient can be switched to oral itraconazole for up to 12 months. If symptomatic major airway obstruction takes place, then 40–80 mg prednisone daily for 2 weeks should be considered [130] . While it is well known that there is generally no added benefit of antifungal treat-ment in broncholithiasis or fibrosing mediastinitis, such treatment should be considered in patients with elevated erythrocyte sedimentation rate or complement fixation titers for H. capsulatum over 1: 32, as these patients may


have active ongoing infection. A broncholith, if detected free in the bronchus, can be removed via bronchoscope [130, 131] .

In patients with hemoptysis from fibrosing mediasti-nitis, hemostasis can be achieved by argon plasma coagu-lation or Nd-YAG laser therapy using a flexible bronchos-copy [91] . Surgical intervention should be considered for broncholiths embedded in the bronchial wall, granulo-ma-like appearances, bronchoesophageal fistulas, supe-rior vena cava obstruction or severe airway stenosis [129] .

Prognosis of the patient with EB histoplasmosis is rel-atively good. In cases reported to date, all patients with EB histoplasmosis were alive at the time of report, after appropriate therapy. Surgical approaches, including lo-bectomy, segmentectomy or closure of the bronchoesoph-ageal fistula, were required in 8 (72%) cases; therapeutic bronchoscopy was required in 2 (18%) using argon plas-ma coagulation or Nd-YAG laser for hemoptysis. This presentation also required bronchial artery embolization in 3 (27%). Only 2 patients (18%) received oral antifungal therapy while steroids were used in 5 cases (45%).

Pseudallescheria boydii (anamorph Scedosporium api-ospermum ) is a species of filamentous mold histological-ly resembling Aspergillus species. It cannot be differenti-ated from Aspergillus except on the fungal cultures. Transplant recipients receive a number of immunosup-pressive medications that result in an increased risk of infection. Scedosporium has also been recovered from more than 8% of sputum cultures of patients with cystic fibrosis. Thus these patients are potentially a reservoir for airway inoculation following lung transplantation and being at a greater risk of developing the infection. It has been known to respond poorly to treatment with AmB. Rapid identification of the organism is essential for favor-able outcome because this organism is often sensitive to imidazoles [132] . We have encountered an EB infection with this fungus in a lung transplant recipient with cystic fibrosis. The patient was colonized with the fungus previ-

ously and developed disseminated disease following lung transplantation. The patient is being maintained on an experimental oral azole preparation for the last year ( fig. 8 ).

Concluding Remarks

EBFI usually occurs by inhalation of fungal organ-isms. Its incidence and prevalence is unknown. It is like-ly that the condition is under-recognized and under-re-ported. The immune status plays a major role in the de-velopment of the disease. In most patients with EBFI, bronchoscopic examination correlates with the radio-graphic findings. Bronchospasm, pneumothorax and bleeding are seen as complications in very small percent-ages (4.6, 0.4 and 0.7%, respectively) with flexible bron-choscopy [133] . In the literature, no additional risk re-lated with EBFI was mentioned, either. Therefore, it is safe and helpful to make a correct diagnosis via obtaining materials. Bronchoscopic descriptions of airway lesions include mass lesions, yellowish-white or reddish polyp-oid lesions, plaques and ulcerative lesions. Tissue necrosis may cause yellowish-white pseudomembranous-type le-sions especially in patients with aspergillosis and zygo-mycosis. Fungal organisms can also cause granulomas. When obtaining a specimen, washing, brushing, and BAL or biopsy, contamination must be avoided and inter-ventional bronchoscopic techniques should be used as needed. Fungal infection should be in the differential di-agnosis of any type of EB lesion, particularly in an im-munocompromised patient.

Acknowledgment

D.K. is supported by the NIH/National Cancer Institute (USA) and the Scientific and Technological Research Council of Turkey (Tubitak).

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Endobronchial Fungal Disease: An Under-Recognized Entity