**10. Fungal lung disease in CF**

Clinical manifestations of respiratory fungal diseases in adult CF patients are very heterogeneous, ranging from asymptomatic colonisation to chronic infections, allergic disorders or invasive diseases in immunosuppressed CF patients following lung transplantation.

*Aspergillus* spp. are amongst the most widespread filamentous fungi in the environment, especially in areas with high humidity [86]. In CF patients, the most frequently isolated species is *Aspergillus fumigatus*, accounting for 67–73% of *Aspergillus*-positive sputum cultures [87]. Isolation of other species such as *A. flavus*, *A. niger* and *A. terreus* is less frequent but not rare (4, 4 and 2% of *Aspergillus*-positive sputum cultures, respectively) [87]. Notably, the prevalence of isolation of *Aspergillus* spp. from sputum cultures in CF patients increases with age, possibly reaching 46–78% in adult CF patients, although with important interregion and inter-centre variability [88–90]. However, knowledge of the prevalence of *Aspergillus* spp. isolation from sputum does not automatically allow to infer the prevalence of the various *Aspergillus*-related manifestations in CF patients, which range from asymptomatic colonisation to invasive diseases, especially in patients post-lung transplantation.

Allergic bronchopulmonary aspergillosis (ABPA) refers to a complex hypersensitivity reaction which often occurs in patients affected by CF or asthma. ABPA is beyond the scope of discussion in this chapter.

In CF patients, the disease-related progressive damage of the lungs may favour the development of chronic *Aspergillus* infection, commonly defined as '*Aspergillus* bronchitis', although aspergilloma(s) might also develop in some cases, especially in pre-existing cavities or bronchiectasis [91–93]. *Aspergillus* bronchitis has an estimated prevalence of ~2–8% in CF patients and may be suspected in the case of pulmonary exacerbation unresponsive to antibacterial treatment [94, 95]. As per Baxter et al.'s [96] classification, diagnosis of *Aspergillus* bronchitis can be made in the presence of a positive sputum galactomannan, high levels of *Aspergillus*-specific IgG and negative total and *Aspergillus*-specific IgE. Since *Aspergillus* bronchitis does reflect infection and not an immune-mediated response as in ABPA, corticosteroids are not the cornerstone of treatment. Treatment with azole derivatives is the current standard of care, although the overall duration of treatment is still not clearly

defined [97]. Invasive aspergillosis is described as the infection progresses across tissues and invades the vessels, with subsequent necrosis [96]. Usually, invasive aspergillosis is observed in severely immunocompromised non-CF populations, such as haematology patients with prolonged neutropenia and patients receiving high dosages of corticosteroids or other immunosuppressive agents. Clinical symptoms usually include fever, chest pain, shortness of breath and/or cough [96]. Haemoptysis and pneumothorax might also develop in some cases [98, 99]. Invasive aspergillosis is rarely seen in patients affected by CF. However, it could develop in end-stage CF patient and in immunosuppressed CF patients following lung transplantation, frequently in the form of *Aspergillus* tracheobronchitis, occurring mainly in the first 3 months after transplants and associated with increased mortality (39%) [100, 101]. Frequent symptoms of *Aspergillus* tracheobronchitis are severe dyspnoea, cough and wheezing [97]. The histopathological examination may show different features: (1) obstructive bronchial aspergillosis; (2) ulcerative tracheobronchitis (characterised by the invasion of the tracheobronchial mucosa and cartilage); and (3) pseudomembranous tracheobronchitis (characterised by inflammation and invasion of the tracheobronchial tree). Invasive aspergillosis is usually treated with systemic azole therapy (possibly associated with nebulised amphotericin B in some cases of tracheobronchitis) [97]. The US guidelines recommend a minimum of 6 to 12 weeks of therapy for patients with invasive pulmonary aspergillosis and at least 3 months in the case of *Aspergillus* tracheobronchitis [97].
