Introduction

Patients with cystic fibrosis (CF) suffer from chronic infections of the lung and multiple recurrent bronchopulmonary disease exacerbations. Besides bacteria such as Pseudomonas aeruginosa, some filamentous fungi such as Aspergillus spp., Scedosporium spp. and Exophiala spp. are gaining increasing importance as cause of CF bronchopulmonary exacerbations. The prevalence of these pathogenic fungi ranges from 1.9 to 56.7% [1, 2], and their pathogenicity may differ from that of bacteria as fungi may differ in their ability to colonize the airways. Therefore, their pathogenicity may be dependent on certain immunological pathways modifying patients’ susceptibility. Predisposing factors such as defective muco-ciliary clearance, prolonged antibiotic treatments, local inflammation, and the use of inhaled and systemic corticosteroids may facilitate fungal growth in the CF lungs.

The fungal biota is dominated by filamentous fungi such as Aspergillus fumigatus, Aspergillus terreus, Scedosporium apiospermum, and yeasts such as Candida albicans and Candida glabrata [1, 2]. However, rare fungi such as Exophiala dermatitidis, Trichosporon mycotoxinivorans and Rasamsonia argillacea can colonize the airways of CF patients, causing significant clinical infections. Therapy can be challenging as some of the moulds are multi-drug resistant, for example Lomentospora prolificans. Others like A. fumigatus usually tend to be easily treatable. Nevertheless, an increasing number of azole-resistant Aspergillus species have been described in the recent years (for a review, see Hamprecht et al. in this special issue). In this context, this review will address therapeutic strategies and prevention of fungal infections in patients with CF.

Since criteria for invasive fungal infections (pneumonia) in CF patients have not been defined yet, the following criteria for “highly probable” invasive pulmonary fungal infection were considered by the authors:

  1. 1.

    Increased sputum production.

  2. 2.

    Multiple isolation of the same fungal species from sputum or bronchoalveolar lavage (BAL) (at least two culture-positive samples in 6 months).

  3. 3.

    Pulmonary infiltrate(s) on chest CT scan or X-ray.

  4. 4.

    Treatment failure with antibiotic therapy (two and more antibiotic treatments, duration two or more weeks).

  5. 5.

    Unexplained lung function decline (exclusion of new CF-related diseases, e.g. diabetes mellitus).

  6. 6.

    Exclusion of new/other bacteria (e.g. non-tuberculous mycobacteria or Pseudomonas aeruginosa).

  7. 7.

    Exclusion of allergic bronchopulmonary aspergillosis.

Antifungal Treatment Strategies

Aspergillus spp.

Aspergillus spp. are the most frequent colonizing fungal pathogens in patients with CF. In a recent study examining 25,975 sputum samples from patients with CF, Aspergillus spp. were detected in 35% of samples (29% with A. fumigatus) [2]. The inhalation of Aspergillus conidia can chiefly result in two clinical scenarios, either Aspergillus colonization of the airways or allergic bronchopulmonary aspergillosis (ABPA), but sensitization, aspergilloma and pulmonary infections may also occur. Aspergillus infections are treated with antifungal drugs. In contrast, the mainstay of treatment of acute exacerbations of ABPA is corticosteroids, which may be augmented chronically with antifungal agents. The use of the anti-IgE monoclonal antibody omalizumab has been reported in small case series [3,4,5], often with an antifungal therapy to reduce fungal burden and prevent exacerbations. The relatively small number of antifungal agents limits treatment options currently available. One of the major concerns in patients with CF is that they do not achieve adequate therapeutic levels with the usual doses and require higher doses, up to 30–50% of recommended dose [6,7,8,9]. In addition, there is a lack of prospective intervention studies. In a recently published Cochrane review, no randomized controlled trials that evaluate the use of antifungal therapies for the treatment of ABPA in CF patients were found [10].

For Aspergillus infections, especially in invasive infections, voriconazole is the recommended treatment according to almost all guidelines based on a significant survival benefit, which is maintained in multiple real-life retrospective studies [11,12,13]. Until now, no consensus recommendations for treatment of Aspergillus infections specifically in the CF context have been reached. Therefore, when treating Aspergillus infections in CF, most clinicians will refer to the aforementioned guidelines with voriconazole as first-line therapy. In addition to voriconazole, posaconazole can also be recommended for Aspergillus infections and its use has been evaluated in severely ill patients. In 67 non-CF patients receiving posaconazole therapy for at least 6 months, a response was seen in 41 patients; 6 patients died, 9 had an adverse event, and 11 showed clinical and/or radiological deterioration. Therefore, at 6 months, posaconazole treatment was successful for 41 (61%) of 67 patients and failed for 26 (39%) of 67. Overall improvement at 6 months was observed in 9 patients (13%). There were 41 evaluable patients at 12 months, of whom 2 had primary posaconazole therapy. Nineteen of these patients responded to therapy, 7 died, 9 had an adverse event, and 6 showed clinical and/or radiological deterioration. Therefore, at 12 months, posaconazole therapy was successful for 19 (46%) out of the 41 patients and failed for 22 patients (54%). Overall improvement at 12 months was observed in 6 patients (15%). The 7 patients who died in the first 12 months of posaconazole therapy succumbed to a respiratory failure secondary to pneumonia. There were no instances of massive hemoptysis or non-respiratory causes of death [14].

A high number of Aspergillus-colonized patients and patients with ABPA or with Aspergillus bronchitis (discussed in another paper in this special issue) are receiving azoles with the accompanying concern of azole resistance. In a recent publication, the emerging azole resistance in A. fumigatus has been described and discussed [15]. The resistance phenotype is associated with key mutations in the cyp51A gene, including TR34/L98H, TR53 and TR46/Y121F/T289A resistance mechanisms (for a review, see also Hamprecht et al. in this special issue). Early detection of resistance is of paramount importance. Therefore, in the case of azole resistance, azole monotherapy should be avoided. Liposomal amphotericin B or a combination of voriconazole and an echinocandin is recommended for azole-resistant aspergillosis. Resistance to azoles might emerge as a new therapeutic challenge in several countries. Although de novo azole resistance occurs occasionally in patients during azole therapy, the main threat is the acquisition of resistance through the environment. In this setting, the evolution of resistance is attributed to the widespread use of azole-based fungicides [15], increasing the risk of failure of antifungal treatment in patients with CF.

In a study from Burgel et al. [16], A. fumigatus was isolated from the sputum of 131/249 (52.6%) adult patients with CF. In this cohort, 47/131 (35.9%) patients had received previous treatment with itraconazole. Interestingly, reduced susceptibility of A. fumigatus isolates to itraconazole (minimum inhibitory concentration or MIC > 2 mg/L) was confirmed in 6/131 (4.6%) subjects. A further important issue regarding the risk of aspergillosis arises following lung transplantation. As CF is one of the most common indications for lung transplantation, identifying risk factors for worse outcome after transplantation is crucial [17, 18]. Pre-transplantation Aspergillus colonization is a risk factor for the development of a post-transplantation infection. In a study encompassing 93 patients with CF who underwent lung transplantation, 70% (65/93) of the patients had pre-transplantation Aspergillus colonization. Thirty-six patients had positive intra-operative Aspergillus culture from the native lung BAL. Overall, 22.5% (20/93) of transplanted patients with CF developed invasive aspergillosis. Median time to aspergillosis was 42 days post-transplantation. Positive intra-operative Aspergillus culture and treatment for acute cellular rejection within 90 days post-transplantation were independent risk factors for aspergillosis. Antifungal prophylaxis with either inhaled amphotericin B or voriconazole (intravenous followed by oral voriconazole) was administered to 61% (57/93) of CF lung transplant recipients. One-year mortality rate was 16% (15/93). But interestingly, invasive aspergillosis was not associated with increased risk of death [19]. However, other studies have clearly identified Aspergillus spp. as a risk factor for increased post-transplantation mortality [20, 21].

Candida spp.

In the aforementioned German study, about 75% of patients with CF were colonized by yeasts, mainly C. albicans (38%), Candida dubliniensis (12%), C. glabrata (9%), Candida parapsilosis (3%), Candida lusitaniae (2%) and Candida krusei (1%) [2]. These results are similar to those previously reported on fungal colonization of the respiratory tract in CF [22,23,24]. The pathogenicity of these organisms and their influence on disease progression in CF is less clearly understood and continues to be debated. In the late 1990s, registry data from 7010 patients with CF showed the association of Candida spp. and lower FEV1 [25], although whether this is due to a direct effect of Candida or an observation for its predilection for damaged pulmonary parenchyma is unknown. In terms of pathogenicity in CF, Candida spp. can cause localized and systemic infections and induce oral and genital thrush, vascular access device-related infections and post-transplantation complications [26]. The potential of Candida spp. to cause lung function decline implementing a significant impact was demonstrated in three different studies in patients with CF [27]. However, whether treatment against Candida spp. influences the course of disease or the drop of lung function remains unknown and needs further investigation. In the very rare cases of highly probable pulmonary infection due to Candida spp., the accurate identification of the infecting Candida species is crucial in determining which antifungal agent to use, because fluconazole-resistant Candida species exist [28]. In C. albicans infections, it is recommended to start with an azole, preferably fluconazole, and to modify treatment if needed according to susceptibility tests. Echinocandins (e.g. caspofungin, anidulafungin, micafungin) are effective drugs for C. glabrata and C. tropicalis infections. Amphotericin B is also useful for Candida infections but has the disadvantage of nephrotoxicity, hypokalemia and acute infusion-related side effects [13]. It remains, however, unusual that Candida spp. are identified as causing acute pulmonary infection in CF requiring treatment and more research is needed to determine their true position as pathogenic organisms in CF.

Scedosporium Species and Lomentospora prolificans

Fungi of the genus Scedosporium and Scedosporium prolificans, recently renamed as Lomentospora prolificans [29], are the second most frequent colonizing, allergenic or invasive fungal pathogens in patients with CF [30]. Prevalence rates from patients with CF in single centres in Europe and Australia range from 3.4 to 17.4% [1, 31, 32]. One large prospective and multi-centre study on the prevalence of these fungi in Germany revealed a mean prevalence of 3.1% with a range from 0.0 to 10.5% [33]. In this study, all participating centres used a selective medium for isolation of Scedosporium and Lomentospora species from 11,600 respiratory samples collected from 2346 patients with CF. The benefit of the SceSel+ agar could be demonstrated by showing a missing rate of 54% if no selective media had been used. The therapy of Scedosporium/Lomentospora infections can be very challenging as these fungi are known to be highly resistant to antifungal drugs [33, 34]. Regarding the antifungal therapy of these infections, the European guidelines recommend voriconazole/triazoles as first-line treatment together with surgical debridement when possible but these relate to non-CF patients [35]. Although favourable results have been observed following these recommendations, the outcome remained poor with mortality rates >65% and around 100% when infection with central nervous system involvement or dissemination occurs [36].

In non-transplanted patients with CF, the situation is not comparable to immunosuppressed patients. Patients with CF may experience a subtle increase in symptoms of infection that results in a slow decline in lung function test. In addition, the clinical picture is characterized by increased respiratory symptoms (increased sputum production, cough and dyspnoea) as well as failure to respond to conventional antibiotic treatment targeted at their colonizing bacteria (see also above). Fungal pulmonary infections in CF have in the authors’ opinion no indication for surgery as the causative fungus likely infects all lobes of the lungs and the resultant resection permanently removes what may be viable pulmonary parenchyma. In rare cases, it might be discussed and indicated. In this context, systemic antifungal therapy is recommended for pulmonary infections caused by Scedosporium/Lomentospora species. Four cases treated with antifungal drugs due to a suspected pulmonary scedosporiosis have been reported since 2013. The first case describes an adolescent with CF and Scedosporium apiospermum infection who has been treated successfully with systemic application of amphotericin B and voriconazole in addition to inhaled voriconazole [37]. Also in a 35-year-old female with S. apiospermum infection, treatment was successful by using systemic caspofungin and voriconazole together with inhaled amphotericin B [38]. A third case revealed a rare manifestation of an endo-bronchial acute manifestation of a scedosporiosis. Treatment with voriconazole revealed no clinical improvement. Therefore, a bronchoscopy was initiated that showed an obstruction by mucus plugs and bronchial cast which were removed during the procedure [39]. The fourth case describes a 24-year-old female with CF who developed an acute infection caused by S. apiospermum. Treatment with posaconazole failed, but the combination of oral voriconazole and terbinafine stabilized the patient’s clinical status who ultimately underwent lung transplantation. After lung transplantation, the BALs were negative for Scedosporium species [40]. Therefore, we recommend as antifungal treatment for pulmonary infections due to Scedosporium species an oral triazole (voriconazole, posaconazole or isavuconazole), together with an intravenous echinocandin (caspofungin or micafungin) and inhaled amphotericin B. Good experience already exists over years with inhaled amphotericin B. Experience from the post-lung transplantation arena with inhaled amphotericin B to prevent or treat (add on) invasive aspergillosis has demonstrated that this mode of delivery leads to high local drug concentration [41].

In terms of in vitro activity of double combinations against Scedosporium spp. and L. prolificans, studies have been performed to support clinical decisions. Combinations of voriconazole with amphotericin B or echinocandins have shown synergistic effect against both S. apiospermum and L. prolificans [42] as well as terbinafine plus itraconazole, miconazole or voriconazole against L. prolificans [43,44,45]. But combination of voriconazole with terbinafine or liposomal amphotericin B also demonstrated variable outcome regarding the treatment of scedosporiosis [46,47,48,49,50,51,52,53,54,55]. In vitro data evaluating antifungal combinations using more than two antifungals are rare in the literature. Two triple combinations (amphotericin B plus voriconazole plus anidulafungin or micafungin) have been reported. They were tested against L. prolificans. In vitro results showed synergy for the triple antifungal combinations against L. prolificans [42]. However, when tested in a murine model of disseminated Lomentospora infection, the triple combination of amphotericin B plus voriconazole and micafungin did not show significant improvement compared to the double combinations of micafungin plus amphotericin B or voriconazole [56].

Interestingly, combinations of antifungals with miltefosine, antipsychotic drugs or cysteine derivatives might be promising therapeutic strategies and have been already tested for treatment of scedosporiosis [57,58,59,60].

Exophiala dermatitidis

Exophiala dermatitidis was first described to be associated with CF by Haase et al. [61] in 1990. Numerous studies have reported that this fungus may colonize the respiratory tract of CF patients with a rate of occurrence ranging from 1 to 19% [62,63,64]. Outside the human body, E. dermatitidis usually occurs in warm and humid areas and is therefore believed to originate in tropical climates [65]. It is also encountered worldwide in the man-made environment, for example in dishwashers, steam baths and sauna facilities [66, 67]. Detection of this fungus can be problematic on routine sputum testing, and prolonged culture on dedicated plates may be necessary to confirm its presence.

Kusenbach et al. [68] described a severe pneumonia in a 7-year-old girl with CF already in 1992. It seemed highly probable that E. dermatitidis was the causal agent for fungal pneumonia in this case. Following therapy with amphotericin B and flucytosine, the clinical course and radiological appearance improved, but definitive eradication of E. dermatitidis was only achieved after treatment with itraconazole.

In a retrospective study, the clinical records of 17 patients with CF who had positive sputum tests for E. dermatitidis were analysed [64]. Analysis showed that four patients received antifungal therapy due to suspected infection. Patient one was a 22-year-old male who received posaconazole for 3 months after failure of i.v. antibiotics and itraconazole. Respiratory symptoms subsided, and results from sputum culture were negative again. Patient two, a 34-year-old male, was treated with voriconazole with no success. Treatment led to negative sputum cultures regarding E. dermatitidis but without influencing respiratory symptoms. As the patient suffered from significant gastro-oesophageal reflux disease, fundoplication was performed which resulted in some improvement in respiratory symptoms. Patient three was a 34-year-old female not responding to antibiotic treatment. After implementing an antifungal treatment with voriconazole, clinical response was difficult to interpret, as emesis was significant leading to termination of the antifungal treatment. Sputum cultures only revealed sparse growth of E. dermatitidis at treatment termination. Patient four was a 12-year-old boy developing multiple filled cavities in the lungs. Treatment with i.v. amphotericin B for 14 days initially, followed by posaconazole for seven months, resulted in clinical and radiological response. Recurrent fungal infection due to E. dermatitidis may be successfully treated also with posaconazole.

As highlighted by these cases, antifungal treatment may be difficult and hampered by limited effectiveness and adverse events; nonetheless, positive treatment outcomes can occur. Biofilm formation might be the cause of limited effectiveness. Kirchhoff et al. [69] found that E. dermatitidis can form biofilm and that invasive isolates exhibit significantly higher biofilm-forming ability than do isolates from patients with CF. The metabolic activity and the biomass involved in biofilm are strain specific. Exophiala dermatitidis biofilm is susceptible to the antifungal agents micafungin and voriconazole during the early steps of biofilm formation. The antibiotic colistin reduces as well the fungal growth rate, especially during treatment of mature biofilms. In this context, a therapeutic failure should lead to change in antifungal treatment from itraconazole to posaconazole or even to micafungin if fungal infection due to E. dermatitidis is highly probable.

Trichosporon mycotoxinivorans

Trichosporon spp. are basidiomycetous yeast-like anamorphic organisms (Basidiomycota, Tremellomycetes, Trichosporonales). Trichosporon species are uncommon pathogens in patients with CF, but in rare cases, they have the ability to cause life-threatening infections, especially in immunocompromised patients. Yeast-like Trichosporon spp. can be detected throughout the environment, but they grow predominantly in tropical and temperate areas. Members of this genus can colonize the gastrointestinal tract, respiratory tract, skin and vagina. Superficial infections are more common in immunocompetent hosts, but Trichosporon spp. can cause deep-seated mucosa-associated or superficial infections. Very rare is invasive trichosporonosis, mostly in patients with malignancies [70]. The first but severe human case was described in a patient with CF in 2009 [71]. This 20-year-old male with CF initially presented with a pneumothorax and was afterwards treated with antibiotics due to pyrexias up to 40 °C. Gram staining of sputum collected at the time of admission revealed no bacteria but 30 budding yeasts and 30 polymorphonuclear leucocytes per field. On day six of hospital stay, the yeast was identified as Trichosporon species. The initially commenced liposomal amphotericin B therapy was stopped, and voriconazole was started due to concerns of intrinsic drug resistance. The therapy could not stop the severe life-threatening infection, and the patient died on day 11 of hospital stay. Autopsy was performed which revealed diffuse haemorrhagic and suppurative consolidation of the lungs with chronic bronchiectasis. Cultures of tissue collected from each lobe post-mortem grew Trichosporon species, and histology demonstrated diffuse infiltration of the lung parenchyma with budding yeasts. In this case report, it remains unclear whether the treatment failure at the beginning of treatment was the reason for this fulminant clinical course or whether an undiagnosed immune deficiency was the underlying issue.

Amphotericin B and lipid formulations as well as the echinocandins have limited efficacy against Trichosporon species. Triazoles are considered the therapeutic class of choice on the basis of in vitro data, animal models and individual case descriptions [72,73,74,75,76]. Shah et al. [77] described four additional cases with CF and Trichosporon mycotoxinivorans infection but none of them had a clinical course as fulminant as described by Hickey et al. [71]. One patient received antifungal treatment due to failure of antibiotic treatment. Therapy was started with oral voriconazole, then combined with inhaled amphotericin B. The biggest cohort was analysed by a German research group [78]. Trichosporon species were found in 8 out of 360 (2.2%) patients with CF. Data suggested that age, prior systemic or inhaled steroid treatment, ABPA and possibly CF-related diabetes may predispose to colonization by Trichosporon species. Two of the eight patients received treatment, because of a prolonged severe cough for one of them. For this patient, inhaled amphotericin B led to significant resolution of the symptom. The second patient had a significant drop in lung function, and the severe clinical symptoms responded poorly to antibiotic treatment. Therefore, i.v. amphotericin B was started as susceptibility testing revealed good efficacy of amphotericin B, posaconazole and voriconazole. After 8 weeks of amphotericin B treatment, the patient’s condition improved considerably and oral therapy with voriconazole was initiated, but it was changed to posaconazole due to side effects (impaired colour vision). In an immunocompromised patient with no response to antifungal monotherapy, a combined antifungal therapy should be discussed. A neutropenic patient with acute myeloid leukaemia experienced a breakthrough infection of Trichosporon asahii during posaconazole treatment. Treatment was then changed to a combination therapy with voriconazole and liposomal amphotericin B, and the infection resolved [79]. As recommended for other fungi, it is also crucial to performing susceptibility testing in patients with CF suffering from lung infections with Trichosporon spp.

Other Fungal Species

In addition to the already mentioned fungi, others can be detected in CF specimens including Alternaria, Cladosporium and Penicillium species, as well as Paecilomyces variotii, Acrophialophora fusispora and Rasamsonia argillacea (e.g. Geosmithia argillacea) which was initially identified as Penicillium emersonii [1]. The clinical consequences for patients with CF are unknown, and therapeutic intentions are not defined yet.

As for all indications and therapies, an adequate monitoring of side effects is mandatory as well as the monitoring of plasma concentrations of antifungals [80].

Prevention

The high prevalence of fungi in CF and the risk of a range of fungal related diseases from allergy to severe infections raise the question of prevention.

In a German study, a high percentage (75%) of yeast colonization was found [2]. This can probably be explained by recurrent use of corticosteroids and antibiotic treatments against chronic bacterial infections and the resulting advantage for yeast growth [1, 81, 82]. As reported in other studies, C. albicans was the most prevalent species, followed by C. dubliniensis [83, 84]. Therefore, in patients with long-term or recurrent corticosteroid treatment or with inhaled, oral or even i.v. antibiotic treatment, screening should be considered for fungal colonization and fungal infection.

Jensen et al. [85] speculated that the oral cavity may be an unrecognized reservoir of resistant Candida species, especially C. glabrata following azole or echinocandin treatment. In addition, there are concerns about a changing epidemiology towards Candida species less susceptible to fluconazole combined with the acquisition of echinocandin resistance, in particular among C. glabrata isolates.

Additionally, azithromycin, a routinely used macrolide in CF care, may be implicated in Aspergillus colonization. Azithromycin reduces neutrophils and IL-8 [86]. Multivariate analysis has identified an independent association between low body mass index and ABPA (p = 0.004) and intriguingly between long-term azithromycin use and Aspergillus colonization (p = 0.001). This latter association might be due to the inhibitory effect of azithromycin on recruitment and activation of neutrophils, which are crucial in host defences against Aspergillus [87].

As patients with CF inhale several different drugs once, twice or even sometimes three times daily, the inhalation device is one risk factor if disinfection is not done hygienic adequately. In a study of patients with CF, a total of 170 nebulizers from 149 subjects were screened by wetting a sterile cotton swab with sterile water and swabbing each drug chamber. The swab was then plated out on Sabouraud and on SceSel+ agar and incubated at 27 °C for up to 2 weeks. Overall, 86/149 (57.7%) of subjects had positive fungal cultures from at least one of their devices, with 39/149 (26.2%) being yeasts, 47/149 (31.5%) moulds and 20/149 (13.4%) a combination of yeasts and moulds. Aspergillus fumigatus was the most frequent mould isolated followed by Penicillium spp., P. commune being the most common species from this genus. Several Lecanicillium sp. isolates were also identified. Exophiala species were also isolated from five devices. The most frequent yeast to contaminate devices was Candida guilliermondii followed by C. parapsilosis. Contamination with environmental basidiomycetous yeasts in the genera Rhodotorula and Cryptococcus (but not C. neoformans) was also common. Interestingly, the most common cause of oral colonization and infection, C. albicans was isolated only on a single occasion. This study suggests that inhalation devices can play an important role as an individual risk factor as contamination with fungi can occur [88].

The prevention of infection or colonization with Scedosporium/Lomentospora species is difficult as it occurs only in low numbers of patients. These organisms naturally live in soil and water, and therefore, patients who have a hobby of gardening may be at increased risk. Therefore, we recommend awareness of the risk of acquiring fungal colonization when gardening. Colonization by Scedosporium or Lomentospora species is associated with younger age (p < 0.005) and absence of H. influenzae (p < 0.001). In addition, patients colonized by these fungi had more often ABPA (p < 0.01) and have been colonized more often with the mucoid phenotype of Pseudomonas aeruginosa (p < 0.05) [89]. Although difficult, clinicians should be mindful of these associations, particularly in children who have naturally closer exposure to soil and water.

A new risk factor for acquisition of fungi has been recently identified and is now recognized by patients with CF. Dishwashers can host the black yeast E. dermatitidis which can be found to grow on the rubber seals of the doors [67]. Therefore, to prevent colonization with Exophiala species, special precautions regarding dishwashers use can be recommended. Patients should be aware of this entity when opening a dishwasher and should not clean the rubber seals of the dishwasher doors themselves. Some patients may reasonably consider the use of masks, but currently there is insufficient evidence to support or oppose this.

In terms of ABPA, our research group have reported that pet ownership is a risk factor for ABPA [89]. One hundred and nine patients were included in the study. The mean age of the total group was 25.4 ± 13.2 years. Adjusted analysis revealed that ABPA (p = 0.029) was associated with pet ownership in patients with CF. Furthermore, ABPA in pet owners with CF was associated with an increased number of exacerbations (p = 0.043). A significant higher proportion of pet owners (65.5%) were sensitized to A. fumigatus in unadjusted analyses compared to non-pet owners (33.3%). In addition, the rate of sensitization to dust mite, dog and cats was higher in pet owners compared to non-pet owners. In particular, with regard to sensitization to house dust mite (25.5% pet owners and 7.4% non-pet owners) and dogs (23.6% pet owners versus 5.6% non-pet owners), the difference was significant. These results suggest screening for ABPA if patients are pet owners and if ABPA is recurrent, pet ownership should be excluded.

The aim should be to introduce these relevant risk factors to patients and their families to enable an adequate prevention of fungal colonization or even infections. Communication of specific risks should include gardening, dishwasher and pet ownership. Long-term corticosteroid therapy and antibiotics always have to be considered under a risk benefit calculation not only regarding fungi but also other side effects.

New Future Therapies

Currently, the treatment for fungal pulmonary infections is limited to few drugs, with relevant side effects, drug interactions and variable host response. Therefore, decision regarding when to commence treatment and with which agent is a challenge. However, there is a light on the horizon with new antifungal drugs in the pipeline and the use of antifungal therapeutic drug monitoring in daily practice.

With the development of ravuconazole and albaconazole (isavuconazole is already commercialized), two new azoles exist potentially enlarging therapeutic options in cases where additional azoles are needed. The group of echinocandins received a new addition with aminocandin [90]. A glucan synthase inhibitor, MK-3118, is a derivate of enfumafungin that has an antifungal activity profile similar to that of echinocandin and is orally available. Biafungin is also an echinocandin but is long acting and developed for the treatment of Candida infections, with potent activity against both Candida and Aspergillus spp., including azole- and echinocandin-resistant isolates [91].

E1210, a glycosylphosphatidylinositol (GPI) anchor biosynthesis inhibitor, inhibits fungal GPI-anchored protein biosynthesis through the inhibition of inositol acyltransferase [92]. It is a broad-spectrum investigational agent resulting in the inability to form cell walls and to bind to host cells.

Another new drug in the pipeline is T-2307, an arylamidine derivative. While it appears that T-2307 may interfere with the mitochondrial function of yeasts, its mechanism of action is not completely understood, but T-2307 is taken up into cells via transporter-mediated systems, leading to collapse of fungal mitochondrial membrane potential [93].

Trials are commencing using monoclonal antibodies as an antifungal therapeutic strategy. Efungumab is one of these antibodies. The spectrum of activity of efungumab (Novartis Pharmaceuticals) is limited to Candida spp., including fluconazole-resistant organisms, when used as monotherapy or in combination with other antifungal agents (such as fluconazole, caspofungin and amphotericin B) [94].

As antifungal treatment may be life-saving not only for patients with CF but also for immunocompromised patients in general, novel therapeutic options based on completely different strategies are very encouraging. The potential of several T-cell-based therapeutic approaches in the prophylaxis and treatment of infectious diseases with a particular focus on persistent viral infections and opportunistic fungal infections is promising [95]. Antifungal immune responses could be improved by adaptive transfer of pathogen-specific T cells directed against invasive and pulmonary fungal infections, particularly infections with Candida spp., Aspergillus spp. and mucoromycetes, especially after allogeneic stem-cell transplantation. T-cell responses are MHC class I restricted (for CD8-positive T cells) or MHC class II restricted (for CD4-positive T cells), and thus, an effective T-cell response needs to match the genetic background of the patient. T-cell transfer approaches have been used to obtain these pathogen-specific T cells. Anti-pathogen-specific T cells can be expanded ex vivo under appropriate conditions (usually with the help of recombinant cytokines, synthetic peptides or cellular components representing the pathogen). Responder T cells are identified by interferon-Îł production, removed via an interferon capture assay and transferred into the patient [96].

Compared to existing antifungal drugs, a new antiseptic drug belonging to chloramins and named N-chlorotaurine has also very promising properties. This new drug shows strong in vitro effects with fungicidal activity against multi-resistant fungi such as Lomentospora prolificans or Scedosporium boydii [97,98,99,100,101,102,103].

Better estimation of host risk of the development of allergic or invasive forms, for instance through the identification of informative genetic polymorphisms, will allow optimization of prophylactic and therapeutic strategies. The indications for the use of therapeutic drug monitoring to improve therapeutic efficacy and control toxicity are also an unresolved issue, as is the role of combination antifungal therapy, given the potential for synergism and antagonism. New immunomodulatory strategies, including vaccine development and taking advantage of the immunomodulatory effects of antifungal agents, may be clinically relevant and therapeutically exploitable. Future research will decide if these new approaches are able to lower morbidity in addition to the new antifungal drugs.