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Influenza-associated pulmonary aspergillosis (IAPA) and COVID-19-associated pulmonary aspergillosis (CAPA) are increasingly recognised as important complications in patients requiring intensive care for severe viral pneumonia. The diagnosis can typically be made in 10–20% of patients with severe influenza or COVID-19, but only when appropriate diagnostic tools are used. Bronchoalveolar lavage sampling for culture, galactomannan testing, and PCR forms the cornerstone of diagnosis, whereas visual examination of the tracheobronchial tract during bronchoscopy is required to detect invasive Aspergillustracheobronchitis. Azoles are the first-choice antifungal drugs, with liposomal amphotericin B as an alternative in settings where azole resistance is prevalent. Despite antifungal therapy, IAPA and CAPA are associated with poor outcomes, with fatality rates often exceeding 50%. In this Review, we discuss the mechanistic and clinical aspects of IAPA and CAPA. Moreover, we identify crucial knowledge gaps and formulate directions for future research.

In the Netherlands, access to direct-acting antivirals (DAAs) against hepatitis C virus (HCV) has been unrestricted for chronic infection since 2015. We evaluated whether the nationwide incidence of HCV infections in individuals with HIV has changed since 2015.

Direct-acting antivirals effectively treat chronic hepatitis C virus (HCV) infection but there is a paucity of data on their efficacy for acute HCV, when immediate treatment could prevent onward transmission. We assessed the efficacy of grazoprevir plus elbasvir treatment in acute HCV infection and investigated whether treatment can be shortened during the acute phase of HCV infection.

Invasive pulmonary aspergillosis typically occurs in an immunocompromised host. For almost a century, influenza has been known to set up for bacterial superinfections, but recently patients with severe influenza were also reported to develop invasive pulmonary aspergillosis. We aimed to measure the incidence of invasive pulmonary aspergillosis over several seasons in patients with influenza pneumonia in the intensive care unit (ICU) and to assess whether influenza was an independent risk factor for invasive pulmonary aspergillosis.

ABSTRACTAzole resistance in Aspergillus fumigatusis increasingly reported. Here, we describe the validation of the AsperGenius, a new multiplex real-time PCR assay consisting of two multiplex real-time PCRs, one that identifies the clinically relevant Aspergillusspecies, and one that detects the TR34, L98H, T289A, and Y121F mutations in CYP51A and differentiates susceptible from resistant A. fumigatusstrains. The diagnostic performance of the AsperGenius assay was tested on 37 bronchoalveolar lavage (BAL) fluid samples from hematology patients and 40 BAL fluid samples from intensive care unit (ICU) patients using a BAL fluid galactomannan level of =1.0 or positive culture as the gold standard for detecting the presence of Aspergillus. In the hematology and ICU groups combined, there were 22 BAL fluid samples from patients with invasive aspergillosis (IA) (2 proven, 9 probable, and 11 nonclassifiable). Nineteen of the 22 BAL fluid samples were positive, according to the gold standard. The optimal cycle threshold value for the presence of Aspergilluswas <36. Sixteen of the 19 BAL fluid samples had a positive PCR (2 Aspergillusspecies and 14 A. fumigatussamples). This resulted in a sensitivity, specificity, and positive and negative predictive values of 88.9%, 89.3%, 72.7%, and 96.2%, respectively, for the hematology group and 80.0%, 93.3%, 80.0%, and 93.3%, respectively, in the ICU group. The CYP51A real-time PCR confirmed 12 wild-type and 2 resistant strains (1 TR34-L98H and 1 TR46-Y121F-T289A mutant). Voriconazole therapy failed for both patients. The AsperGenius multiplex real-time PCR assay allows for sensitive and fast detection of Aspergillusspecies directly from BAL fluid samples. More importantly, this assay detects and differentiates wild-type from resistant strains, even if BAL fluid cultures remain negative.

ABSTRACTAt present, voriconazole (VOR) is the drug of first choice for treating invasive pulmonary aspergillosis (IPA). However, particularly in advanced stages of disease and in the severely immunocompromised host, the mortality remains substantial. The combination of VOR with an echinocandin may improve the therapeutic outcome. We investigate here whether combining VOR and anidulafungin (ANI) in advanced IPA in transiently neutropenic rats results in a higher therapeutic efficacy. Since VOR is metabolized more rapidly in rodents than in humans, dosage adjustment for VOR is necessary to obtain an area under the plasma concentration-time curve (AUC) in rodents that is equivalent to that of humans. In this study, the pharmacokinetics of VOR and ANI in rats were elucidated, and dosage schedules were applied that produced AUCs similar to those of humans. The developed dose schedules were well tolerated by the rats, without effects on renal and hepatic functions. VOR showed excellent efficacy in early IPA (100% rat survival). In advanced IPA, VOR was less efficacious (50% rat survival), whereas a significant decrease in galactomannan concentrations in lungs and sera was found in surviving rats. ANI administered in advanced IPA resulted in 22% rat survival, and the serum concentrations of fungal galactomannan were slightly but not significantly decreased. The addition of ANI to VOR did not result in significantly increased therapeutic efficacy in advanced IPA, resulting in 67% rat survival and a significant decrease in galactomannan concentration in serum. In conclusion, VOR monotherapy is therapeutically effective in the treatment of advanced-stage IPA and superior to the use of ANI. Combining both agents does not significantly improve the therapeutic outcome.

ABSTRACTDiagnosing catheter-related bloodstream infection (CRBSI) still often involves tip culture. The conventional method is the semiquantitative roll plate method. However, the use of a quantitative sonication technique could have additional value, as it may detect endoluminal microorganisms more easily. Because endoluminal infection tends to occur in long-term central venous catheters, we compared both techniques for patients with long-term tunnelled catheters. For 313 consecutive Hickman catheter tips from 279 hematological patients, colonization detection rates were compared by performing both techniques in a random order, using conventional detection cutoffs. Additionally, for the subgroup of patients with clinical suspicion of CRBSI (n= 89), the diagnostic values of both techniques were compared. The overall tip colonization rate was 25%. For each technique, the detection rate tended to be better if that technique was performed first. The diagnostic performance for the subgroup of patients with clinical suspicion of CRBSI was limited and not different for both methods. Sensitivity and specificity were 45% and 84%, respectively, for sonication versus 35% and 90%, respectively, for the roll plate technique. The fact that 35 of 40 patients with CRBSI received antimicrobial therapy before catheter removal and tip culture, in an attempt to salvage the catheter, may partly explain this poor performance. No differences were observed when catheters were stratified according to in situ time below or above the median of 4 weeks. The sonication culture technique was not better than the roll plate method to diagnose tip colonization or CRBSI in patients with long-term tunnelled catheters.

ABSTRACTA high-dose-step-down strategy for caspofungin treatment was evaluated in an experimental model of advanced-stage invasive pulmonary aspergillosis. The therapeutic efficacy of caspofungin in relation to the severity of invasive pulmonary infection caused by Aspergillus fumigatusin transiently neutropenic rats was investigated by using rat survival and the decrease in the fungal burden as the parameters of efficacy. When treatment was started at either 16 h or 24 h after fungal inoculation, caspofungin administered intraperitoneally at 4 mg/kg of body weight/day for 10 days was highly effective (100% and 93% rat survival, respectively). However, only 27% rat survival was obtained when treatment was started at 72 h, when the rats had advanced-stage infection. Increasing the dose from 4 to 10 mg/kg/day could compensate for the decrease in efficacy and resulted in 67% rat survival. The high dose of 10 mg/kg/day for 10 days did not appear to be necessary since a high-dose-step-down dosing schedule with 10 mg/kg/day for 3 days followed by 4 mg/kg/day for 7 days was equally effective. At 10 days after the end of treatment with 10 mg/kg/day caspofungin, the level of neither A. fumigatusDNA nor A. fumigatusgalactomannan in the infected left lung was significantly decreased. In contrast, A. fumigatusgalactomannan concentrations in serum were significantly decreased. The levels of creatinine, blood urea nitrogen, alanine aminotransferase, and asparate aminotransferase were not elevated during treatment. Caspofungin is effective for the treatment of invasive pulmonary aspergillosis in transiently neutropenic rats and is even effective in rats with advanced-stage infection. In this model, the administration of high-dose-step-down treatment was as effective as treatment with high doses for the whole treatment period.

Objectives: The use of an antibiotic lock (AB-lock) for the treatment of catheter-related bloodstream infection (CRBSI) has been suggested, but randomized trials have never been performed. Methods: A randomized, blinded, multicentre trial was set up to compare an AB-lock—containing vancomycin for Gram-positive or ceftazidime for Gram-negative bacteria—with placebo, in addition to parenteral AB therapy. We included only CRBSI from a long-term intravascular device (LTID) whether tunnelled or totally implanted. Results: During 30 months, 174 patients with an LTID and bacteraemia were evaluated, of whom 85 had a CRBSI. Forty-six patients were included. Frequent reasons for exclusion were: catheter not vacant for >8–12 h/day for the AB-lock (n =10); yeast infection or mixed Gram-positive/negative infections (n =13); catheter removal preferred by the treating physician (n =7); and CRBSI <14 days after insertion or pocket/tunnel infection (n =10). Forty-four patients met the criteria for modified intention-to-treat analysis. The primary endpoint was failure to cure the CRBSI or relapse with the same strain. On study day 180 by Kaplan–Meier analysis, this occurred in 33% (seven of 21) in the AB-lock arm and in 57% (13 of 23) in the placebo arm (hazard ratio 0.55, P =0.10). A relapse with the same strain occurred in 9/23 with the placebo and 3/21 with the AB-lock (P =0.06). Conclusion: Future studies should take into account the barriers to the use of AB-lock observed in this study. Most importantly, shorter lock dwell times and broader spectrum locks (e.g. antiseptic) should be investigated to target a larger patient population.

The aim of this study was to describe the frequency of positive Aspergillustests in COVID-19 patients and investigate the association between COVID-19 and a positive Aspergillustest result. We compared the proportion of positive Aspergillustests in COVID-19 patients admitted to the intensive care unit (ICU) for?>24?h with two control groups: patients with community-acquired pneumonia with (i) a PCR-confirmed influenza infection (considered a positive control since the link between influenza and invasive aspergillosis has been established) and (ii) Streptococcus pneumoniaepneumonia (in whom positive Aspergillustests are mostly considered to indicate colonization).

Objectives: Absorption of oral voriconazole is good and in contrast to the intravenous (iv) formulation it can be given in patients with renal insufficiency. Furthermore, the acquisition costs are significantly lower. The aim of this study was to compare the incidence of hepatotoxicity in patients treated with the oral formulation of voriconazole with that in patients treated with the iv formulation.Methods: This was a retrospective observational study. A total of 35 patients with haematological disease and an invasive fungal infection were treated with oral voriconazole during the entire regimen. We compared the incidence of hepatotoxicity with that in 11 patients treated intravenously during the first week.Results: The incidence of increased liver enzymes was comparable between both groups. Voriconazole was discontinued in two patients in the oral group and one patient in the iv group because of hepatotoxicity. The incidence of liver enzyme elevations in the entire study cohort of 46 patients was higher than that previously reported in a comparable study population (P < 0.001). However, clinically significant hepatotoxicity was infrequently observed (3/46 or 6.5%).Conclusions: In 35 patients with invasive fungal infections we instituted oral voriconazole therapy from day 1 and found an incidence of hepatotoxicity comparable to 11 controls treated intravenously.