Case study observational research: inflammatory cytokines in the bronchial epithelial lining fluid of COVID-19 patients with acute hypoxemic respiratory failure.

BACKGROUND: In this study, the concentrations of inflammatory cytokines were measured in the bronchial epithelial lining fluid (ELF) and plasma in patients with acute hypoxemic respiratory failure (AHRF) secondary to severe coronavirus disease 2019 (COVID-19). METHODS: We comprehensively analyzed the concentrations of 25 cytokines in the ELF and plasma of 27 COVID-19 AHRF patients. ELF was collected using the bronchial microsampling method through an endotracheal tube just after patients were intubated for mechanical ventilation. RESULTS: Compared with those in healthy volunteers, the concentrations of interleukin (IL)-6 (median 27.6 pmol/L), IL-8 (1045.1 pmol/L), IL-17A (0.8 pmol/L), IL-25 (1.5 pmol/L), and IL-31 (42.3 pmol/L) were significantly greater in the ELF of COVID-19 patients than in that of volunteers. The concentrations of MCP-1 and MIP-1ß were significantly greater in the plasma of COVID-19 patients than in that of volunteers. The ELF/plasma ratio of IL-8 was the highest among the 25 cytokines, with a median of 737, and the ELF/plasma ratio of IL-6 (median: 218), IL-1ß (202), IL-31 (169), MCP-1 (81), MIP-1ß (55), and TNF-α (47) were lower. CONCLUSIONS: The ELF concentrations of IL-6, IL-8, IL-17A, IL-25, and IL-31 were significantly increased in COVID-19 patients. Although high levels of MIP-1 and MIP-1ß were also detected in the blood samples collected simultaneously with the ELF samples, the results indicated that lung inflammation was highly compartmentalized. Our study demonstrated that a comprehensive analysis of cytokines in the ELF is a feasible approach for understanding lung inflammation and systemic interactions in patients with severe pneumonia.

Prediction of acute lung injury assessed by chest computed tomography, oxygen saturation/fraction of inspired oxygen ratio, and serum lactate dehydrogenase in patients with COVID-19.

INTRODUCTION: In treating acute hypoxemic respiratory failure (AHRF) caused by coronavirus disease 2019 (COVID-19), clinicians choose respiratory therapies such as low-flow nasal cannula oxygenation, high-flow nasal cannula oxygenation, or mechanical ventilation after assessment of the patient's condition. Chest computed tomography (CT) imaging contributes significantly to diagnosing COVID-19 pneumonia. However, the costs and potential harm to patients from radiation exposure need to be considered. This study was performed to predict the quantitative extent of COVID-19 acute lung injury using clinical indicators such as an oxygenation index and blood test results. METHODS: We analyzed data from 192 patients with COVID-19 AHRF. Multiple logistic regression was used to determine correlations between the lung infiltration volume (LIV) and other pathophysiological or biochemical laboratory parameters. RESULTS: Among 13 clinical parameters, we identified the oxygen saturation/fraction of inspired oxygen ratio (SF ratio) and serum lactate dehydrogenase (LD) concentration as factors associated with the LIV. In the binary classification of an LIV of ≥20 % or not and with the borderline LD = 2.2 × [SF ratio]-182.4, the accuracy, precision, diagnostic odds ratio, and area under the summary receiver operating characteristic curve were 0.828, 0.818, 23.400, and 0.870, respectively. CONCLUSIONS: These data suggest that acute lung injury due to COVID-19 pneumonia can be estimated using the SF ratio and LD concentration without a CT scan. These findings may provide significant clinical benefit by allowing clinicians to predict acute lung injury levels using simple, minimally invasive assessment of oxygenation capacity and biochemical blood tests.

Activation of neurons and satellite glial cells in the DRG produces morphine-induced hyperalgesia.

Activation of neurons and glial cells in the dorsal root ganglion is one of the key mechanisms for the development of hyperalgesia. The aim of the present study was to examine the role of neuroglial activity in the development of opioid-induced hyperalgesia. Male rats were treated with morphine daily for 3 days. The resultant phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 in the dorsal root ganglion was analyzed by immunohistochemistry and Western blotting. Pain hypersensitivity was analyzed using behavioral studies. The amount of cytokine expression in the dorsal root ganglion was also analyzed. Repeated morphine treatment induced hyperalgesia and marked induction of phosphorylated ERK1/2 in the neurons and satellite glial cells on day 3. An opioid receptor antagonist, toll like receptor-4 inhibitor, MAP/ERK kinase (MEK) inhibitor and gap junction inhibitor inhibited morphine-induced hyperalgesia and ERK1/2 phosphorylation. Morphine treatment induced alteration of cytokine expression, which was inhibited by the opioid receptor antagonist, toll like receptor-4 inhibitor, MEK inhibitor and gap junction inhibitor. Dexamethasone inhibited morphine-induced hyperalgesia and ERK1/2 phosphorylation after morphine treatment. The peripherally restricted opioid receptor antagonist, methylnaltrexone, inhibited hyperalgesia and ERK1/2 phosphorylation. Morphine activates ERK1/2 in neurons and satellite glial cells in the dorsal root ganglion via the opioid receptor and toll like receptor-4. ERK1/2 phosphorylation is gap junction-dependent and is associated with the alteration of cytokine expression. Inhibition of neuroinflammation by activation of neurons and glia might be a promising target to prevent opioid-induced hyperalgesia.

Choice of respiratory therapy for COVID-19 patients with acute hypoxemic respiratory failure: a retrospective case series study.

Background: In the treatment of acute hypoxemic respiratory failure (AHRF) due to coronavirus 2019 (COVID-19), physicians choose respiratory management ranging from low-flow oxygen therapy to more invasive methods, depending on the severity of the patient's symptoms. Recently, the ratio of oxygen saturation (ROX) index has been proposed as a clinical indicator to support the decision for either high-flow nasal cannulation (HFNC) or mechanical ventilation (MV). However, the reported cut-off value of the ROX index ranges widely from 2.7 to 5.9. The objective of this study was to identify indices to achieve empirical physician decisions for MV initiation, providing insights to shorten the delay from HFNC to MV. We retrospectively analyzed the ROX index 6 hours after initiating HFNC and lung infiltration volume (LIV) calculated from chest computed tomography (CT) images in COVID-19 patients with AHRF. Methods: We retrospectively analyzed the data for 59 COVID-19 patients with AHRF in our facility to determine the cut-off value of the ROX index for respiratory therapeutic decisions and the significance of radiological evaluation of pneumonia severity. The physicians chose either HFNC or MV, and the outcomes were retrospectively analyzed using the ROX index for initiating HFNC. LIV was calculated using chest CT images at admission. Results: Among the 59 patients who required high-flow oxygen therapy with HFNC at admission, 24 were later transitioned to MV; the remaining 35 patients recovered. Four of the 24 patients in the MV group died, and the ROX index values of these patients were 9.8, 7.3, 5.4, and 3.0, respectively. These index values indicated that the ROX index of half of the patients who died was higher than the reported cut-off values of the ROX index, which range from 2.7-5.99. The cut-off value of the ROX index 6 hours after the start of HFNC, which was used to classify the management of HFNC or MV as a physician's clinical decision, was approximately 6.1. The LIV cut-off value on chest CT between HFNC and MV was 35.5%. Using both the ROX index and LIV, the cut-off classifying HFNC or MV was obtained using the equation, LIV = 4.26 × (ROX index) + 7.89. The area under the receiver operating characteristic curve, as an evaluation metric of the classification, improved to 0.94 with a sensitivity of 0.79 and specificity of 0.91 using both the ROX index and LIV. Conclusion: Physicians' empirical decisions associated with the choice of respiratory therapy for HFNC oxygen therapy or MV can be supported by the combination of the ROX index and the LIV index calculated from chest CT images.

IGF1-driven induction of GPCR kinase 2 in the primary afferent neuron promotes resolution of acute hyperalgesia.

Dynamic regulation of G-protein-coupled receptor (GPCR) kinase 2 (GRK2) expression restores cellular function by protecting from overstimulation via GPCR and non-GPCR signaling. In the primary afferent neurons, GRK2 negatively regulates nociceptive tone. The present study tested the hypothesis that induction of GRK2 in the primary afferent neurons contributes to the resolution of acute pain after tissue injury. GRK2 expression in the dorsal root ganglion (DRG) was analyzed at 1 and 7 days after the incision. Intraperitoneal administration of a GRK2 inhibitor was performed 7 days post-incision in male Sprague-Dawley rats who underwent plantar incisions to analyze the pain-related behavioral effect of the GRK2 inhibitor. Separately, GRK2 expression was analyzed after injecting insulin-like growth factor 1 (IGF1) into the rat hind paw. In addition, an IGF1 receptor (IGF1R) inhibitor was administered in the plantar incision rats to determine its effect on the incision-induced hyperalgesia and GRK2 expression. Plantar incision induced an increase in GRK2 in the DRG at 7 days, but not at 1 day post-incision. Acute hyperalgesia after the plantar incision disappeared by 7 days post-incision. Intraperitoneal injection of the GRK2 inhibitor at this time reinstated mechanical hyperalgesia, although the GRK2 inhibitor did not produce hyperalgesia in naive rats. After the incision, IGF1 expression increased in the paw, but not in the DRG. Intraplantar injection of IGF1 increased GRK2 expression in the ipsilateral DRG. IGF1R inhibitor administration prevented both the induction of GRK2 and resolution of hyperalgesia after the plantar incision. These findings demonstrate that induction of GRK2 expression driven by tissue IGF1 has potent analgesic effects and produces resolution of hyperalgesia after tissue injury. Dysregulation of IGF1-GRK2 signaling could potentially lead to failure of the spontaneous resolution of acute pain and, hence, development of chronic pain after surgery.

Myocardial injury in a patient with severe coronavirus disease: A case report.

INTRODUCTION: Coronavirus disease (COVID-19) can lead to severe disease or death and is characterized by a wide range of mild to severe symptoms. In addition to the lungs, studies have reported the involvement of the stomach, intestine, and angiotensin-converting enzyme 2 receptors in the heart. CASE REPORT: We present a case of a patient with COVID-19 who died soon after developing multi-organ failure and myocardial injury due to COVID-19-associated pneumonia. A 71-year-old man who contracted COVID-19 was admitted to the hospital after presenting with fever for 7 days and developed dyspnea. Following treatment, his respiratory status worsened. Thus, he was transferred to our hospital for intensive care on day 11. Physical examination revealed fever, dyspnea, respiratory distress, and no chest pain. Invasive positive pressure ventilation was initiated for acute respiratory distress syndrome on day 14. On day 15, we observed renal, liver, and coagulation dysfunction, indicating multi-organ failure. Chest radiography did not show clear signs of an increased cardiothoracic ratio or pulmonary congestion. An electrocardiogram (ECG) showed signs of myocardial infarction, which was confirmed by elevated troponin I and creatine kinase levels. The patient's circulatory dynamics did not improve on medication, and he died on day 16. CONCLUSIONS: We report the case of a patient with severe COVID-19 who died from an exacerbation of myocardial injury. Clinicians should not only evaluate respiration but also assess the heart by performing a 12-lead ECG, echocardiogram, and myocardial injury marker examination. Together, these tools can help predict which patients will develop severe COVID-19.