Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress toward therapeutics. Namely, high-throughput therapeutic assays typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well leukocyte recruitment in an air-blood barrier array (L-ABBA-96) that enables in vivo-like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 and found a dose-dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently Food and Drug Administration-approved for severe Coronavirus Disease 2019 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.

SARS-CoV-2 can cause a variety of post-acute sequelae including Long COVID19 (LC), a complex, multisystem disease characterized by a broad range of symptoms including fatigue, cognitive impairment, and post-exertional malaise. The pathogenesis of LC is incompletely understood. In this study, we performed comprehensive cellular and transcriptional immunometabolic profiling within a cohort that included SARS-CoV-2-naïve controls (NC, N=30) and individuals with prior COVID-19 (~4-months) who fully recovered (RC, N=38) or went on to experience Long COVID symptoms (N=58). Compared to the naïve controls, those with prior COVID-19 demonstrated profound metabolic and immune alterations at the proteomic, cellular, and epigenetic level. Specifically, there was an enrichment in immature monocytes with sustained inflammasome activation and oxidative stress, elevated arachidonic acid levels, decreased tryptophan, and variation in the frequency and phenotype of peripheral T-cells. Those with LC had increased CD8 T-cell senescence and a distinct transcriptional profile within CD4 and CD8 T-cells and monocytes by single cell RNA sequencing. Our findings support a profound and persistent immunometabolic dysfunction that follows SARS-CoV-2 which may form the pathophysiologic substrate for LC. Our findings suggest that trials of therapeutics that help restore immune and metabolic homeostasis may be warranted to prevent, reduce, or resolve LC symptoms.

Immunomodulators tocilizumab and baricitinib have been used for the treatment of severe COVID-19, however, there are only few published studies comparing their efficacy.

All consecutive non-ICU hospitalized severe COVID-19 patients who received baricitinib or tocilizumab, were included retrospectively. Primary outcomes were mortality or intubation on day 14, time to oxygen therapy weaning and duration of hospitalization. Safety was measured as treatment-related adverse events.

321 hospitalized patients with severe COVID-19 were included (mean age 62.4 years ± 14.7); 241 (75.1%) received baricitinib (mean age 64.2 years ± 15.2) and 80 (24.9%) tocilizumab (mean age 57.3 ± 11.7). Patients who received baricitinib presented significantly lower risk of mortality or intubation on day 14, compared to the tocilizumab group after adjusting for age, sex, vaccination, Charlson comorbidity index, body mass index, remdesivir administration and WHO ordinal scale at enrollment (OR: 0.42, 95% CI: 0.20-0.86). In the augmented inverse-probability weighting regression, the protective role of baricitinib remained statistically significant (OR: 0.76, 95% CI: 0.66-0.88). No difference in secondary bacterial infections was detected, but tocilizumab was associated with significant higher rate of liver injury (Odds Ratio, 95%CI, p < 0.001).

Our study suggests survival and safety are significantly better for baricitinib compared to tocilizumab in severe COVID-19. Clinical randomized trials are needed for confirmation.

Since the COVID-19 pandemic, it has caused a great threat to the global economy and public health, initiatives have been launched to control the spread of the virus. To explore the efficacy of drugs, a large number of clinical trials have been carried out, with the purpose of providing guidelines based on high-quality evidence for clinicians. We mainly discuss therapeutic agents for COVID-19 and explain the mechanism, including antiviral agents, tocilizumab, Janus kinase (JAK) inhibitors, neutralizing antibody therapies and corticosteroids. In addition, the COVID-19 vaccine has been proven to be efficacious in preventing SARS-CoV-2 infection. We systematically analyzed four mainstream vaccine platforms: messenger RNA (mRNA) vaccines, viral vector vaccines, inactivated vaccines and protein subunit vaccines. We evaluated the therapeutic effects of drugs and vaccines through enumerating the most typical clinical trials. However, the emergence of novel variants has further complicated the interpretation of the available clinical data, especially vaccines and antibody therapies. In the post-epidemic era, therapeutic agents are still the first choice for controlling the progression of disease, whereas the protective effect of vaccines against different strains should be assessed comprehensively.

Influenza infections are often complicated by secondary bacterial infections such as MRSA pneumonia, which increase morbidity and mortality. Viral infections lead to an inflammatory response that includes elevated levels of IL-6 and interferons. IL-6 activates the JAK/STAT signaling pathway, amplifying downstream inflammation. Given the clinical efficacy of the JAK inhibitor baricitinib in reducing disease severity in COVID-19, we evaluated its impact in a murine model of influenza, MRSA, and post-influenza MRSA pneumonia. Additionally, because IL-6 inhibitory therapies have improved outcomes during COVID-19, we evaluated the impact of IL-6 deletion on post-influenza MRSA pneumonia. In our studies, baricitinib effectively inhibited the JAK/STAT pathway in the lungs, as demonstrated by decreased interferon-stimulated genes (ISGs) and STAT3 phosphorylation. Despite this inhibition, baricitinib did not cause a global suppression of cytokines. Notably, baricitinib treatment did not impair either antiviral or antibacterial host immunity, inflammatory cell recruitment, or lung tissue injury. IL-6 deficiency did not alter weight loss, inflammatory cell recruitment, or bacterial burden during post-influenza MRSA pneumonia. These findings suggest that both JAK inhibition via baricitinib and IL-6 deletion do not enhance host defense or limit tissue injury in murine models of influenza and post-influenza MRSA pneumonia.

In December 2022, China classified COVID-19 as a category B infectious disease. This ended 2 years of close epidemiological surveillance of COVID-19. The objective of this questionnaire was to assess the infection status in the COVID-19 pandemic since December in Henan Province, China, and the prevalence of infection in people who were taking ursodeoxycholic acid (UDCA) during this period. We distributed questionnaires to patients attending the gastroenterology clinic at the First Affiliated Hospital of Henan University of Chinese Medicine. The questionnaire lasted for 3 weeks and a total of 660 were collected, of which the number of people taking UDCA was 70. This is the first investigation into the rate of infection among those taking UDCA during the time of the COVID-19 pandemic. Our results showed that the overall infection rate among those taking UDCA was 71.43% (n = 50), with a 10% (n = 7) rate of asymptomatic infections, which was significantly lower than the 85.42% (n = 504) and 6.27% (n = 37) rates among respondents who did not take. The administration of UDCA showed a trend toward reducing the rate of COVID-19 infection, but the difference was not statistically significant when compared to patients with shorter durations of medication use. While less than 30% of participants remained uninfected during the study period, indicating a potential protective effect, it is important to note that complete prevention of SARS-CoV-2 infection by UDCA was not observed.

Acute upper respiratory tract infections are a major public health issue, with uncontrolled inflammation triggered by upper respiratory viruses being a significant cause of patient deterioration or death. This study focuses on the Janus kinase-signal transducer and activator of transcription Rho-associated coiled-coil containing protein kinase (JAK-STAT-ROCK) signaling pathway, providing an in-depth analysis of the interplay between uncontrolled inflammation after upper respiratory tract infections and the development of neurodegenerative diseases. It offers a conceptual framework for understanding the lung-brain-related immune responses and potential interactions. The relationship between the ROCK-JAK-STAT signaling pathway and inflammatory immunity is a complex and multi-layered research area and exploring potential common targets could open new avenues for the prevention and treatment of related inflammation.

COVID-19 is an emerging viral pandemic caused by SARS-CoV-2, which is the causative agent of unprecedented disease-causing public health threats globally. Worldwide, this outbreak is wreaking havoc due to failure in risk assessment regarding the urgency of the pandemic. As per the reports, many secondary complications which include neurological, nephrological, gastrointestinal, cardiovascular, immune, and hepatic abnormalities, are linked with COVID -19 infection which is associated with prominent respiratory disorders including pneumonia. Hindering the initial binding of the virus with Angiotensin-converting enzyme 2 (ACE2) through the spike protein is one potential boulevard of monoclonal antibodies. Although some drug regimens and vaccines have shown safety in trials, none have been entirely successful yet. This review highlights, some of the potential antibodies (tocilizumab, Sarilumab, Avdoralimab, Lenzilumab, Interferon (alfa /beta /gamma)) screened against SARS-CoV-2 and the most promising drugs (Favipiravir, Hydroxychloroquine, Niclosamide, Ribavirin, Baricitinib, Remdesivir, Arbidol Losartan, Ritonavir, Lopinavir, Baloxavir, Nitazoxanide, Camostat) in various stages of development with their synthetic protocol and their clinical projects are discussed to counter COVID -19.

G-protein-coupled receptors (GPCRs) play a crucial role in modulating physiological responses and serve as the main drug target. Specifically, salmeterol and salbutamol, which are used for the treatment of pulmonary diseases, exert their effects by activating the GPCR β2-adrenergic receptor (β2AR). In our study, we employed coarse-grained molecular dynamics simulations with the Martini 3 force field to investigate the dynamics of drug molecules in membranes in the presence and absence of β2AR. Our simulations reveal that, in more than 50% of the flip-flop events, the drug molecules use the β2AR surface to permeate the membrane. The pathway along the GPCR surface is significantly more energetically favorable for the drug molecules, which was revealed by umbrella sampling simulations along spontaneous flip-flop pathways. Furthermore, we assessed the behavior of drugs with intracellular targets, such as kinase inhibitors, whose therapeutic efficacy could benefit from this observation. In summary, our results show that β2AR surface interactions can significantly enhance the membrane permeation of drugs, emphasizing their potential for consideration in future drug development strategies.

Cytokines play a crucial role in the pathophysiology of autoimmune and inflammatory diseases, with over 50 cytokines undergoing signal transduction through the Signal Transducers and Activators of Transcription (STAT) signaling pathway. Recent studies have solidly confirmed the pivotal role of STATs in autoimmune and inflammatory diseases. Therefore, this review provides a detailed summary of the immunological functions of STATs, focusing on exploring their mechanisms in various autoimmune and inflammatory diseases. Additionally, with the rapid advancement of structural biology in the field of drug discovery, many STAT inhibitors have been identified using structure-based drug design strategies. In this review, we also examine the structures of STAT proteins and compile the latest research on STAT inhibitors currently being tested in animal models and clinical trials for the treatment of immunological diseases, which emphasizes the feasibility of STATs as promising therapeutic targets and provides insights into the design of the next generation of STAT inhibitors.

Early in the course of the SARS-CoV-2 pandemic it was hypothesised that host genetics played a role in the pathophysiology of COVID-19 including a suggestion that the CCR5-Δ32 mutation may be protective in SARS-CoV-2 infection. Leronlimab is an investigational CCR5-specific humanized IgG4 monoclonal antibody currently in development for HIV-1 infection. We aimed to explore the impact of leronlimab on the severity of disease symptoms among participants with mild-to-moderate COVID-19.

The TEMPEST trial was a randomized, double-blind, placebo-controlled study in participants with mild-to-moderate COVID-19. Participants were randomly assigned in a 2:1 ratio to receive subcutaneous leronlimab (700 mg) or placebo on days 0 and 7. The primary efficacy endpoint was assessed by change in total symptom score based on fever, myalgia, dyspnea, and cough, at end of treatment (day 14).

Overall, 84 participants were randomized and treated with leronlimab (n = 56) or placebo (n = 28). No difference was observed in change in total symptom score (P = 0.8184) or other pre-specified secondary endpoints between treatments. However, in a post hoc analysis, 50.0% of participants treated with leronlimab demonstrated improvements from baseline in National Early Warning Score 2 (NEWS2) at day 14, compared with 20·8% of participants in the placebo group (post hoc; p = 0.0223). Among participants in this trial with mild-to-moderate COVID-19 adverse events rates were numerically but not statistically significantly lower in leronlimab participants (33.9%) compared with placebo participants (50.0%).

At the time the TEMPEST trial was designed although CCR5 was known to be implicated in COVID-19 disease severity the exact pathophysiology of SARS-CoV-2 infection was poorly understood. Today it is well accepted that SARS-CoV-2 infection in asymptomatic-to-mild cases is primarily characterized by viral replication, with a heightened immune response, accompanied by diminished viral replication in moderate-to-severe disease and a peak in inflammatory responses with excessive production of pro-inflammatory cytokines in critical disease. It is therefore perhaps not surprising that no differences between treatments were observed in the primary endpoint or in pre-specified secondary endpoints among participants with mild-to-moderate COVID-19. However, the results of the exploratory post hoc analysis showing that participants in the leronlimab group had greater improvement in NEWS2 assessment compared to placebo provided a suggestion that leronlimab may be associated with a lower likelihood of people with mild-to-moderate COVID-19 progressing to more severe disease and needs to be confirmed in other appropriately designed clinical trials.

gov number, NCT04343651 https://classic.

gov/ct2/show/NCT04343651.

Long COVID, a type of post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC) defined by medically unexplained symptoms following infection with SARS-CoV-2, is a newly recognized infection-associated chronic condition that causes disability in some people. Substantial progress has been made in defining its epidemiology, biology, and pathophysiology. However, there is no cure for the tens of millions of people believed to be experiencing long COVID, and industry engagement in developing therapeutics has been limited. Here, we review the current state of knowledge regarding the biology and pathophysiology of long COVID, focusing on how the proposed mechanisms explain the physiology of the syndrome and how they provide a rationale for the implementation of a broad experimental medicine and clinical trials agenda. Progress toward preventing and curing long COVID and other infection-associated chronic conditions will require deep and sustained investment by funders and industry.

To adequately prepare for potential hazards caused by emerging and reemerging infectious diseases, the WHO has issued a list of high-priority pathogens that are likely to cause future outbreaks and for which research and development (R&D) efforts are dedicated, known as paramount R&D blueprints. Within R&D efforts, the goal is to obtain effective prophylactic and therapeutic approaches, which depends on a comprehensive knowledge of the etiology, epidemiology, and pathogenesis of these diseases. In this process, the accessibility of animal models is a priority bottleneck because it plays a key role in bridging the gap between in-depth understanding and control efforts for infectious diseases. Here, we reviewed preclinical animal models for high priority disease in terms of their ability to simulate human infections, including both natural susceptibility models, artificially engineered models, and surrogate models. In addition, we have thoroughly reviewed the current landscape of vaccines, antibodies, and small molecule drugs, particularly hopeful candidates in the advanced stages of these infectious diseases. More importantly, focusing on global trends and novel technologies, several aspects of the prevention and control of infectious disease were discussed in detail, including but not limited to gaps in currently available animal models and medical responses, better immune correlates of protection established in animal models and humans, further understanding of disease mechanisms, and the role of artificial intelligence in guiding or supplementing the development of animal models, vaccines, and drugs. Overall, this review described pioneering approaches and sophisticated techniques involved in the study of the epidemiology, pathogenesis, prevention, and clinical theatment of WHO high-priority pathogens and proposed potential directions. Technological advances in these aspects would consolidate the line of defense, thus ensuring a timely response to WHO high priority pathogens.

Our study aimed to describe the group of severe COVID-19 patients at an institutional level, and determine factors associated with different outcomes.

A retrospective chart review of patients admitted with severe acute hypoxic respiratory failure due to COVID-19 infection. Based on outcomes, we categorized 3 groups of severe COVID-19: (1) Favorable outcome: progressive care unit admission and discharge (2) Intermediate outcome: ICU care (3) Poor outcome: in-hospital mortality.

Eighty-nine patients met our inclusion criteria; 42.7% were female. The average age was 59.7 (standard deviation (SD):13.7). Most of the population were Caucasian (95.5%) and non-Hispanic (91.0%). Age, sex, race, and ethnicity were similar between outcome groups. Medicare and Medicaid patients accounted for 62.9%. The average BMI was 33.5 (SD:8.2). Moderate comorbidity was observed, with an average Charlson Comorbidity index (CCI) of 3.8 (SD:2.6). There were no differences in the average CCI between groups(p = 0.291). Many patients (67.4%) had hypertension, diabetes (42.7%) and chronic lung disease (32.6%). A statistical difference was found when chronic lung disease was evaluated; p = 0.002. The prevalence of chronic lung disease was 19.6%, 27.8%, and 40% in the favorable, intermediate, and poor outcome groups, respectively. Smoking history was associated with poor outcomes (p = 0.04). Only 7.9% were fully vaccinated. Almost half (46.1%) were intubated and mechanically ventilated. Patients spent an average of 12.1 days ventilated (SD:8.5), with an average of 6.0 days from admission to ventilation (SD:5.1). The intermediate group had a shorter average interval from admission to ventilator (77.2 hours, SD:67.6), than the poor group (212.8 hours, SD:126.8); (p = 0.001). The presence of bacterial pneumonia was greatest in the intermediate group (72.2%), compared to the favorable group (17.4%), and the poor group (56%); this was significant (p<0.0001). In-hospital mortality was seen in 28.1%.

Most patients were male, obese, had moderate-level comorbidity, a history of tobacco abuse, and government-funded insurance. Nearly 50% required mechanical ventilation, and about 28% died during hospitalization. Bacterial pneumonia was most prevalent in intubated groups. Patients who were intubated with a good outcome were intubated earlier during their hospital course, with an average difference of 135.6 hours. A history of cigarette smoking and chronic lung disease were associated with poor outcomes.

Studies have highlighted a possible crosstalk between the pathogeneses of COVID-19 and systemic lupus erythematosus (SLE); however, the interactive mechanisms remain unclear. We aimed to elucidate the impact of COVID-19 on SLE using clinical information and the underlying mechanisms of both diseases.

RNA-seq datasets were used to identify shared hub gene signatures between COVID-19 and SLE, while genome-wide association study datasets were used to delineate the interaction mechanisms of the key signaling pathways. Finally, single-cell RNA-seq datasets were used to determine the primary target cells expressing the shared hub genes and key signaling pathways.

COVID-19 may affect patients with SLE through hematologic involvement and exacerbated inflammatory responses. We identified 14 shared hub genes between COVID-19 and SLE that were significantly associated with interferon (IFN)-I/II. We also screened and obtained four core transcription factors related to these hub genes, confirming the regulatory role of the IFN-I/II-mediated Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway on these hub genes. Further, SLE and COVID-19 can interact via IFN-I/II and IFN-I/II receptors, promoting the levels of monokines, including interleukin (IL)-6/10, tumor necrosis factor-α, and IFN-γ, and elevating the incidence rate and risk of cytokine release syndrome. Therefore, in SLE and COVID-19, both hub genes and core TFs are enriched within monocytes/macrophages.

The interaction between SLE and COVID-19 promotes the activation of the IFN-I/II-triggered JAK-STAT signaling pathway in monocytes/macrophages. These findings provide a new direction and rationale for diagnosing and treating patients with SLE-COVID-19 comorbidity.

Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress towards therapeutics. Namely, high throughput therapeutic screening systems typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well Leukocyte recruitment in an Air-Blood Barrier Array (L-ABBA-96) that enables in vivo -like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 (IL-8) and found a dose dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently FDA-approved for severe COVID-19 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.

Cytometry comprises powerful techniques for analyzing the cell heterogeneity of a biological sample by examining the expression of protein markers. These technologies impact especially the field of oncoimmunology, where cell identification is essential to analyze the tumor microenvironment. Several classification tools have been developed for the annotation of cytometry datasets, which include supervised tools that require a training set as a reference (i.e. reference-based) and semisupervised tools based on the manual definition of a marker table. The latter is closer to the traditional annotation of cytometry data based on manual gating. However, they require the manual definition of a marker table that cannot be extracted automatically in a reference-based fashion. Therefore, we are lacking methods that allow both classification approaches while maintaining the high biological interpretability given by the marker table.

We present a new tool called GateMeClass (Gate Mining and Classification) which overcomes the limitation of the current methods of classification of cytometry data allowing both semisupervised and supervised annotation based on a marker table that can be defined manually or extracted from an external annotated dataset. We measured the accuracy of GateMeClass for annotating three well-established benchmark mass cytometry datasets and one flow cytometry dataset. The performance of GateMeClass is comparable to reference-based methods and marker table-based techniques, offering greater flexibility and rapid execution times.

GateMeClass is implemented in R language and is publicly available at https://github.com/simo1c/GateMeClass.

In COVID-19, cytokine release syndrome can cause severe lung tissue damage leading to acute respiratory distress syndrome (ARDS). Here, we address the effects of IFNγ, TNFα, IL-1β and IL-6 on the growth arrest of alveolar A549 cells, focusing on the role of the IFN regulatory factor 1 (IRF1) transcription factor. The efficacy of JAK1/2 inhibitor baricitinib has also been tested. A549 WT and IRF1 KO cells were exposed to cytokines for up to 72 h. Cell proliferation and death were evaluated with the resazurin assay, analysis of cell cycle and cycle-regulator proteins, LDH release and Annexin-V positivity; the induction of senescence and senescence-associated secretory phenotype (SASP) was evaluated through β-galactosidase staining and the quantitation of secreted inflammatory mediators. While IL-1 and IL-6 proved ineffective, IFNγ plus TNFα caused a proliferative arrest in A549 WT cells with alterations in cell morphology, along with the acquisition of a secretory phenotype. These effects were STAT and IRF1-dependent since they were prevented by baricitinib and much less evident in IRF1 KO than in WT cells. In alveolar cells, STATs/IRF1 axis is required for cytokine-induced proliferative arrest and the induction of a secretory phenotype. Hence, baricitininb is a promising therapeutic strategy for the attenuation of senescence-associated inflammation.

The ACTT risk profile, which was developed from ACTT-1 (Adaptive COVID-19 Treatment Trial-1), demonstrated that hospitalized patients with COVID-19 in the high-risk quartile (characterized by low absolute lymphocyte count [ALC], high absolute neutrophil count [ANC], and low platelet count at baseline) benefited most from treatment with the antiviral remdesivir. It is unknown which patient characteristics are associated with benefit from treatment with the immunomodulator baricitinib.

To apply the ACTT risk profile to the ACTT-2 cohort to investigate potential baricitinib-related treatment effects by risk quartile.

Post hoc analysis of ACTT-2, a randomized, double-blind, placebo-controlled trial. (ClinicalTrials.gov: NCT04401579).

Sixty-seven trial sites in 8 countries.

Adults hospitalized with COVID-19 (n = 999; 85% U.S. participants).

Baricitinib+remdesivir versus placebo+remdesivir.

Mortality, progression to invasive mechanical ventilation (IMV) or death, and recovery, all within 28 days; ALC, ANC, and platelet count trajectories.

In the high-risk quartile, baricitinib+remdesivir was associated with reduced risk for death (hazard ratio [HR], 0.38 [95% CI, 0.16 to 0.86]; P = 0.020), decreased progression to IMV or death (HR, 0.57 [CI, 0.35 to 0.93]; P = 0.024), and improved recovery rate (HR, 1.53 [CI, 1.16 to 2.02]; P = 0.002) compared with placebo+remdesivir. After 5 days, participants receiving baricitinib+remdesivir had significantly larger increases in ALC and significantly larger decreases in ANC compared with control participants, with the largest effects observed in the high-risk quartile.

Secondary analysis of data collected before circulation of current SARS-CoV-2 variants.

The ACTT risk profile identifies a subgroup of hospitalized patients who benefit most from baricitinib treatment and captures a patient phenotype of treatment response to an immunomodulator and an antiviral. Changes in ALC and ANC trajectory suggest a mechanism whereby an immunomodulator limits severe COVID-19.

National Institute of Allergy and Infectious Diseases.

Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.

Several clinical trials have evaluated the efficacy and safety of baricitinib in COVID-19 patients. Recently, there have been reports on critical patients, which are different from previous research results. The meta-analysis was performed to investigate the effects of baricitinib in COVID-19, by pooling data from all clinically randomized controlled trials (RCTs) available to increase power to testify.

Studies were searched in PubMed, Embase, and Cochrane Library databases on January 31, 2023. We performed a meta-analysis to estimate the efficacy and safety of baricitinib for the treatment of hospitalized adults with COVID-19. This study is registered with INPLASY, number 202310086.

A total of 3010 patients were included in our analyses. All included studies were randomized controlled trials or prospective study. There was no difference in 14-day mortality between the two groups [OR 0.23 (95% CI 0.03-1.84), I2 = 72%, P = 0.17]. In subgroup analyses we found that baricitinib did not seem to improve significantly in 24-day mortality critically ill patients [OR 0.60 (95% CI 0.35-1.02), I2 = 0%, P = 0.06]. Fortunately, baricitinib have led to faster recovery and shorter hospital stays for COVID-19 patients. There were no difference in infections and infestations, major adverse cardiovascular events, deep vein thrombosis and pulmonary embolism.

Baricitinib did not increase the incidence of adverse reactions. At the same time, we can find that it reduces the mortality of COVID-19 patients, not including the critically ill.

Coronavirus disease 2019 (COVID-19) is a highly contagious viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It has various effects on asthma, allergic rhinitis, atopic dermatitis, and urticaria and may change the course of the disease depending on the severity of the infection and control status of the disease. Conversely, these diseases may also impact the course of COVID-19. Patients with chronic urticaria and atopic dermatitis may have COVID-19-induced disease exacerbations and biological treatments reduce the risk of exacerbations. Poor asthma control is linked to severe COVID-19 while allergic asthma is associated with lower risk of death and a lower rate of hospitalization due to COVID-19 compared with nonallergic asthma. The use of intranasal corticosteroids is associated with lower rates of hospitalization due to COVID-19 in patients with allergic rhinitis, whereas the effect of inhaled corticosteroids is confounded by asthma severity. These observations reinforce the importance of keeping allergic diseases under control during pandemics. The use of biologicals during COVID-19 is generally regarded as safe, but more evidence is needed. The pandemic substantially changed the management of allergic disorders such as home implementation of various biologicals, allergen immunotherapy, food introduction, and increased use of telemedicine and even home management of anaphylaxis to reduce emergency department burden and reduce risk of infection. Physicians need to be aware of the potential impact of COVID-19 on allergic diseases and educate their patients on the importance of continuing prescribed medications and adhering to their treatment plans to maintain optimal control of their disease.

Numerous pharmacological interventions are now under investigation for the treatment of the 2019 coronavirus pandemic (COVID-19), and the evidence is rapidly evolving. Our aim is to evaluate the comparative efficacy and safety of these drugs.

We searched for randomized clinical trials (RCTs) on the efficacy and safety of novel oral antivirals for the treatment of hospitalized COVID-19 patients until November 30, 2022, including baricitinib, ivermectin (IVM), favipiravir (FVP), chloroquine (CQ), lopinavir and ritonavir (LPV/RTV), hydroxychloroquine (HCQ), and hydroxychloroquine plus azithromycin (HCQ+AZT). The main outcomes of this network meta-analysis (NMA) were in-hospital mortality, adverse event (AE), recovery time, and improvement in peripheral capillary oxygen saturation (SpO2). For dichotomous results, the odds ratio (OR) was used, and the 95% confidence interval (CI) was determined. We also used meta-regression to explore whether different treatments affected efficacy and safety. STATA 15.0 was used to conduct the NMA. The research protocol was registered with PROSPERO (#CRD 42023415743).

Thirty-six RCTs, with 33,555 hospitalized COVID-19 patients, were included in this analysis. First, we compared the efficacy of different novel oral antivirals. Baricitinib (OR 0.56, 95% CI: 0.35 to 0.90) showed the highest probability of being the optimal probiotic species in reducing in-hospital mortality and suggested that none of the interventions reduced AE better than placebo. In terms of safety outcomes, IVM ranked first in improving the recovery time of hospitalized COVID-19 patients (mean difference (MD) -1.36, 95% CI: -2.32 to -0.39). In addition, patients were most likely to increase SpO2 (OR 1.77, 95% CI: 0.09 to 3.45). The meta-regression revealed no significant differences between participants using different novel oral antivirals in all outcomes in hospitalized COVID-19 patients.

Currently, baricitinib has reduced in-hospital mortality in hospitalized COVID-19 patients, with moderate certainty of evidence. IVM appeared to be a safer option than placebo in improving recovery time, while FVP was associated with increased SpO2 safety outcomes. These preliminary evidence-based observations should guide clinical practice until more data are made public.

Host kinases play essential roles in the host cell cycle, innate immune signaling, the stress response to viral infection, and inflammation. Previous work has demonstrated that coronaviruses specifically target kinase cascades to subvert host cell responses to infection and rely upon host kinase activity to phosphorylate viral proteins to enhance replication. Given the number of kinase inhibitors that are already FDA approved to treat cancers, fibrosis, and other human disease, they represent an attractive class of compounds to repurpose for host-targeted therapies against emerging coronavirus infections. To further understand the host kinome response to betacoronavirus infection, we employed multiplex inhibitory bead mass spectrometry (MIB-MS) following MERS-CoV and SARS-CoV-2 infection of human lung epithelial cell lines. Our MIB-MS analyses revealed activation of mTOR and MAPK signaling following MERS-CoV and SARS-CoV-2 infection, respectively. SARS-CoV-2 host kinome responses were further characterized using paired phosphoproteomics, which identified activation of MAPK, PI3K, and mTOR signaling. Through chemogenomic screening, we found that clinically relevant PI3K/mTOR inhibitors were able to inhibit coronavirus replication at nanomolar concentrations similar to direct-acting antivirals. This study lays the groundwork for identifying broad-acting, host-targeted therapies to reduce betacoronavirus replication that can be rapidly repurposed during future outbreaks and epidemics. The proteomics, phosphoproteomics, and MIB-MS datasets generated in this study are available in the Proteomics Identification Database (PRIDE) repository under project identifiers PXD040897 and PXD040901.

In COVID-19, an uncontrolled inflammatory response might worsen lung damage, leading to acute respiratory distress syndrome (ARDS). Recent evidence points to the induction of inducible nitric oxide synthase (NOS2/iNOS) as a component of inflammatory response since NOS2 is upregulated in critical COVID-19 patients. Here, we explore the mechanisms underlying the modulation of iNOS expression in human alveolar cells.

A549 WT and IRF1 KO cells were exposed to a conditioned medium of macrophages treated with SARS-CoV-2 spike S1. Additionally, the effect of IFNγ, IL-1β, IL-6, and TNFα, either alone or combined, was addressed. iNOS expression was assessed with RT-qPCR and Western blot. The effect of baricitinib and CAPE, inhibitors of JAK/STAT and NF-kB, respectively, was also investigated.

Treatment with a conditioned medium caused a marked induction of iNOS in A549 WT and a weak stimulation in IRF1 KO. IFNγ induced NOS2 and synergistically cooperated with IL-1β and TNFα. The inhibitory pattern of baricitinb and CAPE indicates that cytokines activate both IRF1 and NF-κB through the JAK/STAT1 pathway.

Cytokines secreted by S1-activated macrophages markedly induce iNOS, whose expression is suppressed by baricitinib. Our findings sustain the therapeutic efficacy of this drug in COVID-19 since, besides limiting the cytokine storm, it also prevents NOS2 induction.

Cancer cells favor the generation of myeloid cells with immunosuppressive and inflammatory features, including myeloid-derived suppressor cells (MDSCs), which support tumor progression. The anti-apoptotic molecule, cellular FLICE (FADD-like interleukin-1β-converting enzyme)-inhibitory protein (c-FLIP), which acts as an important modulator of caspase-8, is required for the development and function of monocytic (M)-MDSCs. Here, we assessed the effect of immune checkpoint inhibitor (ICI) therapy on systemic immunological landscape, including FLIP-expressing MDSCs, in non-small cell lung cancer (NSCLC) patients. Longitudinal changes in peripheral immunological parameters were correlated with patients' outcome. In detail, 34 NSCLC patients were enrolled and classified as progressors (P) or non-progressors (NP), according to the RECIST evaluation. We demonstrated a reduction in pro-inflammatory cytokines such as IL-8, IL-6, and IL-1β in only NP patients after ICI treatment. Moreover, using t-distributed stochastic neighbor embedding (t-SNE) and cluster analysis, we characterized in NP patients a significant increase in the amount of lymphocytes and a slight contraction of myeloid cells such as neutrophils and monocytes. Despite this moderate ICI-associated alteration in myeloid cells, we identified a distinctive reduction of c-FLIP expression in M-MDSCs from NP patients concurrently with the first clinical evaluation (T1), even though NP and P patients showed the same level of expression at baseline (T0). In agreement with the c-FLIP expression, monocytes isolated from both P and NP patients displayed similar immunosuppressive functions at T0; however, this pro-tumor activity was negatively influenced at T1 in the NP patient cohort exclusively. Hence, ICI therapy can mitigate systemic inflammation and impair MDSC-dependent immunosuppression.

To assess the role of baricitinib alone or in combination with other therapies as a treatment for patients with COVID-19.

Systematic literature search was conducted in the WHO COVID-19 coronavirus disease database to find clinical studies on use of baricitinib for treatment of COVID-19 between December 1, 2019 and September 30, 2021. Two independent set of reviewers identified the eligible studies fulfilling the inclusion criteria, relevant data was extracted and a qualitative synthesis of evidence performed. The risk of bias was evaluated with validated tools.

A total of 267 articles were found to be eligible after primary screening of titles and abstracts. Following assessment of full texts, 19 studies were finally included for this systematic review, out of which 16 are observational, and 3 are interventional studies. Collating the results from these observational and interventional studies, baricitinib used as add-on to standard therapy, either alone or in combination with other drugs, was found to have favorable outcomes in hospitalized patients with moderate to severe COVID-19. Furthermore, ongoing trials indicate that the drug is being extensively studied across the world for its safety and efficacy in COVID-19.

Baricitinib significantly improves clinical outcomes in hospitalized patients with COVID-19 pneumonia, and further evidence will establish the drug as a standard treatment among such patients.

Risk of severe disease and death due to COVID-19 is increased in certain patient demographic groups, including those of advanced age, male sex, and obese body mass index. Investigations of the biological variations that contribute to this risk have been hampered by heterogeneous severity, with immunologic features of critical disease potentially obscuring differences between risk groups. To examine immune heterogeneity related to demographic risk factors, we enrolled 38 patients hospitalized with clinically homogeneous COVID-19 pneumonia - defined as oxygen saturation less than 94% on room air without respiratory failure, septic shock, or multiple organ dysfunction - and performed single-cell RNA-Seq of leukocytes collected at admission. Examination of individual risk factors identified strong shifts within neutrophil and monocyte/dendritic cell (Mo/DC) compartments, revealing altered immune cell type-specific responses in higher risk COVID-19 patient subgroups. Specifically, we found transcriptional evidence of altered neutrophil maturation in aged versus young patients and enhanced cytokine responses in Mo/DCs of male versus female patients. Such innate immune cell alterations may contribute to outcome differences linked to these risk factors. They also highlight the importance of diverse patient cohorts in studies of therapies targeting the immune response in COVID-19.

Despite advances in the treatment and mitigation of critical illness caused by infection with SARS-CoV-2, millions of survivors have a devastating, post-acute infection syndrome known as long COVID. A large proportion of patients with long COVID have nervous system dysfunction, which is also seen in the distinct but overlapping condition of post-intensive care syndrome (PICS), putting survivors of COVID-19-related critical illness at high risk of long-lasting morbidity affecting multiple organ systems and, as a result, engendering measurable deficits in quality of life and productivity. In this Series paper, we discuss neurological, cognitive, and psychiatric sequelae in patients who have survived critical illness due to COVID-19. We review current knowledge of the epidemiology and pathophysiology of persistent neuropsychological impairments, and outline potential preventive strategies based on safe, evidence-based approaches to the management of pain, agitation, delirium, anticoagulation, and ventilator weaning during critical illness. We highlight priorities for current and future research, including possible therapeutic approaches, and offer considerations for health services to address the escalating health burden of long COVID.

To determine the effectiveness of baricitinib in patients with coronavirus disease 2019 (COVID-19), investigate whether baricitinib prevents the need for invasive mechanical ventilation and identify patient subgroups that would benefit from baricitinib.

This observational matched-cohort study was conducted by the Japan COVID-19 Task Force, a nationwide multicenter consortium. Patients with COVID-19 aged ≥18 years were identified from 70 hospitals in Japan. Among patients with confirmed COVID-19 from February 2020 to September 2021, those receiving baricitinib were propensity-score matched with controls.

Among 3309 patients, 144 propensity score-matched pairs were identified. Thirteen (9.0%) patients in the baricitinib group and 27 (18.8%) in the control group required invasive mechanical ventilation during the disease course (odds ratio, 0.43). Although the baricitinib group had more severe disease, there were no significant differences in the intensive care unit admission rates (odds ratio, 1.16) and mortality rates (odds ratio, 0.74) between groups. In subgroup analyses, baricitinib was associated with a significant reduction in the need for invasive mechanical ventilation in patients requiring oxygen support (odds ratio, 0.28), with rapid shadow spread on chest radiography (odds ratio, 0.11), or treated with remdesivir (odds ratio, 0.27), systemic corticosteroids (odds ratio, 0.31), or anticoagulants (odds ratio, 0.17).

Baricitinib is effective at preventing the need for invasive mechanical ventilation in patients with COVID-19.

The aim of this study was to investigate (a) the effects of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway inhibitor (baricitinib) on the multiple organ dysfunction syndrome (MODS) in a rat model of hemorrhagic shock (HS) and (b) whether treatment with baricitinib attenuates the activation of JAK/STAT, NF-κB, and NLRP3 caused by HS.

Posttraumatic MODS, which is in part due to excessive systemic inflammation, is associated with high morbidity and mortality. The JAK/STAT pathway is a regulator of numerous growth factor and cytokine receptors and, hence, is considered a potential master regulator of many inflammatory signaling processes. However, its role in trauma-hemorrhage is unknown.

An acute HS rat model was performed to determine the effect of baricitinib on MODS. The activation of JAK/STAT, NF-κB, and NLRP3 pathways were analyzed by western blotting in the kidney and liver.

We demonstrate here for the first time that treatment with baricitinib (during resuscitation following severe hemorrhage) attenuates the organ injury and dysfunction and the activation of JAK/STAT, NF-κB, and NLRP3 pathways caused by HS in the rat.

Our results point to a role of the JAK/STAT pathway in the pathophysiology of the organ injury and dysfunction caused by trauma/hemorrhage and indicate that JAK inhibitors, such as baricitinib, may be repurposed for the treatment of the MODS after trauma and/or hemorrhage.

Severe COVID-19 is associated with innate immunopathology, and CD14, a proximal activator of innate immunity, has been suggested as a potential therapeutic target.

We conducted the COVID-19 anti-CD14 Treatment Trial (CaTT), a Phase II randomized, double-blind, placebo-controlled trial at 5 US-sites between April 12, 2021 and November 30, 2021 (NCT04391309). Hospitalized adults with COVID-19 requiring supplemental oxygen (<30 LPM) were randomized 1:1 to receive 4 daily doses of intravenous IC14, an anti-CD14 monoclonal antibody, or placebo. All participants received remdesivir. The primary outcome was time-to-resolution of illness, defined as improvement on the 8-point NIH-Ordinal COVID-19 Scale to category ≤3. Secondary endpoints were safety and exploratory endpoints were pro-inflammatory and antiviral mediators in serum on days 0-5 & 7. The trial was stopped after 40 patients were randomized and treated due to slow enrollment.

40 participants were randomized and treated with IC14 (n = 20) or placebo (n = 20). The median time-to-recovery was 6 days (95% CI, 5-11) in the IC14 group vs. 5 days (95% CI, 4-10) in the Placebo group (recovery rate ratio: 0.77 (95% CI, 0.40, 1.48) (log-rank p = 0.435). The number of adverse events was similar in each group, and no IC14-attributable secondary infections occurred. In repeated-measures mixed-effects analyses, IC14 treatment increased serum sCD14 concentrations, an expected pharmacodynamic effect. Pre-planned, exploratory analyses suggested that IC14 treatment decreased the trajectories of circulating MIP-1β and TNF-α.

IC14 treatment did not improve time-to-resolution of illness in hypoxemic patients with COVID-19 in this small trial. Results of exploratory analyses suggested IC14 had biologic effects that warrant future clinical investigation.

National Institute of Allergy and Infectious Diseases.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus infected over 688 million people worldwide, causing public health concern and approximately 6.8 million deaths due to COVID-19. COVID-19, especially severe cases, is characterized by exacerbated lung inflammation with an increase of pro-inflammatory cytokines. In addition to antiviral drugs, there is a need for anti-inflammatory therapies to treat all phases of COVID-19. One of the most attractive drug targets for COVID-19 is the SARS-CoV-2 main protease (MPro), an enzyme responsible for cleaving polyproteins formed after the translation of viral RNA, which is essential for viral replication. MPro inhibitors, therefore, have the potential to stop viral replication and act as antiviral drugs. Considering that several kinase inhibitors are known for their action in inflammatory pathways, this could also be investigated toward a potential anti-inflammatory treatment for COVID-19. Therefore, the use of kinase inhibitors against SARS-CoV-2 MPro may be a promising strategy to find molecules with dual activity─antiviral and anti-inflammatory. Considering this, the potential of six kinase inhibitors against SARS-CoV-2 MPro were evaluated in silico and in vitro, including Baricitinib, Tofacitinib, Ruxolitinib, BIRB-796, Skepinone-L, and Sorafenib. To assess the inhibitory potential of the kinase inhibitors, a continuous fluorescent-based enzyme activity assay was optimized with SARS-CoV-2 MPro and MCA-AVLQSGFR-K(Dnp)-K-NH2 (substrate). BIRB-796 and Baricitinib were identified as inhibitors of SARS-CoV-2 MPro, presenting IC₅₀ values of 7.99 and 25.31 μM, respectively. As they are also known for their anti-inflammatory action, both are prototype compounds with the potential to present antiviral and anti-inflammatory activity against SARS-CoV-2 infection.