Inhaled CD24-Enriched Exosomes (EXO-CD24) as a Novel Immune Modulator in Respiratory Disease.

Acute Respiratory Distress Syndrome (ARDS) is a major health concern with urgent unmet need for treatment options. There are three million new ARDS cases annually, and the disease's mortality rate is high (35-46%). Cluster of differentiation 24 (CD24), a long-known protein with multifaceted functions, is a small, heavily glycosylated, membrane-anchored protein which functions as an immune checkpoint control. CD24 allows for immune discrimination between Damage-Associated Molecular Patterns and Pathogen-Associated Molecular Patterns derived from pathogens. Exosomes are intraluminal vesicles which play an important role in intercellular communication. Exosomes offer the advantage of targeted delivery, which improves safety and efficacy. The safety and efficacy of EXO-CD24 is promising, as was shown in >180 ARDS patients in phase 1b/2a, phase 2b, and compassionate use. CD24 binds Damage-associated molecular patterns (DAMPs) and inhibits the activation of the NF-ĸB pathway, a pivotal mediator of inflammatory responses. In contrast to anti-inflammatory therapies that are cytokine-specific or steroids that shut down the entire immune system, EXO-CD24 acts upstream, reverting the immune system back to normal activity. Herein, the safety and efficacy of mEXO-CD24 is shown in murine models of several pulmonary diseases (sepsis, allergic asthma, Chronic Obstructive Pulmonary Disease(COPD), fibrosis). EXO CD24 can suppress the hyperinflammatory response in the lungs in several pulmonary diseases with a significant unmet need for treatment options.

Association of a Third Dose of BNT162b2 Vaccine With Incidence of SARS-CoV-2 Infection Among Health Care Workers in Israel.

Importance: Administration of a BNT162b2 booster dose (Pfizer-BioNTech) to fully vaccinated individuals aged 60 years and older was significantly associated with lower risk of SARS-CoV-2 infection and severe illness. Data are lacking on the effectiveness of booster doses for younger individuals and health care workers. Objective: To estimate the association of a BNT162b2 booster dose with SARS-CoV-2 infections among health care workers who were previously vaccinated with a 2-dose series of BNT162b2. Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary medical center in Tel Aviv, Israel. The study cohort included 1928 immunocompetent health care workers who were previously vaccinated with a 2-dose series of BNT162b2, and had enrolled between August 8 and 19, 2021, with final follow-up reported through September 20, 2021. Screening for SARS-CoV-2 infection was performed every 14 days. Anti-spike protein receptor binding domain IgG titers were determined at baseline and 1 month after enrollment. Cox regression with time-dependent analysis was used to estimate hazard ratios of SARS-CoV-2 infection between booster-immunized status and 2-dose vaccinated (booster-nonimmunized) status. Exposures: Vaccination with a booster dose of BNT162b2 vaccine. Main Outcomes and Measures: The primary outcome was SARS-CoV-2 infection, as confirmed by reverse transcriptase-polymerase chain reaction. Results: Among 1928 participants, the median age was 44 years (IQR, 36-52 years) and 1381 were women (71.6%). Participants completed the 2-dose vaccination series a median of 210 days (IQR, 205-213 days) before study enrollment. A total of 1650 participants (85.6%) received the booster dose. During a median follow-up of 39 days (IQR, 35-41 days), SARS-CoV-2 infection occurred in 44 participants (incidence rate, 60.2 per 100 000 person-days); 31 (70.5%) were symptomatic. Five SARS-CoV-2 infections occurred in booster-immunized participants and 39 in booster-nonimmunized participants (incidence rate, 12.8 vs 116 per 100 000 person-days, respectively). In a time-dependent Cox regression analysis, the adjusted hazard ratio of SARS-CoV-2 infection for booster-immunized vs booster-nonimmunized participants was 0.07 (95% CI, 0.02-0.20). Conclusions and Relevance: Among health care workers at a single center in Israel who were previously vaccinated with a 2-dose series of BNT162b2, administration of a booster dose compared with not receiving one was associated with a significantly lower rate of SARS-CoV-2 infection over a median of 39 days of follow-up. Ongoing surveillance is required to assess durability of the findings.

Management of acute exacerbations of COPD in the emergency department and its associations with clinical variables.

Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) is a common cause for emergency department (ED) visits. Still, large scale studies that assess the management of AECOPD in the ED are limited. Our aim was to evaluate treatment characteristics of AE-COPD in the ED on a national scale. A prospective study as part of the COPD Israeli survey, conducted between 2017 and 2019, in 13 medical centers. Patients hospitalized with AECOPD were included and interviewed. Clinical data related to their ED and hospital stay were collected. 344 patients were included, 38% females, mean age of 70 ± 11 years. Median (IQR) time to first ED treatment was 59 (23-125) minutes and to admission 293 (173-490) minutes. Delayed ED treatment (> 1 h) was associated with older age (p = 0.01) and lack of a coded diagnosis of COPD in hospital records (p = 0.01). Long ED length-of-stay (> 5 h) was linked with longer hospitalizations (p = 0.01). Routine ED care included inhalations of short-acting bronchodilators (246 patients, 72%) and systemic steroids (188 patients, 55%). Receiving routine ED care was associated with its continuation during hospitalization (p < 0.001). In multivariate analysis, predictors for patients not receiving routine care were obesity (adjusted odds ratio 0.5, 95% CI 0.3-0.8, p = 0.01) and fever (AOR 0.3, 95% CI 0.1-0.6, p < 0.01), while oxygen saturation < 91% was an independent predictor for ED routine treatment (AOR 3.6, 95% CI 2.1-6.3, p < 0.01). Our findings highlight gaps in the treatment of AECOPD in the ED on a national scale, with specific predictors for their occurrence.

Routine in-hospital interventions during acute exacerbation of COPD are associated with improved 30-day care.

BACKGROUND: Implementing standard of care therapy for chronic obstructive pulmonary disease (COPD) has barriers. Hospitalization with an acute exacerbation of COPD (AECOPD) is a major adverse event that could also be an opportunity to improve patients' long-term care. OBJECTIVES: To evaluate which in-hospital interventions during AECOPD are associated with improved 30-day care. METHODS: This was a prospective study that included patients from 10 medical centers across Israel, hospitalized with AECOPD between 2017 and 2019. Patients were approached during hospitalization in internal medicine departments. A semi-structured follow-up call was performed 30 days after discharge, and six COPD areas of care were assessed. Multivariate analyses were used to analyze predictors for each area of care. RESULTS: 234 patients were included (mean age 69 years and 34% females). A lower 30-day readmission rate was independently associated with smoking cessation and prescription of renin-angiotensin blockers. Initiating or continuing long acting bronchodilators (LABD) during admission was an independent predictor for their 30-day use. Among patients with prior LABD treatment, only 38% continued at 30-days if it was not prescribed during admission (OR 4, 95% CI 1.98-8.08, p<0.01). In-hospital daily respiratory physiotherapy was an independent predictor for smoking cessation (AOR 5.1, 95% CI 1.1-23, p=0.04), while smoking cessation recommendation was not (p=0.28). Initiating a smoking cessation program (5%) or pulmonary rehabilitation (1%) after discharge was performed only by patients with a written referral. CONCLUSION: Routine procedures during hospitalization for AECOPD could impact patients' long-term care in areas with proven effects on disease outcomes.

Assessment of a close respiratory follow-up schedule at 3 and 6 months after acute COVID-19 and its related investigations.

BACKGROUND: Respiratory sequela after acute COVID-19 is common and requires medical follow-up. Considering its vast economic impact, there is still no consensus regarding the mid-term follow-up plan after recovery. OBJECTIVE: To evaluate the necessity of a close pulmonary follow-up schedule after acute COVID-19 and its related investigations. METHODS: A prospective cohort study including adult patients after acute COVID-19 pneumonia. Patients were invited or referred to a 3- and 6-month follow-up visits at a large pulmonary institute in a tertiary center. Before each visit, patients completed demographic and clinical questionnaires, pulmonary function tests (PFTs), and chest CT scans. RESULTS: 168 patients were included after completing both visits (medians of 80 and 177 days). Their mean age was 58 ± 15 and 52% recovered from severe or critical COVID-19. Between the two visits, there was no change in DLCOc (mean 73 ± 18 %predicted in both visits) and FVC (mean 90 ± 16 vs. 89 ± 16 %predicted). The COPD assessment tool and modified Medical Research Council scale had inverse correlations with the DLCOc, and similarly did not change between the visits. Occupational exposures were the only factor associated with a change in DLCOc during follow-up (3% decrease, p = 0.04). An improvement in chest CT findings at the second visit was not associated with a change in PFTs. CONCLUSIONS: Most clinical variables did not change during a close follow-up schedule in the first six months after acute COVID-19. Such a follow-up plan does not appear necessary and should be personalized to limit excessive costs and resources.

Early Detection of Inflammation-Prone STEMI Patients Using the CRP Troponin Test (CTT).

Elevated concentrations of C-reactive protein (CRP) early during an acute coronary syndrome (ACS) may reflect the magnitude of the inflammatory response to myocardial damage and are associated with worse outcome. However, the routine measurement of both CRP and cardiac troponin simultaneously in the setting of ST-segment myocardial infarction (STEMI) is not used broadly. Here, we sought to identify and characterize individuals who are prone to an elevated inflammatory response following STEMI by using a combined CRP and troponin test (CTT) and determine their short- and long-term outcome. We retrospectively examined 1186 patients with the diagnosis of acute STEMI, who had at least two successive measurements of combined CRP and cardiac troponin (up to 6 h apart), all within the first 48 h of admission. We used Chi-Square Automatic Interaction Detector (CHAID) tree analysis to determine which parameters, timing (baseline vs. serial measurements), and cut-offs should be used to predict mortality. Patients with high CRP concentrations (above 90th percentile, >33 mg/L) had higher 30 day and all-cause mortality rates compared to the rest of the cohort, regardless of their troponin test status (above or below 118,000 ng/L); 14.4% vs. 2.7%, p < 0.01. Furthermore, patients with both high CRP and high troponin levels on their second measurement had the highest 30-day mortality rates compared to the rest of the cohort; 21.4% vs. 3.7%, p < 0.01. These patients also had the highest all-cause mortality rates after a median follow-up of 4.5 years compared to the rest of the cohort; 42.9% vs. 12.7%, p < 0.01. In conclusion, serial measurements of both CRP and cardiac troponin might detect patients at increased risk for short-and long-term mortality following STEMI. We suggest the future use of the combined CTT as a potential early marker for inflammatory-prone patients with worse outcomes following ACS. This sub-type of patients might benefit from early anti-inflammatory therapy such as colchicine and anti-interleukin-1ß agents.

Lung ultrasound in internal medicine: A bedside help to increase accuracy in the diagnosis of dyspnea.

BACKGROUND: Dyspnea is one of the most frequent causes of admission in Internal Medicine wards, leading to a sizeable utilization of medical resources. STUDY DESIGN AND METHODS: The role of bedside lung ultrasound (LUS) was evaluated in 130 consecutive patients (age: 81±9years), in whom blindly collected LUS results were compared with data obtained by clinical examination, medical history, blood analysis, and chest X-ray. Dyspnea etiology was classified as "cardiac" (n=80), "respiratory" (n=36) or "mixed" (n=14), according to the discharge diagnosis (congestive heart failure either alone [n=80] or associated with pneumonia [n=14], pneumonia [n=24], and obstructive disventilatory syndrome [n=12]). An 8-window LUS protocol was applied to evaluate B-line distribution, "interstitial syndrome" pattern, pleural effusion and images of static or dynamic air bronchogram/focal parenchymal consolidation. RESULTS: The presence of a generalized "interstitial syndrome" at the initial LUS evaluation allowed to discriminate "cardiac" from "pulmonary" Dyspnea with high sensitivity (93.75%; confidence intervals: 86.01%-97.94%) and specificity (86.11%; 70.50%-95.33%). Positive and negative predictive values were 93.76% (86.03%-97.94%) and 86.09% (70.47%-95.32%), respectively. Moreover, LUS diagnostic accuracy for the diagnosis of pneumonia was not inferior to that of chest X-ray. CONCLUSIONS: Bedside LUS evaluation contributes with high sensitivity and specificity to the differential diagnosis of Dyspnea. This holds true not only in the emergency setting, but also in the sub-acute Internal Medicine arena. A wider use of this portable technique in our wards is warranted.