Racial disparities in COVID-19 hospitalizations do not lead to disparities in outcomes.

OBJECTIVES: The objective of the study is the identification of racial differences in characteristics and comorbidities in patients hospitalized for COVID-19 and the impact on outcomes. STUDY DESIGN: The study design is a retrospective observational study. METHODS: Data for all patients admitted to seven community hospitals in Michigan, United States, with polymerase chain reaction confirmed diagnosis of COVID-19 from March 10 to April 15, 2020 were analyzed. The primary outcomes of racial disparity in inpatient mortality and intubation were analyzed using descriptive statistics and multivariate regression models. RESULTS: The study included 336 Black and 408 White patients. Black patients were younger (62.9 ± 15.0 years vs 71.8 ± 16.4, P < .001), had a higher mean body mass index (32.4 ± 8.6 kg/m2 vs 28.8 ± 7.5, P < .001), had higher prevalence of diabetes (136/336 vs 130/408, P = .02), and presented later (6.6 ± 5.3 days after symptom onset vs. 5.4 ± 5.4, P = .006) compared with White patients. Younger Black patients had a higher prevalence of obesity (age <65 years, 69.9%) than older Black patients (age >65 years, 39.2%) and younger White patients (age < 65, 55.1%). Intubation did not reach statistical significance for racial difference (Black patients 61/335 vs. 54/406, P = .08). Mortality was not higher in Black patients (65/335 vs. 142/406 in White patients, odds ratio 0.61, 95% confidence interval: 0.37 to 0.99, 2-sided P = .05) in multivariate analysis, accounting for other risk factors associated with mortality. CONCLUSIONS: Higher prevalence of obesity and diabetes in young Black populations may be the critical factor driving disproportionate COVID-19 hospitalizations in Black populations. Hospitalized Black patients do not have worse outcomes compared with White patients.

Ambient pCO2 modulates intracellular pH, intracellular oxidant generation, and interleukin-8 secretion in human neutrophils.

Although neutrophils are a critical component of the inflammatory process, their functional regulation is incompletely understood. Of note, although pCO2 varies physiologically and pathologically in the neutrophilic milieu, its affect on neutrophil biological processes is unresolved. We demonstrate here that neutrophils respond to hypo- and hypercarbia, (0.04% and 10%) by increasing and decreasing, respectively, intracellular oxidant production (basally and in response to opsonized Escherichia coli and phorbol esters). Further, hypo- and hypercarbia increase and decrease, respectively, the release of IL-8 from LPS-stimulated cells; both effects are attenuated by the carbonic anhydrase inhibitor, acetazolamide. Anion exchange did not restore pH(i) under hypocarbic conditions, however partial restoration of pH(i) under hypercarbic conditions was achieved by Na+/H+ exchange and vacuolar ATPases. Abrogation of pCO2-induced changes in pH(i) prevented hypocarbia-induced generation of reactive oxidant species. These observations suggest that CO2 modifies neutrophil activity significantly by altering pH(i).

Liquid and ion transport by fetal airway and lung epithelia of mice deficient in sodium-potassium-2-chloride transporter.

Chloride (Cl(-)) movement across fetal lung epithelia is thought to be mediated by the sodium-potassium-2-Cl(-) cotransporter NKCC1. We studied the role of NKCC1 in Cl(-) and liquid secretion in late-gestation NKCC-null (-/-) and littermate control fetal mouse lung. NKCC -/- mice had decreased lung water compared with littermate controls (wet/dry: control, 8.01 +/- 0.09; NKCC -/-, 7.06 +/- 0.14). Liquid secretion by 17-d NKCC -/- distal lung explants was similar to control explants. Bumetanide inhibited basal liquid secretion in control but not NKCC -/- explants (expansion over 48 h: control, 35 +/- 4%; NKCC -/- 46 +/- 7%). Treatment with 4,4'-diisothiocyanto-stilbene-2,2'-disulfonic acid (DIDS) decreased liquid secretion in both control and NKCC -/- explants. Basal transepithelial potential difference (PD) of control tracheal explants was higher than that of NKCC -/- (control, -13.7 +/- 0.5 mV; NKCC -/-, -11.6 +/- 0.6 mV). Amiloride (10(-)(4) M) inhibited basal PD to the same extent in control and NKCC -/- mice. Terbutaline-stimulated hyperpolarization was less in NKCC -/- than in control tracheas (DeltaPD: control, -10.8 +/- 1.33 mV; NKCC -/-, -6.1 +/- 0.7 mV) and was inhibited by DIDS and acetazolamide in NKCC -/- but not wild-type explants. We conclude that NKCC is rate-limiting for transcellular Cl(-) transport, and that alternative anion transport mechanisms can sustain liquid production at near-normal levels in the fetal NKCC -/- mouse lung.

Anti-proteinase 3 antibody activation of neutrophils can be inhibited by alpha1-antitrypsin.

Wegener's granulomatosis (WG) is classically associated with the presence of cytoplasmic antineutrophil cytoplasmic autoantibodies (c-ANCA). Proteinase 3 (PR3), the target antigen for c-ANCA, is inhibited by the antiprotease alpha1-antitrypsin (A1AT), and recent studies have demonstrated that WG patients who are A1AT-deficient have a worse clinical course, suggesting that a protease-antiprotease imbalance may play a role in WG. We evaluated the effect of A1AT on anti-PR3 antibody-induced activation of neutrophils. The neutrophil was chosen because of its central role in the pathogenesis of WG. Isolated neutrophils from healthy controls were incubated with tumor necrosis factor (TNF)-alpha to induce surface expression of PR3. Subsequently, they were stimulated with a monoclonal antibody to PR3, resulting in a significant increase in respiratory burst. Addition of A1AT (1 mg/ml) to the TNF-alpha- primed cells before the addition of the anti-PR3 antibody resulted in a 47% reduction in anti-PR3 antibody-induced activation. A1AT mediated this inhibitory action by preventing anti-PR3 antibody binding to PR3 on the cell, thereby preventing the PR3-FcgammaR11a cross-linkage required for cell activation. Further, anti-PR3 antibody-induced activation of neutrophils from WG patients can be reduced by 56% with A1AT. These data suggest that protease-antiprotease interactions may play a pivotal role in neutrophil activation in WG.

Alpha1-antitrypsin deficiency: biological answers to clinical questions.

Alpha1-antitrypsin (alpha1AT) deficiency is a common lethal hereditary disorder of white persons of European descent. The condition is characterized by reduced serum levels of alpha1AT, a 52-kDa glycoprotein synthesized chiefly in the liver and, to a lesser extent, by macrophages and neutrophils. Alpha1AT acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases such as neutrophil elastase cathepsin G and proteinase 3. The clinical manifestations of alpha1AT deficiency occur chiefly in the lung, with a high risk of emphysema occurring by the third or fourth decade of life. Cigarette smoking accelerates the development of emphysema in persons with alpha1AT deficiency. There is also an increased risk of liver disease in alpha1AT deficiency, which occurs mostly in childhood. In this review, we will define further the diagnosis of alpha1AT deficiency and its clinical manifestations and describe the therapeutic strategies that are currently being developed to treat the hepatic and pulmonary disease associated with this condition.

Regulation and functional significance of airway surface liquid pH.

In gastrointestinal tissues, cumulative evidence from both in vivo and in vitro studies suggests a role for the cystic fibrosis transmembrane conductance regulator (CFTR) in apical epithelial bicarbonate conductance. Abnormal lumenal acidification is thus hypothesized to play a role in the genesis of cystic fibrosis (CF) pancreatic disease. However, consensus regarding CFTR's participation in pH regulation of airway surface liquid (ASL) and thus the contribution of ASL pH to the etiology of CF lung disease, is lacking. The absence of data reflects difficulties in both sampling ASL in vivo and modeling ASL biology in vitro. Here we evaluate the evidence in support of a lumenal acidification hypothesis in the CF lung, summarize current knowledge of pH regulation in the normal airway and illustrate how hyper-acidified airway secretions could contribute to the pathogenesis of CF lung disease.

Role of IL-18 in CD4+ T lymphocyte activation in sarcoidosis.

Sarcoidosis is a granulomatous disease of unknown etiology associated with the expansion of IL-2-producing activated CD4(+) T lymphocytes. A number of factors including the recently described IL-18 have been implicated in IL-2 expression in vitro. We investigated the role of IL-18 in IL-2 expression in sarcoidosis. Eighteen individuals with sarcoidosis and 15 normal controls were studied. IL-18R expression and epithelial lining fluid (ELF) concentrations of IL-18 were significantly elevated in the sarcoid group (p = 0.0143 and 0.0024, respectively). Both AP1 and NF-kappaB, transcription factors that regulate IL-2 gene expression, were activated in vivo in sarcoid pulmonary CD4(+) T lymphocytes. Transcription factor activity was not detected in pulmonary CD4(+) T lymphocytes from normal controls or from peripheral blood CD4(+) T lymphocytes from individuals with sarcoidosis, further evidence of compartmentalization of the lymphoproliferative process in this condition. We examined the effects of IL-18 on AP1 and NF-kappaB in Jurkat T cells in vitro. These effects were both time and dose dependent. Examination of transcription factor activation and IL-2 gene expression in Jurkat T cells revealed that sarcoid but not normal ELF activated AP1 and NF-kappaB, induced IL-2 gene transcription, and up-regulated IL-2 protein production. Addition of IL-18 to normal ELF also induced IL-2 mRNA accumulation, whereas correspondent depletion of IL-18 from sarcoid ELF using neutralizing Abs abrogated all of the effects. These data strongly implicate IL-18 in the pathogenesis of sarcoidosis via activation of AP1 and NF-kappaB, leading to enhanced IL-2 gene expression and IL-2 protein production and concomitant T cell activation.

Altered intracellular pH regulation in neutrophils from patients with cystic fibrosis.

Cystic fibrosis (CF) is a condition characterized by neutrophil-mediated lung damage and bacterial colonization. The physiological basis for reported functional alterations in CF neutrophils, including increased release of neutrophil elastase, myeloperoxidase, and oxidants, is unknown. These processes are, however, regulated by intracellular pH (pH(i)). We demonstrate here that pH(i) regulation is altered in neutrophils from CF patients. Although resting pH(i) is similar, pH(i) after acid loading and activation (N-formyl-methionyl-leucyl-phenylalanine and phorbol 12-myristate 13-acetate) is more acidic in CF cells than in normal cells. Furthermore, patients with non-CF-related bronchiectasis handle acid loading and activation in a fashion similar to subjects with normal neutrophils, suggesting that chronic pulmonary inflammation alone does not explain the difference in pH(i). This is further supported by data showing that normal neutrophils exposed to the CF pulmonary milieu respond by increasing pH(i) as opposed to decreasing pH(i) as seen in activated CF neutrophils. These pH(i) differences in activated or acid-loaded CF neutrophils are abrogated by ZnCl(2) but not by amiloride and bafilomycin A(1), suggesting that passive proton conductance is abnormal in CF. In addition, DIDS, which inhibits HCO(3)(-)/Cl(-) exchange, causes alkalinization of control but not of CF neutrophils, suggesting that anion transport is also abnormal in CF neutrophils. In summary, we have shown that pH(i) regulation in CF neutrophils is intrinsically abnormal, potentially contributing to the pulmonary manifestations of the condition.

Increased elastase release by CF neutrophils is mediated by tumor necrosis factor-alpha and interleukin-8.

Cystic fibrosis (CF) is a lethal, hereditary disorder characterized by a neutrophil-dominated inflammation of the lung. We sought to determine whether neutrophils from individuals with CF release more neutrophil elastase (NE) than neutrophils from normal subjects. Our results showed that peripheral blood neutrophils (PBNs) from normal subjects and individuals with CF contained similar amounts of NE, but after preincubation with CF bronchoalveolar lavage (BAL) fluid, significantly more NE was released by CF PBNs, a release that was amplified further by incubation with opsonized Escherichia coli. To determine which components of CF BAL fluid stimulated this excessive NE release from CF PBNs, we repeated the experiments after neutralization or immunoprecipitation of tumor necrosis factor (TNF)-alpha and interleukin (IL)-8 in CF BAL fluid. We found that subsequent NE release from CF PBNs was reduced significantly when TNF-alpha and IL-8 were removed from CF BAL fluid. When TNF-alpha and IL-8 were used as activating stimuli, CF PBNs released significantly greater amounts of NE compared with PBNs from control subjects and individuals with bronchiectasis. These results indicate that CF PBNs respond abnormally to TNF-alpha and IL-8 in CF BAL fluid and react to opsonized bacteria by releasing more NE. This may help explain the increased NE burden seen in this condition.

Neutrophil CD11b and soluble ICAM-1 and E-selectin in community acquired pneumonia.

It was hypothesized that there would be an upregulation of systemic neutrophil CD11b expression in pneumonia. Expression of CD11b and concentrations of soluble intercellular adhesion molecule (ICAM)-1 and E-selectin were evaluated as potential surrogate markers of the severity of pneumonia. Possible age-related immunosenescence in relation to neutrophil CD11b expression in elderly patients with pneumonia was examined for. In patients with community-acquired pneumonia (n = 36) neutrophil CD11b expression was measured by flow cytometry and soluble ICAM-1 and E-selectin concentrations by enzyme-linked immunosorbent assay. An upregulation of neutrophil CD11b expression and increased soluble adhesion molecule concentrations on admission were confirmed, but the concentrations did not correlate with patient Acute Physiology and Chronic Health Evaluation II scores. Neutrophil CD11b expression was similar between elderly (age range 70-100 yrs) and younger (age range 18-70 yrs) patients with pneumonia. In conclusion, there is evidence of neutrophil and endothelial cell activation in pneumonia as indicated by upregulation of CD11b and increased soluble intercellular adhesion molecule and E-selectin, however, they do not appear to be good surrogate markers of severity of infection. Advanced age does not influence adhesion molecule expression in pneumonia.

Circulating interleukin 6 and interleukin 10 in community acquired pneumonia.

BACKGROUND: Inflammatory cytokine concentrations correlate with severity of sepsis. We hypothesised that patients with community acquired pneumonia (CAP) associated with systemic inflammatory response syndrome (SIRS) would have greater interleukin 6 (IL-6) production due to activation of the inflammatory cytokine cascade, matched by a significant anti-inflammatory cytokine response. Interleukin 10 (IL-10) was evaluated as a potential surrogate marker of severity of sepsis in CAP and age related impairment of the cytokine response was studied in elderly patients with CAP. METHODS: Circulating immunoreactive IL-6 and IL-10 levels were measured in 38 patients with CAP subdivided into a group fulfilling the criteria for SIRS (n = 28) and a non-SIRS group (n = 10) in a variety of age groups and correlated with APACHE II scores. RESULTS: 80% had circulating IL-6 levels (median 46.7 pg/ml, range 4.6-27,000) and 60% had circulating IL-10 levels (median 15.5 pg/ml, range 2.5-765). Concentrations of both were significantly increased in patients with SIRS compared with non-SIRS patients. Those with activation of the inflammatory cytokine cascade (IL-6 positive) produced more IL-10 than IL-6 negative patients. Older patients had a similar cytokine response. Both cytokines correlated positively with APACHE II scores. CONCLUSIONS: This is the first demonstration of circulating IL-10 in CAP. A greater counter-inflammatory response in patients with SIRS and in IL-6 positive patients suggests a potential immunomodulatory role for IL-10 in controlling the inflammatory cytokine response in CAP. IL-10 concentrations correlate with severity of illness in CAP and may be of prognostic importance. There is no age related impairment in the cytokine response.

Effect of growth hormone on human alveolar macrophage oxidative metabolism.

BACKGROUND: Growth hormone (GH) has diverse immunological actions and has been shown to augment oxidative metabolism in rat peritoneal and porcine alveolar macrophages and both human and animal neutrophils. A study was performed to determine the effects of GH on human alveolar macrophages in vitro. METHODS: Macrophages were harvested from 10 patients undergoing bronchoalveolar lavage and incubated with 0, 10 and 100 nmol/ml GH for four hours. Oxidative metabolism was assessed by means of a fluorescent assay using FMLP and E coli as stimulants. Fluorescence was measured using flow cytometry. RESULTS: No difference in basal or stimulated oxidative metabolism was found between the GH and control groups. CONCLUSIONS: GH does not have a direct stimulatory action on human alveolar macrophages in vitro. However, this does not exclude an indirect effect in vivo. The results contrast with previous studies on animal alveolar macrophages.

[Dysphonia and inhalation of corticoids: a prospective study]. / La dysphonie et l'inhalation des corticoides: une étude prospective.

Dysphonia or hoarseness is a well recognised but poorly understood complication of inhaled steroid therapy. 20 asthmatics were investigated, using a perceptual rating score of hoarseness, videolaryngoscopy and videostroboscopy, prior to and after three months of high dose inhaled steroid therapy (1 mg/day). A group of 22 healthy volunteers acted as controls. Prior to commencing inhaled steroid therapy six of the asthmatics were hoarse. Erythema and oedema was noted in 10 asthmatics and vocal fold nodules in 2 asthmatics. 4 of the control group had erythema and oedema. There was significantly more vocal fold pathology in the asthmatic group, p = 0.0135. After three months of inhaled steroid therapy, improvement in voice was noted in 2 of the 6 hoarse asthmatics. This was associated with resolution of vocal fold nodules in one case and with resolution of oedema in another. One asthmatic developed a mid glottic chink. This study demonstrates that asthmatics have significantly more vocal fold pathology than healthy controls. These findings improve with commencement of inhaled steroid therapy. The development of steroid induced myopathy of the vocal folds is a possible cause for the development of a mid glottic chink in one of our subjects. Further studies are necessary to investigate this area further.

United States radiation safety and regulatory considerations for radiofrequency hyperthermia systems.

The control of Radiofrequency (RF) radiation (including microwave radiation) that is emitted by therapeutic medical devices is the responsibility of the Food and Drug Administration's (FDA) Bureau of Radiological Health (BRH). Several studies of RF emissions from various shortwave (27 MHz) and microwave (2450 MHz) diathermy devices have been conducted by the Electromagnetics Branch of the Bureau's Division of Electronic Products. BRH studies have led to a proposed standard for microwave diathermy devices operating above 900 MHz. Shortwave diathermy devices used in physical therapy situations have been found to produce relatively high levels of unintended exposures (sometimes exceeding present U.S. exposure standards) to device operators and to the nonprescribed tissues of the patient. BRH is initiating further studies to ascertain the need for controls to be placed on these shortwave devices to ensure safety and medical effectiveness. Radiation safety standards, which presently exist in the United States, allow much higher unintended human exposures than do the standards existing in the several eastern European countries. A trend to lower permissible exposures to 5 mW/cm2 or even 1 mW/cm2 is under way in the U.S. The various provisions of FDA's Medical Device regulations apply to investigational as well as commercially-marketed RF/microwave devices and require both safety and medical effectiveness aspects of performance to be addressed by their manufacturer. A set of microwave radiation safety considerations has been developed by BRH for newly emerging cancer therapy protocols which utilize microwave hyperthermia devices.