Successful long-term terbinafine therapy in an asthmatic patient with Aspergillus sensitization and bronchiectasis

Abstract

Severe asthma with fungal sensitization (SAFS) is estimated to affect ~25% of patients with poorly controlled asthma. Tri-azole therapy is effective in only 60–80% and side effects are common. We report a 25 years-old woman with severe asthma, Aspergillus sensitization and marked bronchiectasis that developed a rare Achilles-tendinopathy with both itraconazole and voriconazole. She started a trial with terbinafine as salvage therapy that led to a striking improvement and long-term control of her respiratory disease.

The negative cofactor 2 complex is a key regulator of drug resistance in Aspergillus fumigatus

“…We show that the A. fumigatus NctA and NctB (Negative cofactor two A and B) are part of the same transcriptional regulatory complex and demonstrate that the NCT complex is a key regulator of ergosterol biosynthesis and the azole exporter CDR1B. We also report that loss of the NCT complex leads to a multi-drug-resistance phenotype, including the azoles (itraconazole, voriconazole and posaconazole) as well as the salvage therapeutic amphotericin B 18 and terbinafine, an agent used in the treatment of chronic and allergic disease 19 . Furthermore, loss of this complex results in a notable increase in the immunogenic properties of A. fumigatus, but does not result in loss of virulence.…”

“…Given the pleiotropic nature of the NCT complex, we cannot exclude that further factors may be contributing to the high levels of azole resistance evident in the nctA and nctB null mutants especially in light of our evidence showing that they are hypersensitive to the cell wall acting agents, and recent data showing a link between reductions in β-1,3-glucan synthesis and the delayed fungicidal effects of voriconazole 70 . The most striking phenotypes that we have observed for the nctA and the nctB null mutants aside from the resistance to the azole class of antifungals is their resistance to the salvage therapeutic amphotericin B and terbinafine, which can be used in the management of patients with chronic or allergic disease 19 . Cross-resistance to the azoles and terbinafine is understandable, as both act on the ergosterol biosynthetic pathway (terbinafine, inhibits the action of squalene epoxidase, an enzyme that catalyses the conversion of squalene to squalene 2,3-epoxide in the ergosterol biosynthesis pathway 71 ).…”

Mold burden in house dust and its relationship with asthma control

“…Sensitization to this mold has been amply recognized as a risk factor for severe asthma [25]. Although this effect is probably mediated by allergy to Aspergillus-derived proteins or disruption and activation of airway epithelial barrier [26], this mold also has the ability to colonize the asthmatic airways in what is known as severe asthma with fungal sensitization (SAFS) [27,28] or, in its highest expression of lung damage and bronchiectasis, known as allergic bronchopulmonary aspergillosis (ABPA) [29]. Although in our study we did not perform more specific tests (skin prick test or serum IgE to Aspergillus), the sole association of this mold burden with a reduced lung function might suggest a causative role of this fungus in asthma deterioration.…”