COVID-19: a case for inhibiting IL-17? Pacha, Omar; Sallman, Mary Alice; Evans, Scott E
Nature reviews. Immunology,
06/2020, Letnik:
20, Številka:
6
Journal Article
Since its discovery in 1957, respiratory syncytial virus (RSV) has been widely recognized as a common and deadly pathogen. Although early studies focused on the impact of RSV on the health of ...children, more recent data show that RSV imposes a significant burden on individuals aged ≥ 70 years. RSV also substantially harms the health of individuals with cardiopulmonary diseases.
Early efforts to develop an RSV vaccine were hampered by toxicity due to antibody-enhanced viral pneumonia and a lack of efficacy in vaccines that targeted the postfusion configuration of the F fusion protein, which is crucial to the pathogenesis of RSV-mediated injury. A newer wave of vaccines has targeted a stabilized prefusion F protein, generating effective neutralizing antibodies and reducing the burden of mild and severe RSV lower respiratory tract injury. This review focuses on the burden of RSV in patients with pulmonary diseases, highlights the tumultuous path from the early days of RSV vaccine development to the modern era, and offers insights into key gaps in knowledge that must be addressed to adequately protect the vulnerable population of patients with severe pulmonary diseases.
RSV vaccination with bivalent RSVPreF or RSVPreF3OA, which target the stabilized prefusion F protein, can be broadly recommended to adults with pulmonary diseases aged ≥ 60 years. However, more data are needed to understand how these vaccinations affect key clinical outcomes in individuals with pulmonary disease.
Summary Background Ticagrelor is an effective antiplatelet therapy for patients with coronary atherosclerotic disease and might be more effective than aspirin in preventing recurrent stroke and ...cardiovascular events in patients with acute cerebral ischaemia of atherosclerotic origin. Our aim was to test for a treatment-by-ipsilateral atherosclerotic stenosis interaction in a subgroup analysis of patients in the Acute Stroke or Transient Ischaemic Attack Treated with Aspirin or Ticagrelor and Patient Outcomes (SOCRATES) trial. Methods SOCRATES was a randomised, double-blind, controlled trial of ticagrelor versus aspirin in patients aged 40 years or older with a non-cardioembolic, non-severe acute ischaemic stroke, or high-risk transient ischaemic attack from 674 hospitals in 33 countries. We randomly allocated patients (1:1) to ticagrelor (180 mg loading dose on day 1 followed by 90 mg twice daily for days 2–90, given orally) or aspirin (300 mg on day 1 followed by 100 mg daily for days 2–90, given orally) within 24 h of symptom onset. Investigators classified all patients into atherosclerotic and non-atherosclerotic groups for the prespecified, exploratory analysis reported in this study. The primary endpoint was the time to occurrence of stroke, myocardial infarction, or death within 90 days. Efficacy analysis was by intention to treat. The SOCRATES trial is registered with ClinicalTrials.gov , number NCT01994720. Findings Between Jan 7, 2014, and Oct 29, 2015, we randomly allocated 13 199 patients (6589 50% to ticagrelor and 6610 50% to aspirin). Potentially symptomatic ipsilateral atherosclerotic stenosis was reported in 3081 (23%) of 13 199 patients. We found a treatment-by-atherosclerotic stenosis interaction (p=0·017). 103 (6·7%) of 1542 patients with ipsilateral stenosis in the ticagrelor group and 147 (9·6%) of 1539 patients with ipsilateral stenosis in the aspirin group had an occurrence of stroke, myocardial infarction, or death within 90 days (hazard ratio 0·68 95% CI 0·53–0·88; p=0·003). In 10 118 patients with no ipsilateral stenosis, 339 (6·7%) of 5047 patients in the ticagrelor group had an occurrence of stroke, myocardial infarction, or death within 90 days compared with 350 (6·9%) of 5071 in the aspirin group (0·97 0·84–1·13; p=0·72). There were no significant differences in the proportion of life-threatening bleeding or major or minor bleeding events in patients with ipsilateral stenosis in the ticagrelor group compared with the aspirin group. Interpretation In this prespecified exploratory analysis, ticagrelor was superior to aspirin at preventing stroke, myocardial infarction, or death at 90 days in patients with acute ischaemic stroke or transient ischaemic attack when associated with ipsilateral atherosclerotic stenosis. An understanding of stroke mechanisms and causes is important to deliver safe and efficacious treatments for early stroke prevention. Funding AstraZeneca.
Fungal infections are of increasing incidence and importance in immunocompromised and immunocompetent patients. Timely diagnosis relies on appropriate use of laboratory testing in susceptible ...patients.
The relevant literature related to diagnosis of invasive pulmonary aspergillosis, invasive candidiasis, and the common endemic mycoses was systematically reviewed. Meta-analysis was performed when appropriate. Recommendations were developed using the Grading of Recommendations Assessment, Development, and Evaluation approach.
This guideline includes specific recommendations on the use of galactomannan testing in serum and BAL and for the diagnosis of invasive pulmonary aspergillosis, the role of PCR in the diagnosis of invasive pulmonary aspergillosis, the role of β-d-glucan assays in the diagnosis of invasive candidiasis, and the application of serology and antigen testing in the diagnosis of the endemic mycoses.
Rapid, accurate diagnosis of fungal infections relies on appropriate application of laboratory testing, including antigen testing, serological testing, and PCR-based assays.
Lower respiratory tract infections caused by influenza A continue to exact unacceptable worldwide mortality, and recent epidemics have emphasized the importance of preventative and containment ...strategies. We have previously reported that induction of the lungs' intrinsic defenses by aerosolized treatments can protect mice against otherwise lethal challenges with influenza A virus. More recently, we identified a combination of Toll like receptor (TLR) agonists that can be aerosolized to protect mice against bacterial pneumonia. Here, we tested whether this combination of synthetic TLR agonists could enhance the survival of mice infected with influenza A/HK/8/68 (H3N2) or A/California/04/2009 (H1N1) influenza A viruses. We report that the TLR treatment enhanced survival whether given before or after the infectious challenge, and that protection tended to correlate with reductions in viral titer 4 d after infection. Surprisingly, protection was not associated with induction of interferon gene expression. Together, these studies suggest that synergistic TLR interactions can protect against influenza virus infections by mechanisms that may provide the basis for novel therapeutics.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is a strong need for a new broad-spectrum antiinfluenza therapeutic, as vaccination and existing treatments are only moderately effective. We previously engineered a lectin, H84T banana lectin ...(H84T), to retain broad-spectrum activity against multiple influenza strains, including pandemic and avian, while largely eliminating the potentially harmful mitogenicity of the parent compound. The amino acid mutation at position 84 from histidine to threonine minimizes the mitogenicity of the wild-type lectin while maintaining antiinfluenza activity in vitro. We now report that in a lethal mouse model H84T is indeed nonmitogenic, and both early and delayed therapeutic administration of H84T intraperitoneally are highly protective, as is H84T administered subcutaneously. Mechanistically, attachment, which we anticipated to be inhibited by H84T, was only somewhat decreased by the lectin. Instead, H84T is internalized into the late endosomal/lysosomal compartment and inhibits virus–endosome fusion. These studies reveal that H84T is efficacious against influenza virus in vivo, and that the loss of mitogenicity seen previously in tissue culture is also seen in vivo, underscoring the potential utility of H84T as a broad-spectrum antiinfluenza agent.
From the influenza pandemic of 1918–1919 to the most recent COVID-19 pandemic, respiratory infections remain a leading cause of mortality worldwide 1, 2. Concurrently, the development of ...high-throughput omics technologies has revolutionised research about host responses to known and emerging respiratory pathogens 3, accelerating our understanding of highly prevalent pulmonary diseases 4. Notably, omics technology-based characterisation of pathogens and host pathophysiology have critically supported diagnostic and therapeutic global health efforts during both the influenza A H1N1 and SARS-CoV-2 pandemics 5–7. Nonetheless, elucidation of key immune response mechanisms and development of host-targeted therapeutics remain important unrealised research and clinical priorities in the global fight against lower respiratory tract infections (LTRIs) 8, 9.
Descriptive omics-based clinical research provides valuable early steps in understanding host immune responses to respiratory pathogens in our global efforts to mitigate the impacts of severe respiratory infections with rapidly evolving technologies
https://bit.ly/4bjJsvL
Alveolar type 1 (AT1) cells cover >95% of the gas exchange surface and are extremely thin to facilitate passive gas diffusion. The development of these highly specialized cells and its coordination ...with the formation of the honeycomb-like alveolar structure are poorly understood. Using new marker-based stereology and single-cell imaging methods, we show that AT1 cells in the mouse lung form expansive thin cellular extensions via a non-proliferative two-step process while retaining cellular plasticity. In the flattening step, AT1 cells undergo molecular specification and remodel cell junctions while remaining connected to their epithelial neighbors. In the folding step, AT1 cells increase in size by more than 10-fold and undergo cellular morphogenesis that matches capillary and secondary septa formation, resulting in a single AT1 cell spanning multiple alveoli. Furthermore, AT1 cells are an unexpected source of VEGFA and their normal development is required for alveolar angiogenesis. Notably, a majority of AT1 cells proliferate upon ectopic SOX2 expression and undergo stage-dependent cell fate reprogramming. These results provide evidence that AT1 cells have both structural and signaling roles in alveolar maturation and can exit their terminally differentiated non-proliferative state. Our findings suggest that AT1 cells might be a new target in the pathogenesis and treatment of lung diseases associated with premature birth.
For millions of people, taking immunosuppressive medication to control or prevent disease is a daily reality 1. Rheumatological disease, inflammatory lung disease, organ transplantation and graft-
...versus
-host disease are but a few of the immune dysregulation syndromes that may require short- or long-term immunosuppressive therapy (IST). Patients taking ISTs are frequently regarded as immunocompromised, sharing risks of increased infection susceptibility with cancer patients receiving chemotherapy, those with profound neutropenia from haematological malignancies, and individuals living with HIV. In the context of the immune-mediated respiratory failure associated with coronavirus disease 2019 (COVID-19), an apparent paradox arises: can ISTs both promote and protect against severe COVID-19?
Lessons learned from a large registry analysis show worse COVID-19 outcomes for patients previously exposed to glucocorticoids
https://bit.ly/306rNrk
Bacterial pneumonias exact unacceptable morbidity on patients with cancer. Although the risk is often most pronounced among patients with treatment-induced cytopenias, the numerous contributors to ...life-threatening pneumonias in cancer populations range from derangements of lung architecture and swallow function to complex immune defects associated with cytotoxic therapies and graft-versus-host disease. These structural and immunologic abnormalities often make the diagnosis of pneumonia challenging in patients with cancer and impact the composition and duration of therapy. This article addresses host factors that contribute to pneumonia susceptibility, summarizes diagnostic recommendations, and reviews current guidelines for management of bacterial pneumonia in patients with cancer.
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