Distinct Type 1 Immune Networks Underlie the Severity of Restrictive Lung Disease after COVID-19.

The variable etiology of persistent breathlessness after COVID-19 have confounded efforts to decipher the immunopathology of lung sequelae. Here, we analyzed hundreds of cellular and molecular features in the context of discrete pulmonary phenotypes to define the systemic immune landscape of post-COVID lung disease. Cluster analysis of lung physiology measures highlighted two phenotypes of restrictive lung disease that differed by their impaired diffusion and severity of fibrosis. Machine learning revealed marked CCR5+CD95+ CD8+ T-cell perturbations in mild-to-moderate lung disease, but attenuated T-cell responses hallmarked by elevated CXCL13 in more severe disease. Distinct sets of cells, mediators, and autoantibodies distinguished each restrictive phenotype, and differed from those of patients without significant lung involvement. These differences were reflected in divergent T-cell-based type 1 networks according to severity of lung disease. Our findings, which provide an immunological basis for active lung injury versus advanced disease after COVID-19, might offer new targets for treatment.

ACE-2-like enzymatic activity is associated with immunoglobulin in COVID-19 patients.

Many mechanisms responsible for COVID-19 pathogenesis are well-established, but COVID-19 includes features with unclear pathogenesis, such as autonomic dysregulation, coagulopathies, and high levels of inflammation. The receptor for the SARS-CoV-2 spike protein receptor-binding domain (RBD) is angiotensin-converting enzyme 2 (ACE2). We hypothesized that some COVID-19 patients may develop antibodies that have a negative molecular image of RBD sufficiently similar to ACE2 to yield ACE2-like catalytic activity-ACE2-like abzymes. To explore this hypothesis, we studied patients hospitalized with COVID-19 who had plasma samples available obtained about 7 days after admission. ACE2 is a metalloprotease that requires Zn2+ for activity. However, we found that the plasma from some patients studied could specifically cleave a synthetic ACE2 peptide substrate, even though the plasma samples were collected using disodium EDTA anticoagulant. When we spiked plasma with synthetic ACE2, no ACE2 substrate cleavage activity was observed unless Zn2+ was added or the plasma was diluted to decrease EDTA concentration. After processing samples by 100 kDa size exclusion columns and protein A/G adsorption, which depleted immunoglobulin by >99.99%, the plasma samples did not cleave the ACE2 substrate peptide. The data suggest that some patients with COVID-19 develop antibodies with abzyme-like activity capable of cleaving synthetic ACE2 substrate. Since abzymes can exhibit promiscuous substrate specificities compared to the enzyme whose active site image they resemble, and since proteolytic cascades regulate many physiologic processes, anti-RBD abzymes may contribute to some otherwise obscure COVID-19 pathogenesis. IMPORTANCE: We provide what we believe to be the first description of angiotensin-converting enzyme 2 (ACE2)-like enzymatic activity associated with immunoglobulin in COVID-19 patients. COVID-19 includes many puzzling clinical features that have unclear pathogenesis, including a hyperinflammatory state, abnormalities of the clotting cascade, and blood pressure instability. We hypothesized that some patients with COVID-19 patients may produce antibodies against SARS-CoV-2 with enzymatic activity, or abzymes, that target important proteolytic regulatory cascades. The receptor-binding domain (RBD) of the SARS-CoV-2 spike protein binds ACE2 on the surface of the future host cell. This means that the RBD has a negative molecular image of ACE2. We hypothesized that some antibodies produced against the RBD would have, in turn, a negative molecular image of the RBD sufficiently similar to ACE2 to have ACE2-like catalytic activity. In other words, some anti-RBD antibodies would be ACE2-like abzymes. Abzymes elicited by SARS-CoV-2 infection have the potential to affect host physiology.

Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial.

There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19+ B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 107 and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .

Tick bites, IgE to galactose-alpha-1,3-galactose and urticarial or anaphylactic reactions to mammalian meat: The alpha-gal syndrome.

The recent recognition of a syndrome of tick-acquired mammalian meat allergy has transformed the previously held view that mammalian meat is an uncommon allergen. The syndrome, mediated by IgE antibodies against the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal), can also involve reactions to visceral organs, dairy, gelatin and other products, including medications sourced from non-primate mammals. Thus, fittingly, this allergic disorder is now called the alpha-gal syndrome (AGS). The syndrome is strikingly regional, reflecting the important role of tick bites in sensitization, and is more common in demographic groups at risk of tick exposure. Reactions in AGS are delayed, often by 2-6 h after ingestion of mammalian meat. In addition to classic allergic symptomatology such as urticaria and anaphylaxis, AGS is increasingly recognized as a cause of isolated gastrointestinal morbidity and alpha-gal sensitization has also been linked with cardiovascular disease. The unusual link with tick bites may be explained by the fact that allergic cells and mediators are mobilized to the site of tick bites and play a role in resistance against ticks and tick-borne infections. IgE directed to alpha-gal is likely an incidental consequence of what is otherwise an adaptive immune strategy for host defense against endo- and ectoparasites, including ticks.

IgE to common food allergens is associated with cardiovascular mortality in the National Health and Examination Survey and the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: In individuals without symptomatic food allergy, food-specific IgE is considered clinically irrelevant. However, recent studies have suggested that galactose-α-1,3-galactose (alpha-gal) IgE is associated with cardiovascular (CV) disease. OBJECTIVE: We sought to determine whether sensitization to common food allergens is associated with CV mortality. METHODS: The association between IgE sensitization to foods and CV mortality ascertained to 2019 was examined in the National Health and Examination Survey (NHANES) 2005-2006 and the Wake Forest site of the Multi-Ethnic Study of Atherosclerosis (MESA) cohort; MESA enrolled adults without baseline clinical CV diseases between 2000 and 2002. Total and specific IgE was measured to cow's milk, egg, peanut, shrimp, and a panel of aeroallergens (NHANES), and to cow's milk, alpha-gal, peanut, dust mite, and timothy grass (MESA). Cox proportional hazard models were constructed, adjusting for sex, age, race/ethnicity, smoking, education, and asthma. RESULTS: A total of 4414 adults from NHANES (229 CV deaths) and 960 from MESA (56 CV deaths) were included. In NHANES, sensitization to at least 1 food was associated with higher CV mortality (hazard ratio [HR], 1.7 [95% confidence interval (CI), 1.2-2.4], P = .005). Milk sensitization was particularly associated (HR, 2.0 [95% CI, 1.1-3.8], P = .026), a finding replicated in MESA (HR, 3.8 [95% CI, 1.6-9.1], P = .003). Restricting analyses in NHANES to consumers of the relevant allergen strengthened food sensitization relationships, unmasking shrimp and peanut sensitization as additional risk factors for CV mortality. CONCLUSIONS: The finding that food sensitization is associated with increased risk of CV mortality challenges the current paradigm that sensitization without overt allergy is benign. Further research is needed to clarify mechanisms of this association.

Alpha-Gal IgE Prevalence Patterns in the United States: An Investigation of 3,000 Military Recruits.

BACKGROUND: IgE to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) is an important cause of allergic reactions to mammalian meat. The "alpha-gal syndrome" is strongly associated with a preceding history of tick bites and in the United States is most commonly reported in parts of the southeast, but there has been limited investigation into national alpha-gal sensitization patterns and the relevance of other risk factors. OBJECTIVE: To systematically investigate alpha-gal IgE prevalence, regional patterns, and risk factors. METHODS: Alpha-gal IgE was measured by ImmunoCAP in biobanked serum samples collected from 3000 service members who presented for intake to 1 of 10 military bases in the central/eastern United States. Alpha-gal IgE sensitization (cutoff 0.1 international units/mL) was related to home of record at enlistment. RESULTS: Of the cohort, 2456 (81.9%) subjects were male, median age was 19 years (interquartile range: 18-22 years), and alpha-gal IgE was detected in 179 (6.0%). Home of record spanned all 50 states, with a median of 36 recruits per state (range: 3-261). The highest prevalence rates were in Arkansas (39%), Oklahoma (35%), and Missouri (29%), with several other southeastern states >10%. Granular mapping revealed sensitization patterns that closely mimicked county-level Amblyomma americanum reports and Ehrlichia chaffeensis infections. Sensitization was associated with male sex, rural residence, and White race in univariate and multivariable models. CONCLUSIONS: In this systematic survey, the prevalence of alpha-gal IgE among incoming military personnel was 6.0%. There were significant regional differences, with an overall pattern consistent with the known range of the lone star tick (A. americanum) and highest frequency in an area including Arkansas, Oklahoma, and Missouri.

Immunoglobulin G4 in eosinophilic esophagitis: Immune complex formation and correlation with disease activity.

BACKGROUND: Recent studies have shown deposition of immunoglobulin G4 (IgG4) and food proteins in the esophageal mucosa of eosinophilic esophagitis (EoE) patients. Our aims were to assess whether co-localization of IgG4 and major cow's milk proteins (CMPs) was associated with EoE disease activity and to investigate the proteins enriched in proximity to IgG4 deposits. METHODS: This study included adult subjects with EoE (n = 13) and non-EoE controls (n = 5). Esophageal biopsies were immunofluorescence stained for IgG4 and CMPs. Co-localization in paired samples from active disease and remission was assessed and compared to controls. The proteome surrounding IgG4 deposits was evaluated by the novel technique, AutoSTOMP. IgG4-food protein interactions were confirmed with co-immunoprecipitation and mass spectrometry. RESULTS: IgG4-CMP co-localization was higher in the active EoE group compared to paired remission samples (Bos d 4, p = .02; Bos d 5, p = .002; Bos d 8, p = .002). Co-localization was also significantly higher in the active EoE group compared to non-EoE controls (Bos d 4, p = .0013; Bos d 5, p = .0007; Bos d 8, p = .0013). AutoSTOMP identified eosinophil-derived proteins (PRG 2 and 3, EPX, RNASE3) and calpain-14 in IgG4-enriched areas. Co-immunoprecipitation and mass spectrometry confirmed IgG4 binding to multiple food allergens. CONCLUSION: These findings further contribute to the understanding of the interaction of IgG4 with food antigens as it relates to EoE disease activity. These data strongly suggest the immune complex formation of IgG4 and major cow's milk proteins. These immune complexes may have a potential role in the pathophysiology of EoE by contributing to eosinophil activation and disease progression.

Alpha-gal syndrome: A review for the dermatologist.

Alpha-gal syndrome (AGS) is an allergy to "red meat" and other mammalian products due to immunoglobulin E (IgE) antibodies against the sugar moiety galactose-alpha-1,3-galactose (alpha-gal), which is acquired following tick bites. Clinically, AGS presents with urticaria, abdominal pain, nausea, and occasionally anaphylaxis, and has wide inter- and intra-personal variability. Because symptom onset is generally delayed by 2 to 6 hours after meat consumption, AGS can be easily confused with other causes of urticaria and anaphylaxis, such as chronic spontaneous urticaria (CSU) and mast cell activation syndrome (MCAS). Diagnosis relies on a combination of clinical history, positive alpha-gal IgE blood testing and improvement on a mammalian-restricted diet. Management of the syndrome centers primarily on avoidance of mammalian meats (and occasionally dairy and other products) as well as acute management of allergic symptoms. Counseling about tick avoidance measures is also important as AGS will wane over time in many patients.

The Economic Value of Health Benefits Associated with Urban Park Investment.

The allocation of resources towards the development and enhancement of urban parks offers an effective strategy for promoting and improving the health and well-being of urban populations. Investments in urban parks can result in a multitude of health benefits. The increased usage of greenspace by park users has been linked to positive physical and mental health outcomes. Additionally, the expansion of greenspace in urban areas can mitigate harmful impacts from air pollutants, heat, noise, and climate-related health risks. While the health benefits attributed to urban parks and greenspaces are well documented, few studies have measured the economic value of these benefits. This study applied a novel ecohealth economic valuation framework to quantify and estimate the potential economic value of health benefits attributed to the development of a proposed park in the downtown core of Peterborough, Canada. The results indicated that development of the small urban park will result in annual benefits of CAD 133,000 per year, including CAD 109,877 in the avoided economic burden of physical inactivity, CAD 23,084 in health savings associated with improved mental health, and CAD 127 in health savings attributed to better air quality. When including the economic value of higher life satisfaction, the economic benefit is more than CAD 4 million per year. The study demonstrates the value of developing and enhancing urban parks as a strategy to improve population health and well-being, and as a means of cost savings to the medical system.

Efficacy of Low-Cost Sensor Networks at Detecting Fine-Scale Variations in Particulate Matter in Urban Environments.

The negative health impacts of air pollution are well documented. Not as well-documented, however, is how particulate matter varies at the hyper-local scale, and the role that proximal sources play in influencing neighborhood-scale patterns. We examined PM2.5 variations in one airshed within Indianapolis (Indianapolis, IN, USA) by utilizing data from 25 active PurpleAir (PA) sensors involving citizen scientists who hosted all but one unit (the control), as well as one EPA monitor. PA sensors report live measurements of PM2.5 on a crowd sourced map. After calibrating the data utilizing relative humidity and testing it against a mobile air-quality unit and an EPA monitor, we analyzed PM2.5 with meteorological data, tree canopy coverage, land use, and various census variables. Greater proximal tree canopy coverage was related to lower PM2.5 concentrations, which translates to greater health benefits. A 1% increase in tree canopy at the census tract level, a boundary delineated by the US Census Bureau, results in a ~0.12 µg/m3 decrease in PM2.5, and a 1% increase in "heavy industry" results in a 0.07 µg/m3 increase in PM2.5 concentrations. Although the overall results from these 25 sites are within the annual ranges established by the EPA, they reveal substantial variations that reinforce the value of hyper-local sensing technologies as a powerful surveillance tool.

Enhanced SARS-CoV-2 IgG durability following COVID-19 mRNA booster vaccination and comparison of BNT162b2 with mRNA-1273.

BACKGROUND: BNT162b2 (Pfizer/BioNTech, Comirnaty) and mRNA-1273 (Moderna, Spikevax) are messenger RNA (mRNA) vaccines that elicit antibodies against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike receptor-binding domain (S-RBD) and have been approved by the US Food and Drug Administration to combat the coronavirus disease 2019 (COVID-19) pandemic. Because vaccine efficacy and antibody levels waned over time after the 2-shot primary series, the US Food and Drug Administration authorized a booster (third) dose for both mRNA vaccines to adults in the fall of 2021. OBJECTIVE: To evaluate the magnitude and durability of S-RBD immunoglobulin (Ig)G after the booster mRNA vaccine dose in comparison to the primary series. We also compared S-RBD IgG levels after BNT162b2 and mRNA-1273 boosters and explored effects of age and prior infection. METHODS: Surrounding receipt of the second and third homologous mRNA vaccine doses, adults in an employee-based cohort provided serum and completed questionnaires, including information about previous COVID-19 infection. The IgG to S-RBD was measured using an ImmunoCAP-based system. A subset of samples were assayed for IgG to SARS-CoV-2 nucleocapsid by commercial assay. RESULTS: There were 228 subjects who had samples collected between 7 and 150 days after their primary series vaccine and 117 subjects who had samples collected in the same time frame after their boost. Antibody levels from 7 to 31 days after the primary series and booster were similar, but S-RBD IgG was more durable over time after the boost, regardless of prior infection status. In addition, mRNA-1273 post-boost antibody levels exceeded BNT162b2 out to 5 months. CONCLUSION: The COVID-19 mRNA vaccine boosters increase antibody durability, suggesting enhanced long-term clinical protection from SARS-CoV-2 infection compared with the 2-shot regimen.

Heat and air quality related cause-based elderly mortalities and emergency visits.

The combined effects of heat events and poor air quality conditions can severely affect population health. A novel correlational method was developed to assess the impact of the short-term variations of environmental variables (air pollutants and ambient conditions) on community health responses (mortalities and emergency department visits). A multi-dimensional clustering approach was proposed by combining hierarchical and k-means clustering to promote flexibility and robustness to improve the correlation procedure. The study focused on the health records of the elderly population and people diagnosed with cardiorespiratory causes. The study investigated multiple health records on different levels of investigation: total, elderly, cause-based, and elderly cause-based records. The developed method was validated by investigating the short-term impact of ambient air temperature, relative humidity, ground-level ozone, and fine particulate matter on the health records during hot and warm seasons in the municipalities of Mississauga and Brampton, Peel Region, Ontario, Canada for 15 years. The analysis confirmed the association between moderate levels of environmental variables and increased short-term daily total deaths and emergency department visits, while the elderly sector showed higher vulnerability to environmental changes. Furthermore, the association with extreme heat conditions and poor air quality levels was affirmed with cause-based mortalities and emergency visits; the correlation was strongest with elderly cause-based health records. Findings confirm that cardiorespiratory patients, especially elderly people, were at the greatest risk of poor environmental conditions.

Food antigen consumption and disease activity affect food-specific IgG4 levels in patients with eosinophilic esophagitis (EoE).

INTRODUCTION: High levels of serum food-specific IgG4 (sIgG4) have been reported in patients with EoE. The objective of this study was to examine whether serum sIgG4 levels to foods and aeroallergens are higher in EoE patients than allergic controls and to investigate the association between sIgG4 and EoE clinical characteristics. METHODS: This was a case-control study nested in a prospective EoE Cohort. EoE cases were defined per consensus guidelines, and controls were individuals with symptoms who were confirmed to be EoE-negative on upper endoscopy. Demographic and clinical information was prospectively collected. Serum IgE and sIgG4 were measured to foods and aeroallergens by ImmunoCAP. Mean levels of sIgG4 were compared between cases and controls, and logistic regression models were used to examine predictors of elevated milk sIgG4 levels. RESULTS: The analysis included 123 individuals (EoE n = 93, control n = 30) with a similar distribution of allergic disease between EoE patients and controls (86% vs. 93%; p = .30). EoE patients had significantly higher sIgG4 levels to all allergens evaluated, with the exception of birch (p = .24). Milk sIgG4 levels were independently associated with milk consumption (OR 4.95; p = .01) and the presence of sIgE to milk (OR 4.23; p = .008). CONCLUSION: Serum sIgG4 levels to food and aeroallergen proteins were higher in patients with EoE than non-EoE controls, and higher levels of milk sIgG4 were independently associated with milk consumption and the presence of sIgE to milk proteins. Whether sIgG4 plays a pathogenic role in EoE or could be used as an EoE biomarker remains unknown and warrants further study.

Review on Short Term Dual Antiplatelet Therapy Following Percutaneous Coronary Intervention with Drug Eluting Stent.

The optimal duration of dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) have been a debatable topic for several decades. With the newer generation drug eluting stents, risk of major adverse cardiovascular events (MACE) has significantly reduced and hence, shorter duration of DAPT (one to three months) is now recommended especially in patients with high bleeding risk. Our review highlights the current guidelines and the recommendations from the recent trials.

Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA) in a Patient Taking Lisdexamfetamine.

Stimulant medications like amphetamines have been associated with various cardiovascular complications like coronary artery spasm, coronary dissections and thrombus formation, the pathophysiology of which is theorized to be the endothelial damage induced by the medication and the inflammatory cascade that follows. We report a case of 52-year-old male on lisdexamfetamine, a newer stimulant agent used for attention deficit hyperactivity disorder (ADHD) who presented with sudden chest pain and ECG changes concerning for myocardial infarction and mildly elevated troponins. However, coronary angiogram showed no obstructive coronary artery disease and there was spontaneous resolution of his symptoms and ECG changes.

Trajectory of IgG to SARS-CoV-2 After Vaccination With BNT162b2 or mRNA-1273 in an Employee Cohort and Comparison With Natural Infection.

Three COVID-19 vaccines have received FDA-authorization and are in use in the United States, but there is limited head-to-head data on the durability of the immune response elicited by these vaccines. Using a quantitative assay we studied binding IgG antibodies elicited by BNT162b2, mRNA-1273 or Ad26.COV2.S in an employee cohort over a span out to 10 months. Age and sex were explored as response modifiers. Of 234 subjects in the vaccine cohort, 114 received BNT162b2, 114 received mRNA-1273 and six received Ad26.COV2.S. IgG levels measured between seven to 20 days after the second vaccination were similar in recipients of BNT162b2 and mRNA-127 and were ~50-fold higher than in recipients of Ad26.COV2.S. However, by day 21 and at later time points IgG levels elicited by BNT162b2 were lower than mRNA-1273. Accordingly, the IgG decay curve was steeper for BNT162b2 than mRNA-1273. Age was a significant modifier of IgG levels in recipients of BNT162b2, but not mRNA-1273. After six months, IgG levels elicited by BNT162b2, but not mRNA-1273, were lower than IgG levels in patients who had been hospitalized with COVID-19 six months earlier. Similar findings were observed when comparing vaccine-elicited antibodies with steady-state IgG targeting seasonal human coronaviruses. Differential IgG decay could contribute to differences observed in clinical protection over time between BNT162b2 and mRNA-1273.

Effect of olfactory bulb pathology on olfactory function in normal aging.

Decline of olfactory function is frequently observed in aging and is an early symptom of neurodegenerative diseases. As the olfactory bulb (OB) is one of the first regions involved by pathology and may represent an early disease stage, we specifically aimed to evaluate the contribution of OB pathology to olfactory decline in cognitively normal aged individuals without parkinsonism or dementia. This clinicopathological study correlates OB tau, amyloid ß (Aß) and α-synuclein (αSyn) pathology densities and whole brain pathology load to olfactory identification function as measured with the University of Pennsylvania Smell Identification Test (UPSIT) and clinical data measured proximate to death in a large autopsy study including 138 cases considered non-demented controls during life. Tau pathology was frequently observed in the OB (95% of cases), while both Aß (27% of cases) and αSyn (20% of cases) OB pathologies were less commonly observed. A weak correlation was only observed between OB tau and olfactory performance, but when controlled for age, neither OB tau, Aß or αSyn significantly predict olfactory performance. Moreover, whole brain tau and αSyn pathology loads predicted olfactory performance; however, only αSyn pathology loads survived age correction. In conclusion, OB tau pathology is frequently observed in normally aging individuals and increases with age but does not appear to independently contribute to age-related olfactory impairment suggesting that further involvement of the brain seems necessary to contribute to age-related olfactory decline.