Professional article Zdrav Vestn | januar – februar 2017 | letnik 86 Microbiology and immunology

Professional article

Fungal infections in patients with cystic fibrosis

Glivne okužbe pri bolnikih s cistično fibrozo

Rok Tomazin, Tadeja Matos

Abstract Institute of Microbiology In the last two decades prevalence of fungal infections is increasing for various reasons. One of them and Immunology, Faculty is the advance of medical science and the associated longer life expectancy in some patient groups. of Medicine, University of This includes cystic fibrosis patients who encounter fungal diseases already in their childhood. Fun- Ljubljana, Slovenia gal pathogens isolated in high frequencies from the respiratory tract include Aspergillus fumigatus, Korespondenca/ albicans and Scedosporium apiospermum. In the case of cystic fibrosis, these organisms Correspondence: normaly colonise the respiratory and intestinal mucosae and can cause hipersensitivity reactions Rok Tomazin, and invasive diseases. The -patient interactions are complex and depend on several different e: [email protected] factors which determine what course will the colonisation/infection take. lj.si Ključne besede: Izvleček cistična fibroza; glivne V zadnjem času se pojavnost glivnih okužb povečuje iz različnih razlogov. Eden od njih je napredek okužbe; Aspergillus; v medicinski znanosti in z njim povezana daljša pričakovana življenjska doba določenih skupin bol- Candida; Scedosporium nikov. Sem spadajo tudi bolniki s cistično fibrozo, ki se s problematiko glivnih patogenov srečujejo Key words: že v otroštvu. Največjo vlogo imajo glive Aspergillus fumigatus, in Scedosporium cystic fibrosis; fungal apiospermum. Pri cistični fibrozi so ti organizmi kolonizatorji dihal in prebavil, povzročitelji pre- infections; Aspergillus; občutljivostnih reakcij in v redkih primerih povzročitelji invazivnih okužb. Do kakšnega poteka bo Candida; Scedosporium prišlo, je odvisno od značilnosti posameznega bolnika, glive in okolja ter izredno kompleksnih inte- rakcij med njimi. Citirajte kot/Cite as: Zdrav Vestn. 2017; 86(1–2):42–52

Received: 18. 5. 2016 Cystic fibrosis and fungi Accepted: 7. 12. 2016 Cystic fibrosis (CF) is one of the most in the transport of ions on the respira- common autosomal recessive genetic tory epithelium and the resulting change diseases. One in every twenty-seven in viscosity of the secretions hinder the people carries a recessive allele. The dis- functioning of the mucociliary escala- ease occurs as the result of mutations in tor which creates favourable conditions the CFTR gene (Cystic Fibrosis Trans- for the development of various infec- membrane Conductance Regulator), tions. They are most frequently caused which affects the irregular synthesis of by Staphylococcus aureus, Haemophi- the protein involved in the transport of lus influenzae, Burkholderia cepacia and chloride ions across the membrane of Pseudomonas aeruginosa. The latter is the epithelial cells. Consequently, many considered one of the main causes for organ systems are affected, especially the progressive reduction in pulmonary the respiratory tract (1). Disturbances functions in many CF patients (1,2). In

Fungal infections in patients with cystic fibrosis 1 Microbiology and immunology

recent times, more interest has been paid and Rasamsonia argillacea, whose role in to infections caused by opportunistic CF pathobiology has yet to be defined. pathogenic fungi. Fungi are ubiquitous eukaryotic or- Fungi of the genus Candida ganisms, which may colonise the respir- atory and digestive tracts and causehy- Species of the genus Candida are as- persensitivity reactions and infections in comycetous , which can normally CF patients (3). The most common types be found in the oral and intestinal mu- of fungi isolated in CF patients include cosa, moist areas of the skin, the upper Aspergillus fumigatus, Candida albicans respiratory tract and genital mucosa. and Scedosporium apiospermum (3). They are present in people with a normal Initially, disorders or weakening of the immune response, as well as in patients immune system are not typical for CF with immunodeficiencies. Table 1 sum- patients, therefore the localisation of marises interactions between candida fungi is limited to the respiratory epithe- and a CF patient. lium. Irregular mucus secretion from the Factors associated with the isolation lower respiratory tract causes long-term of yeasts or candida include pancreatic exposure to fungal antigens, which leads insufficiency, osteopenia, mel- to the development of hypersensitivity litus and the concurrent colonisation reactions. Consequently, chronic coloni- with the bacteria P. aeruginosa (4,5). The sation and hypersensitive reactions are high proportion of CF patients colo- the main types of relationship between nised with candida (49.4 %) is mainly fungi and a CF patient. In immunosup- due to the progression of the underlying presed state, which normally occurs af- disease (6). The most frequently isolated ter lung transplantation, the relationship species is C. albicans, followed by Can- between opportunistic pathogens and dida glabrata, , Can- the patient can become more severe. In dida krusei and Candida tropicalis. They such cases, though very rare in CF pa- are often recovered from the sputum, but tients, fungi can invade the lung paren- the clinical significance of these isolates chyma and cause an invasive pulmonary is questionable because of the natural , which, in the absence of an im- occurrence of yeasts in the oral cavity mune response, can progress into multi- and pharynx; there is no proof support- organ disseminated infection associated ing the efficiency of treatment with high mortality. in these cases (7,8). In certain situations, the commensal Clinical mycology in relationship in CF patients turns into cystic fibrosis parasitism. The most commonly en- countered are superficial infections that Every day, CF patients are exposed affect the oral and/or genital mucosa. to an environment inhabited by fungi, There have been documented cases of including moulds and yeasts. A wide oropharyngeal candidosis, the develop- variety of fungi can be isolated from ment of which is enhanced by the im- respiratory samples but the two most paired functioning of the salivary glands, documented and studied agents are A. CF-related diabetes, steroid treatment fumigatus and C. albicans. Other com- and broad-spectrum treat- mon and interesting isolates include S. ment (6). Since there may also be other apiospermum, Exophiala dermatitidis causes for a similar symptomatology in

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CF patients (e.g. vitamin B complex de- ops into sepsis is associated with a high ficiency), microbiological confirmation mortality rate ranging between 30 and is always advised (6). Female CF patients 60 % (13). In order to monitor the pro- often suffer from fungal vulvovaginitis; gression of candidaemia and determine its occurrence is probably underesti- the damage to the organs, a fundoscopy mated as very little attention is paid to and a transoesophageal echocardiog- this type of fungal infections in CF (9). raphy are advised for neutropenic pa- Most superficial candidoses are success- tients (14). The first choice for treatment fully treated with , while se- are from the group of echi- rious cases and chronic recurrences of nocandins, usually (10,11). the infection are treated with itracona- The choice of antifungal medication de- zole (10,11). pends on the type of pathogen and the In addition to the aforementioned su- site of infection, among other factors. perficial infections, Candida spp. can also cause candidaemia and invasive can- Fungi of the genus Aspergillus didosis, which can develop into septic shock if not treated properly. The origin Species of the genus Aspergillus are of the infection is usually endogenous ubiquitous filamentous ascomycete fun- – candida are part of the normal gastro- gi. They are found in the air, water, dust intestinal microbiota. The origin of the and decomposing plants. Respiratory in- infection can also be the various vascu- fection or colonisation occurs through lar catheters on which yeasts form bio- the inhalation of aerosolised conidia. films. Lung transplant patients who re- The latter are small enough (2–5 µm) ceive immunosuppressives after surgery to enter the lower respiratory tract, but are at particularly high risk for invasive in a healthy person they are expelled candidosis (5,6). The haematogenous regularly by the clearance and defensive dissemination of candida mainly affects functions of the respiratory epithelium. the kidneys, spleen, skin, eyes, heart and In CF patients these two functions are meninges (12). Candidaemia that devel- compromised, therefore various types of

Table 1: Summary of the roles of different species of the genus Candida in CF patients.

Infection, Colonisation Surface infection Systemic infections colonisation with Candida spp. Risk factors in CF Diabetes, Diabetes, Immunosuppression after osteopenia, treatment with corticosteroids, transplant colonisation with treatment with broad-spectrum surgery Pseudomonas aeruginosa Clinical significance Short-term: Candidosis of the oral cavity and Candidaemia, / pharynx, disseminated candidosis, Long-term: fungal vulvovaginitis invasive candidosis progression of the underlying disease Medication of choice / Fluconazole, , fluconazole, (10,11) or based on the type of fungus and the results of susceptibility testing (10,11)

Fungal infections in patients with cystic fibrosis 3 Microbiology and immunology

fungi, most commonly A.fumigatus, can Allergens are either components of be isolated from the respiratory tract of a the cell wall or secondary metabolites large number of patients (5). Judging by that are secreted by the fungus into its the cultivation results, the prevalence of immediate surroundings (17). Classi- A. fumigatus is between 6 and 57 % (15). fied as A. fumigatus allergens are vari- The isolation of this fungus from respir- ous polysaccharides, elastases, catalase, atory samples can indicate colonisation, superoxide dismutase, glycopeptides allergic reactions or an infection (13). Ta- and nucleo- and proteolytic enzymes. ble 2 summarises interactions between Hypersensitivity reactions are mostly aspergilli and a CF patient . chronic in nature and are not related to The inhalation of aspergillus conidia a patient’s deteriorated immunity; they leads to different clinical manifestations, can lead to the aggravation of the under- which are difficult to distinguish from lying disease in CF patients (17,18). With each other because they overlap to some the onset of immunosuppression, some extent (15,16): of the aforementioned allergens take on a. intermediate colonisation, when the the role of virulence factors, which en- patient is only temporarily colonised, able the development of an invasive in- b. allergic sensitisation, when a patient fection. becomes sensitive to aspergillus anti- Ranked first among the diseases gens, caused by A. fumigatus is allergic bron- c. chronic colonisation, when a patient chopulmonary (ABPA), is colonised over a long period of which affects between 7 and 9 % of CF time with one or more strains, patients (19). It mostly affects adults (15). d. allergic bronchopulmonary aspergil- In ABPA the conidia typically germinate losis (ABPA), which represents the and the mycelium colonises the bron- intermediate state between colonisa- chial tree without invading the lung pa- tion and infection, renchyma. An inflammatory response to e. aspergilloma, aspergillus antigens develops, regulated f. invasive pulmonary aspergillosis, and by CD4 Th2 cells, which secrete various g. aspergillus bronchitis. inflammatory cytokines, especially IL-4 and IL-10 (17,20). This is followed by the The leading factors related to the iso- invasion of vasoactive substances and lation of moulds in CF patients are: the the emergence of specific antibodies, es- age above 18 years, diminished pulmo- pecially of the IgE class. Such an inflam- nary function and inhalation treatment matory reaction is clinically manifested with antibiotics. as a productive cough, the emergence of Long-term exposure to mould aller- pulmonary infiltrates and central bron- gens, which is the result of inadequate chiectases, and typically also peripheral clearance of the respiratory epithelium, and pulmonary eosinophilia and an in- leads to the occurrence of various hy- crease in the concentration of IgE in the persensitivity reactions. These are most serum (17,20). Possible complications frequently caused by moulds Alternaria include pulmonary fibrosis and chronic alternata, Cladosporium herbarum, Pen- cavitary aspergillosis, which can develop icillium spp. and A. fumigatus, the latter into aspergilloma (21). ABPA diagnosis is playing the most important role in CF based mainly on the clinical features and patients. immunological findings . ABPA mostly

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affects patients with bronchial asthma been used for a few years, all the pros and CF patients; in the latter a correct di- and cons of this treatment remain un- agnosis is more difficult to make because known. Apart from the aforementioned the symptoms of the underlying disease groups of medication used to treat the manifestations of ABPA overlap. ABPA, various antifungal drugs are also The minimum diagnostic criteria for used, lessening the load of aspergilli and ABPA in CF patients are (19): thus reducing episodes of exacerbation a. subacute or acute clinical aggravation and improving the pulmonary func- of the disease in absence of any other tion (22,25). possible cause; CF patients also exhibit the so-called b. elevated total serum IgE levels of allergic sensitisation (AS), which is still > 500 IU/mL, except in patients re- poorly defined. This term is used to de- ceiving corticosteroid treatment who scribe hypersensitity reactions which need to repeat testing after comple- do not meet all of the criteria necessary tion of treatment. If the concentra- for making a diagnosis of ABPA (17). AS tion of IgE is between 200 and 500 supposedly affects between 20 and 65 % IU/mL, tests are repeated after one to of CF patients (16). The problems of es- three months; tablishing the prevalence of AS lie in its c. immediate skin sensitivity to A. fu- overlapping clinical features with ABPA migatus antigens if the patient is not and the use of different diagnostic mi- receiving antihistamine treatment or crobiological methods. Another problem in vitro presence of serum IgE specific is poor comparability of commercially for A. fumigatus; available tests and in-house tests (16). d. detection of precipitating antibodies Recently, differences have been identi- or in vitro presence of serum IgG spe- fied that might enable a relatively simple cific for A. fumigatus, or differentiation between ABPA and AS e. presence of new or recent radiologi- based on the determination of CDC203c cal irregularities in the thorax that basophils concentration, galactomannan persist despite antibiotic treatment or antigen in lower respiratory tract sam- physiotherapy. ples and pecific IgG in serum. In con- trast with ABPA patients, patients with The fungus A. fumigatus can be iso- AS have a lower plasma concentration lated from 60 % of CF patients, but the of CDC203c basophils, a negative ga- cultivation has no diagnostic signifi- lactomannan test (< 0.5) and a positive cance. A.fumigatus-specific serum IgG (< 75µg/ ABPA is traditionally treated with mL) (13,16,27). corticosteroids, which are used in acute In addition to colonisation and hy- aggravation and as maintenance therapy persensitivity reactions, fungi also cause to prevent progressive advancement of infections that can affect several organ the damage to the lung tissue (19,22). systems. They are very aggressive and Currently, apart from corticosteroid associated with high mortality, but are therapy, recombinant monoclonal anti- fortunately relatively rare. Unlike hyper- bodies (e.g. omalizumab) are being in- sensitivity reactions, invasive mycoses troduced to prevent IgE from binding to normally affect immunocompromised effector immune cells (22-24). Because patients. The most significant risk factor this treatment option for ABPA has only for the development of invasive mycoses

Fungal infections in patients with cystic fibrosis 5 Microbiology and immunology

in CF patients is lung transplantation lower respiratory tract with invasion of and the accompanying immunosuppres- hyphae into the lung parenchyma. Typi- sive treatment. cal of the fungus A. fumigatus is angioin- The most common infection is inva- vasion, resulting in thrombosis, infarc- sive pulmonary aspergillosis (IPA) and tion and necrosis of lung tissue (12). CF only rarely disseminated invasive asper- patients also exhibit a non-angioinvasive gillosis (8). The most significant risk fac- type of IPA, which can occur in the ab- tors for the development of IPA in CF pa- sence of neutropenia (6). IPA is associ- tients are colonisation of the respiratory ated with a relatively high mortality (13), tract with A. fumigatus before transplant which in the case of CF normally does surgery and a positive intraoperative cul- not exceed 16 % (29). Diagnosing IPA is ture (28,29). Post-transplant CF patients difficult; it demands the consideration of are exposed to an increased risk for IPA clinical features, and the use of diagnos- as a large proportion of patients are col- tic imaging – especially CT scans of the onised with A. fumigatus (up to 57 %) thorax – and microbiological methods, even before transplantation (15,29). The such as the cultivation of bronchoscopic occurrence of the infection is enabled samples, detection of galactomannan by different virulence factors, especially and β-D-glucan antigenaemia and de- hydrolytic enzymes (elastases, proteases, tection of aspergillus DNA in the af- phospholipases, catalase) and gliotoxin, fected tissues, bronchoalveolar lavage which further weaken the functioning and blood. The gold standard for diag- of the mucociliary escalator, damage the nosis remains the detection of aspergilli respiratory epithelium and participate in in the primarily sterile clinical sample the formation of (30,31). with cultivation and histopathological IPA usually occurs approximately a evidence of the invasion in the affected month and a half after lung transplan- tissue (32). tation and affects about one fifth of the is the drug of choice in patients (29). The infection starts in the CF patients with IPA. When voricona-

Table 2: Summary of the roles of different species of the Aspergillus genus in CF patients

Infection, Colonisation Hypersensitivity reactions Infections colonisation with Aspergillus spp. Risk factors in case Age above 18, Long-term exposure to Lung transplant immunosuppression, of CF inhalation treatment with fungal allergens uncontrolled/untreated ABPA, antibiotics, colonisation of respiratory organs with FEV1 reduction aspergilli before a lung transplant Clinical significance Long-term colonisation as ABPA, AS Invasive (pulmonary) aspergillosis, a risk for the development chronic cavitary aspergillosis, of hypersensitivity reactions aspergilloma, and infections aspergillus bronchitis Medication of choice / Corticosteroids, Voriconazole, recombinant monoclonal amphotericin B (10,11) antibodies, triazoles (voriconazole or itraconazole) (10,11,22)

Key: ABPA – allergic bronchopulmonary aspergillosis, AS – allergic sensitisation, FEV1 – forced expiratory volume in one second

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zole is not the optimal choice, ampho- cell wall, which appears in form as tericin B is recommended (10,11). a young culture and becomes increas- In CF patients, unlike in any other ingly filamentous as it matures. In parts patient group, the fungus A. fumigatus of the world with a moderate climate it creates unique clinical features, referred is rarely isolated from nature; it is mostly to as aspergillus bronchitis. It was first associated with the human environment, described in 2006 and defined six years such as spas, saunas and dishwashers. later (33,34). Aspergillus bronchitis is de- In short, it can be found in a warm and scribed as chronic inflammation of the moist environment (35,36). We assume lower respiratory tract (bronchitis) with that the original natural habitat of E. der- A. fumigatus confirmed in the culture matitidis is the tropical rainforest (35). of bronchoscopic samples or detected In medicine, E. dermatitidis is known with molecular methods, and the pres- as the cause of infections of the skin and ence of increased specific IgG in the se- subcutaneous tissue, especially in tropi- rum (31,33,34). The most significant fac- cal climates. There are also rare docu- tor that helps to differentiate between mented cases of infections affecting the colonisation and aspergillus bronchitis is central nervous system (37). The role of clinical improvement in a patient receiv- E. dermatitidis in CF is still unknown. ing antifungal treatment; the medication Table 3 summarises interactions between proves ineffective in A.fumigatus coloni- E. dermatitidis and a CF patient. sation. The value of antifungal treatment In Europe, E. dermatitidis is isolated in these cases is not yet well defined, but from 5 to 19 % of respiratory samples; antifungals from the group of triazoles, descriptions of supposed invasive infec- especially itraconazole and voriconazole, tions are rare (38-41). None of the docu- should be considered (33,34). mented cases meet the criteria for a con- firmed invasive mycosis – the described Exophiala dermatitidis diagnoses are usually based on the isola- tion of E. dermatitidis from the sputum. Among the fungi often associated Improvement was noted with antifungal with the colonisation of the respiratory treatment. The patients can be treated tract in CF patientswe also find the fun- exclusively with amphotericin B or with gus Exophiala dermatitidis, which the a combination of amphotericin B and general public usually refers to as »black . Treatment with itraconazole yeast«. It is a fungus with a melaninated has proved to be the most efficient (36-

Table 3: Overview of the emerging fungal pathogens and their clinical significance in CF.

Exophiala dermatitidis Scedosporium apiospermum Rasamsonia argillacea Risk factors in case Age above 12, Unknown. Unknown. of CF pancreatic insufficiency, colonisation with A. fumigatus Clinical Colonisation, invasive infections Colonisation, invasive Colonisation, invasive significance during immunosuppression infections during infections during immunosuppression immunosuppression Treatment Amphotericin B ± flucytosine, Voricozanole, Echinocandins? (54,56) itraconazole (36-39) posacozanole (50-52)

Fungal infections in patients with cystic fibrosis 7 Microbiology and immunology

39). There are, however, reports of a long- mentospora, Petriella, Petriellopsis, Pseu- term colonisation of the respiratory tract dallescheria and, of course, Scedospori- where even several months of itracona- um (44). Consequently, the term zole treatment did not eliminate from /Scedosporium the sputum (42). apiospermum complex is usedto refer to Most research indicates that E. der- most of the frequently isolated, medically matitidis has the role of a coloniser in CF relevant species. For easier understand- and that the isolation from the respira- ing, we will discuss S. apiospermum. tory tract normally does not indicate an Globally speaking, S. apiospermum is the infection. At the moment, the identified second most frequent mould isolated risk factors for the colonisation with E. from respiratory samples in CF patients dermatitidis are the age above 12, pancre- and is associated with chronic colonisa- atic insufficiency and the colonisation tion (45,46). The prevalence is between with A. fumigatus (40,43). It is interest- 5.7 and 10 % (47). Invasive scedosporiosis ing that the occurrence of E. dermatitidis is very rare in CF patients and there have drops after the age of 35 (41). The coloni- been only eight documented cases since sation is supposedly also dependent on 1996; unfortunately, all of them ended in the patient’s genotype: it was most com- death (47,48). Most of the patients had mon in patients with a mutation of the a previously detected colonisation with CFTR gene at position 508 on chromo- S. apiospermum. Therefore the isolation some 7 (genotype ∆F508/∆F508) (40). It of this mould from the respiratory tract is mostly a chronic colonisation, which is a contraindication for lung transplan- can be established only after an extend- tation (47). Apart from invasive infec- ed incubation period on classic and/or tions, there have also been documented specific mycological media with the ad- cases of allergic bronchopulmonary sce- dition of erythritol and chlorampheni- dosporiosis (49). col (40). For the isolation of E. dermatiti- Scedosporiosis is difficult to treat be- dis, clinical samples have to be incubated cause the fungus is resistant to several for 5 to 7 days on average (43). antifungal drugs. S. apiospermum fungi are intrinsically resistant to ampho- Fungi from the genus Scedosporium tericin B and flucytosine, and usually re- act only to triazole treatment; voricona- Apart from A. fumigatus, Scedospori- zole and may be used (50). um apiospermum is another important In vitro activity against S. apiospermum filamentous fungus that causes invasive is also exhibited by the more recent isa- infections in CF patients; it causes ex- vuconazole (50). For now, voriconazole tremely rapid, aggressive infections quite remains the drug of choice (52). resistant to antifungal treatment. Table 3 summarises interactions between S. api- Rasamsonia argillacea ospermum and a CF patient. Scedosporium spp. are filamentous Rasamsonia argillacea is a filamen- ascomycetes found mainly in water and tous ascomycete fungus. It belongs to the soil all around the world. Their chang- group of the so-called emerging patho- ing makes classification dif- gens as its significance in medicine has ficult: today, the species once belonging been researched only in the past few to genus Scedosporium are reclassified years. R. argillacea is a thermotolerant into the genera Parascedosporium, Lo- mould, which morphologically resem-

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bles the genera of Penicillium and Pae- trations for the group are cilomyces (53,54). It is, therefore, often low (54,56). misidentified and its prevalence is thus probably underestimated. 2.6 % of CF Conclusion patients are supposedly colonised (55). Table 3 summarises interactions between People are constantly in contact with R. argillacea and a CF patient. fungi as these are normally present in R. argillacea is most frequently iso- our environment. In CF patients the in- lated from respiratory samples in CF haled fungi are not expelled from the patients and in patients with chronic lower respiratory tract because of the granulomatous disease (54). Similarly to impaired clearance function, which ena- E. dermatitidis, R. argillacea is isolated bles their growth and leads to different using dithiothreitol liquefaction of vis- clinical conditions. These usually in- cous clinical samples from the lower res- clude hypersensitivity reactions because piratory tract (43). R. argillacea forms a a normally functioning immune system complex of related, morphologically in- prevents fungal invasion. The latter can separable species, among which the most occur after lung transplantation due to common are R. argillacea sensu stricto, immunosuppressive treatment, the most R. piperina and R. aegroticola (55). The common mycoses being invasive pulmo- clinical significance of the isolation of nary aspergillosis and scedosporiosis. species from the R. argillacea complex in The diagnosis and treatment of invasive CF patients is still unknown, but it prob- mycoses are very difficult and demand ably just indicates colonisation of the close cooperation between clinicians respiratory epithelium (54,56). and microbiologists. Further research The correct identification of moulds will improve the understanding of in- is not only important to obtain epide- fections caused by fungi, which are rela- miologica information, but is also neces- tively well-known in medicine, such as sary to choose the correct antifungals in Candida, Aspergillus and Scedosporium. the event of an infection. It is typical for At the same time, we will obtain more the R. argillacea fungus to exhibit high information on the role of E. dermati- minimal inhibitory concentrations for tidis and R. argillacea, the two relatively amphotericin B and antifungals from unknown species compared to candida the group, especially voriconazole, and aspergilli. while the minimal inhibitory concen-

References 1. Lyczak JB, Cannon CL, Pier GB. Lung infections covery of filamentous fungi in individuals with associated with cystic fibrosis. Clin Microbiol Rev. cystic fibrosis. J Cyst Fibros. 2010;9(2):110–6. 2002;5(2):194–222. 5. Chotirmall SH, Greene CM, McElvaney NG. Can- 2. Emerson J, Rosenfeld M, McNamara S, Ramsey B, dida species in cystic fibrosis: a road less travelled. Gibson RL. Pseudomonas aeruginosa and other Med Mycol. 2010;48.Supp 1:S114-24. predictors of mortality and morbidity in young 6. Chotirmall SH, McElvaney NG. Fungi in the cystic children with cystic fibrosis. Pediatr Pulmonol. fibrosis lung: bystanders or pathogens? Int J Bio- 2002;34(2):91–100. chem Cell Biol. 2014;52:161–73. 3. Liu JC, Modha EM, Gaillard EA. What is the clini- 7. LiPuma JJ. The changing microbial epidemi- cal significance of filamentous fungi positive spu- ology in cystic fibrosis. Clin Microbiol Rev. tum cultures in patients with cystic fibrosis? J Cys 2010;23(2):299–323. Fibros. 2013;12(3):187–93. 8. Chmiel JF, Aksamit TR, Chotirmall SH, Dasen- 4. Sudfeld CR, Dasenbrook EC, Merz WG, Carroll brook EC, Elborn JS, LiPuma JJ, et al. Antibiotic KC, Boyle MP. Prevalence and risk factors for re- management of lung infections in cystic fibrosis. II.

Fungal infections in patients with cystic fibrosis 9 Microbiology and immunology

Nontuberculous mycobacteria, anaerobic bacteria, fibrosis: a systematic review. Clin Exp Allergy. and fungi. Ann Am Thorac Soc. 2014;11(8):1298– 2014;44(10):1210–27. 306. 26. Chishimba L, Langridge P, Powell G, Niven RM, 9. Lyon A, Gun E, Haworth CS, Bilton D. Is genital Denning DW. Efficacy and safety of nebulised Candida infection a significant problem for adults amphotericin B (NAB) in severe asthma with with cystic fibrosis. J Cyst Fibros. 2004;3:S99. fungal sensitisation (SAFS) and allergic bron- 10. Čižman M, Beović B. Kako predpisujemo proti- chopulmonary aspergillosis (ABPA). J Asthma. mikrobna zdravila v bolnišnicah. 2. izd. Ljubljana: 2015;52(3):289–95. Sekcija za protimikrobno zdravljenje Slovenskega 27. Gernez Y, Walters J, Mirković B, Gillian ML, Col- zdravniškega društva; 2013. p. 148–53. leen DE, Davies ZA, et al. Blood basophil activa- 11. The Sanford Guide to Antimicrobial Therapy, Web tion is a reliable biomarker of allergic bronchopul- Edition [cited 3.8.2016].Available froM. http:// monary aspergillosis in cystic fibrosis. Eur Respir webedition.sanfordguide.com/. J. 2015;ERJ-01068. 12. Brooks GF, Carroll KC, Butel JS, Morse SA, Mi- 28. Pappas PG, Alexander BD, Andes DR, Hadley S, etzner TA. Jawetz, Melnick, & Adelberg‘s Medical Kauffman CA, Freifeld A, et al. Invasive fungal Microbiology. 26th ed. New York: Lange medical infections among organ transplant recipients: re- books; 2013. sults of the Transplant-Associated Infection Sur- 13. Global action found for fungal infections (GAFFI). veillance Network (TRANSNET). Clin Infect Dis. 2016 [cited 4.5.2016]. Available from: http://www. 2010;50(8):1101–11. gaffi.org/. 29. Luong ML, Chaparro C, Stephenson A, Rotstein C, 14. Corneley OA, Bassetti M, Calandra T, Garbino J, Singer LG, Waters V, et al. Pretransplant Aspergil- Kullberg BJ, Lortholary O, et al. ESCMID guide- lus colonization of cystic fibrosis patients and the line for the diagnosis and management of Can- incidence of post–lung transplant invasive asper- dida diseases 2012:non-neutropenic adult patients. gillosis. Transplantation. 2014;97(3):351–7. Clin Microbiol Infect. 2012;18.s7:19–37 30. Latgé JP. The pathobiology of Aspergillus fumiga- 15. Baxter CG, Dunn G, Jones AM, Webb K, Gore R, tus. Trends Microbiol. 2001;9(8):382–9. Richardson MD, Denning DW. Novel immuno- 31. Felton IC, Simmonds NJ. Aspergillus and cystic fi- logic classification of aspergillosis in adult cystic brosis: old disease–new classifications. Curr Opin fibrosis. J Allergy Clin Immunol. 2013;132(3):560– Pulm Med. 2014;20(6):632–8. 6. 32. De Pauw B, Walsh TJ, Donnelly JP, Stevens DA, 16. Maturu VN, Agarwal R. Prevalence of Aspergillus Edwards JE, Calandra T, et al. Revised definitions sensitization and allergic bronchopulmonary as- of invasive fungal disease from the European or- pergillosis in cystic fibrosis: systematic review and ganization for research and treatment of cancer/ meta-analysis. Clin Exp Allergy. 2015;45(12):1765– invasive fungal infections cooperative group and 78. the national institute of allergy and infectious dis- 17. Knutsen AP, Bush RK, Demain JG, Denning DW, eases mycoses study group (EORTC/MSG) con- Dixit A, Fairs A, et al. Fungi and allergic lower res- sensus group. Clin Infect Dis. 2008;46(12):1813–21. piratory tract diseases. J Allergy Clin Immunol. 33. Shoseyov D, Brownlee KG, Conway SP, Kerem E. 2012;129(2):280–91 Aspergillus bronchitis in cystic fibrosis. Chest. 18. Moss RB. Allergic bronchopulmonary aspergil- 2006;130(1):222–6. losis and Aspergillus infection in cystic fibrosis. 34. Chrdle A, Mustakim S, Bright-Thomas RJ, Baxter Curr Opin Pulm Med. 2010;16(6) 598–603. CG, Felton T, Denning DW. Aspergillus bronchitis 19. Knutsen AP, Slavin RG. Allergic bronchopulmo- without significant immunocompromise. Ann N nary aspergillosis in asthma and cystic fibrosis. Y Acad Sci. 2012;1272(1):73–85. Clin Dev Immunol. 2011;843763. 35. Sudhadham M, Sihanonth P, Sivichai S, Chaiyarat 20. Murray PR, Rosenthal KS, Pfaller MA. Medical R, Dorrestein GM, Menken SBJ, De Hoog GS, et. microbiology. 7th ed: Philadelphia: Mosby: Else- al. The neurotropic black yeast Exophiala dermati- vier; 2013 tidis has a possible origin in the tropical rain for- 21. Kosmidis C, Denning DW. The clinical spectrum of est. Stud Mycol. 2008;61:145–55. pulmonary aspergillosis. Thorax. 2015;70(3):270–7. 36. Zalar P, Novak M, De Hoog GS, Gunde-Cimerman 22. Wong R, Wong M, Robinson PD, Fitzgerald DA. N. Dishwashers–a man-made ecological niche ac- Omalizumab in the management of steroid de- commodating human opportunistic fungal patho- pendent allergic bronchopulmonary aspergillo- gens. Fungal Biol. 2011;115.10:997–1007. sis (ABPA) complicating cystic fibrosis. Paediatr 37. Kenney RT, Kwon-Chung KJ, Waytes AT, Melnick, Respir Rev. 2013;14(1):22–4. DA, Pass HI, Merino MJ, et al. Successful treat- 23. de Benedictis FM, Bush A. Corticosteroids in res- ment of systemic Exophiala dermatitidis infection piratory diseases in children. Am J Respir Crit in a patient with chronic granulomatous disease. Care Med. 2012;185(1):12–23. Clin Infect Dis. 1992;14(1):235–42. 24. Tanou K, Elias Z, Kaditis AG. Omalizumab 38. Kusenbach G, Skopnik H, Haase G, Friedrichs F, therapy for allergic bronchopulmonary asper- Döhmen H. Exophiala dermatitidis pneumonia in gillosis in children with cystic fibrosis: a syn- cystic fibrosis. Eur J Pediatr. 1992;151(5):344–6. thesis of published evidence. Pediatr Pulmonol. 39. Diemert D, Kunimoto D, Sand C, Rennie R. 2014;49(5):503–7. Sputum isolation of Wangiella dermatitidis in 25. Moreira AS, Silva D, Reis Ferreira A, Delgado L. patients with cystic fibrosis. Scand J Infect Dis. Antifungal treatment in allergic bronchopul- 2001;33(10):777–9. monary aspergillosis with and without cystic

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40. Lebecque P, Leonard A, Huang D, Reychler G, Bo- with cystic fibrosis. Med Mycol. 2010;48 Suppl: eras A, Leal T, Symoens F. Exophiala (Wangiella) S108–13. dermatitidis and cystic fibrosis–Prevalence and 49. Cimon B, Carrère J, Vinatier JF, Chazalette JP, risk factors. Med Mycol. 2010;48 Supp 1:S4–9. Chabasse D, Bouchara JP. Clinical significance 41. Kondori N, Gilljam M, Lindblad A, Jönsson B, of Scedosporium apiospermum in patients with Moore ERB, Wennerås C. High rate of Exophiala cystic fibrosis. Eur J Clin Microbiol Infect Dis. dermatitidis recovery in the airways of patients 2000;19(1):53–6. with cystic fibrosis is associated with pancreatic 50. Sahi H, Avery RK, Minai OA, Hall G, Mehta insufficiency. J Clin Microbiol. 2011;49(3):1004–9. AC, Raina P, et al. Scedosporium apiospermum 42. Blaschke-Hellmessen R, Lauterbach I, Paul KD, (Pseudoallescheria boydii) infection in lung Tintelnot K, Weissbach G. Detection of Exophiala transplant recipients. J Heart Lung Transplant. dermatitidis (Kano) De Hoog 1977 in septicemia 2007;26(4):350–6. of a child with acute lymphatic leukemia and in 51. Pfaller MA, Messer SA, Rhomberg PR, Jones RN, patients with cystic fibrosis. Mycoses. 1994;37 Sup- Castanhiera M. In vitro activity of isavuconazole pl 1:89–96. and comparator antifungal agents tested against 43. Masoud-Landgraf L, Badura A, Eber E, Feierl G, a global collection of opportunistic yeasts and Marth E, Buzina W. Modified culture method de- moulds. J Clin Microbiol. 2013;JCM-00863. tects a high diversity of fungal species in cystic fi- 52. Tortorano AM, Richardson M, Roilides E, van brosis patients. Med Mycol. 2014;52(2):179–86. Diepeningenet A, Caira M, Munoz P, et al. ESC- 44. Lackner M, de Hoog GS, Yang L, Ferreira Moreno MID and ECMM joint guidelines on diagnosis L, Ahmed SA, et al. Proposed nomenclature for and management of hyalohyphomycosis: Fusari- Pseudallescheria, Scedosporium and related gen- um spp , Scedosporium spp. and others. Clin Mi- era. Fungal Divers. 2014;67(1):1–10. crobiol Infect. 2014;20(s3):27–46. 45. Bernhardt A, Sedlacek L, Wagner S, Schwarz C, 53. Houbraken J, Spierenburg H, Frisvad JS. Rasamso- Würstl B, Tintelnot K. Multilocus sequence typ- nia, a new genus comprising thermotolerant and ing of Scedosporium apiospermum and Pseu- thermophilic Talaromyces and Geosmithia spe- dallescheria boydii isolates from cystic fibrosis cies. Antonie van Leeuwenhoek. 2012;101(2):403– patients. J Cyst Fibros. 2013;12(6):592–8. 21. 46. Zouhair R, Rougeron A, Razafimandimby B, 54. Giraud S, Favennec L, Bougnoux ME, Bouchara JP. Kobi A, Bouchara JP, Giraud S. Distribution of Rasamsonia argillacea species complex: taxonomy, the different species of the Pseudallescheria boy- pathogenesis and clinical relevance. Future Micro- dii/Scedosporium apiospermum complex in biol. 2013;8(8):967–78. French patients with cystic fibrosis. Med Mycol. 55. Steinmann J, Giraud S, Schmidt D, Sedlacek L, 2013;51(6):603–13. Hamprecht A, Houbraken J, et al. Validation of a 47. Morio F, Horeau-Langlard D, Gay-Andrieu F, Ta- novel real-time PCR for detecting Rasamsonia ar- larmin JP, Haloun A, Treilhaud M, et al. Dissemi- gillacea species complex in respiratory secretions nated Scedosporium/Pseudallescheria infection from cystic fibrosis patients. New Microbes New after double-lung transplantation in patients with Infect. 2014;2(3):72–8. cystic fibrosis. J Clin Microbiol. 2010;48(5):1978– 56. Matos T, Cerar Kišek T, Praprotnik M, Krivec U, 82. Pirš M. First recovery of Rasamsonia argillacea 48. Borghi E, Iatta R, Manca A, Montagna MT, Morace species complex isolated in adolescent patient G. Chronic airway colonization by Scedosporium with cystic fibrosis in Slovenia–case report and apiospermum with a fatal outcome in a patient review of literature. Mycoses. 2015;58(8):506–10.

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