Reduced mortality, complications, and economic burden among medicare beneficiaries receiving influenza antivirals.

INTRODUCTION: Antiviral therapy may be underutilized in patients at high risk for increased clinical and economic burden (e.g. older adults). We aimed to examine the benefits associated with antiviral treatment of seasonal influenza among treated and untreated Medicare beneficiaries. METHODS: This retrospective study of Medicare Claims Research Identifiable Files identified patients ≥66 years old with an influenza diagnosis in outpatient setting between October 2016-March 2019 (flu seasons 2016-2018). Index date defined as date of first claim with influenza diagnosis; baseline as the 12 months pre-index. Treated patients received antivirals ≤2 days from index. Untreated patients had no antivirals ≤6 months post-index. Treated/untreated patients were 1:1 propensity score matched. Outcomes (death, all-cause and respiratory-related healthcare resource utilization [HCRU] and costs) were assessed until death or up to 6 months post-index. Descriptive statistics were reported; Kaplan-Meier estimation was used for survival over time. RESULTS: Among 116,901 matched patient pairs, all-cause mortality within 6 months from index diagnosis was 1.6% among treated versus 4.3% among untreated patients. Rates (treated versus untreated) of all-cause inpatient hospitalizations during follow-up were 13.9% versus 22.7% and respiratory-related hospitalizations were 4.2% versus 9.0%. Mean (SD) total all-cause and respiratory-related costs were $9,830 ($18,616.0) and $900 ($4016.4) among the treated, respectively, versus $13,207 ($24,405.1) and $2,024 ($7,623.7) among untreated, respectively. All differences were statistically significant (p < 0.001). CONCLUSIONS: Lack of antiviral treatment is associated with increased mortality, HCRU, and economic burden in older Medicare beneficiaries with seasonal influenza. Future research should investigate whether the choice of antivirals affects influenza burden.

Previous studies have shown that antiviral drugs help prevent flu-related complications and lower healthcare utilization and costs. However, these previous studies have focused on working aged people with existing health problems. Our study looks at how antiviral treatment can lower the health and financial burden caused by the flu in older adults. Using a Medicare claims database from the 2016­2018 flu season, we identified 116,901 matched (treated versus untreated) patient pairs. All-cause mortality within 6 months from the index diagnosis (defined as the first claim with a flu diagnosis) was 1.6% among treated versus 4.3% among untreated patients. Rates (treated versus untreated) of all-cause inpatient hospitalizations during follow-up (defined as 6 months after the index diagnosis date) were 13.9% versus 22.7% and respiratory-related hospitalizations were 4.2% versus 9.0%. Mean total all-cause and respiratory-related costs were $9,830 and $900 among the treated, respectively, versus $13,207 and $2,024 among untreated, respectively. All differences were statistically significant (p < 0.001). This analysis of older adults with the flu found that prompt antiviral treatment is associated with lower rates of mortality and acute complications, reduced hospitalization, and lower healthcare costs. Use of antiviral treatment for patients at high risk of flu, such as older adults, is warranted.

Safety and Efficacy of Baloxavir Marboxil in Influenza-infected Children 5-11 Years of Age: A Post Hoc Analysis of a Phase 3 Study.

BACKGROUND: miniSTONE-2 (NCT03629184) was a global, phase 3, randomized, controlled study that investigated the safety and efficacy of single-dose baloxavir marboxil in otherwise healthy children 1-<12 years of age and showed a positive risk-benefit profile. This post hoc analysis evaluated the safety and efficacy of baloxavir versus oseltamivir in children 5-11 years old with influenza. METHODS: Children received single-dose baloxavir or twice-daily oseltamivir for 5 days. Safety was the primary objective. Efficacy and virological outcomes included time to alleviation of symptoms, duration of fever and time to cessation of viral shedding by titer. Data were summarized descriptively. RESULTS: Ninety-four children 5-11 years old were included (61 baloxavir and 33 oseltamivir). Baseline characteristics were similar between the groups. The incidence of adverse events was balanced and low in both treatment groups, with the most common being vomiting (baloxavir 5% vs. oseltamivir 18%), diarrhea (5% vs. 0%) and otitis media (0% vs. 5%). No serious adverse events or deaths occurred. Median (95% CI) time to alleviation of symptoms with baloxavir was 138.4 hours (116.7-163.4) versus 126.1 hours (95.9-165.7) for oseltamivir; duration of fever was comparable between groups [41.2 hours (23.5-51.4) vs. 51.3 hours (30.7-56.8), respectively]. Median time to cessation of viral shedding was shorter in the baloxavir group versus oseltamivir (1 vs. ≈3 days). CONCLUSIONS: Safety, efficacy and virological results in children 5-11 years were similar to those from the overall study population 1-<12 years of age. Single-dose baloxavir provides an additional treatment option for pediatric patients 5-11 years old with influenza.

Development stage-specific proteomic profiling uncovers small, lineage specific proteins most abundant in the Aspergillus Fumigatus conidial proteome.

BACKGROUND: The pathogenic mold Aspergillus fumigatus is the most frequent infectious cause of death in severely immunocompromised individuals such as leukemia and bone marrow transplant patients. Germination of inhaled conidia (asexual spores) in the host is critical for the initiation of infection, but little is known about the underlying mechanisms of this process. RESULTS: To gain insights into early germination events and facilitate the identification of potential stage-specific biomarkers and vaccine candidates, we have used quantitative shotgun proteomics to elucidate patterns of protein abundance changes during early fungal development. Four different stages were examined: dormant conidia, isotropically expanding conidia, hyphae in which germ tube emergence has just begun, and pre-septation hyphae. To enrich for glycan-linked cell wall proteins we used an alkaline cell extraction method. Shotgun proteomic resulted in the identification of 375 unique gene products with high confidence, with no evidence for enrichment of cell wall-immobilized and secreted proteins. The most interesting discovery was the identification of 52 proteins enriched in dormant conidia including 28 proteins that have never been detected in the A. fumigatus conidial proteome such as signaling protein Pil1, chaperones BipA and calnexin, and transcription factor HapB. Additionally we found many small, Aspergillus specific proteins of unknown function including 17 hypothetical proteins. Thus, the most abundant protein, Grg1 (AFUA_5G14210), was also one of the smallest proteins detected in this study (M.W. 7,367). Among previously characterized proteins were melanin pigment and pseurotin A biosynthesis enzymes, histones H3 and H4.1, and other proteins involved in conidiation and response to oxidative or hypoxic stress. In contrast, expanding conidia, hyphae with early germ tubes, and pre-septation hyphae samples were enriched for proteins responsible for housekeeping functions, particularly translation, respiratory metabolism, amino acid and carbohydrate biosynthesis, and the tricarboxylic acid cycle. CONCLUSIONS: The observed temporal expression patterns suggest that the A. fumigatus conidia are dominated by small, lineage-specific proteins. Some of them may play key roles in host-pathogen interactions, signal transduction during conidial germination, or survival in hostile environments.

The proteomic signature of Aspergillus fumigatus during early development.

Aspergillus fumigatus is a saprophytic fungus that causes a range of diseases in humans including invasive aspergillosis. All forms of disease begin with the inhalation of conidia, which germinate and develop. Four stages of early development were evaluated using the gel free system of isobaric tagging for relative and absolute quantitation to determine the full proteomic profile of the pathogen. A total of 461 proteins were identified at 0, 4, 8, and 16 h and fold changes for each were established. Ten proteins including the hydrophobin rodlet protein RodA and a protein involved in melanin synthesis Abr2 were found to decrease relative to conidia. To generate a more comprehensive view of early development, a whole genome microarray analysis was performed comparing conidia to 8 and 16 h of growth. A total of 1871 genes were found to change significantly at 8 h with 1001 genes up-regulated and 870 down-regulated. At 16 h, 1235 genes changed significantly with 855 up-regulated and 380 down-regulated. When a comparison between the proteomics and microarray data was performed at 8 h, a total of 22 proteins with significant changes also had corresponding genes that changed significantly. When the same comparison was performed at 16 h, 12 protein and gene combinations were found. This study, the most comprehensive to date, provides insights into early pathways activated during growth and development of A. fumigatus. It reveals a pathogen that is gearing up for rapid growth by building translation machinery, generating ATP, and is very much committed to aerobic metabolism.

Profiling the Aspergillus fumigatus proteome in response to caspofungin.

The proteomic response of Aspergillus fumigatus to caspofungin was evaluated by gel-free isobaric tagging for relative and absolute quantitation (iTRAQ) as a means to determine potential biomarkers of drug action. A cell fractionation approach yielding 4 subcellular compartment fractions was used to enhance the resolution of proteins for proteomic analysis. Using iTRAQ, a total of 471 unique proteins were identified in soluble and cell wall/plasma membrane fractions at 24 and 48 h of growth in rich media in a wild-type drug-susceptible strain. A total of 122 proteins showed at least a 2-fold change in relative abundance following exposure to caspofungin (CSF) at just below the minimum effective concentration (0.12 µg/ml). The largest changes were seen in the mitochondrial hypoxia response domain protein (AFUA_1G12250), the level of which decreased >16-fold in the secreted fraction, and ChiA1, the level of which decreased 12.1-fold in the cell wall/plasma membrane fraction. The level of the major allergen and cytotoxin AspF1 was also shown to decrease by 12.1-fold upon the addition of drug. A subsequent iTRAQ analysis of an echinocandin-resistant strain (fks1-S678P) was used to validate proteins specific to drug action. A total of 103 proteins in the 2 fractions tested by iTRAQ were differentially expressed in the wild-type susceptible strain but not significantly changed in the resistant strain. Of these potential biomarkers, 11 had levels that changed at least 12-fold. Microarray analysis of the susceptible strain was performed to evaluate the correlation between proteomics and genomics, with a total of 117 genes found to be changing at least 2-fold. Of these, a total of 22 proteins with significant changes identified by iTRAQ also showed significant gene expression level changes by microarray. Overall, these data have the potential to identify biomarkers that assess the relative efficacy of echinocandin drug therapy.