Keywords

Introduction

Endobronchial fungal infections (EBFIs), though infrequent, are being recognized with increasing frequency with widespread use of flexible bronchoscopy. Predisposing causes of EBFIs are listed in Table 9.1. These infections are most likely a consequence of initial colonization in patients receiving immunosuppressive therapy [1] or those who are on continuous mechanical ventilation [2]. Lung or other solid organ transplantation and diabetes mellitus are other major risk factors for EBFI. The purpose of this chapter is to highlight the presentation of EBFI and its associated complications and mortality and to outline suggested management therapies.

Table 9.1 Predisposing factors for fungal infections
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Salient clinical features of EBFIs are summarized in Table 9.2. Aspergillus species, Coccidioides immitis, Zygomycetes, Candida species, Cryptococcus neoformans, and Histoplasma capsulatum are the most common agents that cause EBFI [3]. Although full demographic information is incomplete in patients with EBFIs, coccidioidomycosis was reported more frequently in younger patients, with a mean age of 30 years. Most EBFIs seemed to occur in males and male/female (M/F) ratios for each type of EBFI listed above was as follows: aspergillosis (1.7/1), coccidioidomycosis (3.8/1), zygomycosis (2.5/1), candidiasis (2/1), and cryptococcosis (3.5/1). Interestingly, histoplasmosis has been reported more frequently in female patients, with an M/F ratio of 0.4/1 [3]. Endemic fungal infections seem to be more common in men than in women, perhaps because estrogen may have an inhibitory effect on the growth cycle of fungi [4].

Table 9.2 Fungal infections and clinical features
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Endobronchial Aspergillosis

Aspergillus species commonly colonize airways in immunosuppressed patients and have been recovered from as many as 57 % patients with cystic fibrosis [5]. Aspergillus species remain the primary fungal cause of infection in patients’ postlung transplantation with infection rates ranging up to 22 % [6, 7]. Most aspergillus infections fit into the category of invasive pulmonary aspergillosis and up to 20 % of patients have simultaneous tracheobronchial involvement [8, 9]. A. fumigatus, A. flavus, A. nidulans, and A. niger are the types of aspergillosis infections most commonly reported in the literature.

Aspergillus spp. in the tracheobronchial and pulmonary systems may present with a wide variety of manifestations [10]. Alveolar macrophages normally are capable of killing the aspergillus conidia. If these cells are low in number or are defective, the Aspergillus conidia will begin to germinate and form hyphae. During hyphal growth, the fungus produces various metabolites, such as complement inhibitors, proteases, and mycotoxins that help to negate host defenses [10]. Predisposing factors which support hyphal growth include immunosuppressive drugs, radiation therapy, antilymphocytic therapy, hematopoietic malignancy, granulocytopenia, uremia, diabetes mellitus, aplastic anemia, and miliary tuberculosis (Table 9.1) [11]. The mechanisms by which lung transplant recipients have a unique predilection for aspergillosis are as follows: 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 alveolar phagocytic function, and overall greater requirement of immunosuppression all of which can cause airway colonization and disease process by Aspergillus [12, 13]. Patients who undergo pulmonary resection surgery could also develop bronchial stump aspergillosis. Bronchial stump infections by Aspergillus can be reduced by using unbraided nylon monofilament instead of silk sutures [14].

The various forms of tracheobronchial aspergillosis include invasive tracheobronchitis, ulcerative tracheobronchitis, and pseudomembranous tracheobronchitis. Histopathological examination is key to distinguish these entities from one another.

Fever is not a common symptom as the patients are usually immunocompromised. Most patients present with worsening dyspnea or hemoptysis, the latter occurs due to direct invasion of the blood vessel wall (Table 9.2).

Although varied radiographic findings are seen in different forms of pulmonary aspergillosis, in the appropriate clinical setting, the presence of the “air crescent sign” of aspergilloma or the “halo sign” of invasive aspergillosis on computed tomography of the chest may support clinical suspicion of EB aspergillosis (Table 9.3) [10, 15]. Tracheal or bronchial 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 aspergillosis on a high-resolution CT. Obstructive bronchial aspergillosis can cause lobar or segmental lung collapse due to obstructive fungal casts [16, 17].

Table 9.3 Radiologic features in the endobronchial fungal infections
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Among lung transplant recipients, tracheobronchial aspergillosis may be diagnosed on routine surveillance bronchoscopies. The pseudomembranous form is the most severe condition and is usually fatal despite treatment with antifungal agents. Tracheobronchial aspergillosis is an obstructive form of bronchial aspergillosis [17]. Patients with obstructive bronchial aspergillosis can expectorate fungal casts in the shape of the bronchial tree. Aspergillosis is often found in EB mucosa in association with other presentations of Aspergillus infection and hence its nature (primary or secondary) is difficult to establish [10, 18]. In a review of pulmonary aspergillosis, tracheobronchial aspergillosis was described in 16 % of patients. Of these, invasive tracheobronchitis, ulcerative tracheobronchitis, and pseudomembranous tracheobronchitis were reported in 7, 10, and 7 % of patients, respectively. Obstructive bronchial aspergillosis was seen in 5 % of patients. Parenchymal invasion was seen with tracheobronchial and pseudomembranous forms in 7 and 6 % of patients, respectively [3]. Combined forms of tracheobronchial and allergic bronchopulmonary aspergillosis together and obstructive bronchial aspergillosis and organizing pneumonia were found very rarely. Aspergilloma with EB involvement was the least common combination (4 %) [14, 19].

Data regarding the utility of the galactomannan antigen assay, the beta-d-glucan assay, or the polymerase chain reaction (PCR) for the diagnosis of invasive aspergillosis in the lung transplant recipients are limited [20]. Using an index cutoff value of ≥1, the assay had a sensitivity of 60 % and a specificity of 98 % [6]. A retrospective study compared performance of an Aspergillus real-time PCR assay with the galactomannan assay in 150 BAL specimens from lung transplant recipients who underwent bronchoscopy for surveillance or diagnostic evaluation [21]. The sensitivity and specificity of an Aspergillus fumigatus-specific PCR were 85 and 96 %, respectively, and the sensitivity and specificity of the galactomannan assay (using a cutoff value ≥0.5) were 93 and 89 %, respectively. Beta-d-glucan is a cell wall component of all fungi. Serum assays for beta-d-glucan to screen for invasive fungal infections including Aspergillus spp., Candida spp., Pneumocystis, and other fungi are available. However, they have not been adequately studied in lung transplant recipients.

Coccidioidomycosis

Coccidioidomycosis is an endemic fungal infection with approximately 100,000 cases being newly diagnosed every year and 0.5 % progressing to disseminated coccidioidomycosis [21]. This infection occurs after inhalation of arthroconidia and can be seen in any age group. The true incidence of endobronchial involvement is, however, unknown. Coccidioidomycosis is reported in 1–8 % of all cases of solid organ transplantation in endemic areas [22]. Infection by C. immitis is also common in other groups of immunosuppressed patients [23]. Spores of C. immitis (3–5 µm) can travel as far as the terminal airways or even the alveoli. Once an arthroconidium is inhaled, it transforms to a spherical structure of 70 µm or larger with internal septations. Within each of the subcompartments of spherical structures, individual cells, called endospores, evolve. After several days, mature spherules rupture, releasing endospores, which are capable of producing more spherules. Cell-mediated or humoral immunity of normal individuals can block the last step of dissemination using macrophages and complement activation [24]. However, immunocompromised hosts, especially infants, pregnant females, diabetic patients, non-Caucasians, and patients with human immunodeficiency virus (HIV), are considered to be at increased risk of developing the disease [22]. Patients at particular risk for coccidioidomycosis include African Americans and patients with low CD4 cell counts (<200–250 cells/µL), or those with a history of oropharyngeal or esophageal candidiasis. Patients on protease inhibitor therapy may have a reduced risk [1].

In coccidiomycosis, dyspnea and stridor are the most common symptoms due to either the parenchymal disease or extrinsic compression of the airway by the enlarged lymph nodes [3]. Coccidioidomycosis produces a wide variety of pulmonary infiltrates including pneumonia and nodules with cavities or miliary pattern [24]. In a review, 16 % of patients had disease confined to trachea and/or mainstem bronchus without evidence of parenchymal disease, but 37 % of them had infiltrates. One patient later developed cavitary lesion and 31 % of them had hilar or mediastinal lymphadenopathy [3].

Zygomycosis

Zygomycosis (Mucormycosis) is an opportunistic infection from fungi of the class Zygomycetes. Of all the species causing infections in humans (Mucor, Rhizopus, Absidia, and Chlamydoconidia), Mucor is the most common culprit. It is a ubiquitous organism, abundantly present in soil and decaying matter. It enters the body by inhalation of aerosolized spores [19, 25]. In over 90 case reports of pulmonary mucormycosis, 34 % had endobronchial (EB) involvement and Mucor was isolated in over 64 % cases [3]. Zygomycetes have an enzyme, ketone reductase that allows them to thrive in high-glucose environments and hence patients with uncontrolled diabetes are at higher risk. Iron overload and deferoxamine therapy also increase the risk of mucormycosis [26]. The deferoxamine–iron chelate, called feroxamine, is absiderophore for the Zygomycetes; increased iron uptake by the fungus stimulates fungal growth and may lead to clinical infection. The increased serum iron in diabetic patients from impaired transferrin binding may also contribute to their increased risk of infection. The most common underlying condition in EB mucormycosis was diabetes mellitus (65 %) in one study [26]. Hematologic malignancies, prolonged neutropenia, treatment with corticosteroids or deferoxamine, bronchogenic cancer, renal transplantation and acquired immunodeficiency syndrome were other reported risk factors [19, 25]. 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 asymptomatic for a considerable period of time. However, patients who inhale a large inoculum often develop a severe and potentially fatal diffuse pulmonary infection [27]. 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 organism, 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 [27, 28]. Patients with EB disease mainly present with dyspnea and hemoptysis; the latter can sometimes be massive due to angioinvasion leading to bronchoarterial fistulas (19 %) [3].

In patients with EB mucormycosis, radiographic findings are usually non-specific and can vary from focal consolidation to mass effect [27–29]. Specific radiologic signs of infarction, or cavitary lesions including air crescent sign, have seldom been reported [3].

Endobronchial Candidiasis

Candida species are normal commensals of the human skin and gastrointestinal tract. Esophageal and laryngeal candidiasis are well described in the literature, but EB candidiasis is less commonly recognized. One study, however, found that 57 % of EB involvements were among lung transplant recipients. Most EB infections are caused by Candida albicans and produce unilateral bronchial involvement. Tracheal involvement with C. albicans has been reported in 2 cases, and there is a single published case report of C. parapsilosis with fungus ball formation [3]. Conditions that predispose to the development of Candidiasis are age, endocrine disorders, malignancy, alteration of immunologic status, antibiotic therapy, neutropenia, and aplastic anemia. In immunocompromised hosts, Candida infection can occur in association with other fungi such as Aspergillus and Mucor [30]. Clinical manifestations of EB infection with candida range from those related to local mucosal infections to widespread dissemination with multisystem organ failure [31].

For EB candidiasis, there are no specific radiographic findings mentioned in the literature [32]. Almost every case reported in the literature had a normal chest radiograph.

Cryptococcosis

Cryptococcosis is caused by the yeast-like fungus C. neoformans. Thought it can be found worldwide, it has a higher prevalence in the USA and in Australia [16]. The reported incidence of new cases of cryptococcosis is 1.9 in males and 0.26 in females per 100,000 in endemic regions such as California, and 0.02–0.03 in other parts of the USA [33]. Humans become infected by inhaling basidiospores which have small polysaccharide capsules that facilitates its deposition in the alveoli and terminal bronchioles [34]. The incidence of direct airway involvement is unknown. In total, 8.3 % of patients with acquired immunodeficiency syndrome and disseminated disease were reported to have EB involvement [35]. Predisposing factors for C. neoformans, include HIV infection, malignancy, cirrhosis, renal failure, chronic lung diseases, diabetes mellitus, sarcoidosis, stem cell and solid organ transplantation, sickle cell disease, and steroid therapy [34]. However, in patients with EB disease, only 23 % were had underlying diseases of myocarditis, diabetes mellitus, and acquired immunodeficiency syndrome but without evidence of disseminated disease. Conversely, 17 % of immunocompetent cases had dissemination to the central nervous system besides the EB involvement suggesting high virulence of the organism. In EB cryptococcosis, dyspnea and hemoptysis were the most common symptoms. If systemic infection exists, fever, cough, and headache can also be seen in addition to these manifestations. Some patients may develop acute respiratory distress syndrome. In most cases of EB involvement, the disease is identified incidentally on abnormal chest radiographs, biopsy of lung masses, or cultures of lung specimens obtained for other reasons [34].

Residence in endemic areas, the organism load, and depressed immune status positively correlate with the severity of disease [36, 37]. In one review, 81 % were from endemic areas, and all were immunocompetent [3].

The radiographic findings of pulmonary cryptococcosis vary from well-defined, small, non-calcified nodules, with or without cavitation to lobar infiltrates and hilar or mediastinal adenopathy. Pleural effusions have also been occasionally reported [33]. In EB cryptococcosis, “fungus ball” has been reported in 46 % of the cases. Abscess with an air-fluid level was also seen in 15 % of the patients with EB involvement.

Histoplasmosis

Histoplasmosis is the most common endemic respiratory mycosis in the central USA and in Latin America. In the USA, it is most often encountered in the Midwestern states in the Ohio, Missouri, and Mississippi River valleys. Individuals are infected by inhaling the aerosolized microconidia form of the fungus. Infection is mostly self-limited; only 1 % of affected individuals develop chronic disease [36, 37]. Airway involvement from histoplasmosis can be direct or indirect, though direct invasion of the airways is relatively uncommon. In most cases, airways are indirectly involved by either enlarged or calcified lymph nodes or fibrosing mediastinitis [3]. Residence in endemic areas for histoplasmosis, organism load, and depressed immune status positively correlate with severity of disease [3, 37, 38] (Table 9.1).

Most people infected by histoplasmosis remain asymptomatic, yet around 10–40 % can develop self-limiting influenza-like illness. The duration of symptoms depends upon the extent of exposure, underlying lung disease, general immune status, and specific immunity to H. capsulatum. Mediastinal lymph nodes are the most common site of involvement, while EB involvement is rare [39]. In a review, patients presented mainly with hemoptysis (72 %) mainly related to fibrosing mediastinitis. Expectoration of broncholiths is also a rare manifestation of EB histoplasmosis [3].

Histoplasma polysaccharide antigen (HPA) test is an initial test for the diagnosis of disseminated histoplasmosis that takes 2–4 weeks for completion. Detection of circulating HPA in urine, serum, and other body fluids has an increasingly important role in the rapid diagnosis of disseminated histoplasmosis. Sensitivity is greater in urine than in serum, and the sensitivity of the urine assay for the diagnosis of disseminated histoplasmosis is approximately 90 %. In patients who have other fungal infections, including coccidioidomycosis, blastomycosis, paracoccidioidomycosis, and penicilliosis, false positive reactions for HPA in urine may occur. The HPA test is often negative in isolated pulmonary disease. In such patients, direct examination and culture of sputum, BAL, or transbronchial biopsy can be performed. Bone marrow, lymph node, liver, or a skin or mucous membrane lesion provides other diagnostic sources [40].

Radiographic findings of pulmonary histoplasmosis are non-specific and varied. They can vary from a solitary nodule to fibrocystic disease. There are no radiologic markers of EB involvement except for those related to fibrosing mediastinitis. Interstitial markings and lymph node enlargement are the most prominent features [35, 36]. A non-specific infiltrative pattern (72 %), lymph node enlargement (63 %), and calcification (36 %) all have been detected. The presence of splenic calcifications may also suggest prior histoplasmosis.

Pseudallescheria boydii Infection

Pseudallescheria boydii (Scedosporium apiospermum) is a saprophytic mold that is ubiquitous and found in multiple environmental sources. It has been classically associated with mycetoma [41]. More recently, it has been reported to cause infections in solid organ transplant recipients and also colonize the airways of lung transplant recipients. An inherent resistance to amphotericin B is a characteristic of this group of fungi and early identification along with therapy with newer azoles is key in the management [41, 42]. In bone marrow transplant recipients, Pseudallescheria boydii has been reported to be associated with increased mortality, early infection, and fungemia. Treatment with voriconazole in this patient population has shown a trend toward improved mortality (Fig. 9.1) [41, 42].

Fig. 9.1
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Pseudallescheria boydii infection involving the right bronchial anastomosis in a lung transplant recipient for cystic fibrosis

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Bronchoscopy

According to the published literature, lesions of EBFI predominantly involve the lobar and segmental bronchi unilaterally (70 %), while bilateral (15 %) and tracheal involvement (9 %) are uncommon. The characteristics of the lesions include yellowish white necrotic plaques, ulcerative lesions, irregular–sessile nodules, granulomatous lesions, EB masses (hemorrhagic or non-hemorrhagic), hyperemic mucosa and bronchial stenosis, and anastomotic infection, especially in transplant patients (Fig. 9.1; Table 9.2) [3, 18, 20].

More specifically, 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. 9.2). In invasive tracheobronchitis, necrotic white mucosa can be seen [18]. In the ulcerative form, there is focal fungal invasion ulcer of the tracheobronchial mucosa and/or cartilage [18, 43, 44]. The pseudomembranous form is characterized by extensive inflammation and invasion of the bronchial mucosa with a pseudomembrane composed of necrotic debris and hyphae [12, 45, 46] (Fig. 9.3). In patients with A. niger, black pigmentation can also be seen. In addition, white masses of calcium oxalate crystals are also present. The fungus produces oxalic acid with an affinity to bind tissue calcium forming these crystals (Fig. 9.4).

Fig. 9.2
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Obstructive Aspergillus tracheobronchitis. Adapted from [17]. With permission from American College of Chest Physicians

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Fig. 9.3
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Pseudomembranous tracheobronchial aspergillosis: an autopsy specimen of a lung transplant recipient. Histological examination confirming the presence of the fungus

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Fig. 9.4
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Dark black pigments of Aspergillus niger and white calcium oxalate crystals involving the right upper lobe bronchus of a lung transplant recipient

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Proliferation of coccidioidomycosis accounts for the inflammatory appearance of the bronchi in endobronchial coccidioidomycosis. Bronchitis and bronchiolitis have been reported in association with parenchymal lesions and are occasionally accompanied by inflammatory debris filling the lumen, or mucosal ulceration [14]. Other reported EB abnormalities are sessile–irregular and submucosal nodules (45 %). In patients with mediastinal or hilar lymphadenopathy, extrinsic compression of the airways has also been reported [3].

In endobronchial zygomycosis, the disease presented as a mass lesion in 32 % of patients or a grayish white fibrinous plug obstructing the bronchus in 26 %. It also caused sloughing of mucosa, granular lesions, ulcers, stenotic lesions, or pseudomembrane formation in about 39 % patients [47].

In Candidiasis, multiple white plaques are a characteristic feature of mucosal invasion on EB examination [31]. Pseudomembrane formation and hemorrhagic bronchitis are other common presentations (Fig. 9.5).

Fig. 9.5
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Candidial plaques in a 68-year-old male postlung transplantation

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The most common presentation of EB cryptococcosis is a white or hemorrhagic mass. Intense mucosal inflammation, gelatinous mass, nodules, plaques, pseudomembranes, and/or ulcerative lesions have also been reported.

Endobronchial histoplasmosis can present as mild–severe stenosis of the trachea, carinae, or main bronchi from the enlarged or calcified lymph nodes. EB disease can be due to compression caused by a calcified lymph node between the bronchus and a vessel or esophagus. Chronic compression between calcified lymph nodes, the airways, and the esophagus can cause disruption of the bronchial and esophageal wall leading to the development of a bronchoesophageal fistula. Fibrosing mediastinitis can cause hyperemia, or mucosal edema with diffuse spider-like microvasculature in the airways due to distal obstruction of the bronchial blood vessels (Fig. 9.6). Direct EB involvement may mimic tumor [3]. The most prominent finding of EB histoplasmosis in a review was hyperemic mucosa in 27 %. Masses, mucosal hemorrhage, and broncholiths were other EB findings [3]. (Table 9.4)

Fig. 9.6
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Bronchoscopic view of fibrosing mediastinitis (a, b). Note the presence of erythema, mucosal edema, and prominent blood vessels

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Table 9.4 Bronchoscopic findings in various endobronchial fungal infections
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Pathology

Fungi are eukaryotic one-celled organisms that rarely cause diseases. These are more complex than bacteria. Tubular aggregates of fungi are called “hyphae.” If it shows constriction, it is called “pseudohyphae.” Discrete fungal cells called yeast or spores and spore-forming bodies are known as “conidia” or “sporangia.” Demonstration of fungi in the tissue or culture growth lead to diagnosis. Some fungi can be visible on hematoxylin and eosin stains. Gomori methenamine silver (GMS), Grocott silver stain, and periodic acid–Schiff (PAS) stains are needed for screening and confirmation. A diagnosis of a particular fungus can be made based on the morphology and size [48] (Table 9.5).

Table 9.5 Diagnostic features of fungi
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Diagnosis

Bronchial washings and/or brushings provide a diagnosis in 36 % of patients. Bronchoalveolar lavage (BAL) culture is positive in 25 % of cases. The time required for fungal growth in culture is usually several weeks when incubated at 25–30 °C. The specimen is inoculated into media like Sabouraud’s dextrose agar-containing cycloheximide and chloramphenicol. The cycloheximide is left out if a mold requires identification. Culture identifies the organism responsible for the infection and is very helpful in selecting the most suitable treatment [3].

Endobronchial biopsy of the lesion can be diagnostic in 46 % of patients. Serology could be diagnostic in as many as 20 % of cases among all patients with coccidioidomycosis, aspergillosis, and cryptococcosis [3]. Diagnosis is established at necropsy in as many as 12 % of patients.

Aspergillosis is known to be a common colonizer of the respiratory tract; thus, sputum cultures are not reliable. A tissue diagnosis is most definitive; however, when this is not available, multiple positive cultures in appropriate clinical context may suggest the diagnosis. Serological test for the detection of galactomannan antigen has been reported to have 81 % sensitivity and 89 % specificity [49]. However, far lower sensitivity (30 %) has been reported in lung transplant recipients with invasive aspergillosis [50]. PCR and nucleic acid sequence-based amplification are other advanced methods for establishing the diagnosis of aspergillosis and may support EB involvement [23]. Histopathological examination and culture of EB biopsies in 35 %, bronchial washing, and brushing material in 40 % and BAL in 28 % of patients are the main confirmatory tests for EB aspergillosis. Presumptive diagnosis of respiratory tract disease can be made in the absence of a tissue biopsy if Aspergillus spp. are cultured from a respiratory sample, a compatible lesion or syndrome is present, and no alternative causative process is identified. Although serum galactomannan antigen testing and PCR-based techniques may be useful, they have not been studied in patients with HIV infection.

The diagnosis of EB coccidioidomycosis is established by demonstration of spherules on a wet preparation of the EB specimen. Potassium hydroxide solution, calcofluor staining, or Papanicolaou staining are usually used for this purpose [51]. The diagnosis of coccidioidomycosis was made by surgical, laryngoscopic, or EB biopsy of an airway lesion in 3, 5, and 66 % of the patients, respectively. A bronchial brush of a lesion provided the diagnosis rarely. Skin and paravertebral mass biopsy may also lead to diagnosis. Culture of BAL is reported to be positive in 32 % cases and exclusively diagnostic in 13 %. Although serology was available in 74 % of the patients, it was helpful for presumptive diagnosis in only 3 % of the patients [3]. Thus, it is not recommended as a diagnostic test due to impaired serologic responses among immunocompromised hosts [24]. The mainstays of diagnosis of coccidioidomycosis are histopathological identification and cultures [52]. In cases of pulmonary coccidioidomycosis, results of culture of respiratory specimens (sputum, BAL fluid, or transbronchial biopsy) are frequently positive. The diagnosis can also be established by demonstration of the typical spherule on histopathological examination of involved tissue.

In endobronchial mucormycosis, biopsy reveals characteristic broad, non-septate hyphae with right-angle branching on calcofluor white or methenamine silver stains. However, the absence of hyphae does not rule out the diagnosis in a proper clinical setting. Sputum or BAL specimens may also show the characteristic hyphae. In published cases of EB mucormycosis, bronchial washing and brushings were diagnostic in 52 % of the cases and EB biopsy was diagnostic in 45 % patients. However, in 26 % patients the diagnosis was established at necropsy [3].

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 [3, 28]. However, there are no established criteria to confirm airway candidiasis. Primary pulmonary candidiasis may be associated with EB involvement. However, ruling out of other organisms causing airway involvement is essential.

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 suggests extrapulmonary spread [53]. 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 evaluation in immunocompromised hosts with pulmonary cryptococcosis [34]. In EB cryptococcosis, serology in 77 % of the patients, EB biopsy in 69 %, other bronchoscopic material in 46 %, and BAL culture in 15 % were helpful in making the diagnosis. Blood fungal cultures are also specific and should be performed. The diagnosis of pulmonary cryptococcosis can be made by culture of sputum, BAL fluid, pleural fluid, and transbronchial biopsy specimen. The measurement of cryptococcal antigen in the BAL can be a rapid, simple way to make the diagnosis [54].

In the appropriate clinical setting, detection of the histoplasmosis on a bronchoscopy specimen culture or glycoprotein antigen detection in urine or serum by complement fixation helps 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 [3]. In 82 % of the patients, diagnosis was established by the EB biopsy.

Differential Diagnosis

For fungus ball, the air crescent sign is often considered to be characteristic of mycetomas but has also been described in bronchogenic carcinoma, retained foreign body following thoracotomy, hemorrhage into a cavity, Wegener’s granulomatosis, sclerosing haemangioma, echinococcal cyst, tuberculosis, and Rasmussen aneurysm in a tuberculous cavity [55]. The air crescent sign may also be seen in angioinvasive aspergillosis, where it corresponds pathologically to a space caused by retraction of an area of retracted infarcted lung (Table 9.6) [56].

Table 9.6 Differential diagnosis for pulmonary fungal infections
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Complications

Complications of EBFI are disease dissemination to other sites (i.e., brain, meninges, skin, liver, spleen, kidneys, adrenals, heart, and eyes). Sepsis syndrome and blood vessel invasion can also be seen which can lead to hemoptysis, pulmonary infarction, myocardial infarction, cerebral emboli, cerebral infarction, or blindness. Other complications associated with EBFI are listed in Table 9.7 [3].

Table 9.7 Complications of endobronchial fungal infection
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Treatment

Suggested treatment for EB aspergillosis is similar to that for invasive aspergillosis, which includes intravenous AmB (1–1.5 mg/kg/day), liposomal AmB (5 mg/kg/day), and/or 400 mg/day of oral itraconazole. Voriconazole, 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 (400 mg every 12 h for 2 doses then 200 mg every 12 h for oral voriconazole). Duration of therapy is guided by clinical response. 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 neutropenia and neutrophil function and reduction of immunosuppression [57, 58]. Other possible therapies include caspofungin alone (though some experts have raised concerns about its efficacy in severe disease) or in combination with voriconazole, intravenous AmB, or liposomal AmB. The role of aerosolized AmB in therapy remains controversial, although authors have reported it to be effective [58–60]. Local instillation directly to the cavity for fungus ball or pleural space can also be advocated [61]. Further studies are needed to determine optimal therapy. Liposomal and standard AmB inhaled formulations have been studied more extensively in the context of prophylaxis in lung transplantation [58]. Posttransplant antifungal prophylactic or preemptive therapies are used in many transplant centers, especially in patients with cystic fibrosis where Aspergillus is a common colonizer [23, 51].

In coccidioidomycosis, therapies utilized in reported cases have generally followed the Infectious Diseases Society of America (IDSA) guidelines. These include intravenous AmB (0.5–0.7 mg/kg/day), oral ketoconazole (400 mg/day), oral or intravenous fluconazole (400–800 mg/day), or oral itraconazole (200 mg twice a day) either singly or in combination. According to these guidelines, a total intravenous AmB dose of 1.5–3.0 g is followed by oral azole therapy lasting from 3 to 24 months depending on the response. Among immunocompromised hosts, lifelong suppressive therapy may be required. Surgical resection may also be required for localized refractory lesions or those associated with significant hemoptysis [59]. In 38 EB coccidioidomycosis cases, 26 (68 %) patients received a course of intravenous AmB 10 (26 %), 2 cases oral ketoconazole, 8 cases oral fluconazole, and 3 cases itraconazole before or after the course of AmB. Two patients received multiple azoles and another 2 received fluconazole therapy alone. Therapy duration was at least 12 months.

Mucor species are resistant to azoles and echinocandins. The recommended therapy is high-dose intravenous AmB or liposomal AmB, as well as surgical or EB resection, in appropriate clinical settings [3]. As Mucor is angioinvasive and a rapidly growing fungus, surgical intervention should be early and aggressive. Concomitant systemic treatment is also required [62]. In a large review, 85 % of patients who underwent surgical treatment survived their disease.

Management of EB candidiasis is similar to systemic infection. Systemic therapy for primary candidiasis consists of either intravenous AmB or liposomal AmB in severely ill patients or oral fluconazole in milder presentations [18]. Caspofungin is a more recent alternative, particularly for azole-resistant yeasts. In our literature search, 8 patients (57 %) received intravenous AmB and/or aerosolized AmB, 5 (36 %) patients received fluconazole and remaining 2 (14 %) received itraconazole (14 %).

In pulmonary cryptococcosis, recommended therapy is intravenous AmB (0.7 mg/kg/day) plus flucytosine (100 mg/kg/day) as induction therapy for 3–4 weeks, followed by oral fluconazole [3]. The optimal duration of maintenance therapy with fluconazole is unclear. In immunocompromised hosts, at least a 6–12-month course of therapy should be considered. It is recommended that all HIV-infected individuals continue maintenance therapy for life. Itraconazole is an acceptable prophylactic alternative [63]. There are no specific recommendations for the treatment of EB disease. Hence, a regimen similar to that for systemic infection should be acceptable. Therapy duration varied from 3 to 18 months. With appropriate therapy, 62 % of patients were alive at the time of reporting [3].

According to the IDSA guidelines for pulmonary histoplasmosis, if the patient is critically ill, intravenous AmB (0.7–1.0 mg/kg/day) is considered, with the total AmB treatment amount 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 [64]. While it is well known that there is generally no added benefit of antifungal treatment 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 [3, 39]. Prognosis of the patient with EB histoplasmosis is relatively good. In cases reported to date, all patients with EB histoplasmosis were alive at the time of report, after appropriate therapy. Surgical approaches, including lobectomy, segmentectomy, or closure of the bronchoesophageal fistula, were required in 72 % of the cases. Only 18 % received oral antifungal therapy while steroids were used in 45 %.

Therapeutic bronchoscopy may be required in as many as 30 % of patients with EB fungal infections. Such procedures were performed to excise or vaporize the mass lesions in 5 %, to stop hemoptysis in 6 % and to place a stent or perform balloon dilatation for stenotic airways in 8 and 9 %, respectively [3].

Prevention

HIV-infected patients are routinely treated with prophylactic antifungal drugs to try to avoid infection with opportunistic fungal pathogens, particularly C. neoformans. Transplant patients may also benefit from prophylactic antifungal agents. Itraconazole has shown some benefits as prophylaxis against invasive fungal infections in transplant patients. Patients likely to have prolonged neutropenia should avoid activities that increase exposure to environmental fungal spores, such as gardening or working with potted plants and fresh flowers, cleaning, building work, and handling uncooked vegetables [65].

Treatment Outcomes

Forty-five percentage of the lung transplant recipients with EB aspergillosis may require bronchoplasty for stenosis. EB involvement with Aspergillus may indicate a poor prognosis [44, 66]. Nine percentage of EB aspergillosis with invasive disease and concomitant massive hemoptysis is associated with grave prognosis. For Aspergillosis, if the suture material from prior surgery is present in the EB tree, it should be removed with scissors or burned with laser photoablation [67].

In Mucormycosis, if disease is not detected early enough, mortality is very high. Of the 31 reports, 77 % were treated with intravenous AmB (1 mg/kg/day), 42 % of the patients underwent surgery, and 3 % had endoscopic removal of a plug with rigid bronchoscope. Reported mortality was 52 % [3]. In candidiasis, reported mortality was 21 % [3].

For coccidioidomycosis, airway disease may require stent, tracheostomy, and surgical management to prevent complete obstruction of the airway [3].

In histoplasmosis, a broncholith, if detected free in the bronchus, can be removed via bronchoscope. In patients with hemoptysis from fibrosing mediastinitis, hemostasis can be achieved by argon plasma coagulation or laser photoresection using a flexible bronchoscopy [63]. As reported in the literature, therapeutic bronchoscopy was required in 18 % using argon plasma coagulation or Nd-YAG laser for hemoptysis. This presentation also required bronchial artery embolization 27 % [3].

Prognosis

An exhaustive review of literature reveals that complete cure can be achieved in 36 % of patients with aspergillosis, 11 % with coccidioidomycosis, 35 % with zygomycosis, 78 % with candidiasis, 62 % with cryptococcosis, and 100 % with histoplasmosis [3].

Overall, reported mortality from EB aspergillosis is approximately 48 %. For coccidioidomycosis, even if AmB was used, 3 patients died, 4 were alive, and the survival status of 31 patients was unknown [3].

Although extended follow-up was not available for all patients, 48 % with aspergillosis, 8 % with coccidioidomycosis, 52 % with zygomycosis with 21 % candidiasis, and 31 % with cryptococcosis had expired despite appropriate therapy [3].

Summary and Recommendations

EBFI usually occurs by inhalation of fungal organisms. Its true incidence and prevalence remains unknown. Immunocompromised individuals are affected much more than immunocompetent ones. Serologic examination may support the clinical suspicion. In most patients with EBFI, bronchoscopic examination correlates with the radiographic findings. Bronchospasm, pneumothorax, and bleeding are seen as complications in very small percentages with flexible bronchoscopy [3, 68]. Bronchoscopic descriptions of airway lesions include mass lesions, yellowish white or reddish polypoid lesions, fragile mucosa, plaques, and ulcerative lesions. Tissue necrosis-mimicking tumors may cause yellowish white pseudomembranous-type lesions especially in patients with aspergillosis and zygomycosis. Fungal organisms can also cause granulomas. Washing, brushing, and BAL or biopsy is required to confirm the diagnosis. Interventional bronchoscopic techniques may be required for removal of the deceased tissue. Fungal infections should feature in the differential diagnosis of any kind of EB disease, especially in an immunocompromised host.