Efficacy and Safety of Reparixin in Patients with Severe COVID-19 Pneumonia: A Phase 3, Randomized, Double-Blind Placebo-Controlled Study.

INTRODUCTION: Polymorphonuclear cell influx into the interstitial and bronchoalveolar spaces is a cardinal feature of severe coronavirus disease 2019 (COVID-19), principally mediated by interleukin-8 (IL-8). We sought to determine whether reparixin, a novel IL-8 pathway inhibitor, could reduce disease progression in patients hospitalized with severe COVID-19 pneumonia. METHODS: In this Phase 3, randomized, double-blind, placebo-controlled, multicenter study, hospitalized adult patients with severe COVID-19 pneumonia were randomized 2:1 to receive oral reparixin 1200 mg three times daily or placebo for up to 21 days or until hospital discharge. The primary endpoint was the proportion of patients alive and free of respiratory failure at Day 28, with key secondary endpoints being the proportion of patients free of respiratory failure at Day 60, incidence of intensive care unit (ICU) admission by Day 28 and time to recovery by Day 28. RESULTS: Of 279 patients randomized, 182 received at least one dose of reparixin and 88 received placebo. The proportion of patients alive and free of respiratory failure at Day 28 was similar in the two groups {83.5% versus 80.7%; odds ratio 1.63 [95% confidence interval (CI) 0.75, 3.51]; p = 0.216}. There were no statistically significant differences in the key secondary endpoints, but a numerically higher proportion of patients in the reparixin group were alive and free of respiratory failure at Day 60 (88.7% versus 84.6%; p = 0.195), fewer required ICU admissions by Day 28 (15.8% versus 21.7%; p = 0.168), and a higher proportion recovered by Day 28 compared with placebo (81.6% versus 74.9%; p = 0.167). Fewer patients experienced adverse events with reparixin than placebo (45.6% versus 54.5%), most mild or moderate intensity and not related to study treatment. CONCLUSIONS: This trial did not meet the primary efficacy endpoints, yet reparixin showed a trend toward limiting disease progression as an add-on therapy in COVID-19 severe pneumonia and was well tolerated. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04878055, EudraCT: 2020-005919-51.

Bacterial and viral co-infections complicating severe influenza: Incidence and impact among 507 U.S. patients, 2013-14.

BACKGROUND: Influenza acts synergistically with bacterial co-pathogens. Few studies have described co-infection in a large cohort with severe influenza infection. OBJECTIVES: To describe the spectrum and clinical impact of co-infections. STUDY DESIGN: Retrospective cohort study of patients with severe influenza infection from September 2013 through April 2014 in intensive care units at 33 U.S. hospitals comparing characteristics of cases with and without co-infection in bivariable and multivariable analysis. RESULTS: Of 507 adult and pediatric patients, 114 (22.5%) developed bacterial co-infection and 23 (4.5%) developed viral co-infection. Staphylococcus aureus was the most common cause of co-infection, isolated in 47 (9.3%) patients. Characteristics independently associated with the development of bacterial co-infection of adult patients in a logistic regression model included the absence of cardiovascular disease (OR 0.41 [0.23-0.73], p=0.003), leukocytosis (>11K/µl, OR 3.7 [2.2-6.2], p<0.001; reference: normal WBC 3.5-11K/µl) at ICU admission and a higher ICU admission SOFA score (for each increase by 1 in SOFA score, OR 1.1 [1.0-1.2], p=0.001). Bacterial co-infections (OR 2.2 [1.4-3.6], p=0.001) and viral co-infections (OR 3.1 [1.3-7.4], p=0.010) were both associated with death in bivariable analysis. Patients with a bacterial co-infection had a longer hospital stay, a longer ICU stay and were likely to have had a greater delay in the initiation of antiviral administration than patients without co-infection (p<0.05) in bivariable analysis. CONCLUSIONS: Bacterial co-infections were common, resulted in delay of antiviral therapy and were associated with increased resource allocation and higher mortality.

Severe Influenza in 33 US Hospitals, 2013-2014: Complications and Risk Factors for Death in 507 Patients.

BACKGROUND: Influenza A (H1N1) pdm09 became the predominant circulating strain in the United States during the 2013-2014 influenza season. Little is known about the epidemiology of severe influenza during this season. METHODS: A retrospective cohort study of severely ill patients with influenza infection in intensive care units in 33 US hospitals from September 1, 2013, through April 1, 2014, was conducted to determine risk factors for mortality present on intensive care unit admission and to describe patient characteristics, spectrum of disease, management, and outcomes. RESULTS: A total of 444 adults and 63 children were admitted to an intensive care unit in a study hospital; 93 adults (20.9%) and 4 children (6.3%) died. By logistic regression analysis, the following factors were significantly associated with mortality among adult patients: older age (>65 years, odds ratio, 3.1 [95% CI, 1.4-6.9], P=.006 and 50-64 years, 2.5 [1.3-4.9], P=.007; reference age 18-49 years), male sex (1.9 [1.1-3.3], P=.031), history of malignant tumor with chemotherapy administered within the prior 6 months (12.1 [3.9-37.0], P<.001), and a higher Sequential Organ Failure Assessment score (for each increase by 1 in score, 1.3 [1.2-1.4], P<.001). CONCLUSION: Risk factors for death among US patients with severe influenza during the 2013-2014 season, when influenza A (H1N1) pdm09 was the predominant circulating strain type, shifted in the first postpandemic season in which it predominated toward those of a more typical epidemic influenza season.

Integrin α6ß1 Expressed in ESCs Instructs the Differentiation to Endothelial Cells.

Adhesion of embryonic stem cells (ESCs) to the extracellular matrix may influence differentiation potential and cell fate decisions. Here, we investigated the inductive role of binding of integrin α6ß1 expressed in mouse (m)ESCs to laminin-1 (LN1) in mediating the differentiation of ESCs to endothelial cells (ECs). We observed that α6ß1 binding to LN1 was required for differentiation to ECs. α6ß1 functioned by recruiting the adaptor tetraspanin protein CD151, which activated FAK and Akt signaling and mediated the EC lineage-specifying transcription factor Er71. In contrast, association of the ESC-expressed α3ß1, another highly expressed LN1 binding integrin, with CD151, prevented α6ß1-mediated differentiation. CD151 thus functioned as a bifurcation router to direct ESCs toward ECs when α6ß1 associated with CD151, or prevented transition to ECs when α3ß1 associated with CD151. These observations were recapitulated in mice in which α6 integrin or CD151 knockdown reduced the expression of Er71-regulated angiogenesis genes and development of blood vessels. Thus, interaction of α6ß1 in ESCs with LN1 activates α6ß1/CD151 signaling which programs ESCs toward the EC lineage fate.

Therapeutic administration of the chemokine CXCL1/KC abrogates autoimmune inflammatory heart disease.

Myocarditis, often due to an aberrant immune response to infection, is a major cause of dilated cardiomyopathy. Microbial pattern recognition receptors, such as TLRs, orchestrate the cytokine and chemokine responses that augment or limit the severity of myocarditis. Using the mouse model of experimental autoimmune myocarditis (EAM), in which disease is induced by immunization with a heart-specific self peptide and the agonist to multiple TLRs, complete Freund's adjuvant, we found that increased serum concentrations of the chemokine CXCL1/KC correlated directly with decreased severity of myocarditis. To directly test whether CXCL1/KC caused the amelioration of myocarditis, we treated mice, after challenge with heart-specific self peptide, with exogenous recombinant CXCL1/KC. We found that the administration of recombinant mouse CXCL1/KC completely abrogated heart inflammatory infiltration and cardiomyocyte damage. Moreover, we show that TLR4 signaling is required to increase serum protein concentrations of CXCL1/KC in EAM, and we demonstrate that the administration of the TLR4 agonist LPS significantly decreased severity and prevalence of EAM and reduced the number of heart-specific self peptide reactive effector T cells. These findings reveal a novel function of CXCL1/KC in the context of organ-specific autoimmune disease that may prove useful for the treatment of inflammatory conditions that underlie human heart disease.

Role of endothelial injury in disease mechanisms and contribution of progenitor cells in mediating endothelial repair.

Recent research on the endothelium demonstrates complex interactions of endothelial cells with circulating immune cells, mediators such as cytokines, hormones and growth factors, and with the underlying parenchymal cells. These disparate interactions are involved in promotion of vascular development; maintenance of tissue homeostasis; and regulation of vascular repair. Injury to the endothelial monolayer is the sine qua non of organ dysfunction with endothelial repair the necessary first step needed for recovery. Thus, the capacity of the endothelium to regenerate itself is a key determinant of organ repair and survival after injury. Using the example of the lung, we will review the current state of knowledge regarding the importance of endothelium in the above mentioned processes with a focus on the role of stem cells, both endogenous (i.e., localized within the vessel wall) as well as exogenous (i.e., arriving in the vessel wall from distant sites such as the bone marrow) in promoting endothelial repair and regeneration. The subject of endothelial regeneration and the ways in which stem and progenitor cells contribute to this process has promise in treating vascular diseases. As we will highlight in this review, some questions have been addressed but many more remain and need to be addressed before cell-based therapies become a viable option.

Interaction of a specific population of human embryonic stem cell-derived progenitor cells with CD11b+ cells ameliorates sepsis-induced lung inflammatory injury.

Human embryonic stem cells differentiated under mesoderm-inducing conditions have important therapeutic properties in sepsis-induced lung injury in mice. Single cell suspensions obtained from day 7 human embryoid bodies (d7EBs) injected i.v. 1 hour after cecal ligation and puncture significantly reduced lung inflammation and edema as well as production of tumor necrosis factor-α and interferon-γ in lungs compared with controls, whereas interleukin-10 production remained elevated. d7EB cell transplantation also reduced mortality to 50% from 90% in the control group. The protection was ascribed to d7EB cell interaction with lung resident CD11b+ cells, and was correlated with the ability of d7EB cells to reduce it also reduced production of proinflammatory cytokines by CD11+ cells, and to endothelial NO synthase-derived NO by d7EB cells, leading to inhibition of inducible macrophage-type NO synthase activation in CD11b+ cells. The protective progenitor cells were positive for the endothelial and hematopoietic lineage marker angiotensin converting enzyme (ACE). Only the ACE+ fraction modulated the proinflammatory profile of CD11b+ cells and reduced mortality in septic mice. In contrast to the nonprotective ACE-cell fraction, the ACE+ cell fraction also produced NO. These findings suggest that an ACE+ subset of human embryonic stem cell-derived progenitor cells has a highly specialized anti-inflammatory function that ameliorates sepsis-induced lung inflammation and reduces mortality.

The many faces of scleroderma sine scleroderma: a literature review focusing on cardiopulmonary complications.

Scleroderma sine scleroderma (ssSSc) is an occult form of systemic sclerosis that may cause diagnostic difficulties due to the absence of skin involvement. Delays in the diagnosis of ssSSc means lost opportunites to address and treat the often lethal involvement of internal organs such as the lungs and heart. In this systemic review we collected all published cases of ssSSc using EMBASE, MEDLINE, PubMed, and Web of Science from 1950 to present. Our purpose was to describe the range and frequency of the clinical manifestations of ssSSc. A total of 108 published cases of ssSSc were analyzed. Lung involvement was present in 66% of cases. Peripheral vascular system involvement was present in all patients whereas gastrointestinal manifestations were present in 82% of the cases. Overall the clinical presentation is subtle and heightened clinical awareness is required to facilitate prompt recognition and treatment.

Association of the shrinking lung syndrome in systemic lupus erythematosus with pleurisy: a systematic review.

OBJECTIVES: To report 2 patients with systemic lupus erythematosus and typical shrinking lung syndrome (SLS) in which pleuritic chest pain was the predominant symptom. In addition, to record the prevalence of pleuritic chest pain in all reported cases of patients with SLS and diaphragmatic dysfunction. METHODS: We conducted a comprehensive search of the English literature to record the association of pleurisy and SLS in all reported cases using the MEDLINE database from 1965 to present. RESULTS: Of the 77 patients with SLS reported in the literature, 50 (65%) patients had pleuritic chest pain at the time of evaluation. Treatment with anti-inflammatory agents improved symptoms in the majority of cases. CONCLUSIONS: Pleuritic inflammation and pain may have an important role in the pathogenesis of SLS. A possible mechanism linking pleural inflammation and diaphragm dysfunction may be via a reflex inhibition of diaphragmatic activation.

Upregulation of antiphospholipid antibodies following cyclophosphamide therapy in patients with systemic lupus erythematosus.

OBJECTIVE: We have observed several cases of patients with systemic lupus erythematosus (SLE) who developed antiphospholipid antibodies (aPL) or full blown antiphospholipid syndrome (APS) after being successfully treated with cyclophosphamide (CYC). To further evaluate the significance of this phenomenon we undertook a retrospective study of our patient population with SLE. METHODS: The charts of 320 patients with SLE, either CYC treated (n = 117) or non-treated (n = 203), were reviewed. The disease activity over time was evaluated using the European Consensus Lupus Activity Measurement (ECLAM) scoring system, as well as initial and cumulative anti-dsDNA antibody titers and C3, C4 complement levels. aPL titers (IgG and IgM) were documented for all patients. Seroconversion was defined as the de novo appearance of aPL antibodies at a titer higher than the 99th percentile of 100 normal sera, tested on 2 occasions 12 weeks apart. RESULTS: Seroconversion occurred in 22 out of 117 patients treated with CYC as compared with 2 out of 203 non-CYC treated patients [odds ratio (OR) = 23.27, 95% confidence interval (CI) 5.36-101.01]. Six patients from the seroconverted CYC treated group were diagnosed with APS compared to none in the non-CYC treated group. The association between seroconversion and CYC remained significant after adjustment for ECLAM score after treatment, prednisone dose and disease duration (OR = 13.4, 95% CI 2.67-67.50). Seroconversion occurred despite successful disease remission as judged by significant decrease of: anti-dsDNA antibody titers (p < 0.01), ECLAM scores (p < 0.01), and C3 (p < 0.01) and C4 levels (p < 0.01). CONCLUSION: Our data suggest that CYC therapy might be associated with upregulation of aPL and development of antiphospholipid syndrome despite suppression of SLE activity.

Cryptogenic organizing pneumonia associated with primary Sjogren's syndrome.

The association of cryptogenic organizing pneumonia (COP) with primary Sjogren's syndrome (PSS) is extremely rare. We report a case of simultaneous diagnosis of PSS and COP. A 70-year-old female presented with fever, non-productive cough and dyspnea of 2 months' duration. She had experienced sicca symptoms for the past 2 years. The chest radiograph revealed a right lower lobe infiltrate, which was unresponsive to antibiotics. Bronchoscopy, bronchoalveolar lavage and an open lung biopsy established the diagnosis of COP, while a lip biopsy was consistent with PSS. The patient improved on steroids. Organizing pneumonia may be one of the early manifestations of PSS. Exclusion of PSS should be part of a thorough evaluation of the patient with COP.

E3 ubiquitin ligase Cblb regulates the acute inflammatory response underlying lung injury.

The E3 ubiquitin ligase Cblb has a crucial role in the prevention of chronic inflammation and autoimmunity. Here we show that Cblb also has an unexpected function in acute lung inflammation. Cblb attenuates the sequestration of inflammatory cells in the lungs after administration of lipopolysaccharide (LPS). In a model of polymicrobial sepsis in which acute lung inflammation depends on the LPS receptor (Toll-like receptor 4, TLR-4), the loss of Cblb expression accentuates acute lung inflammation and reduces survival. Loss of Cblb significantly increases sepsis-induced release of inflammatory cytokines and chemokines. Cblb controls the association between TLR4 and the intracellular adaptor MyD88. Expression of wild-type Cblb, but not expression of a Cblb mutant that lacks E3 ubiquitin ligase function, prevents the activity of a reporter gene for the transcription factor nuclear factor-kappaB (NF-kappaB) in monocytes that have been challenged with LPS. The downregulation of TLR4 expression on the cell surface of neutrophils is impaired in the absence of Cblb. Our data reveal that Cblb regulates the TLR4-mediated acute inflammatory response that is induced by sepsis.