The Role of Biomarkers in the Diagnosis and Management of Pneumonia.

Biomarkers are used in the diagnosis, severity determination, and prognosis for patients with community-acquired pneumonia (CAP). Selected biomarkers may indicate a bacterial infection and need for antibiotic therapy (C-reactive protein, procalcitonin, soluble triggering receptor expressed on myeloid cells). Biomarkers can differentiate CAP patients who require hospital admission and severe CAP requiring intensive care unit admission. Biomarker-guided antibiotic therapy may limit antibiotic exposure without compromising outcome and thus improve antibiotic stewardship. The authors discuss the role of biomarkers in diagnosing, determining severity, defining the prognosis, and limiting antibiotic exposure in CAP and ventilator-associated pneumonia patients.

2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia.

RATIONALE: New evidence is available examining the use of corticosteroids in sepsis, acute respiratory distress syndrome (ARDS) and community-acquired pneumonia (CAP), warranting a focused update of the 2017 guideline on critical illness-related corticosteroid insufficiency. OBJECTIVES: To develop evidence-based recommendations for use of corticosteroids in hospitalized adults and children with sepsis, ARDS, and CAP. PANEL DESIGN: The 22-member panel included diverse representation from medicine, including adult and pediatric intensivists, pulmonologists, endocrinologists, nurses, pharmacists, and clinician-methodologists with expertise in developing evidence-based Clinical Practice Guidelines. We followed Society of Critical Care Medicine conflict of interest policies in all phases of the guideline development, including task force selection and voting. METHODS: After development of five focused Population, Intervention, Control, and Outcomes (PICO) questions, we conducted systematic reviews to identify the best available evidence addressing each question. We evaluated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation approach and formulated recommendations using the evidence-to-decision framework. RESULTS: In response to the five PICOs, the panel issued four recommendations addressing the use of corticosteroids in patients with sepsis, ARDS, and CAP. These included a conditional recommendation to administer corticosteroids for patients with septic shock and critically ill patients with ARDS and a strong recommendation for use in hospitalized patients with severe CAP. The panel also recommended against high dose/short duration administration of corticosteroids for septic shock. In response to the final PICO regarding type of corticosteroid molecule in ARDS, the panel was unable to provide specific recommendations addressing corticosteroid molecule, dose, and duration of therapy, based on currently available evidence. CONCLUSIONS: The panel provided updated recommendations based on current evidence to inform clinicians, patients, and other stakeholders on the use of corticosteroids for sepsis, ARDS, and CAP.

Respiratory Musculature Evaluated by Computed Tomography in the Setting of Prolonged Mechanical Ventilation.

BACKGROUND: Diaphragm atrophy has been observed in subjects who undergo invasive mechanical ventilation. We propose a new method to assess for respiratory muscle (RM) changes in subjects who undergo invasive mechanical ventilation by assessing for changes in respiratory muscles through computed tomography (CT). METHODS: A retrospective case series study was conducted on subjects who underwent invasive mechanical ventilation and received at least 2 chest CT scans during admission. Exclusion criteria included history of chronic mechanical ventilation dependence and neuromuscular disease. Respiratory muscle cross-sectional area (CSA) was measured at the T6 vertebrae. RESULTS: Fourteen subjects were included: mean (± SD) age, BMI, and admission APACHE II scores were 54.0 y (± 14.9), 32.6 kg/m2 (± 10.9), and 23.5 (± 6.0), respectively. Ten (71%) subjects were male. Mean length of time between CT chest scans was 7.5 d (± 3.3). Mean duration of invasive mechanical ventilation was 4.5 d (± 3.4). The percentage change in TM CSA among those who underwent invasive mechanical ventilation was 10.5% (± 6.1). CONCLUSIONS: We demonstrated that serial analysis of respiratory muscle CSA through CT chest scans can be a method to assess for respiratory muscle atrophy in subjects undergoing mechanical ventilation. Future prospective studies involving larger populations are needed to better understand how this method can be used to predict outcomes in mechanically ventilated patients.

Siglec-9 Restrains Antibody-Dependent Natural Killer Cell Cytotoxicity against SARS-CoV-2.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection alters the immunological profiles of natural killer (NK) cells. However, whether NK antiviral functions are impaired during severe coronavirus disease 2019 (COVID-19) and what host factors modulate these functions remain unclear. We found that NK cells from hospitalized COVID-19 patients degranulate less against SARS-CoV-2 antigen-expressing cells (in direct cytolytic and antibody-dependent cell cytotoxicity [ADCC] assays) than NK cells from mild COVID-19 patients or negative controls. The lower NK degranulation was associated with higher plasma levels of SARS-CoV-2 nucleocapsid antigen. Phenotypic and functional analyses showed that NK cells expressing the glyco-immune checkpoint Siglec-9 elicited higher ADCC than Siglec-9- NK cells. Consistently, Siglec-9+ NK cells exhibit an activated and mature phenotype with higher expression of CD16 (FcγRIII; mediator of ADCC), CD57 (maturation marker), and NKG2C (activating receptor), along with lower expression of the inhibitory receptor NKG2A, than Siglec-9- CD56dim NK cells. These data are consistent with the concept that the NK cell subpopulation expressing Siglec-9 is highly activated and cytotoxic. However, the Siglec-9 molecule itself is an inhibitory receptor that restrains NK cytotoxicity during cancer and other viral infections. Indeed, blocking Siglec-9 significantly enhanced the ADCC-mediated NK degranulation and lysis of SARS-CoV-2-antigen-positive target cells. These data support a model in which the Siglec-9+ CD56dim NK subpopulation is cytotoxic even while it is restrained by the inhibitory effects of Siglec-9. Alleviating the Siglec-9-mediated restriction on NK cytotoxicity may further improve NK immune surveillance and presents an opportunity to develop novel immunotherapeutic tools against SARS-CoV-2 infected cells. IMPORTANCE One mechanism that cancer cells use to evade natural killer cell immune surveillance is by expressing high levels of sialoglycans, which bind to Siglec-9, a glyco-immune checkpoint molecule on NK cells. This binding inhibits NK cell cytotoxicity. Several viruses, such as hepatitis B virus (HBV) and HIV, also use a similar mechanism to evade NK surveillance. We found that NK cells from SARS-CoV-2-hospitalized patients are less able to function against cells expressing SARS-CoV-2 Spike protein than NK cells from SARS-CoV-2 mild patients or uninfected controls. We also found that the cytotoxicity of the Siglec-9+ NK subpopulation is indeed restrained by the inhibitory nature of the Siglec-9 molecule and that blocking Siglec-9 can enhance the ability of NK cells to target cells expressing SARS-CoV-2 antigens. Our results suggest that a targetable glyco-immune checkpoint mechanism, Siglec-9/sialoglycan interaction, may contribute to the ability of SARS-CoV-2 to evade NK immune surveillance.

Evaluation of a Closed Suction System With Integrated Tube-Scraping Technology.

BACKGROUND: Endotracheal tube (ETT) scraping or sweeping refers to mucus removal from an ETT that can increase airway resistance. The study objective was to evaluate the effect of ETT scraping on the duration of mechanical ventilation, time to first successful spontaneous breathing trial (SBT), duration of hospital stay, and occurrence of ventilator-associated events (VAEs). METHODS: This was a single-center, randomized clinical trial of adult subjects intubated between October 2019-October 2021. Subjects were randomly assigned to either ETT suctioning via a standard in-line suction catheter (control group) or ETT suctioning and scraping via a suction catheter with balloon-sweeping technology (experimental group). Airway suctioning was performed as clinically indicated, and the ETT was scraped every time a respiratory therapist suctioned the subject. The study outcome was duration of mechanical ventilation, time to first successful SBT, hospital length of stay, and VAE rate. Intent-to-treat statistical analysis was performed. RESULTS: Of 272 randomized subjects, the median age was 63 (interquartile range [IQR] 52-73) y; 143 (53%) were males, and 154 (57%) had a primary diagnosis of acute respiratory failure. There were no significant differences between the groups in median duration (h) of mechanical ventilation (72 [37-187] vs 70.6 [37-148], P = .58). There was no significant difference between the study groups in median time (h) to the first successful SBT (46.7 [IQR 30-87] vs 45.7 [IQR 27-95], P = .81), length of hospital stay (P = .76), the incidences of ventilator-associated conditions (P = .13), or infection-related ventilator-associated complications (P = .47). CONCLUSIONS: ETT suctioning plus scraping, compared to ETT suctioning alone, did not significantly improve the duration of mechanical ventilation, time to first successful SBT, length of hospital stay, and VAEs. These study findings do not support the routine use of ETT scraping for mechanically ventilated patients.

Markers of fungal translocation are elevated during post-acute sequelae of SARS-CoV-2 and induce NF-κB signaling.

Long COVID, a type of post-acute sequelae of SARS-CoV-2 (PASC), has been associated with sustained elevated levels of immune activation and inflammation. However, the mechanisms that drive this inflammation remain unknown. Inflammation during acute coronavirus disease 2019 could be exacerbated by microbial translocation (from the gut and/or lung) to blood. Whether microbial translocation contributes to inflammation during PASC is unknown. We did not observe a significant elevation in plasma markers of bacterial translocation during PASC. However, we observed higher levels of fungal translocation - measured as ß-glucan, a fungal cell wall polysaccharide - in the plasma of individuals experiencing PASC compared with those without PASC or SARS-CoV-2-negative controls. The higher ß-glucan correlated with higher inflammation and elevated levels of host metabolites involved in activating N-methyl-d-aspartate receptors (such as metabolites within the tryptophan catabolism pathway) with established neurotoxic properties. Mechanistically, ß-glucan can directly induce inflammation by binding to myeloid cells (via Dectin-1) and activating Syk/NF-κB signaling. Using a Dectin-1/NF-κB reporter model, we found that plasma from individuals experiencing PASC induced higher NF-κB signaling compared with plasma from negative controls. This higher NF-κB signaling was abrogated by piceatannol (Syk inhibitor). These data suggest a potential targetable mechanism linking fungal translocation and inflammation during PASC.

Identification and Prevention of Extubation Failure by Using an Automated Continuous Monitoring Alert Versus Standard Care.

BACKGROUND: Postextubation monitoring helps identify patients at risk of developing respiratory failure. This study aimed to evaluate the effect of our standard respiratory therapist (RT) assessment tool versus an automated continuous monitoring alert to initiate postextubation RT-driven care on the re-intubation rate. METHODS: This was a single-center randomized clinical trial from March 2020 to September 2021 of adult subjects who received mechanical ventilation for > 24 h and underwent planned extubation in the ICU. The subjects were assigned to the standard RT assessment tool or an automated monitoring alert to identify the need for postextubation RT-driven care. The primary outcome was the need for re-intubation due to respiratory failure within 72 h. Secondary outcomes included re-intubation within 7 d, ICU and hospital lengths of stay, hospital mortality, ICU cost, and RT time associated with patient assessment and therapy provision. RESULTS: Of 234 randomized subjects, 32 were excluded from the primary analysis due to disruption in RT-driven care during the surge of patients with COVID-19, and 1 subject was excluded due to delay in the automated monitoring initiation. Analysis of the primary outcome included 85 subjects assigned to the standard RT assessment group and 116 assigned to the automated monitoring alert group to initiate RT-driven care. There was no significant difference between the study groups in re-intubation rate, median length of stay, mortality, or ICU costs. The RT time associated with patient assessment (P < .001) and therapy provided (P = .031) were significantly lower in the automated continuous monitoring alert group. CONCLUSIONS: In subjects who received mechanical ventilation for > 24 h, there were no significant outcome or cost differences between our standard RT assessment tool or an automated monitoring alert to initiate postextubation RT-driven care. Using an automated continuous monitoring alert to initiate RT-driven care saved RT time. (ClinicalTrials.gov registration NCT04231890).

Corrigendum: Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

[This corrects the article DOI: 10.3389/fimmu.2021.686240.].

Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients.

A disruption of the crosstalk between the gut and the lung has been implicated as a driver of severity during respiratory-related diseases. Lung injury causes systemic inflammation, which disrupts gut barrier integrity, increasing the permeability to gut microbes and their products. This exacerbates inflammation, resulting in positive feedback. We aimed to test whether severe Coronavirus disease 2019 (COVID-19) is associated with markers of disrupted gut permeability. We applied a multi-omic systems biology approach to analyze plasma samples from COVID-19 patients with varying disease severity and SARS-CoV-2 negative controls. We investigated the potential links between plasma markers of gut barrier integrity, microbial translocation, systemic inflammation, metabolome, lipidome, and glycome, and COVID-19 severity. We found that severe COVID-19 is associated with high levels of markers of tight junction permeability and translocation of bacterial and fungal products into the blood. These markers of disrupted intestinal barrier integrity and microbial translocation correlate strongly with higher levels of markers of systemic inflammation and immune activation, lower levels of markers of intestinal function, disrupted plasma metabolome and glycome, and higher mortality rate. Our study highlights an underappreciated factor with significant clinical implications, disruption in gut functions, as a potential force that may contribute to COVID-19 severity.

Early Identification of Extubation Failure Using Integrated Pulmonary Index and High-Risk Factors.

BACKGROUND: Early detection and prevention of extubation failure offers the potential to improve patient outcome. The primary aim of this study was to compare the predictive ability of the Integrated Pulmonary Index and presence of high-risk factors in determining extubation failure. METHODS: A retrospective cross-sectional study of intubated adult subjects receiving mechanical ventilation for > 24 h was conducted at an academic medical center. The primary outcome was extubation failure, defined as the need for re-intubation or rescue noninvasive ventilation within 48 h after planned extubation. RESULTS: Among 216 subjects, 170 (78.7%) were successfully extubated, and 46 (21.3%) failed extubation. Extubation failure group had higher body mass index (26.21 vs 28.5 kg/m2, P = .033), rapid shallow breathing index during spontaneous breathing trial (43 vs 53.5, P = .02), and APACHE II score (11.86 vs 15.73, P < .001). Presence of ≥3 high-risk factors (odds ratio 3.11 [95% CI 1.32-7.31], P = .009), APACHE II > 12 on extubation day (odds ratio 2.98 [95% CI 1.22-7.27], P = .02), and Integrated Pulmonary Index decrease within 1 h after extubation (odds ratio 7.74 [95% CI 3.45-17.38], P < .001) were independently associated with extubation failure. The failed extubation group had higher ICU mortality (8.8% vs 19.6%; absolute difference 10.7% [95% CI -1.9% to 23.4%], P = .040) and hospital mortality (10% vs 22%; absolute difference 16.1% [95% CI 2.2-30%], P = .005) compared to the successful group. CONCLUSIONS: Among subjects receiving mechanical ventilation for > 24 h, decreasing Integrated Pulmonary Index within the first hour postextubation was a predictor of extubation failure and was superior to other weaning variables collected in this retrospective study. The presence of ≥ 3 high-risk factors was also independently associated with extubation failure. Future clinical studies are required to prospectively test the ability of postextubation Integrated Pulmonary Index monitoring to guide additional interventions designed to reduce re-intubation rates and improve patient outcome.

Novel application of respiratory muscle index obtained from chest computed tomography to predict postoperative respiratory failure after major non-cardiothoracic surgery.

BACKGROUND: Postoperative respiratory failure (PRF) is a serious complication associated with significant morbidity and mortality. We propose a new method to predict PRF by utilizing computed tomography (CT) of the chest to assess degree of respiratory muscle wasting prior to surgery. METHODS: Patients who received a chest CT and required invasive mechanical ventilation (MV) after major non-cardiothoracic surgery were included. Exclusion criteria included cardiothoracic surgery. Respiratory muscle index (RMI) was calculated at the T6 vertebra measured on Slice-O-Matic® software. RESULTS: Thirty three patients met inclusion with a mean (±SD) age, BMI, and APACHE II score of 62.2 years (±12.1), 28.1 kg/m2 (±7.8), and 14.1 (±4.7). Most patients were female (n = 22 [67%]). Eleven patients (33%) developed PRF with a mean of 6.0 (±10.7) initial ventilation days. There was no difference in baseline demographics between groups. RMI values for the PRF group were significantly lower when compared to the non-PRF group: 22.7 cm2/m2 (±5.3) vs. 28.5 cm2/m2 (±5.9) (p = 0.008). CONCLUSION: Presence of respiratory muscle wasting prior to surgery was found to be associated with postoperative respiratory failure.

COVID-19 Severity Is Associated with Differential Antibody Fc-Mediated Innate Immune Functions.

Beyond neutralization, antibodies binding to their Fc receptors elicit several innate immune functions including antibody-dependent complement deposition (ADCD), antibody-dependent cell-mediated phagocytosis (ADCP), and antibody-dependent cell-mediated cytotoxicity (ADCC). These functions are beneficial, as they contribute to pathogen clearance; however, they also can induce inflammation. We tested the possibility that qualitative differences in SARS-CoV-2-specific antibody-mediated innate immune functions contribute to coronavirus disease 2019 (COVID-19) severity. We found that anti-S1 and anti-RBD antibodies from hospitalized COVID-19 patients elicited higher ADCD but lower ADCP compared to antibodies from nonhospitalized COVID-19 patients. Consistently, higher ADCD was associated with higher systemic inflammation, whereas higher ADCP was associated with lower systemic inflammation during COVID-19. Our study points to qualitative, differential features of anti-SARS-CoV-2 specific antibodies as potential contributors to COVID-19 severity. Understanding these qualitative features of natural and vaccine-induced antibodies will be important in achieving optimal efficacy and safety of SARS-CoV-2 vaccines and/or COVID-19 therapeutics.IMPORTANCE A state of hyperinflammation and increased complement activation has been associated with coronavirus disease 2019 (COVID-19) severity. However, the pathophysiological mechanisms that contribute to this phenomenon remain mostly unknown. Our data point to a qualitative, rather than quantitative, difference in SARS-CoV-2-specific antibodies' ability to elicit Fc-mediated innate immune functions as a potential contributor to COVID-19 severity and associated inflammation. These data highlight the need for further studies to understand these qualitative features and their potential contribution to COVID-19 severity. This understanding could be essential to develop antibody-based COVID-19 therapeutics and SARS-CoV-2 vaccines with an optimal balance between efficacy and safety.

The Association of an Alpha-2 Adrenergic Receptor Agonist and Mortality in Patients With COVID-19.

There is a need for treatments to reduce coronavirus disease 2019 (COVID-19) mortality. Alpha-2 adrenergic receptor (α2 AR) agonists can dampen immune cell and inflammatory responses as well as improve oxygenation through physiologic respiratory parameters. Therefore, α2 AR agonists may be effective in reducing mortality related to hyperinflammation and acute respiratory failure in COVID-19. Dexmedetomidine (DEX) is an α2 AR agonist used for sedation. We performed a retrospective analysis of adults at Rush University System for Health hospitals between March 1, 2020 and July 30, 2020 with COVID-19 requiring invasive mechanical ventilation and sedation (n = 214). We evaluated the association of DEX use and 28-day mortality from time of intubation. Overall, 28-day mortality in the cohort receiving DEX was 27.0% as compared to 64.5% in the cohort that did not receive DEX (relative risk reduction 58.2%; 95% CI 42.4-69.6). Use of DEX was associated with reduced 28-day mortality on multivariable Cox regression analysis (aHR 0.19; 95% CI 0.10-0.33; p < 0.001). Adjusting for time-varying exposure to DEX also demonstrated that DEX was associated with reduced 28-day mortality (aHR 0.51; 95% CI 0.28-0.95; p = 0.03). Earlier DEX use, initiated <3.4 days from intubation, was associated with reduced 28-day mortality (aHR 0.25; 95% CI 0.13-0.50; p < 0.001) while later DEX use was not (aHR 0.64; 95% CI 0.27-1.50; p = 0.30). These results suggest an α2 AR agonist might reduce mortality in patients with COVID-19. Randomized controlled trials are needed to confirm this observation.

The Role of Interleukin-8 in Lung Inflammation and Injury: Implications for the Management of COVID-19 and Hyperinflammatory Acute Respiratory Distress Syndrome.

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS CoV-2) has resulted in the global spread of Coronavirus Disease 2019 (COVID-19) and an increase in complications including Acute Respiratory Distress Syndrome (ARDS). Due to the lack of therapeutic options for Acute Respiratory Distress Syndrome, recent attention has focused on differentiating hyper- and hypo-inflammatory phenotypes of ARDS to help define effective therapeutic strategies. Interleukin 8 (IL-8) is a pro-inflammatory cytokine that has a role in neutrophil activation and has been identified within the pathogenesis and progression of this disease. The aim of this review is to highlight the role of IL-8 as a biomarker and prognostic factor in modulating the hyperinflammatory response in ARDS. The crucial role of IL-8 in lung inflammation and disease pathogenesis might suggest IL-8 as a possible new therapeutic target to efficiently modulate the hyperinflammatory response in ARDS.

Extracorporeal membrane oxygenation in the management of granulomatosis with polyangiitis.

Granulomatosis with polyangiitis (GPA, also known as Wegener's granulomatosis) is a type of systematic vasculitis that primarily involves the lung and kidney. Diffuse alveolar hemorrhage (DAH) and associated acute respiratory failure are uncommon but devastating complications of GPA. Experience in using extracorporeal membrane oxygenation (ECMO) to manage DAH caused by GPA is limited. We report two GPA patients with DAH that were successfully managed using ECMO support. Examining 13 cases identified in the literature and two of our own, we observed that most patients experienced rapid deterioration in respiratory function in conjunction with a precedent respiratory infection. All 15 patients received veno-venous ECMO support. The median duration of ECMO support was 11 days (interquartile range: 7.5-20.75 days). Bleeding was the most common complication, seen in four (26.7%) cases. All patients were successfully weaned off ECMO after a median length of hospital stay of 42 days (interquartile range: 30-78 days). We demonstrated that the use of ECMO is a reasonable and effective support option in the management of GPA patients with DAH. The risk of bleeding is high but maybe reduced using a lower anticoagulation goal.

Sound transmission in human thorax through airway insonification: an experimental and computational study with diagnostic applications.

Pulmonary diseases and injury lead to structural and functional changes in the lung parenchyma and airways, often resulting in measurable sound transmission changes on the chest wall surface. Additionally, noninvasive imaging of externally driven mechanical wave motion in the chest (e.g., using magnetic resonance elastography) can provide information about lung stiffness and other structural property changes which may be of diagnostic value. In the present study, a comprehensive computational simulation (in silico) model was developed to simulate sound wave propagation in the airways, parenchyma, and chest wall under normal and pathological conditions that create distributed structural (e.g., pneumothoraces) and diffuse material (e.g., fibrosis) changes, as well as a localized structural and material changes as may be seen with a neoplasm. Experiments were carried out in normal subjects to validate the baseline model. Sound waves with frequency content from 50 to 600 Hz were introduced into the airways of three healthy human subjects through the mouth, and transthoracic transmitted waves were measured by scanning laser Doppler vibrometry at the chest wall surface. The computational model predictions of a frequency-dependent decreased sound transmission due to pneumothorax were consistent with experimental measurements reported in previous work. Predictions for the case of fibrosis show that while shear wave motion is altered, changes to compression wave propagation are negligible, and thus, insonification, which primarily drives compression waves, is not ideal to detect the presence of fibrosis. Results from the numerical simulation of a tumor show an increase in the wavelength of propagating waves in the immediate vicinity of the tumor region. Graphical abstract.

Role of Antithrombin III and Tissue Factor Pathway in the Pathogenesis of Sepsis.

The pathobiology of the septic process includes a complex interrelationship between inflammation and the coagulations system. Antithrombin (AT) and tissue factor are important components of the coagulation system and have potential roles in the production and amplification of sepsis. Sepsis is associated with a decrease in AT levels, and low levels are also associated with the development of multiple organ failure and death. Treatment strategies incorporating AT replacement therapy in sepsis and septic shock have not resulted in an improvement in survival or reversal of disseminated intravascular coagulation.