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Cystic fibrosis (CF) is characterised by chronic airway infection with bacteria and fungi. Infections caused by Scedosporium/Lomentospora species can occur and are difficult to treat. Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. Our aim was to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment.
In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV1, radiology, and symptoms.
This data suggests that combined treatment is superior to monotherapy in patients with CF.
]. The role of bacterial pathogens in bronchopulmonary infections is well investigated. Pseudomonas aeruginosa is the most relevant pathogen in bacterial exacerbations [
Döring G, Flume P, Heijerman H, Elborn JS, Consensus Study Group. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J. Cyst. Fibros. 2012;11:461–79. https://doi.org/10.1016/j.jcf.2012.10.004.
]. However, the contribution of individual pathogens to chronic disease and acute lung exacerbations is often difficult to determine due to the complex composition of the lung microbiome in CF. In particular, the implication of fungal pathogens, such as Aspergillus spp., Scedosporium spp., Exophiala spp., Rasamsonia spp., Trichosporon spp., and Candida spp., in CF airways remains nebulous due to limitations of current diagnostics regarding the identification of the presence and pathogenicity of fungal species. However, fungi are being increasingly detected in CF and have been moving into the focus in the past years. Fungal species may colonize the respiratory tract asymptomatically [
]. Nevertheless, there are patients with CF whose decreased lung function is strictly related to the isolation of fungi such as Scedosporium as the only potential pathogen [
Prospective multicenter German study on pulmonary colonization with Scedosporium /Lomentospora species in cystic fibrosis: epidemiology and new association factors.
]. Most commonly described complications caused by fungi are allergic reactions like allergic bronchopulmonary aspergillosis (ABPA) and other allergic bronchopulmonary mycoses in a relevant number of patients [
]. Fungal infections due to Scedosporium spp. and Lomentospora prolificans have been mentioned commonly in immunocompromised patients such as those after solid organ transplantation [
Scedosporium apiospermum and S. prolificans mixed disseminated infection in a lung transplant recipient: an unusual case of long-term survival with combined systemic and local antifungal therapy in intensive care unit.
]. In a study of patients after lung transplantation, mould infections are described in 5.5%. The three-month all-cause mortality in this cohort was 21.7% [
]. In addition to pulmonary infections, osteomyelitis has been described in lung-transplanted patients as a severe complication under immunosuppression [
]. Here we focus on pulmonary fungal infections due to Scedosporium/Lomentospora in CF and the effectiveness of antifungal treatment. One major question in this study is whether two or three drugs might be better than a single one to improve outcomes after treatment of scedosporiosis.
2. Methods
2.1 Subjects
In this multicentre study patients with a fungal lung infection were included that was highly suspected to be caused by a Scedosporium/Lomentospora species. CF centres which treated a patient because of a pulmonary scedosporiosis (including Scedosporium spp. and Lomentospora prolificans) could include their patients in this analysis. Twelve CF centres participated in this study from January 2008 to December 2014. These centres provide clinical care for about 1500 patients. Since criteria for invasive fungal infections in patients with CF had not been defined when the study was started, inclusion criteria for this study were defined as shown in Table 1.
Table 1Inclusion criteria for this study
1. Increased sputum production. 2. Multiple isolation of the same Scedosporium/Lomentospora species from sputum or bronchoalveolar lavage (≥twice over a 6-month period). 3. Pulmonary infiltrate(s) on chest CT scan or X-ray. 4. Treatment failure with antibiotic therapy (≥2 x antibiotic treatment, duration ≥ two weeks). 5. Unclear lung function decline (exclusion of new CF-related diseases: e.g. diabetes mellitus). 6. Exclusion of new/other bacteria (e.g. non-tuberculous mycobacteria or P. aeruginosa). 7. Exclusion of allergic bronchopulmonary aspergillosis.
In addition to the Cystic Fibrosis Foundation consensus conference guideline on ABPA [20] patients with an elevated total-IgE level (>50% in the last 6 month and an elevated Aspergillus-specific IgE (increase of one CAP class) have been excluded from the study.
A new episode of a Scedosporium/Lomentospora infection in the same patient was defined as follows: new antifungal treatment after a minimum time period of longer than three months, in addition to the criteria 1 to 7.
a In addition to the Cystic Fibrosis Foundation consensus conference guideline on ABPA [
] patients with an elevated total-IgE level (>50% in the last 6 month and an elevated Aspergillus-specific IgE (increase of one CAP class) have been excluded from the study.
b Treatment was not randomised (centres' decision).
Outcome parameters used in this study were lung function [FEV1 (forced expiratory volume in 1 s) % predicted], radiological results of chest CT-scan or chest X-ray (diameter, density and number of infiltrates before and after therapy), and patients' respiratory symptoms (cough, amount and colour of sputum, dyspnoea, and exercise capacity). Parameters were measured at the beginning of suspected scedosporiosis and at follow up (between days 28 and 84). Response to therapy was defined by at least one of the three following parameters: >5% increase in FEV1, reduction of infiltrates in chest CT-scan/X-ray, and reduction of respiratory symptoms.
2.3 Clinical measurements
Basic data of the patients were collected and are shown in Table 2.
Table 2Baseline characteristics of CF patients with pulmonary scedosporiosis.
In the case of pulmonary scedosporiosis: age at start of antifungal treatment.
year, MV ± SD (range)
24.1 ± 7.6 (10–39)
Age at first colonisation by Scedosporium/Lomentospora species
21.4 ± 8.5 (5–39)
Male sex, n (%)
12 (39)
CFTR ΔF508 homozygous, n (%)
16 (52)
BMI, kg/m2, MV ± SD (range)
18.5 ± 2.5 (15–26)
Percent predicted FEV1, MV ± SD (range)
50.5 ± 19.2 (18–95)
Diabetes, n (%)
12 (39)
Exacerbation p.a., MV ± SD (range)
2.8 ± 1.0 (1.5–6.0)
Colonisation by P. aeruginosa, n (%)
22 (71)
Colonisation by Aspergillus spp., n (%)
13 (42)
Total IgE, kU/l, MV ± SD (range)
153 ± 127 (4–479)
IgG, mg/dl, MV ± SD (range)
1499 ± 353 (830–2356)
CRP, mg/dl, MV ± SD (range)
51.5 ± 42.4 (0.0–175.0)
Steroids inhaled, n (%)
19 (61)
p.a.: per annum.
CFTR: Cystic fibrosis transmembrane conductance regulator; BMI: body mass index; FEV1: forced expiratory volume by 1 s; CRP: C reactive protein; MV: mean value; SD: standard deviation; kU: kilo Units.
† In the case of pulmonary scedosporiosis: age at start of antifungal treatment.
Expectorated sputa and/or bronchoalveolar lavage fluids were cultured for bacteria and examined for fungi using standard mycological media and/or a Scedosporium-selective culture medium [
After morphological identification of an isolate as a Scedosporium/Lomentospora species, precise identification was performed by sequencing the internal transcribed spacer (ITS) 1 and 2 regions of ribosomal DNA (rDNA) genes or by a microarray for fungi of the genus Scedosporium/Lomentospora [
To check the present data distributions, normality tests were used. Only subjects with values for all variables were included in the analysis. P values <.05 were considered to be significant. All statistical analyses were performed using GraphPad Prism version 6 (GraphPad Software Inc., La Jolla, CA, USA) and IBM SPSS Statistics version 22 (IBM Corporation, New York, NY, USA).
The study was approved by the Institutional Review Board (EA2/080/11) of the Charité – Universitätsmedizin Berlin, Germany.
3. Results
A total number of 36 episodes of pulmonary fungal infections caused by Scedosporium/Lomentospora species, which occurred in 31 patients with CF, were analysed in this study. 19 (61%) of the patients were female and 12 (39%) were male. The mean age at the time point of fungal infection was 24.1 ± 7.6 years with a range from 10 to 39 years. General data showed that the F508del mutation was the most frequent one, found in 26 of the patients (84%): 16 of these patients (52%) were homozygous and 10 (32%) were heterozygous. Twelve patients (39%) had CF-related diabetes. Inhaled corticosteroids were given in 19 patients, from whom 4/7 (57%) patients belonged to the anti-fungal monotherapy group, 7/13 (53%) to the double combination, and 8/16 (50%) to the triple combination therapy (Table 2).
3.1 Radiology
A CT-scan was available for 26 out of the 31 patients (83.9%) and X-ray for the remaining patients (5; 16.1%) at diagnosis of fungal infection. Radiological findings revealed bronchiectasis and infiltrates in 100% of the patients. Scores could not be analysed because scores for CT-scan were routinely performed in just four of the 12 CF centres. Patients without infiltrates on CT-scan or X-ray were excluded from this study.
3.2 Microbiological findings
Among the 31 patients, 24 (77.4%) were chronically colonised with P. aeruginosa. The second most common bacteria were Staphylococcus aureus with eight patients (25.8%).
Regarding Scedosporium/Lomentospora isolates, precise species identification was performed by molecular methods at the German reference laboratory for scedosporiosis (Robert Koch Institute, Berlin) for 29 out of 31 (93.5%) patients. S. apiospermum was the most frequent species recovered from 15 patients (48.4%), followed by S. boydii which was found in nine patients (29.0%). Scedosporium aurantiacum and S. minutisporum were found in 9.7% and 3.2% of the patients, respectively. In three patients two different Scedosporium species were isolated simultaneously: i) S. apiospermum and S. boydii, ii) S. apiospermum and S. aurantiacum, and iii) S. apiospermum and S. minutisporum. L. prolificans was identified in three patients (9.7%).
3.3 Antibiotic treatment
The median rate of antibiotic treatments (intravenous and oral) was 3.5/year (range 1–6). Also included were elective intravenous antibiotic treatments.
3.4 Time period between diagnosis and onset of treatment
The time between first isolation of Scedosporium/Lomentospora species and the introduction of antifungal treatment against the suspected scedosporiosis was 2.9 ± 3.3 years with a range of 0–11.
Antifungal treatment was documented for 31 patients (Table 3 and Fig. 1). During the study period 36 courses of treatment were administered. These therapies included oral and inhaled azoles (voriconazole and posaconazole), intravenous echinocandins (caspofungin, micafungin), polyenes (inhaled amphotericin B), and allylamine (oral terbinafine). Regimens ranged from a single agent for 1 month to combined treatment with three antifungal drugs for >6 months. Single treatment was administered in 7 out of the 36 courses (19%), double therapy in 13/36 (36%), and triple therapy in 16/36 (44%). The duration of the antifungal treatment was 3.9 ± 2.8 months (range 1–14 months). In 20/36 (56%) antifungal courses a therapeutic response was achieved (regress in radiologically observed infiltrates or symptoms or increase in FEV1).
Table 3Antifungal treatment against Scedosporium/Lomentospora species in cases (n = 36) of pulmonary scedosporiosis.
Species
Antifungal treatment
Scedosporium apiospermum
Scedosporium aurantiacum
Scedosporium minutisporum
Scedosporium boydii
Lomentospora prolificans
Mono therapy (n = 7)
1.
Voriconazole po
ΟΟΟ
X
ΟΟ
2.
Posaconazole po
Ο
Two antifungal agents were used (n = 13)
1.
Voriconazole po
XX
X
Caspofungin iv
2.
Voriconazole po
X
Micafungin iv
3.
Voriconazole po
X
Terbinafine po
4.
Voriconazole po
XX
X
ΟΟX
X
Amphotericin B pi
5.
Voriconazole pi
X
Amphotericin B iv
6.
Voriconazole pi
X
Micafungin iv
Three antifungal agents were used (n = 16)
1.
Voriconazole po
XXXXXXXXX
X
X
XXX
Caspofungin iv
Amphotericin B pi
2.
Posaconazole po
XX
Caspofungin iv
Amphotericin B pi
3.
Itraconazole po
X
X
Caspofungin iv
Amphotericin B pi
➔36 data points were included in Table 3 due to co-infection by two distinct Scedosporium species in three cases.
Patients in the polyene group received amphotericin B by inhalation (25 mg/day) and one patient in the azole group received voriconazole by inhalation (40 mg/day). The inhalation of amphotericin B and voriconazole is an off-label use.
All but one of the responding patients had a combined treatment with a minimum of two antimycotic drugs. Statistical analysis of these three treatment groups revealed a significant difference in outcome between the antifungal treatment with one, two, and three drugs (Fig. 1). Primary reason for cessation of antifungals was the clinical stabilization or improvement of the patients' symptoms. In addition, - but only as a secondary reason - anti-fungal therapy has been stopped or prolonged after radiological diagnostics (prolonged if infiltrate has not been resolved yet or stopped if completely resolved).
4. Discussion
Fungi of the genus Scedosporium/Lomentospora are the second most common moulds in the respiratory tract of patients with CF but little is known about their pathogenicity and clinical relevance. A clear diagnosis of possible clinical manifestations associated with or caused by these fungi in patients with CF is difficult without using invasive methods. The clinical spectrum includes a fungus ball with Scedosporium analogous to an aspergilloma, allergic bronchopulmonary scedosporiosis [
]. In other disease entities, e.g. lung-transplanted patients, life-threatening pulmonary mycosis with Scedosporium spp. has been described with a worse outcome [
Successful treatment of disseminated scedosporium infection in 2 lung transplant recipients: review of the literature and recommendations for management.
]. This study contributes to the field of pulmonary Scedosporium/Lomentospora infections in CF, which have rarely been reported in the literature so far.
The definition of fungal pneumonia has currently been confirmed and published by an international expert group [
], because the typical symptoms of CF are overlapping with symptoms of the specific infection. Diagnosing fungal infections of the lung is challenging, as symptoms of the fungal infection might overlap with normal symptoms of exacerbation because of bacteria. By definition, the gold standard for the diagnosis of a pulmonary fungal infection would be the histological detection of hyphal structures in tissue and the cultural or molecular confirmation of their presence [
Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.
]. This is not feasible, however, because the invasive procedures bronchoscopy and thoracoscopy required for a lung biopsy would put the patients at a high risk of bleeding and pneumothorax. After detecting fungi in the sputum or bronchoalveolar lavage fluid from patients with CF, clinicians have to determine whether this is a harmless colonisation or a significant infection requiring specific treatment. As concluded by Chotirmall and McElvaney [
] in their reviews about fungi in CF, a combination of host and pathogen-related factors determines if a particular fungus will be a bystander or a pathogen in the CF lung at a given time point. Similar to a definition of an Aspergillus infection by Liu et al. [
], the participating centres in our study have proposed a consensus for a case definition of a pulmonary fungal infection with Scedosporium/Lomentospora species, which theoretically includes proven as well as probable scedosporiosis (see Table 1). As different causes for worsening of pulmonary disease in CF are possible, the most common differential diagnoses are included in this definition. In particular, bacterial infections and allergic bronchopulmonary mycosis are excluded. In addition to the Cystic Fibrosis Foundation consensus conference guideline on diagnosing ABPA [
] patients with an elevated total-IgE level (>50% in the last 6 month and an elevated Aspergillus-specific IgE (increase of one CAP class) have been excluded from the study to ensure not including patients with an early stage of an ABPA or ABPM.
In addition, as most patients had been colonised for a long time before the infection became clinically relevant (2.9 ± 3.3 years), with a delay ranging from 0 to 11 years in our study, new or specific infiltrates in radiological diagnostics can raise to the suspicion of fungal infections. As the detection of the infection-causing fungus is one major point in the definition, the use of a selective agar for isolating Scedosporium/Lomentospora species from respiratory samples is crucial (missing rate of about 67% without); we recommend its use as a basic mycological tool to diagnose successfully a related infection in CF [
] showed that patients with a Scedosporium/Lomentospora colonisation were significantly less likely to be colonised with mucoid P. aeruginosa (p = .025), while prior therapy with antistaphylococcal penicillins was a risk factor for colonisation (p = .045). A recently published prospective multicentre study on the epidemiology of Scedosporium/Lomentospora species in Germany revealed that ABPA and mucoid P. aeruginosa colonisation were positively associated with Scedosporium/Lomentospora colonisation [
Prospective multicenter German study on pulmonary colonization with Scedosporium /Lomentospora species in cystic fibrosis: epidemiology and new association factors.
]. Taking this into account allergic reactions might induce a negative immunological pathway that allows Scedosporium/Lomentospora species to cause a severe infection. Interestingly, we detected in our infected patients an elevated total IgE in 61.3% but no cases of ABPA. In the group of patients presented here there was a high number of exacerbations that were treated with antibiotics in the year before the development of a pulmonary Scedosporium/Lomentospora infection. Therefore, we speculate that previous bacterial infections and the chronic use of antibiotics might be a risk factor for the development of a pulmonary fungal infection in CF.
The wide range in age (10–39 years) of affected patients shows a risk for fungal infections over nearly all age groups.
Regarding the contribution of the fungal pathogens, we detected S. apiospermum with a frequency of 61.3% as the main infection-causing pathogen, followed by S. boydii with a frequency of 32.3% of all cases. These results confirm those of the German epidemiological study in which S. apiospermum and S. boydii were most frequently detected, with a frequency of 49% and 29% of all Scedosporium/Lomentospora species, respectively [
]. So far, significant parts in the pathophysiology and duration of colonisation with Scedosporium species in CF are not understood. A study on genotyping of S. apiospermum and S. boydii using multilocus sequence typing including consecutive isolates of patients with CF showed that patients can be colonised by individual strains for years [
]. But the environment might play an important role, as studies with a focus on the detection of Scedosporium species could find these fungi for example in soil and waters [
]. In two patients of our study we could confirm a significant contact to contaminated soil and polluted water during gardening but we could not find any other hint in the remaining patients [
In terms of anti-fungal treatment, L. prolificans and, to a lesser extent, species of the S. apiospermum complex are highly resistant fungi, in contrast to the usually itraconazole- or voriconazole-susceptible A. fumigatus. In a recently published epidemiological study 161 Scedosporium/Lomentospora isolates from 73 patients were tested. The results revealed a wide range of minimal inhibitory concentrations, favouring a combined therapy of azoles with echinocandins in scedosporiosis or with terbinafine in Lomentospora infections.
From a clinical perspective, the resistance status of these fungi and the severity of the infection advocate a broad antifungal combination therapy [
] suggest a combined therapy, mainly a triple therapy, because it is most effective regarding radiology. Nevertheless, we also have to consider that there was no statistical significance between triple or double therapy in terms of lung function and respiratory symptoms. In particular, in all three dimensions three and two antifungal drugs show significant superiority compared to monotherapy. But as aforementioned triple therapy was only superior to a double one in terms of radiological results (Fig. 1).
Therefore, our recommendation for first-line treatment of infections due to fungi belonging to the S. apiospermum complex is the combination of an oral azole (voriconazole/posaconazole/isavuconazole), an intravenous echinocandin, that might be combined with inhaled amphotericin B.
Monotherapy, for example with voriconazole, should not be introduced, since breakthrough infections have been described [
Breakthrough Lung Scedosporium prolificans Infection with Multiple Cavity Lesions in a Patient Receiving Voriconazole for Probable Invasive Aspergillosis Associated With Monoclonal Gammopathy of Undetermined Significance (MGUS).
Breakthrough disseminated scedosporium prolificans infection in a patient with relapsed Leukaemia on prolonged voriconazole followed by posaconazole prophylaxis.
]. Regarding infections caused by the multiresistant L. prolificans, a combined therapy should be started with terbinafine, voriconazole, and possibly miltefosine, as was described in a successfully treated patient with osteomyelitis in Australia. In our study, one patient who suffered from a severe lung infection due to L. prolificans was treated initially with intravenous caspofungin and voriconazole (orally and inhaled) for four weeks and recovered after an additional four weeks of treatment with oral voriconazole and terbinafine. An explanation for the successful treatment in the two other patients could be i) by inhalation of a drug higher levels can be reached in the respiratory tract, ii) all received a combination of antimycotic drugs which lead to a recovery, but iii) the missing eradication of the pathogen – as in the other cases – demonstrates that none of these combinations is fungicidal.
Our data on S. apiospermum infections show superiority of a multiple-drug treatment regime featuring caspofungin intravenously and voriconazole/posaconazole orally for at least three months as the medium duration of therapy in this study was 3.9 month. If tolerated inhaled amphotericin B could be considered to be added as a local applied drug with a high drug level in the bronchial system.
In addition to the recent challenge of treating multiresistant non-tuberculous mycobacteria in patients with CF [
US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary.
US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.
], we are confronted with multiresistant fungi. Both germs are living in soil and water naturally. It is conceivable that the patients' exposure to these natural habitats of the fungi might be a risk factor for the patients' colonisation. The probable association between ABPA and non-tuberculous mycobacteria in CF was already described by Mussaffi and co-workers [
]. Therefore, we recommend being aware of the risk to acquire fungal colonisation when coming in contact with soil and waters.
Although most patients with acute signs of an infection due to Scedosporium/Lomentospora species improved clinically and radiologically after antimycotic treatment, they still harboured these moulds in their respiratory tract. Therefore, an early eradication of the colonising fungus in patients with CF might be considered. Treatment with the new orally available beta-1,3-D-glucan synthase inhibitor SCY-078 could be a therapeutical option, especially in patients with the multiresistant L. prolificans [
Future research should include analysis of epidemiological parameters from the registry to generate more data for risk factor identification. In addition, screening for specific antibodies could support a suspected fungal lung infection. New biomarkers such as fungus-specific CD4(+) T cells are also promising tools for diagnosing fungal infections [
The differentiation between a harmless, asymptomatic colonisation and a clinically significant fungal infection is difficult as symptoms of normal exacerbation and fungal infection might be overlapping. The definition used might be a helpful tool to confirm a fungal infection due to Scedosporium/Lomentospora in CF.
In addition, these data recommend a combined therapy for pulmonary infections with Scedosporium/Lomentospora species in CF. The therapy should include at least two systemic antifungal drugs for at least four weeks. In some cases, a much longer duration will be required, e.g. six months. In addition, inhaled amphotericin B could be considered to be added as a local applied drug with a high drug level in the bronchial system.
Acknowledgments
We would like to thank all patients and all the members of the Cystic Fibrosis Centres participating in this study. We would also like to thank Ursula Erikli for copy-editing.
Authors' contributions
CS, CB, VM, CR, EH, HS, MS, HK, J-PB, TB, PM, JG-O, HS, DH, LS, KT were involved in study design and patient recruitment. CS, CB, KT collected the data. CS, CB, KT analysed the data. CS, KT wrote the paper.
Funding
This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
Döring G, Flume P, Heijerman H, Elborn JS, Consensus Study Group. Treatment of lung infection in patients with cystic fibrosis: current and future strategies. J. Cyst. Fibros. 2012;11:461–79. https://doi.org/10.1016/j.jcf.2012.10.004.
Prospective multicenter German study on pulmonary colonization with Scedosporium /Lomentospora species in cystic fibrosis: epidemiology and new association factors.
Scedosporium apiospermum and S. prolificans mixed disseminated infection in a lung transplant recipient: an unusual case of long-term survival with combined systemic and local antifungal therapy in intensive care unit.
Successful treatment of disseminated scedosporium infection in 2 lung transplant recipients: review of the literature and recommendations for management.
Revised definitions of invasive fungal disease from the European Organization for Research and Treatment of Cancer/Invasive Fungal Infections Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group.
Breakthrough Lung Scedosporium prolificans Infection with Multiple Cavity Lesions in a Patient Receiving Voriconazole for Probable Invasive Aspergillosis Associated With Monoclonal Gammopathy of Undetermined Significance (MGUS).
Breakthrough disseminated scedosporium prolificans infection in a patient with relapsed Leukaemia on prolonged voriconazole followed by posaconazole prophylaxis.
US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis: executive summary.
US Cystic Fibrosis Foundation and European Cystic Fibrosis Society consensus recommendations for the management of non-tuberculous mycobacteria in individuals with cystic fibrosis.
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