Purpose
Invasive pulmonary aspergillosis (IPA) is increasingly reported in patients with severe coronavirus disease 2019 (COVID-19) admitted to the intensive care unit (ICU). Diagnosis and management ...of COVID-19 associated pulmonary aspergillosis (CAPA) are challenging and our aim was to develop practical guidance.
Methods
A group of 28 international experts reviewed current insights in the epidemiology, diagnosis and management of CAPA and developed recommendations using GRADE methodology.
Results
The prevalence of CAPA varied between 0 and 33%, which may be partly due to variable case definitions, but likely represents true variation. Bronchoscopy and bronchoalveolar lavage (BAL) remain the cornerstone of CAPA diagnosis, allowing for diagnosis of invasive
Aspergillus
tracheobronchitis and collection of the best validated specimen for
Aspergillus
diagnostics. Most patients diagnosed with CAPA lack traditional host factors, but pre-existing structural lung disease and immunomodulating therapy may predispose to CAPA risk. Computed tomography seems to be of limited value to rule CAPA in or out, and serum biomarkers are negative in 85% of patients. As the mortality of CAPA is around 50%, antifungal therapy is recommended for BAL positive patients, but the decision to treat depends on the patients’ clinical condition and the institutional incidence of CAPA. We recommend against routinely stopping concomitant corticosteroid or IL-6 blocking therapy in CAPA patients.
Conclusion
CAPA is a complex disease involving a continuum of respiratory colonization, tissue invasion and angioinvasive disease. Knowledge gaps including true epidemiology, optimal diagnostic work-up, management strategies and role of host-directed therapy require further study.
Purpose
Invasive pulmonary aspergillosis is increasingly reported in patients with influenza admitted to the intensive care unit (ICU). Classification of patients with influenza-associated pulmonary ...aspergillosis (IAPA) using the current definitions for invasive fungal diseases has proven difficult, and our aim was to develop case definitions for IAPA that can facilitate clinical studies.
Methods
A group of 29 international experts reviewed current insights into the epidemiology, diagnosis and management of IAPA and proposed a case definition of IAPA through a process of informal consensus.
Results
Since IAPA may develop in a wide range of hosts, an entry criterion was proposed and not host factors. The entry criterion was defined as a patient requiring ICU admission for respiratory distress with a positive influenza test temporally related to ICU admission. In addition, proven IAPA required histological evidence of invasive septate hyphae and mycological evidence for
Aspergillus
. Probable IAPA required the detection of galactomannan or positive
Aspergillus
culture in bronchoalveolar lavage (BAL) or serum with pulmonary infiltrates or a positive culture in upper respiratory samples with bronchoscopic evidence for tracheobronchitis or cavitating pulmonary infiltrates of recent onset. The IAPA case definitions may be useful to classify patients with COVID-19-associated pulmonary aspergillosis (CAPA), while awaiting further studies that provide more insight into the interaction between
Aspergillus
and the SARS-CoV-2-infected lung.
Conclusion
A consensus case definition of IAPA is proposed, which will facilitate research into the epidemiology, diagnosis and management of this emerging acute and severe
Aspergillus
disease, and may be of use to study CAPA.
Type 2 alveolar epithelial (AT2) cells of the lung are fundamental in regulating alveolar inflammation in response to injury. Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in AT2 ...cells is assumed to aggravate alveolar inflammation in acute lung injury (ALI), yet the importance of mtLCFAO to AT2 cell function needs to be defined. Here we show that expression of carnitine palmitoyltransferase 1a (CPT1a), a mtLCFAO rate limiting enzyme, in AT2 cells is significantly decreased in acute respiratory distress syndrome (ARDS). In mice, Cpt1a deletion in AT2 cells impairs mtLCFAO without reducing ATP production and alters surfactant phospholipid abundance in the alveoli. Impairing mtLCFAO in AT2 cells via deleting either Cpt1a or Acadl (acyl-CoA dehydrogenase long chain) restricts alveolar inflammation in ALI by hindering the production of the neutrophilic chemokine CXCL2 from AT2 cells. This study thus highlights mtLCFAO as immunometabolism to injury in AT2 cells and suggests impaired mtLCFAO in AT2 cells as an anti-inflammatory response in ARDS.Impaired mitochondrial long-chain fatty acid β-oxidation (mtLCFAO) in type 2 alveolar epithelial (AT2) cells is thought to aggravate alveolar inflammation in acute lung injury. Here, the authors show that the mtLCFAO rate limiting enzyme CPT1a is decreased in AT2 cells in acute respiratory distress syndrome, highlighting the role of mtLCFAO in immunometabolism in this context.
ABSTRACT Extensive and independent observations of Type Ia supernova (SN Ia) SN 2013dy are presented, including a larger set of UBVRI photometry and optical spectra from a few days before the peak ...brightness to ∼ 200 days after explosion, and ultraviolet (UV) photometry spanning from t -10 days to t +15 days refers to the B band maximum. The peak brightness (i.e., MB = -19.65 0.40 mag; Lmax = 1.95 0.55 × 1043 erg s−1) and the mass of synthesized 56Ni (i.e., M(56Ni) = 0.90 0.26 M ) are calculated, and they conform to the expectation for an SN Ia with a slow decline rate (i.e., Δm15(B) = 0.90 0.03 mag). However, the near infrared (NIR) brightness of this SN (i.e., MH = -17.33 0.30 mag) is at least 1.0 mag fainter than usual. Besides, spectroscopy classification reveals that SN 2013dy resides on the border of "core normal" and "shallow silicon" subclasses in the Branch et al. classification scheme, or on the border of the "normal velocity" SNe Ia and 91T/99aa-like events in the Wang et al. system. These suggest that SN 2013dy is a slow-declining SN Ia located on the transitional region of nominal spectroscopic subclasses and might not be a typical normal sample of SNe Ia.
Drug resistance and tumor recurrence are major obstacles in treating lung cancer patients. Accumulating evidence considers lung cancer stem cells (CSCs) as the major contributor to these clinical ...challenges. Agents that can target lung CSCs could potentially provide a more effective treatment than traditional chemotherapy. Here, we utilized the side-population (SP) method to isolate lung CSCs from A549 and PC-9 cell lines. Subsequently, a high throughput platform, connectivity maps (CMAPs), was used to identify potential anti-CSC agents. An antibiotic, antimycin A (AMA), was identified as a top candidate. SP A549 cells exhibited an elevated stemness profile, including Nanog, β-catenin, Sox2, and CD133, and increased self-renewal ability. AMA treatment was found to suppress β-catenin signaling components and tumor sphere formation. Furthermore, AMA treatment decreased the proliferation of gefitinib-resistant PC-9/GR cells and percentage of SP population. AMA demonstrated synergistic suppression of PC-9/GR cell viability when combined with gefitinib. Finally, AMA treatment suppressed tumorigenesis in mice inoculated with A549 SP cells. Collectively, we have identified AMA using CMAP as a novel antilung CSC agent, which acts to downregulate β-catenin signaling. The combination of AMA and targeted therapeutic agents could be considered for overcoming drug resistance and relapse in lung cancer patients.
Summary
In Austria, a country with a total population of approximately 8.3 million, the published estimates of influenza-associated deaths within the past decade are surprisingly high (up to 6000 ...deaths per year) when compared to neighbouring countries. The objective of our analysis was to provide reliable estimates of the annual influenza-related deaths in Austria. We estimated the seasonal influenza-related excess mortality by calculating the difference between all-cause mortality observed during the influenza season and the baseline values to be expected during that time span if increased influenza activity was absent. Increased influenza activity was defined as moderate, usual or high, categorized by the influenza activity index using weekly data from the Austrian sentinel clinical surveillance system. For obtaining estimates of baseline all-cause mortality, a cyclic regression model was applied to the time series data on weekly all-cause mortality from 2001 to 2009. Austrian seasonal influenza-related excess mortality peaked in the seasons 2002/2003 (1060 excess deaths), 2004/2005 (1102 excess deaths) and 2008/2009 (1192 excess deaths). The rising trend observed is in parallel with the increasing proportion of the Austrian population older than 65 years for the same time span (2001:15.5%; 2009: 17.5%). Our findings on seasonal influenza-related excess mortality are in accordance with the estimates from Germany and Switzerland, which were derived from a similar approach. In order to gain and to preserve higher compliance with influenza vaccination initiatives, it is essential to have reliable data on influenza-related mortality. Thus, the numbers presented so far by Austrian public health institutions must be challenged.
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