Clinical and experimental phenotype of azole-resistant Aspergillus fumigatus with a HapE splice site mutation: a case report View Full Text


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Article Info

DATE

2021-06-14

AUTHORS

Yuya Ito, Takahiro Takazono, Satoru Koga, Yuichiro Nakano, Nobuyuki Ashizawa, Tatsuro Hirayama, Masato Tashiro, Tomomi Saijo, Kazuko Yamamoto, Yoshifumi Imamura, Taiga Miyazaki, Katsunori Yanagihara, Koichi Izumikawa, Hiroshi Mukae

ABSTRACT

BackgroundThe recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate.Case presentationA 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation.ConclusionsThis is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted. More... »

PAGES

573

References to SciGraph publications

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12879-021-06279-1

DOI

http://dx.doi.org/10.1186/s12879-021-06279-1

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1138855959

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/34126952


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23 schema:description BackgroundThe recent increase in cases of azole-resistant Aspergillus fumigatus (ARAf) infections is a major clinical concern owing to its treatment limitations. Patient-derived ARAf occurs after prolonged azole treatment in patients with aspergillosis and involves various cyp51A point mutations or non-cyp51A mutations. The prognosis of patients with chronic pulmonary aspergillosis (CPA) with patient-derived ARAf infection remains unclear. In this study, we reported the case of a patient with ARAf due to HapE mutation, as well as the virulence of the isolate.Case presentationA 37-year-old male was presented with productive cough and low-grade fever. The patient was diagnosed with CPA based on the chronic course, presence of a fungus ball in the upper left lobe on chest computed tomography (CT), positivity for Aspergillus-precipitating antibody and denial of other diseases. The patient underwent left upper lobe and left S6 segment resection surgery because of repeated haemoptysis during voriconazole (VRC) treatment. The patient was postoperatively treated with VRC for 6 months. Since then, the patient was followed up without antifungal treatment but relapsed 4 years later, and VRC treatment was reinitiated. Although an azole-resistant isolate was isolated after VRC treatment, the patient did not show any disease progression in either respiratory symptoms or radiological findings. The ARAf isolated from this patient showed slow growth, decreased biomass and biofilm formation in vitro, and decreased virulence in the Galleria mellonella infection model compared with its parental strain. These phenotypes could be caused by the HapE splice site mutation.ConclusionsThis is the first to report a case demonstrating the clinical manifestation of a CPA patient infected with ARAf with a HapE splice site mutation, which was consistent with the in vitro and in vivo attenuated virulence of the ARAf isolate. These results imply that not all the ARAf infections in immunocompetent patients require antifungal treatment. Further studies on the virulence of non-cyp51A mutations in ARAf are warranted.
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29 schema:keywords Araf
30 Aspergillus
31 Aspergillus fumigatus
32 Aspergillus fumigatus infection
33 CPA patients
34 Case presentationA
35 ConclusionsThis
36 Further studies
37 Galleria mellonella infection model
38 VRC
39 VRC treatment
40 antibodies
41 antifungal treatment
42 aspergillosis
43 azole treatment
44 azole-resistant Aspergillus fumigatus
45 azole-resistant isolates
46 ball
47 biofilm formation
48 biomass
49 case report
50 cases
51 chest
52 chronic course
53 chronic pulmonary aspergillosis
54 clinical concern
55 clinical manifestations
56 concern
57 cough
58 course
59 denial
60 disease
61 disease progression
62 experimental phenotypes
63 fever
64 findings
65 formation
66 fumigatus
67 fumigatus infection
68 growth
69 haemoptysis
70 immunocompetent patients
71 increase
72 infection
73 infection model
74 isolates
75 left lobe
76 limitations
77 lobe
78 low-grade fever
79 major clinical concern
80 males
81 manifestations
82 model
83 months
84 mutations
85 parental strain
86 patients
87 phenotype
88 point mutations
89 positivity
90 presence
91 productive cough
92 prognosis
93 prognosis of patients
94 progression
95 pulmonary aspergillosis
96 radiological findings
97 recent increase
98 report
99 resection surgery
100 respiratory symptoms
101 results
102 site mutation
103 slow growth
104 splice site mutation
105 strains
106 study
107 surgery
108 symptoms
109 tomography
110 treatment
111 treatment limitations
112 upper left lobe
113 upper lobe
114 virulence
115 vivo
116 voriconazole treatment
117 years
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