Isavuconazole as prophylaxis and therapy for invasive fungal diseases: a real-life observational study.

BACKGROUND: Isavuconazole is a relatively new antifungal agent indicated for the management of various invasive fungal diseases (IFDs), including invasive aspergillosis. Information on real-world experience with isavuconazole is scarce. This retrospective observational study aimed to describe the usage of isavuconazole in clinical practice with an in-depth evaluation of individual isavuconazole exposure. METHODS: Patients treated with isavuconazole were evaluated based on retrospective data, including therapeutic drug monitoring (TDM) data and efficacy and safety data. Additionally, we calculated the individual isavuconazole exposure described by the average AUC24 over the first 7 days of treatment by means of non-linear mixed-effects modelling and compared this with the currently desired lower target AUC of 60 mg·h/L. RESULTS: Ninety-nine patients treated with isavuconazole were evaluated. In our real-life cohort, isavuconazole was often deployed off-label in patients with non-classical host factors and infections with non-Aspergillus and non-Mucorales species. Isavuconazole was most often chosen for its safety profile, even after prior triazole treatment with manifestations of toxicity. TDM and subsequent dosage adjustments were frequently performed. The individual average AUC24 over 7 days was above 60 mg·h/L in 29 out of 77 (37.7%) patients. CONCLUSIONS: This overview provides practical insights that can aid clinicians in the management of their patients with IFD. Our study shows that isavuconazole was used in a diverse patient population and was well tolerated overall. Individual isavuconazole exposure reflected by the average AUC24 over the first 7 days of treatment was generally low and variable. Dosage adjustments following TDM were frequently performed. Our experience shows that isavuconazole is a feasible alternative after prior azole treatment.

Dysregulated Innate and Adaptive Immune Responses Discriminate Disease Severity in COVID-19.

The clinical spectrum of COVID-19 varies and the differences in host response characterizing this variation have not been fully elucidated. COVID-19 disease severity correlates with an excessive proinflammatory immune response and profound lymphopenia. Inflammatory responses according to disease severity were explored by plasma cytokine measurements and proteomics analysis in 147 COVID-19 patients. Furthermore, peripheral blood mononuclear cell cytokine production assays and whole blood flow cytometry were performed. Results confirm a hyperinflammatory innate immune state, while highlighting hepatocyte growth factor and stem cell factor as potential biomarkers for disease severity. Clustering analysis revealed no specific inflammatory endotypes in COVID-19 patients. Functional assays revealed abrogated adaptive cytokine production (interferon-γ, interleukin-17, and interleukin-22) and prominent T-cell exhaustion in critically ill patients, whereas innate immune responses were intact or hyperresponsive. Collectively, this extensive analysis provides a comprehensive insight into the pathobiology of severe to critical COVID-19 and highlights potential biomarkers of disease severity.

Chest CT in the Emergency Department for Diagnosis of COVID-19 Pneumonia: Dutch Experience.

Background Clinicians need to rapidly and reliably diagnose coronavirus disease 2019 (COVID-19) for proper risk stratification, isolation strategies, and treatment decisions. Purpose To assess the real-life performance of radiologist emergency department chest CT interpretation for diagnosing COVID-19 during the acute phase of the pandemic, using the COVID-19 Reporting and Data System (CO-RADS). Materials and Methods This retrospective multicenter study included consecutive patients who presented to emergency departments in six medical centers between March and April 2020 with moderate to severe upper respiratory symptoms suspicious for COVID-19. As part of clinical practice, chest CT scans were obtained for primary work-up and scored using the five-point CO-RADS scheme for suspicion of COVID-19. CT was compared with severe acute respiratory syndrome coronavirus 2 reverse-transcription polymerase chain reaction (RT-PCR) assay and a clinical reference standard established by a multidisciplinary group of clinicians based on RT-PCR, COVID-19 contact history, oxygen therapy, timing of RT-PCR testing, and likely alternative diagnosis. Performance of CT was estimated using area under the receiver operating characteristic curve (AUC) analysis and diagnostic odds ratios against both reference standards. Subgroup analysis was performed on the basis of symptom duration grouped presentations of less than 48 hours, 48 hours through 7 days, and more than 7 days. Results A total of 1070 patients (median age, 66 years; interquartile range, 54-75 years; 626 men) were included, of whom 536 (50%) had a positive RT-PCR result and 137 (13%) of whom were considered to have a possible or probable COVID-19 diagnosis based on the clinical reference standard. Chest CT yielded an AUC of 0.87 (95% CI: 0.84, 0.89) compared with RT-PCR and 0.87 (95% CI: 0.85, 0.89) compared with the clinical reference standard. A CO-RADS score of 4 or greater yielded an odds ratio of 25.9 (95% CI: 18.7, 35.9) for a COVID-19 diagnosis with RT-PCR and an odds ratio of 30.6 (95% CI: 21.1, 44.4) with the clinical reference standard. For symptom duration of less than 48 hours, the AUC fell to 0.71 (95% CI: 0.62, 0.80; P < .001). Conclusion Chest CT analysis using the coronavirus disease 2019 (COVID-19) Reporting and Data System enables rapid and reliable diagnosis of COVID-19, particularly when symptom duration is greater than 48 hours. © RSNA, 2020 Online supplemental material is available for this article. See also the editorial by Elicker in this issue.

Aspergillus Test Profiles and Mortality in Critically Ill COVID-19 Patients.

The literature regarding COVID-19-associated pulmonary aspergillosis (CAPA) has shown conflicting observations, including survival of CAPA patients not receiving antifungal therapy and discrepancy between CAPA diagnosis and autopsy findings. To gain insight into the pathophysiology of CAPA, we performed a case-control study in which we compared Aspergillus test profiles in CAPA patients and controls in relation to intensive care unit (ICU) mortality. This was a multinational case-control study in which Aspergillus test results, use of antifungal therapy, and mortality were collected from critically ill COVID-19 patients. Patients were classified using the 2020 European Confederation for Medical Mycology and the International Society for Human and Animal Mycology (ECMM/ISHAM) consensus case definitions. We analyzed 219 critically ill COVID-19 cases, including 1 proven, 38 probable, 19 possible CAPA cases, 21 Aspergillus-colonized patients, 7 patients only positive for serum (1,3)-ß-d-glucan (BDG), and 133 cases with no evidence of CAPA. Mortality was 53.8% in CAPA patients compared to 24.1% in patients without CAPA (P = 0.001). Positive serum galactomannan (GM) and BDG were associated with increased mortality compared to serum biomarker-negative CAPA patients (87.5% versus 41.7%, P = 0.046; 90.0% versus 42.1%, P = 0.029, respectively). For each point increase in GM or 10-point BDG serum concentration, the odds of death increased (GM, odds ratio [OR] 10.208, 95% confidence interval [CI], 1.621 to 64.291, P = 0.013; BDG, OR, 1.247, 95% CI, 1.029 to 1.511, P = 0.024). CAPA is a complex disease, probably involving a continuum of respiratory colonization, tissue invasion, and angioinvasion. Serum biomarkers are useful for staging CAPA disease progression and, if positive, indicate angioinvasion and a high probability of mortality. There is need for a biomarker that distinguishes between respiratory tract colonization and tissue-invasive CAPA disease.

Incidence, risk factors and pre-emptive screening for COVID-19 associated pulmonary aspergillosis in an era of immunomodulant therapy.

PURPOSE: COVID-19 associated pulmonary aspergillosis (CAPA) is associated with increased morbidity and mortality in ICU patients. We investigated the incidence of, risk factors for and potential benefit of a pre-emptive screening strategy for CAPA in ICUs in the Netherlands/Belgium during immunosuppressive COVID-19 treatment. MATERIALS AND METHODS: A retrospective, observational, multicentre study was performed from September 2020-April 2021 including patients admitted to the ICU who had undergone diagnostics for CAPA. Patients were classified based on 2020 ECMM/ISHAM consensus criteria. RESULTS: CAPA was diagnosed in 295/1977 (14.9%) patients. Corticosteroids were administered to 97.1% of patients and interleukin-6 inhibitors (anti-IL-6) to 23.5%. EORTC/MSGERC host factors or treatment with anti-IL-6 with or without corticosteroids were not risk factors for CAPA. Ninety-day mortality was 65.3% (145/222) in patients with CAPA compared to 53.7% (176/328) without CAPA (p = 0.008). Median time from ICU admission to CAPA diagnosis was 12 days. Pre-emptive screening for CAPA was not associated with earlier diagnosis or reduced mortality compared to a reactive diagnostic strategy. CONCLUSIONS: CAPA is an indicator of a protracted course of a COVID-19 infection. No benefit of pre-emptive screening was observed, but prospective studies comparing pre-defined strategies would be required to confirm this observation.

COVID-19-associated Aspergillus tracheobronchitis: the interplay between viral tropism, host defence, and fungal invasion.

Invasive pulmonary aspergillosis is emerging as a secondary infection in patients with COVID-19, which can present as alveolar disease, airway disease (ie, invasive Aspergillus tracheobronchitis), or both. Histopathology of invasive Aspergillus tracheobronchitis in patients with severe COVID-19 confirms tracheal ulcers with tissue invasion of Aspergillus hyphae but without angioinvasion, which differs from patients with severe influenza, where early angioinvasion is observed. We argue that aggregation of predisposing factors (eg, factors that are defined by the European Organisation for Research and Treatment of Cancer and Mycoses Study Group Education and Research Consortium or genetic polymorphisms), viral factors (eg, tropism and lytic effects), immune defence factors, and effects of concomitant therapies will determine whether and when the angioinvasion threshold is reached. Management of invasive Aspergillus tracheobronchitis should include reducing viral lytic effects, rebalancing immune dysregulation, and systemic and local antifungal therapy. Future study designs should involve approaches that aim to develop improved diagnostics for tissue invasion and airways involvement and identify the immune status of the patient to guide personalised immunotherapy.

Uncontrolled maternal chronic respiratory diseases in pregnancy: A new potential risk factor suggested to be associated with anorectal malformations in offspring.

BACKGROUND: Chronic respiratory diseases and use of antiasthmatic medication during pregnancy may both play a role in the etiology of congenital anorectal malformations (ARM). However, it is unclear, whether the medication use or the underlying condition would be responsible. Therefore, our aim was to unravel the role of maternal chronic respiratory diseases from that of antiasthmatic medication in the etiology of ARM. METHODS: We obtained 412 ARM patients and 2,137 population-based controls from the Dutch AGORA data- and biobank. We used maternal questionnaires and follow-up telephone interviews to obtain information on chronic respiratory diseases, antiasthmatic medication use, and potential confounders. Multivariable logistic regression analyses were performed to estimate odds ratios (ORs) with 95% confidence intervals (95% CI). RESULTS: We observed higher risk estimates among women with chronic respiratory diseases with and without medication use (1.4 [0.8-2.7] and 2.0 [0.8-5.0]), both in comparison to women without a chronic respiratory disease and without medication use. Furthermore, increased ORs of ARM were found for women using rescue medication (2.4 [0.8-7.3]) or a combination of maintenance and rescue medication (2.5 [0.9-6.7]). In addition, increased risk estimates were observed for women having nonallergic triggers (2.5 [1.0-6.3]) or experiencing exacerbations during the periconceptional period (3.5 [1.4-8.6]). CONCLUSIONS: Although the 95% CIs of most associations include the null value, the risk estimates all point towards an association between uncontrolled chronic respiratory disease, instead of antiasthmatic medication use, with ARM in offspring. Further in-depth studies towards mechanisms of this newly identified risk factor are warranted.