Genomic Epidemiology Identifies Azole Resistance Due to TR34/L98H in European Aspergillus fumigatus Causing COVID-19-Associated Pulmonary Aspergillosis

Abstract

Aspergillus fumigatus has been found to coinfect patients with severe SARS-CoV-2 virus infection, leading to COVID-19-associated pulmonary aspergillosis (CAPA). The CAPA all-cause mortality rate is approximately 50% and may be complicated by azole resistance. Genomic epidemiology can help shed light on the genetics of A. fumigatus causing CAPA, including the prevalence of resistance-associated alleles. We present a population genomic analysis of 21 CAPA isolates from four European countries with these isolates compared against 240 non-CAPA A. fumigatus isolates from a wider population. Bioinformatic analysis and antifungal susceptibility testing were performed to quantify resistance and identify possible genetically encoded azole-resistant mechanisms. The phylogenetic analysis of the 21 CAPA isolates showed that they were representative of the wider A. fumigatus population with no obvious clustering. The prevalence of phenotypic azole resistance in CAPA was 14.3% (n = 3/21); all three CAPA isolates contained a known resistance-associated cyp51A polymorphism. The relatively high prevalence of azole resistance alleles that we document poses a probable threat to treatment success rates, warranting the enhanced surveillance of A. fumigatus genotypes in these patients. Furthermore, potential changes to antifungal first-line treatment guidelines may be needed to improve patient outcomes when CAPA is suspected.

Epidemiology and Azole Resistance of Clinical Isolates of Aspergillus fumigatus from a Large Tertiary Hospital in Ningxia, China

“…14,15 Azole resistance in A. fumigatus is primarily caused by alterations to the sterol biosynthesis pathway, resulting from point mutations of cyp51A and the insertion of tandem repeats (TR) in the promoter region of cyp51A (such as TR34/L98H and TR46/Y121F/T289A). [16][17][18] However, there are increasing reports of A. fumigatus strains that are resistant to clinical azoles despite lacking cyp51A modifications. 19,20 Extensive research has been conducted on strains with multiple mutations in hmg1 and hmg2, which encode the 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase.…”