Evidence associating neutrophilia, lung damage, hyperlactatemia, blood acidosis, impaired oxygen transport, and mortality in critically ill COVID-19 patients (preprint)

Background: COVID-19 severity and high in-hospital mortality are often associated with severe hypoxemia, hyperlactatemia, and acidosis. Since neutrophil numbers in severe COVID-19 can exceed 80% of the total circulating leukocytes and that they are massively recruited to infected lungs, we investigated whether metabolic acidosis mediated by the glycolytic neutrophils is associated with lung damage and impaired oxygen delivery in critically ill patients. Methods: Based on prospective mortality outcome, 102 critically ill-hospitalized COVID-19 patients were divided into two groups: ICU-Survivors (ICU-S, n=36) and ICU-Non-survivors (ICU-NS, n=66). Blood samples were collected from patients and control subjects to explore correlations between neutrophil counts, lung damage, glycolysis, blood lactate, blood pH, hemoglobin oxygen saturation, and mortality outcome. We also interrogated isolated neutrophils for glycolytic activities and for apoptosis using high-throughput fluorescence imaging complemented with transcriptomic analyses. Stratified survival analyses were conducted to estimate mortality risk associated with higher lactate among predefined subgroups. Results: Neutrophil counts were consistently higher in critically ill patients while exhibiting remarkably lower apoptosis. Transcriptomic analysis revealed miRNAs associated with downregulation of genes involved in neutrophils apoptosis. Both CT lung damage scores and neutrophil counts predicted mortality. Severinghaus fitting of hemoglobin oxygen saturation curve revealed a right-shift indicating lower oxygen capacity in non-survivors, which is consistent with lower blood-pH observed in the same group. Levels of blood lactate were increased in patients but significantly more in the ICU-NS relative to the control group. ROC analysis followed by Kaplan-Meyer survival analysis stratified to the obtained cut-off values showed that CT damage scores, neutrophil counts, and lactate levels are predictors of mortality within 15 days following blood collection. Conclusion: The current results implicate neutrophilia as a potential player in metabolic acidosis and deranged oxygen delivery associating SARS-CoV-2 infection thus contributing to mortality outcome.

Follow-Up In Patients With Respiratory Disability After ARDS Related To COVID-19: A Systematic Review (preprint)

Introduction: Acute Respiratory Distress Syndrome (ARDS) is an acute inflammatory pulmonary process that leads to protein-rich, non-hydrostatic pulmonary edema, undesirable hypoxemia, and lung stiffness. Due to COVID-19, a significant proportion of people who will require hospitalization to treat COVID-19, between 15%-30%, will develop severe respiratory failure, ARDS, and an increased likelihood of intubation for mechanical respiratory support. Aim: To investigate the pulmonary function in COVID-19-related ARDS survivors after hospitalization. Methods: A search was performed on the Greek and international literature, as well as at the online Databases PubMed, Cochrane, Embase, and Google Scholar. Exclusion and integration criteria were set for the studies found, and a flow chart was created for the studies included. Results: Through the search, 352 articles were found matching the subject under study, and after further evaluation, four articles were included. The majority of the articles highlight that after ARDS occurs due to COVID-19, patients face impaired pulmonary function in combination with other physical and psychological symptoms like weakness, anxiety, depression, and generalized functional disability. Conclusions: It is a fact that COVID-19 disease, in severe form and following the need for hospitalization due to the development of ARDS, results in an increased likelihood of prolonged occurrence of some symptoms of impaired respiratory function. Impaired CO2 diffusion is observed in the majority of studies as well as impaired respiratory function regarding prolonged imaging findings and impaired physical function. Keywords: ARDS, SARS-CoV-2, ICU, COVID-19, follow up, respiratory function

Effects of COVID-19 infection in patients with autoimmune pulmonary alveolar proteinosis: a single-center study (preprint)

Background:Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare interstitial lung disease. COVID-19 is associated with worse prognosis in previous lung diseases patients. But the prognosis of aPAP patients after infection with COVID-19 is unclear. In December 2022, China experienced a large-scale outbreak of Omicron variant of the SARS-CoV-2. In this study, we aim to explore the clinical outcomes of aPAP patients infected with COVID-19. Results: A total of 39 aPAP patients were included in this study. 30.77% patients had a decrease in oxygen saturation after COVID-19 infection. We compared the two groups of patients with or without decreased oxygen saturation after COVID-19 infection and found that patients who had previous oxygen therapy (decreased oxygen saturation vs. non decreased oxygen saturation: 6/12 vs. 4/27, P = 0.043), with lower baseline arterial oxygen partial pressure (74.50 ± 13.61 mmHg vs. 86.49 ± 11.92 mmHg, P = 0.009), lower baseline DLCO/VA% [77.0 (74.3, 93.6) % vs. 89.5 (78.2, 97.4) %, P = 0.036], shorter baseline 6MWD [464 (406, 538) m vs. 532 (470, 575) m, P = 0.028], higher disease severity score (P = 0.017), were more likely to have decreased oxygen saturation after COVID-19 infection. Conclusion: aPAP patients with poor baseline respiration have a higher probability of hypoxia after COVID-19 infection, but fatal events were rare.

Sports despite masks: No negative effects of FFP2 face masks on cardiopulmonary exercise capacity in children (preprint)

Introduction: Face masks were recognized as one of the most effective ways for preventing the spread of the COVID-19-virus in adults, the benefits of wearing those were extended to children and adolescents and led to limited physical education (PE) lessons or cancellation of them. This further decreased the amount of physical activity available to children and adolescents during the pandemic. However, there is little published data on the potential adverse effects on wearing the most effective and partially mandatory FFP2/N95 face-masks during PE or physical activity (PA) in this age. Even though the pandemic has been declared as passed by the WHO, the rise of a new pandemic and thus the use of face-masks for limiting its spread is inevitable, so we need to be prepared in a better way for alternative options to lockdown and limitation of PA in such a scenario.Material and Methods 20 healthy children aged 8–10 years performed two identical cardiopulmonary exercise tests as an incremental step test on a treadmill within an interval of two weeks, one time without wearing a protective mask and one time wearing a FFP2 mask. The cardiopulmonary exercise parameter and especially the endexpiratory gas exchange for oxygen and carbon dioxide (petO2 and petCO2) were documented for each step, at rest and 1 minute after reaching physical exhaustion.Results 12 boys (mean age 8.5 ± 1.4 years) and 8 girls (mean age 8.8 ± 1.4 years) showed no adverse events until maximal exertion. The mean parameters measured at peak exercise did not differ significantly between both examinations (mean Peak VO2 = 42.7 ± 9.5 vs 47.8 ± 12.9 ml/min/kg, mean O2pulse 7.84 ± 1.9 ml/min vs. 6.89 ± 1.8, mean VE/VCO2slope 33.4 ± 5.9 vs. 34.0 ± 5.3). The most significant difference was the respiratory exchange rate (RER, 1.01 ± 0.08 vs 0.95 ± 0.08). The measured respiratory gases (end tidal O2 and CO2) decreased respectively increased significantly into nearly each step wearing an additional FFP2-mask without reaching levels of hypercapnia or hypoxia.Conclusion In this study, no significant differences of the cardiorespiratory function at peak exercise could be discerned when wearing a FFP2/N95 face mask. While the end-tidal values for CO2 increased significantly and the end-tidal values for O2 decreased significantly, these values did never reach pathological levels. Furthermore, the children terminated the exercise at a lower RER and heart rate (HR) suggesting a subconscious awareness of the higher strain. Since the detrimental effects of limiting sports during the pandemic are well documented, stopping PE lessons altogether because of the minor physiological effects wearing these masks instead of simply stopping pushing children to perform at their best seems premature and should be reconsidered in the future.

HCG18, LEF1AS1 and lncCEACAM21 as biomarkers of disease severity in the Peripheral Blood Mononuclear Cells of COVID-19 patients (preprint)

Background Even after 3 years from SARS-CoV-2 identification, COVID-19 is still a persistent and dangerous global infectious disease. Significant improvements in our understanding of the disease pathophysiology have now been achieved. Nonetheless, reliable and accurate biomarkers for the early stratification of COVID-19 severity are still lacking. Long noncoding RNAs (LncRNAs) are ncRNAs longer than 200 nucleotides, regulating the transcription and translation of protein‐coding genes and they can be found in the peripheral blood, thus holding a promising biomarker potential. Specifically, peripheral blood mononuclear cells (PBMCs) have emerged as a source of indirect biomarkers mirroring the conditions of tissues: they include monocytes, B and T lymphocytes, and natural killer T cells (NKT), being highly informative for immune-related events. Methods We profiled by RNA-Sequencing a panel of 2,906 lncRNAs to investigate their modulation in PBMCs of a pilot group of COVID-19 patients, followed by qPCR validation in 111 hospitalized COVID-19 patients. Results The levels of four lncRNAs were found to be decreased in association with COVID-19 mortality and disease severity: HLA Complex Group 18-242 and -244 (HCG18-242 and HCG18-244), Lymphoid Enhancer Binding Factor 1-antisense 1 (LEF1-AS1) and lncCEACAM21 (i.e. ENST00000601116.5, a lncRNA in the CEACAM21 locus). Interestingly, these deregulations were confirmed in an independent patient group of hospitalized patients and by the re-analysis of publicly available single-cell transcriptome datasets. The identified lncRNAs were expressed in all of the PBMC cell types and inversely correlated with the neutrophil/lymphocyte ratio (NLR), an inflammatory marker. In vitro, the expression of LEF1-AS1 and lncCEACAM21 was decreased upon THP-1 monocytes exposure to a relevant stimulus, hypoxia. Conclusion The identified COVID-19-lncRNAs are proposed as potential innovative biomarkers of COVID-19 severity and mortality.

Oximetry at admission as a predictor of tomographic and functional impairment after 3-6 months in hospitalized patients with COVID-19.

OBJECTIVE: To investigate characteristics that may be associated with radiologic and functional findings following discharge in patients with severe coronavirus disease 2019 (COVID-19). METHODS: This single-center, prospective, observational cohort study comprised patients aged >18 years who were hospitalized with COVID-19 pneumonia, between May and October 2020. After 3 to 6 months of discharge, patients were clinically evaluated and underwent spirometry, a 6-minute walk test (6MWT), and chest computed tomography (CT). Statistical analysis was performed using association and correlation tests. RESULTS: A total of 134 patients were included (25/114 [22%] were admitted with severe hypoxemia). On the follow-up chest CT, 29/92 (32%) had no abnormalities, regardless of the severity of the initial involvement, and the mean 6MWT distance was 447 m. Patients with desaturation on admission had an increased risk of remaining CT abnormalities: patients with SpO2 between 88 and 92% had a 4.0-fold risk, and those with SpO2 < 88% had a 6.2-fold risk. The group with SpO2 < 88% also walked shorter distances than patients with SpO2 between 88 and 92%. CONCLUSION: Initial hypoxemia was found to be a good predictor of persistent radiological abnormalities in follow-up and was associated with low performance in 6MWT.

Chronic airway epithelial hypoxia exacerbates injury in muco-obstructive lung disease through mucus hyperconcentration.

Unlike solid organs, human airway epithelia derive their oxygen from inspired air rather than the vasculature. Many pulmonary diseases are associated with intraluminal airway obstruction caused by aspirated foreign bodies, virus infection, tumors, or mucus plugs intrinsic to airway disease, including cystic fibrosis (CF). Consistent with requirements for luminal O2, airway epithelia surrounding mucus plugs in chronic obstructive pulmonary disease (COPD) lungs are hypoxic. Despite these observations, the effects of chronic hypoxia (CH) on airway epithelial host defense functions relevant to pulmonary disease have not been investigated. Molecular characterization of resected human lungs from individuals with a spectrum of muco-obstructive lung diseases (MOLDs) or COVID-19 identified molecular features of chronic hypoxia, including increased EGLN3 expression, in epithelia lining mucus-obstructed airways. In vitro experiments using cultured chronically hypoxic airway epithelia revealed conversion to a glycolytic metabolic state with maintenance of cellular architecture. Chronically hypoxic airway epithelia unexpectedly exhibited increased MUC5B mucin production and increased transepithelial Na+ and fluid absorption mediated by HIF1α/HIF2α-dependent up-regulation of ß and γENaC (epithelial Na+ channel) subunit expression. The combination of increased Na+ absorption and MUC5B production generated hyperconcentrated mucus predicted to perpetuate obstruction. Single-cell and bulk RNA sequencing analyses of chronically hypoxic cultured airway epithelia revealed transcriptional changes involved in airway wall remodeling, destruction, and angiogenesis. These results were confirmed by RNA-in situ hybridization studies of lungs from individuals with MOLD. Our data suggest that chronic airway epithelial hypoxia may be central to the pathogenesis of persistent mucus accumulation in MOLDs and associated airway wall damage.

Pathophysiological mechanisms and therapeutic approaches in obstructive sleep apnea syndrome.

Obstructive sleep apnea syndrome (OSAS) is a common breathing disorder in sleep in which the airways narrow or collapse during sleep, causing obstructive sleep apnea. The prevalence of OSAS continues to rise worldwide, particularly in middle-aged and elderly individuals. The mechanism of upper airway collapse is incompletely understood but is associated with several factors, including obesity, craniofacial changes, altered muscle function in the upper airway, pharyngeal neuropathy, and fluid shifts to the neck. The main characteristics of OSAS are recurrent pauses in respiration, which lead to intermittent hypoxia (IH) and hypercapnia, accompanied by blood oxygen desaturation and arousal during sleep, which sharply increases the risk of several diseases. This paper first briefly describes the epidemiology, incidence, and pathophysiological mechanisms of OSAS. Next, the alterations in relevant signaling pathways induced by IH are systematically reviewed and discussed. For example, IH can induce gut microbiota (GM) dysbiosis, impair the intestinal barrier, and alter intestinal metabolites. These mechanisms ultimately lead to secondary oxidative stress, systemic inflammation, and sympathetic activation. We then summarize the effects of IH on disease pathogenesis, including cardiocerebrovascular disorders, neurological disorders, metabolic diseases, cancer, reproductive disorders, and COVID-19. Finally, different therapeutic strategies for OSAS caused by different causes are proposed. Multidisciplinary approaches and shared decision-making are necessary for the successful treatment of OSAS in the future, but more randomized controlled trials are needed for further evaluation to define what treatments are best for specific OSAS patients.

Single-cell RNA sequencing reveals HIF1A as a severity-sensitive immunological scar in circulating monocytes of convalescent comorbidity-free COVID-19 patients (preprint)

COVID-19, caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is characterized by a wide range of clinical symptoms and a poorly predictable disease course. Although in-depth transcriptomic investigations of peripheral blood samples from COVID-19 patients have been performed, the detailed molecular mechanisms underlying an asymptomatic, mild or severe disease course, particularly in patients without relevant comorbidities, remain poorly understood. While previous studies have mainly focused on the cellular and molecular dissection of ongoing COVID-19, we set out to characterize transcriptomic immune cell dysregulation at the single-cell level at different time points in patients without comorbidities after disease resolution to identify signatures of different disease severities in convalescence. With single-cell RNA sequencing we reveal a role for hypoxia-inducible factor 1-alpha (HIF1A) as a severity-sensitive long-term immunological scar in circulating monocytes of convalescent COVID-19 patients. Additionally, circulating complexes formed by monocytes with either T cells or NK cells represent a characteristic cellular marker in convalescent COVID-19 patients irrespective of their preceding symptom severity. Together, these results provide cellular and molecular correlates of recovery from COVID-19 and could help in immune monitoring and in the design of new treatment strategies.

Influence of N95 Mask-related Hypoxemia on Headache, Stress, Anxiety, and Quality of Sleep during COVID-19 Patient Care among Frontline Health Care Professionals.

BACKGROUND: Prolonged use of N95 masks by healthcare workers might affect physical health due to mask-related hypoxia in addition to the psychological effects of N95 masks. We tried to explore the association of N95 mask-related hypoxia and headache with stress, quality of sleep, and anxiety in the current study. MATERIALS AND METHODS: The sample (N = 78) consisted of 41 doctors and 37 nurses involved in COVID-19 patient care and using N95 masks with or without PPE for at least 4 hours. Perceived stress scale (PSS), Coronavirus anxiety scale (CAS), and Pittsburgh sleep quality index (PSQI) were administered, and physical parameters like heart rate and oxygen saturation (SpO2) were measured. RESULTS: Around 42% of the study participants experienced headaches after wearing an N95 mask and had a higher increase in heart rate (mean percent:10.5% vs 6.3%) and decline in SpO2 (mean percent: 2.6% vs 1.5%) compared to those who didn't develop a headache after N95 mask use. Independent samples t-test showed a mean difference for PSS and CAS between those who experienced headaches and those who didn't. The mean PSQI scores among the study participants were 8.91 ± 5.78; the score among those participants with and without headache was 10.57 ± 3.11 and 7.68 ± 2.53, respectively. CONCLUSION: Perceived corona anxiety, poor sleep quality, and corona anxiety are associated with N95-related headaches and SpO2 drop among health professionals who wear N95 masks for at least 4 hours.

Respiratory support with nasal high flow without supplemental oxygen in patients undergoing endoscopic retrograde cholangiopancreatography under moderate sedation: a prospective, randomized, single-center clinical trial.

BACKGROUND: Nasal high flow (NHF) may reduce hypoxia and hypercapnia during an endoscopic retrograde cholangiopancreatography (ERCP) procedure under sedation. The authors tested a hypothesis that NHF with room air during ERCP may prevent intraoperative hypercapnia and hypoxemia. METHODS: In the prospective, open-label, single-center, clinical trial, 75 patients undergoing ERCP performed with moderate sedation were randomized to receive NHF with room air (40 to 60 L/min, n = 37) or low-flow O2 via a nasal cannula (1 to 2 L/min, n = 38) during the procedure. Transcutaneous CO2, peripheral arterial O2 saturation, a dose of administered sedative and analgesics were measured. RESULTS: The primary outcome was the incidence of marked hypercapnia during an ERCP procedure under sedation observed in 1 patient (2.7%) in the NHF group and in 7 patients (18.4%) in the LFO group; statistical significance was found in the risk difference (-15.7%, 95% CI -29.1 - -2.4, p = 0.021) but not in the risk ratio (0.15, 95% CI 0.02 - 1.13, p = 0.066). In secondary outcome analysis, the mean time-weighted total PtcCO2 was 47.2 mmHg in the NHF group and 48.2 mmHg in the LFO group, with no significant difference (-0.97, 95% CI -3.35 - 1.41, p = 0.421). The duration of hypercapnia did not differ markedly between the two groups either [median (range) in the NHF group: 7 (0 - 99); median (range) in the LFO group: 14.5 (0 - 206); p = 0.313] and the occurrence of hypoxemia during an ERCP procedure under sedation was observed in 3 patients (8.1%) in the NHF group and 2 patients (5.3%) in the LFO group, with no significant difference (p = 0.674). CONCLUSIONS: Respiratory support by NHF with room air did not reduce marked hypercapnia during ERCP under sedation relative to LFO. There was no significant difference in the occurrence of hypoxemia between the groups that may indicate an improvement of gas exchanges by NHF. TRIAL REGISTRATION: jRCTs072190021 . The full date of first registration on jRCT: August 26, 2019.

A case series evaluating the effect of esmolol therapy to treat hypoxemia in COVID-19 patients on VV-ECMO.

When COVID-19 ARDS abolishes pulmonary function, VV-ECMO can provide gas exchange. If oxygenation remains insufficient despite maximal VV-ECMO support, the addition of esmolol has been proposed. Conflict exists, however, as to the oxygenation level which should trigger beta-blocker initiation. We evaluated the effect of esmolol therapy on oxygenation and oxygen delivery in patients with negligible native lung function and various degrees of hypoxemia despite maximal VV-ECMO support. We found that, in COVID-19 patients with negligible pulmonary gas exchange, the generalized use of esmolol administration to raise arterial oxygenation by slowing heart rate and thereby match native cardiac output to maximal attainable VV ECMO flows actually reduces systemic oxygen delivery in many cases.

Brain hypoxia, neurocognitive impairment, and quality of life in people post-COVID-19.

OBJECTIVE: Systemic hypoxia occurs in COVID-19 infection; however, it is unknown if cerebral hypoxia occurs in convalescent individuals. We have evidence from other conditions associated with central nervous system inflammation that hypoxia may occur in the brain. If so, hypoxia could reduce the quality of life and brain function. This study was undertaken to assess if brain hypoxia occurs in individuals after recovery from acute COVID-19 infection and if this hypoxia is associated with neurocognitive impairment and reduced quality of life. METHODS: Using frequency-domain near-infrared spectroscopy (fdNIRS), we measured cerebral tissue oxygen saturation (StO2) (a measure of hypoxia) in participants who had contracted COVID-19 at least 8 weeks prior to the study visit and healthy controls. We also conducted neuropsychological assessments and health-related quality of life assessments, fatigue, and depression. RESULTS: Fifty-six percent of the post-COVID-19 participants self-reported having persistent symptoms (from a list of 18), with the most reported symptom being fatigue and brain fog. There was a gradation in the decrease of oxyhemoglobin between controls, and normoxic and hypoxic post-COVID-19 groups (31.7 ± 8.3 µM, 27.8 ± 7.0 µM and 21.1 ± 7.2 µM, respectively, p = 0.028, p = 0.005, and p = 0.081). We detected that 24% of convalescent individuals' post-COVID-19 infection had reduced StO2 in the brain and that this relates to reduced neurological function and quality of life. INTERPRETATION: We believe that the hypoxia reported here will have health consequences for these individuals, and this is reflected in the correlation of hypoxia with greater symptomology. With the fdNIRS technology, combined with neuropsychological assessment, we may be able to identify individuals at risk of hypoxia-related symptomology and target individuals that are likely to respond to treatments aimed at improving cerebral oxygenation.

An Efficacy and Mechanism Driven Study on the Impact of Hypoxia on Lipid Nanoparticle Mediated mRNA Delivery.

Hypoxia is a common hallmark of human disease that is characterized by abnormally low oxygen levels in the body. While the effects of hypoxia on many small molecule-based drugs are known, its effects on several classes of next-generation medications including messenger RNA therapies warrant further study. Here, we provide an efficacy- and mechanism-driven study that details how hypoxia impacts the cellular response to mRNA therapies delivered using 4 different chemistries of lipid nanoparticles (LNPs, the frontrunner class of drug delivery vehicles for translational mRNA therapy utilized in the Moderna and Pfizer/BioNTech COVID-19 vaccines). Specifically, our work provides a comparative analysis as to how various states of oxygenation impact LNP-delivered mRNA expression, cellular association, endosomal escape, and intracellular ATP concentrations following treatment with 4 different LNPs across 3 different cell lines. In brief, we first identify that hypoxic cells express less LNP-delivered mRNA into protein than normoxic cells. Next, we identify generalizable cellular reoxygenation protocols that can reverse the negative effects that hypoxia imparts on LNP-delivered mRNA expression. Finally, mechanistic studies that utilize fluorescence-activated cell sorting, confocal microscopy, and enzyme inhibition reveal that decreases in mRNA expression correlate with decreases in intracellular ATP (rather than with differences in mRNA LNP uptake pathways). In presenting this data, we hope that our work provides a comprehensive efficacy and mechanism-driven study that explores the impact of differential oxygenation on LNP-delivered mRNA expression while simultaneously establishing fundamental criteria that may one day be useful for the development of mRNA drugs to treat hypoxia-associated disease.

Bacterial Lysate from the Multi-Strain Probiotic SLAB51 Triggers Adaptative Responses to Hypoxia in Human Caco-2 Intestinal Epithelial Cells under Normoxic Conditions and Attenuates LPS-Induced Inflammatory Response.

Hypoxia-inducible factor-1α (HIF-1α), a central player in maintaining gut-microbiota homeostasis, plays a pivotal role in inducing adaptive mechanisms to hypoxia and is negatively regulated by prolyl hydroxylase 2 (PHD2). HIF-1α is stabilized through PI3K/AKT signaling regardless of oxygen levels. Considering the crucial role of the HIF pathway in intestinal mucosal physiology and its relationships with gut microbiota, this study aimed to evaluate the ability of the lysate from the multi-strain probiotic formulation SLAB51 to affect the HIF pathway in a model of in vitro human intestinal epithelium (intestinal epithelial cells, IECs) and to protect from lipopolysaccharide (LPS) challenge. The exposure of IECs to SLAB51 lysate under normoxic conditions led to a dose-dependent increase in HIF-1α protein levels, which was associated with higher glycolytic metabolism and L-lactate production. Probiotic lysate significantly reduced PHD2 levels and HIF-1α hydroxylation, thus leading to HIF-1α stabilization. The ability of SLAB51 lysate to increase HIF-1α levels was also associated with the activation of the PI3K/AKT pathway and with the inhibition of NF-κB, nitric oxide synthase 2 (NOS2), and IL-1ß increase elicited by LPS treatment. Our results suggest that the probiotic treatment, by stabilizing HIF-1α, can protect from an LPS-induced inflammatory response through a mechanism involving PI3K/AKT signaling.

Modulation of pulmonary blood flow in patients with acute respiratory failure.

BACKGROUND: Impairment of ventilation and perfusion (V/Q) matching is a common mechanism leading to hypoxemia in patients with acute respiratory failure requiring intensive care unit (ICU) admission. While ventilation has been thoroughly investigated, little progress has been made to monitor pulmonary perfusion at the bedside and treat impaired blood distribution. The study aimed to assess real-time changes in regional pulmonary perfusion in response to a therapeutic intervention. METHODS: Single-center prospective study that enrolled adult patients with ARDS caused by SARS-Cov-2 who were sedated, paralyzed, and mechanically ventilated. The distribution of pulmonary perfusion was assessed through electrical impedance tomography (EIT) after the injection of a 10-ml bolus of hypertonic saline. The therapeutic intervention consisted in the administration of inhaled nitric oxide (iNO), as rescue therapy for refractory hypoxemia. Each patient underwent two 15-min steps at 0 and 20 ppm iNO, respectively. At each step, respiratory, gas exchange, and hemodynamic parameters were recorded, and V/Q distribution was measured, with unchanged ventilatory settings. RESULTS: Ten 65 [56-75] years old patients with moderate (40%) and severe (60%) ARDS were studied 10 [4-20] days after intubation. Gas exchange improved at 20 ppm iNO (PaO2/FiO2 from 86 ± 16 to 110 ± 30 mmHg, p = 0.001; venous admixture from 51 ± 8 to 45 ± 7%, p = 0.0045; dead space from 29 ± 8 to 25 ± 6%, p = 0.008). The respiratory system's elastic properties and ventilation distribution were unaltered by iNO. Hemodynamics did not change after gas initiation (cardiac output 7.6 ± 1.9 vs. 7.7 ± 1.9 L/min, p = 0.66). The EIT pixel perfusion maps showed a variety of patterns of changes in pulmonary blood flow, whose increase positively correlated with PaO2/FiO2 increase (R2 = 0.50, p = 0.049). CONCLUSIONS: The assessment of lung perfusion is feasible at the bedside and blood distribution can be modulated with effects that are visualized in vivo. These findings might lay the foundations for testing new therapies aimed at optimizing the regional perfusion in the lungs.

Silent Hypoxemia in COVID-19 Pneumonia.

In patients suffering from Coronavirus Disease 2019 (COVID-19), dyspnoea is less likely to occur despite hypoxemia. Even if the patient develops severe hypoxemia, it cannot be detected from subjective symptoms. In other words, it becomes more serious without the person or the surroundings noticing it. Initially less talked about, hypoxemia without dyspnoea (silent hypoxemia or happy hypoxia: hypoxemia that does not coincide with dyspnoea) is now experienced in many institutions. Dyspnoea is defined as "the unpleasant sensation that accompanies breathing." Dyspnoea occurs when afferent information is transmitted to the sensory area. Receptors involved in the development of dyspnoea include central and peripheral chemoreceptors, chest wall receptors, lung receptors, upper respiratory tract receptors and corollary discharge receptors. In the present study, we considered mechanisms mediating the silent hypoxemia through three cases experienced at our hospital as a dedicated coronavirus treatment hospital. We have treated about 600 people infected with COVID-19, of which about 10% were severe cases. In the present study, the patients' condition was retrospectively extracted and analysed. We investigated three typical cases of COVID-19 pneumonia admitted to our hospital (men and women between the ages of 58 and 86 with hypoxemia and tachypnoea). Silent hypoxemia is not entirely without dyspnoea, but hypoxemia does not cause dyspnoea commensurate with its severity. The virus may have specific effects on the respiratory control system. In our cases, respiratory rate significantly increased with hypoxemia, and hyperventilation occurred. Therefore, information about hypoxemia is transmitted from the carotid body. Since hyperventilation occurs, it is suggested that information is transmitted to effectors such as respiratory muscles. The fact that these patients did not feel the unpleasant sensation indicates that information is not accurately transmitted to the sensory area of the cerebral cortex. These cases suggest that there may be a problem somewhere in the path from the respiratory centre to the sensory area.