Development Of Respiratory Distress Syndrome Research Articles

Acetaminophen for Prevention and Treatment of Organ Dysfunction in Critically Ill Patients With Sepsis

Acetaminophen (paracetamol) has many pharmacological effects that might be beneficial in sepsis, including inhibition of cell-free hemoglobin-induced oxidation of lipids and other substrates. To determine whether acetaminophen increases days alive and free of organ dysfunction in sepsis compared with placebo. Phase 2b randomized, double-blind, clinical trial conducted from October 2021 to April 2023 with 90-day follow-up. Adults with sepsis and respiratory or circulatory organ dysfunction were enrolled in the emergency department or intensive care unit of 40 US academic hospitals within 36 hours of presentation. Patients were randomized to 1 g of acetaminophen intravenously every 6 hours or placebo for 5 days. The primary end point was days alive and free of organ support (mechanical ventilation, vasopressors, and kidney replacement therapy) to day 28. Treatment effect modification was evaluated for acetaminophen by prerandomization plasma cell-free hemoglobin level higher than 10 mg/dL. Of 447 patients enrolled (mean age, 64 [SD, 15] years, 51% female, mean Sequential Organ Failure Assessment [SOFA] score, 5.4 [SD, 2.5]), 227 were randomized to acetaminophen and 220 to placebo. Acetaminophen was safe with no difference in liver enzymes, hypotension, or fluid balance between treatment arms. Days alive and free of organ support to day 28 were not meaningfully different for acetaminophen (20.2 days; 95% CI, 18.8 to 21.6) vs placebo (19.6 days; 95% CI, 18.2 to 21.0; P = .56; difference, 0.6; 95% CI, -1.4 to 2.6). Among 15 secondary outcomes, total, respiratory, and coagulation SOFA scores were significantly lower on days 2 through 4 in the acetaminophen arm as was the rate of development of acute respiratory distress syndrome within 7 days (2.2% vs 8.5% acetaminophen vs placebo; P = .01; difference, -6.3; 95% CI, -10.8 to -1.8). There was no significant interaction between cell-free hemoglobin levels and acetaminophen. Intravenous acetaminophen was safe but did not significantly improve days alive and free of organ support in critically ill sepsis patients. ClinicalTrials.gov Identifier: NCT04291508.

Effects of ozone exposure on lung injury, inflammation, and oxidative stress in a murine model of non-pneumonic endotoxemia.

Recent studies have identified exposure to environmental levels of ozone as a risk factor for the development of acute respiratory distress syndrome (ARDS), a severe form of acute lung injury (ALI) that can develop in humans with sepsis. The aim of this study was to develop a murine model of ALI to mechanistically explore the impact of ozone exposure on ARDS development. Mice were exposed to ozone (0.8 ppm, 3 hr) or air control followed 24 hr later by intravenous administration of 3 mg/kg lipopolysaccharide (LPS) or PBS. Exposure of mice to ozone + LPS caused alveolar hyperplasia; increased BAL levels of albumin, IgM, phospholipids, and proinflammatory mediators including surfactant protein D and soluble receptor for advanced glycation end products were also detected in BAL, along with markers of oxidative and nitrosative stress. Administration of ozone + LPS resulted in an increase in neutrophils and anti-inflammatory macrophages in the lung, with no effects on proinflammatory macrophages. Conversely, numbers of resident alveolar macrophages decreased after ozone + LPS; however, expression of Nos2, Arg1, Cxcl1, Cxcl2, Ccl2 by these cells increased, indicating that they are activated. These findings demonstrate that ozone sensitizes the lung to respond to endotoxin, resulting in ALI, oxidative stress and exacerbated pulmonary inflammation, and provide support for the epidemiologic association between ozone exposure and ARDS incidence.

Endoscopic Changes of Tracheobronchial Tree Caused by Mucormycosis in Patients with a Novel Coronavirus Infection

The most severe manifestation of COVID-19 is bilateral pneumonia with development of acute respiratory distress syndrome accompanied by cytokine storm, pulmonary edema and death of the patient. In a number of patients, occurrence of mucormycosis of mucous membranes was one of the stages of the lethal outcome development. The arctile presents a clinical case of mucormycosis of the tracheobronchial tree detected by bronchoscopy several days before death in a patient with COVID-19 who was on mechanical ventilation. The endoscopic signs (endoscopic image) are described.

Identifying associations of human surfactant protein A SNPs and allelic variants with retinopathy of prematurity

Retinopathy of prematurity (ROP) is the primary cause of childhood blindness worldwide. Previous studies showed that allelic single nucleotide polymorphic (SNP) variants of the human surfactant protein A genes (SP-A1, SP-A2) are associated with the development of respiratory distress syndrome and bronchopulmonary dysplasia (BPD). In this work, we hypothesized that SP-A SNPs and allelic variants are associated with altered risk of ROP in prematurely born infants. To test this hypothesis, we used a modified PCR-based method to detect variants of the SP-A1 and SP-A2 genes in a cohort of preterm infants. Infants born at <32 weeks’ gestation and/or<1500 grams were enrolled. Scavenged blood samples or cheek swabs were collected and DNA was extracted using the QIAamp DNA Mini Kit. We measured SNPs in SP-A1 and SP-A2 using Taqman probes for allelic discrimination by PCR or PCR/RFLP/sequencing method. Associations of SP-A1 and SP-A2 SNP allele frequencies with ROP and BPD were determined using chi-square and logistic regression analyses. Our results show that, of the total patient cohort (n=59), 42 patients had a BPD diagnosis (23 with ROP and 36 without ROP). DNA analysis of these samples identified associations of SP-A1 and SP-A2 SNPs and variants with ROP. For SP-A1, the following SNP associations were found for ROP using chi-square: rs1059047 (p=0.44), rs1136450 (p=0.63), rs1136451 (p=0.21), rs1059057 (p=0.52). For SP-A2, the following SNPs associations were identified with ROP: rs1059046 (p=0.51), rs17886395 (p=0.050), rs1965707 (p=0.031), rs1965708 (p=0.46). Logistic regression analysis indicated an association of ROP with the SP-A1 6A2 variant (p-value = 0.47, OR (6A2/*)=0.8036, 95%CI [0.2299 - 2.8082], OR (6A2/6A2) = 0.4327, 95%CI [0.1063 - 1.7615]), which conferred protection, as well as an association of ROP with SP-A2 6A2 (p-value = 0.0055) with decreased risk when 1A2 variant is present. We conclude that SP-A1/SP-A2 polymorphisms are associated with the presence of ROP in infants with BPD. The 6A4 SP-A1 and SP-A2 1A2 appear to confer protection in babies against ROP. Further studies will determine the mechanisms of this protective effect. Indiana University, University of Chicago Metcalf Internship Program Grant, The University of Oklahoma Health Sciences Center. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hemoglobin-Mediated Oxidation of Low-Density Lipoprotein (oxLDL) Contributes to Lung Microvascular Endothelial Dysfunction Via Lectin-Like Oxidized LDL Receptor 1 (LOX-1)

Introduction: Lung microvascular endothelial barrier disruption is a critical feature of acute lung injury during several pathologies, including sepsis. Plasma cell-free hemoglobin (CFH) is elevated in approximately 80% of patients with sepsis and is independently associated with development of acute respiratory distress syndrome (ARDS) and mortality. However, the precise signaling mechanisms involved in CFH-mediated lung microvascular barrier dysfunction are incompletely understood. One potential mechanism by which CFH might disrupt the microvascular endothelial barrier is through its known ability to oxidize lipids and lipoproteins, including low-density lipoprotein (LDL). Oxidized LDL (oxLDL) is a known endothelial barrier disruptor, primarily signaling through scavenger receptors such as lectin-like oxidized LDL receptor 1 (LOX-1). We hypothesized that CFH-mediated oxidation of LDL exacerbates lung microvascular endothelial barrier dysfunction via LOX-1. Methods: For experimental studies, LDL was oxidized by combining LDL with CFH in a test tube overnight at 37°C and oxidation of LDL was quantified by TBARS assay. In primary human lung microvascular endothelial cells (HLMVEC), barrier dysfunction was assessed with expert permeability testing (XPerT) assay. HLMVEC were stimulated with vehicle control (PBS), LDL (0.05 mg/mL), CFH (0.5 mg/mL), or LDL oxidized by CFH (LDL+CFH) with or without one-hour pre-treatment of hemoglobin scavenger haptoglobin (1:1) or LOX-1 inhibitor BI-0115 (Boehringer Ingelheim, 10 μM). Cleaved caspase-3 (CST 9661, 1:500) was assessed with immunofluorescence microscopy. To test whether CFH and oxLDL are associated in clinical sepsis, circulating levels of CFH and oxLDL were measured in 60 sepsis patients via ELISA. Results: Oxidation of LDL by CFH (p=0.0006 by TBARS) exacerbated HLMVEC barrier dysfunction (p<0.0001 by XPerT) but was partially prevented by scavenging CFH with haptoglobin (p<0.0001 by XPerT) or blocking LOX-1 receptor (p<0.0001 by XPerT). Oxidation of LDL by CFH stimulation of HLMVEC also increased caspase-3 activation (p<0.0001 by immunofluorescence of cleaved caspase-3). In sepsis patients, circulating oxLDL levels correlated with CFH (r=0.4, p=0.002). Conclusions: Oxidation of LDL by CFH contributes to lung microvascular endothelial injury via LOX-1 receptor and activation of caspase-3; targeting this pathway may hold therapeutic potential to treat pathologies in which CFH is elevated, including sepsis-induced acute lung injury/ARDS. Funding: Parker B. Francis Fellowship (JEM); NIH K99HL166865 (JEM), R01HL158906 (LBW), R01HL164937 (LBW), R21GM144915 (LBW, JAB), R35HL150783 (JAB), RF1AG075341 (JAB). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of SARS-CoV-2 S protein on the proteolytic cleavage of the epithelial Na+ channel ENaC.

Severe cases of COVID-19 are characterized by development of acute respiratory distress syndrome (ARDS). Water accumulation in the lungs is thought to occur as consequence of an exaggerated inflammatory response. A possible mechanism could involve decreased activity of the epithelial Na+ channel, ENaC, expressed in type II pneumocytes. Reduced transepithelial Na+ reabsorption could contribute to lung edema due to reduced alveolar fluid clearance. This hypothesis is based on the observation of the presence of a novel furin cleavage site in the S protein of SARS-CoV-2 that is identical to the furin cleavage site present in the alpha subunit of ENaC. Proteolytic processing of αENaC by furin-like proteases is essential for channel activity. Thus, competition between S protein and αENaC for furin-mediated cleavage in SARS-CoV-2-infected cells may negatively affect channel activity. Here we present experimental evidence showing that coexpression of the S protein with ENaC in a cellular model reduces channel activity. In addition, we show that bidirectional competition for cleavage by furin-like proteases occurs between 〈ENaC and S protein. In transgenic mice sensitive to lethal SARS-CoV-2, however, a significant decrease in gamma ENaC expression was not observed by immunostaining of lungs infected as shown by SARS-CoV2 nucleoprotein staining.

449 Does incorporation of plasma biomarkers to the Lung Injury Prediction Score improve the predictive value for development of acute respiratory distress syndrome?

OBJECTIVES/GOALS: To determine if incorporating specific laboratory values and plasma biomarkers (club cell secretory protein (CC16), matrix metalloproteinase 3 (MMP3), interleukin 8 (IL-8), protein C) to the Lung Injury Prediction (LIP) Score improves the predictive value for development of acute respiratory distress syndrome (ARDS) in ICU patients. METHODS/STUDY POPULATION: Adult patients admitted to the ICU on supplemental oxygen over baseline requirement with a LIP Score ≥6 will be included. Patients admitted to the ICU >24 hours, end-stage renal disease, decompensated heart failure, or <100 µL plasma available will be excluded. Whole blood will be collected from the core lab, centrifuged, and plasma will be stored at -80°C. Protein biomarkers will be measured using enzyme-linked immunosorbent assay. Baseline characteristics, laboratory values, ventilator parameters, and clinical outcomes will be collected from the medical record. ARDS will be defined by the Berlin criteria. Machine learning methods will be used to identify the model with the highest predictive accuracy. Area under the receiver operating characteristic curve of each model will be compared to the LIP Score. RESULTS/ANTICIPATED RESULTS: Research is in progress. Plasma samples and clinical data have been collected for 148 of the 160 samples required to achieve power. Biomarker analysis will take place after sample collection is complete. We anticipate a machine learning model incorporating laboratory values and one or more plasma biomarkers into the LIP Score will outperform the baseline LIP Score for prediction of ARDS development. DISCUSSION/SIGNIFICANCE: Delayed diagnosis and intervention contribute to poor ARDS outcomes. Current predictive models for ARDS have low accuracy and enriching these models with plasma biomarkers may increase their predictive value. Development of accurate models may facilitate earlier ARDS diagnosis and intervention as well as enrichment strategies for ARDS trials.

Immunomodulatory Effects of Fluoroquinolones in Community-Acquired Pneumonia-Associated Acute Respiratory Distress Syndrome.

Community-acquired pneumonia is reported as one of the infectious diseases that leads to the development of acute respiratory distress syndrome. The innate immune system is the first line of defence against microbial invasion; however, its dysregulation during infection, resulting in an increased pathogen load, stimulates the over-secretion of chemokines and pro-inflammatory cytokines. This phenomenon causes damage to the epithelial-endothelial barrier of the pulmonary alveoli and the leakage of the intravascular protein into the alveolar lumen. Fluoroquinolones are synthetic antimicrobial agents with immunomodulatory properties that can inhibit bacterial proliferation as well as exhibit anti-inflammatory activities. It has been demonstrated that the structure of fluoroquinolones, particularly those with a cyclopropyl group, exerts immunomodulatory effects. Its capability to inhibit phosphodiesterase activity leads to the accumulation of intracellular cAMP, which subsequently enhances PKA activity, resulting in the inhibition of transcriptional factor NF-κB and the activation of CREB. Another mechanism reported is the inhibition of TLR and ERK signalling pathways. Although the sequence of events has not been completely understood, significant progress has been made in comprehending the specific mechanisms underlying the immunomodulatory effects of fluoroquinolones. Here, we review the indirect immunomodulatory effects of FQs as an alternative to empirical therapy in patients diagnosed with community-acquired pneumonia.

CLINICAL AND PHARMACOLOGICAL ASPECTS OF APPLYING GLUCOCORTICOSTEROIDS FOR SARS-COVID-2 INFECTION: REVIEW ARTICLE

In recent years, the SARS-CoV-2 pandemic has become one of the unexpected and very serious challenges for public health around the world. Moreover, SARS-CoV-2 infection led to the development of acute respiratory distress syndrome as a result of excessive systemic inflammation, and the development of multiple organ failure, and later death. Moreover, the problem of eliminating excessive systemic inflammation, that is, reducing the production of pro-inflammatory cytokines in SARS-CoV-2, remains open. In this regard, the use of glucocorticosteroids for infection caused by SARS-CoV-2 remains quite controversial. The basis for the routine use of steroids in intensive care protocols for SARS-CoV-2 is clearly insufficient and remains the subject of further research. This review provides an analysis of literary sources, guidelines, and modern international recommendations on pathogenetic therapy of SARS-CoV-2 to prevent and eliminate hyperproduction of pro-inflammatory cytokines using glucocorticosteroid agents. The purpose of the work is to conduct an analysis of modern literary sources regarding the modern features of the clinical and pharmacological justification of the use of glucocorticosteroids in SARS-CoV-2 infection in clinical practice. The analysis of the scientific literature demonstrates that today glucocorticosteroid therapy cannot be recommended for routine use in therapeutic practice in patients with SARS-CoV-2 infection. Thus, with a mild course of SARS-CoV-2 infection, when the patient does not need oxygen support, GCS therapy is contraindicated. With a severe course of SARS-CoV-2, when the patient develops acute respiratory distress syndrome with severe respiratory failure, when there is a need for oxygen therapy, mechanical ventilation or ECMO, the use of corticosteroids is extremely necessary, and may be recommended for mandatory use. There is a pressing need for a comprehensive definition of the optimal glucocorticosteroid agent, indications, dosage, and duration of use in SARS-CoV-2 infection therapy programs. This should be done while considering biomarkers of the severity of the inflammatory process and biomarkers of the body's response to glucocorticosteroid agents.

Lavandula stoechas significantly alleviates cigarette smoke-induced acute lung injury via modulation of oxidative stress and the NF-κB pathway

Cigarette smoke (CS) is one of the major triggering factorsfor oxidative stress and contributes to development of acute lung injury and acute respiratory distress syndrome (ALI/ARDS), both of which are marked by severe lung inflammation. Due to the absence of viable treatment options for ALI/ARDS, methanolic extract of Lavandula stoechas (Ls.Met) was used to evaluate the protective effect against CS-induced ALI in both in vivo and in vitro settings.In order to prepare CS-induced ALI murine models, male Swiss albino mice were exposed to whole-body CS for 10 days. Normal saline (10 mL/kg), Ls.Met (250, 450, 750 mg/kg), and dexamethasone (1 mg/kg) were administered orally to respective animal groups (n = 5/group) 1 h prior to CS-exposure. Twenty-four hrs following the last CS-exposure, bronchoalveolar lavage fluid (BALF) and lungs were harvested to examine the important aspects of ALI. Subsequently, in vitro protective effect of Ls.Met (10 and 100 μM) was assessed against 4% CSE (for 24 h)-stimulated RAW 264.7 macrophages.The presence of phenols and flavonoids was verified by HPLC analysis. Ls.Met dose-dependently and remarkably reduced macrophages and neutrophil invasion into the lungs, lung weight coefficient, albumin exudates into the alveoli, and improved hypoxemia and lung histopathological alterations. Notably, Ls.Met attenuated the CS-induced oxidative stress as evidenced by decreased levels of malondialdehyde, total oxidant status (TOS), and myeloperoxidas, alongside enhanced total antioxidant capacity (TAC) production. Moreover, Ls.Met demonstrated a marked reduction in CS-induced overexpression of proinflammatory cytokines (IL-6, IL-1β, and KC) and inhibited the activation of NF-κB, a key signalling pathway involved in inflammation. Lavandula stoechas could thus be a potential therapeutic option for the treatment of CS-induced ALI.

Evaluation of Glutathione in Spike Protein of SARS-CoV-2 Induced Immunothrombosis and Cytokine Dysregulation.

Thrombotic microangiopathy has been identified as a dominant mechanism for increased mortality and morbidity in coronavirus disease 2019 (COVID-19). In the context of severe COVID-19, patients may develop immunothrombosis within the microvasculature of the lungs, which contributes to the development of acute respiratory distress syndrome (ARDS), a leading cause of death in the disease. Immunothrombosis is thought to be mediated in part by increased levels of cytokines, fibrin clot formation, and oxidative stress. Glutathione (GSH), a well-known antioxidant molecule, may have therapeutic effects in countering this pathway of immunothrombosis as decreased levels of (GSH) have been associated with increased viral replication, cytokine levels, and thrombosis, suggesting that glutathione supplementation may be therapeutic for COVID-19. GSH supplementation has never been explored as a means of treating COVID-19. This study investigated the effectiveness of liposomal glutathione (GSH) as an adjunctive therapy for peripheral blood mononuclear cells (PBMC) treated with SARS CoV-2 spike protein. Upon the addition of GSH to cell cultures, cytokine levels, fibrin clot formation, oxidative stress, and intracellular GSH levels were measured. The addition of liposomal-GSH to PBMCs caused a statistically significant decrease in cytokine levels, fibrin clot formation, and oxidative stress. The addition of L-GSH to spike protein and untreated PBMCs increased total intracellular GSH, decreased IL-6, TGF-beta, and TNF-alpha levels, decreased oxidative stress, as demonstrated through MDA, and decreased fibrin clot formation, as detected by fluorescence microscopy. These findings demonstrate that L-GSH supplementation within a spike protein-treated PBMC cell culture model reduces these factors, suggesting that GSH supplementation should be explored as a means of reducing mediators of immunothrombosis in COVID-19.

Synergistic inhibition effects of andrographolide and baicalin on coronavirus mechanisms by downregulation of ACE2 protein level

The SARS-CoV-2 virus, belonging to the Coronavirus genus, which poses a threat to human health worldwide. Current therapies focus on inhibiting viral replication or using anti-inflammatory/immunomodulatory compounds to enhance host immunity. This makes the active ingredients of traditional Chinese medicine compounds ideal therapies due to their proven safety and minimal toxicity. Previous research suggests that andrographolide and baicalin inhibit coronaviruses; however, their synergistic effects remain unclear. Here, we studied the antiviral mechanisms of their synergistic use in vitro and in vivo. We selected the SARS-CoV-2 pseudovirus for viral studies and found that synergistic andrographolide and baicalein significantly reduced angiotensin-converting enzyme 2 protein level and viral entry of SARS-CoV-2 into cells compared to singal compound individually and inhibited the major protease activity of SARS-CoV-2. This mechanism is essential to reduce the pathogenesis of SARS-CoV-2. In addition, their synergistic use in vivo also inhibited the elevation of pro-inflammatory cytokines, including IL-6 and TNF-α—the primary cytokines in the development of acute respiratory distress syndrome (the main cause of COVID-19 deaths). In conclusion, this study shows that synergistic andrographolide and baicalein treatment acts as potent inhibitors of coronavirus mechanisms in vitro and in vivo—and is more effective together than in isolation.

Retrospectively gated ultrashort-echo-time MRI T1 mapping reveals compromised pulmonary microvascular NO-dependent function in a murine model of acute lung injury.

This study sought to develop noninvasive, in vivo imaging schemes that allow for quantitative assessment of pulmonary microvascular functional status based on the combination of pulmonary T1 mapping and dynamic contrast-enhanced (DynCE) imaging. Ultrashort-echo-time (UTE) imaging at 9.4 T of lung parenchyma was performed. Retrospective gating was based on modulation of the first point in each recorded spoke. T1 maps were obtained using a series of five consecutive images with varying RF angles and analyzed with the variable flip angle approach. The obtained mean T1 lung value of 1078 ± 38 ms correlated well with previous reports. Improved intersession variability was observed, as evident from a decreased standard deviation of motion-resolved T1 mapping (F-test = 0.051). Animals received lipopolysaccharide (LPS) and were imaged at t= 2, 6, and 12 h after administration. The nitric oxide (NO)-dependent function was assessed according to changes in lung T1 after L-NAME injection, while microvascular perfusion and oxidant stress were assessed with contrast-enhanced imaging after injection of gadolinium or 3-carbamoyl-proxyl nitroxide radical, respectively. Retrospectivel gated UTE allowed robust, motion-compensated imaging that could be used for T1 mapping of lung parenchyma. Changes in lung T1 after L-NAME injection indicated that LPS induced overproduction of NO at t= 2 and 6 h after LPS, but NO-dependent microvascular function was impaired at t= 12 h after LPS. DynCE imaging at t= 6 h after LPS injection revealed decreased microvascular perfusion, with increased vascular permeability and oxidant stress. MRI allows to visualize and quantify lung microvascular NO-dependent function and its concomitant impairment during acute respiratory distress syndrome development with high sensitivity. UTE T1 mapping appears to be sensitive and useful in probing pulmonary microvascular functional status.

Multiple Myeloma Patient with Secondary Liver and Tongue Involvement, Complicated by COVID-19-Induced ARDS: An Autopsy Case Report and Literature Review

Background. Liver involvement secondary to multiple myeloma is a rare and uncommon radiologic finding. Such extraosseous secondary lesions as well as tongue involvement require pathohistological confirmation to prevent misdiagnosis. Clinical and laboratory diagnostics are challenging in patients with COVID-19 and underlying multiple myeloma and its secondary lesions, leading to difficulties in treatment and outcomes.
 Case Report. A 64-year-old male patient, not vaccinated against COVID-19, with a history of multiple myeloma presented with symptoms of headache, fatigue, dyspnea, cough, and fever. The patient’s medical history was intricate, involving cholecystectomy and a diagnosis of multiple myeloma, which was subsequently treated with chemotherapy and radiation therapy. Additionally, uncommon liver and tongue involvement secondary to multiple myeloma was found. Upon admission, the patient’s peripheral oxygen saturation was 90%, accompanied by increasing shortness of breath and a respiratory rate of 26 breaths per minute. A positive COVID-19 test was recorded. A lung computed tomography revealed bilateral multifocal areas of ground-glass opacity and consolidation, encompassing the entire pulmonary regions, corresponding to CO-RADS 6. The patient was admitted to the intensive care unit. Despite initiating oxygen support and symptomatic therapy, the patient’s death occurred. Autopsy confirmed the development of severe acute respiratory distress syndrome and bilateral hemorrhagic pneumonia, with multiple myeloma as a contributing factor.
 Conclusions. This case report highlighted the rare occurrence of secondary liver involvement in multiple myeloma, characterized by nodules with distinct imaging features. It underscored the importance of identifying coexisting lesions, such as tongue involvement, and the diagnostic challenges they pose. Additionally, the case emphasized the need for comprehensive clinical assessment in patients with concurrent COVID-19 and underlying multiple myeloma, as it may lead to the development of acute respiratory distress syndrome.

Cord Blood Cortisol Level - A Possible Predictor for Respiratory Distress Syndrome in Preterm Neonates.

Respiratory Distress Syndrome (RDS) is a leading cause of death in premature infants. There are different clinical/ biochemical markers associated with the RDS. One of the potential biochemical markers is cortisol in cord blood. This study aims to correlate cortisol levels in preterm neonates with RDS and to establish whether cord blood cortisol is a reliable predictor for RDS. This prospective analytical study was conducted in a tertiary care hospital over nine months among fifty preterm neonates. Data were collected using proforma, and cord blood was collected at the time of delivery. Cortisol levels were compared and correlated to the development of RDS. The mean ± SD cord blood cortisol level among preterm neonates was 5.97 ± 2.74 (SD) μg/dl. The levels were higher in neonates whose mothers received antenatal steroids and were significantly lower (2.86 ± 1.66 μg/dl) in those who developed RDS. Association between cord blood cortisol level and RDS was found with an odds ratio of 57.4, which was statistically significant. The percentage of babies developing RDS in mothers not covered with antenatal steroids was significantly higher than those covered (p-value is 0.000). The mean cord blood cortisol levels were exceptionally low (1.89 μg/dl) in neonates who expired compared to those who survived (7.02 μg/dl). There is an association between cord blood cortisol levels and RDS. Hence, Cord blood cortisol levels may be used to predict RDS and help initiate early treatment, thus preventing mortality and morbidity.

Leiden mutation (rs6025) in a severe COVID-19 pneumonia patient with Down syndrome: a clinical case

COVID-19 was first reported in December 2019 in Wuhan (Hubei Province, China). Later, the pandemic of this disease took the world by storm, challenging the medical community. Its clinical manifestations vary from asymptomatic to a severe course that requires hospitalization and intensive therapy with oxygen support. The mortality rate in patients with a severe course of COVID-19 can exceed 50% The majority of fatal cases of COVID-19 were associated with thrombotic events, despite the prophylactic use of anticoagulant therapy. Numerous theoretical overviews and research articles indicate the need for genetic testing in patients with COVID-19 to determine the genetic profile of proteins involved in thrombophilia. According to the researchers, the Leiden mutation (G1691A, rs6025) of the FV gene is one of the promising candidates for testing. The aim of the work was to demonstrate the clinical features of the severe course of COVID-19 in the presence of the Leiden mutation. 58 patients with COVID-19 of the intensive care unit were genotyped. The Leiden mutation in the heterozygous state was found only in one patient, who had Down syndrome. The Leiden mutation was detected with a frequency of 1.72% in the investigated group. The described clinical case clearly showed that individuals with Down syndrome, associated with hereditary thrombophilia are at risk of undesirable clinical consequences in the treatment of COVID-19. The condition of the patient with the Leiden mutation was severe when admitted to the hospital. The score according to the sequential organ failure assessment scale was 2 points. Bilateral multisegmental pneumonia was detected on the X-ray. On the second day after admission, due to the development of acute respiratory distress syndrome and multiple organ failure, the patient was transferred to the intensive care unit, where he received oxygen therapy through a facial mask. Medical treatment was carried out according to the protocol: non-steroidal anti-inflammatory drugs, antibacterial therapy, anticoagulants, sympatho¬mimetics, and glucocorticosteroids. Despite the medical measures taken, progression of respiratory failure, renal failure, and portal hypertension was noted. On the 11th day, the patient developed asystole. Resuscitation measures were unsuccessful. Thus, the described case of a severe course of COVID-19 in a carrier of a heterozygous variant of the Leiden mutation with Down syndrome confirms the recommendations regarding the need for genetic testing for thrombophilia in high-risk groups and the appointment of personalized measures to prevent complications.

Sarcopenia and Mortality in Critically Ill COVID-19 Patients.

COVID-19 can manifest as either asymptomatic or progressing to a severe phase in some patients, which may require hospitalization. These patients may experience dyspnea and hypoxia, leading to the development of acute respiratory distress syndrome. Studies have reported an increased risk of severe sarcopenia in COVID-19 patients during and after recovery. This narrative review aimed to summarize and synthesize available studies on the association between sarcopenia and mortality in critically ill COVID-19 patients. A total of 22 studies conducted on hospitalized COVID-19 patients were included in this review. Of those, 17 studies reported a direct association, while 5 studies showed no association between sarcopenia and mortality in severe COVID-19 patients. It is important to maintain muscle quality and quantity in defense against COVID-19. The measurement of lean muscle mass should be included in the risk assessment of severely ill COVID-19 patients as part of the therapy plan.

Blocking P2Y2 purinergic receptor prevents the development of lipopolysaccharide-induced acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality resulting from a direct or indirect injury of the lung. It is characterized by a rapid alveolar injury, lung inflammation with neutrophil accumulation, elevated permeability of the microvascular-barrier leading to an aggregation of protein-rich fluid in the lungs, followed by impaired oxygenation in the arteries and eventual respiratory failure. Very recently, we have shown an involvement of the Gq-coupled P2Y2 purinergic receptor (P2RY2) in allergic airway inflammation (AAI). In the current study, we aimed to elucidate the contribution of the P2RY2 in lipopolysaccharide (LPS)-induced ARDS mouse model. We found that the expression of P2ry2 in neutrophils, macrophages and lung tissue from animals with LPS-induced ARDS was strongly upregulated at mRNA level. In addition, ATP-neutralization by apyrase in vivo markedly attenuated inflammation and blocking of P2RY2 by non-selective antagonist suramin partially decreased inflammation. This was indicated by a reduction in the number of neutrophils, concentration of proinflammatory cytokines in the BALF, microvascular plasma leakage and reduced features of inflammation in histological analysis of the lung. P2RY2 blocking has also attenuated polymorphonuclear neutrophil (PMN) migration into the interstitium of the lungs in ARDS mouse model. Consistently, treatment of P2ry2 deficient mice with LPS lead to an amelioration of the inflammatory response showed by reduced number of neutrophils and concentrations of proinflammatory cytokines. In attempts to identify the cell type specific role of P2RY2, a series of experiments with conditional P2ry2 knockout animals were performed. We observed that P2ry2 expression in neutrophils, but not in the airway epithelial cells or CD4+ cells, was associated with the inflammatory features caused by ARDS. Altogether, our findings imply for the first time that increased endogenous ATP concentration via activation of P2RY2 is related to the pathogenesis of LPS-induced lung inflammation and may represent a potential therapeutic target for the treatment of ARDS and predictably assess new treatments in ARDS.

Cytokine regulation disbalance: the basis for COVID-19 immunopathogenesis

Coronavirus infection activates two main signaling pathways for type I and III IFN and the gene expression and synthesis of proinflammatory cytokines. These cytokines are required for antiviral defense and inflammatory reaction formation. SARS-CoV-2 coronavirus could inhibit the IFN system by depressing signaling pathways for IFN gene expression, synthesis, and secretion. IFN inhibition should be considered the primary reason for coronavirus escape from the immune system and a key factor for COVID-19 immunopathogenesis. Cytokine regulation disbalance in patients with severe COVID-19 is closely associated with low and delayed IFN synthesis, while proinflammatory cytokine production by macrophages and T-lymphocytes continues simultaneously with intensive virus replication. Thus, the reason for COVID-19 immunopathogenesis is the cytokine regulation disbalance where IFN inhibition and intensive proinflammatory cytokine synthesis lead to cytokine storm, inadequate inflammation, respiratory distress syndrome development, respiratory failure, systemic inflammatory complications, and polyorganic failure.

КЛИНИЧЕСКАЯ ЭФФЕКТИВНОСТЬ ПРИМЕНЕНИЯ ПУЛИРОВАННЫХ МЕЗЕНХИМАЛЬНЫХ СТВОЛОВЫХ КЛЕТОК ОБОНЯТЕЛЬНОЙ ВЫСТИЛКИ ДЛЯ ЛЕЧЕНИЯ ПАЦИЕНТОВ С ТЯЖЕЛЫМИ ВНЕБОЛЬНИЧНЫМИ ПНЕВМОНИЯМИ, ОСЛОЖНЕННЫМИ ОСТРЫМ РЕСПИРАТОРНЫМ ДИСТРЕСССИНДРОМОМ

Background. The difficulty in diagnosing COVID-19 is associated with the heterogeneity of clinical manifestations, and treatment is difficult because the course of the disease varies from asymptomatic to severe viral pneumonia, with a cytokine storm and development of acute respiratory distress syndrome (ARDS). Certain hopes in the treatment of COVID-19 and ARDS are currently pinned on the use of mesenchymal stem cells (MSCs), due to their ability to influence the immune system and activate the regeneration of damaged tissues. The aim of the study was to improve the clinical efficacy of existing methods of treating patients with severe community-acquired pneumonia complicated by acute respiratory distress syndrome using cell therapy with pooled MSCs. Material and methods. The subjects of the study were patients with COVID-19-associated pneumonia (U07.1 according to ICD-10), severe course, acute respiratory syndrome (U04) (study group (n=14) and comparison group (n=18)). Clinical and laboratory studies were carried out by routine methods using commercial test systems. Results. Good tolerability and safety of the method of treatment of patients with severe COVID-19 complicated by ARDS using pooled MSCs were shown. 57% of patients who received pooled MSCs did not need to be transferred to mechanical ventilation in the next 7 days. In the study group, 43% of patients survived (6 out of 14), which was significantly higher than in the control group (5.6%, 1 out of 18) (z=2.07; p=0.038). A correlation was found between lactate dehydrogenase (LDH) levels and the outcome of a severe form of coronavirus infection, and criteria were established for selecting patients for cell therapy based on the level of LDH increase by no more than 1.85 times. Administration of pooled MSCs at LDH level higher than 519.8 U/l was ineffective.