Biological effects of corticosteroids on pneumococcal pneumonia in Mice-translational significance.

BACKGROUND: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The primary objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in a mouse model. A secondary objective was to identify shared transcriptomic features of pneumococcal pneumonia and steroid treatment in the mouse model and clinical samples. METHODS: We carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. We also studied lower respiratory tract gene expression from a cohort of 15 mechanically ventilated patients (10 with Streptococcus pneumoniae and 5 controls) to compare with the transcriptional studies in the mice. RESULTS: In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Transcriptomic analyses identified effects of steroid therapy in mice that were also observed in the clinical samples. CONCLUSIONS: In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The transcriptional studies in patients suggest that the mouse model replicates some of the features of pneumonia in patients with Streptococcus pneumoniae and steroid treatment. Overall, these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.

Impact of e-cigarette aerosol on primary human alveolar epithelial type 2 cells.

Electronic cigarettes (e-cigarettes) are designed to simulate combustible cigarette smoking and to aid in smoking cessation. Although the number of e-cigarette users has been increasing, the potential health impacts and biological effects of e-cigarettes are still not fully understood. Previous research has focused on the biological effects of e-cigarettes on lung cancer cell lines and distal airway epithelial cells; however, there have been few published studies on the effect of e-cigarettes on primary lung alveolar epithelial cells. The primary purpose of this study was to investigate the direct effect of e-cigarette aerosol on primary human lung alveolar epithelial type 2 (AT2) cells, both alone and in the presence of viral infection. The Melo-3 atomizer caused direct AT2 cell toxicity, whereas the more popular Juul pod's aerosol did not have a detectable cytotoxic effect on AT2 cells. Juul nicotine aerosol also did not increase short-term susceptibility to viral infection. However, 3 days of exposure upregulated genes central to the generation of reactive oxygen species, lipid peroxidation, and carcinogen metabolism and downregulated key innate immune system genes related to cytokine and chemokine signaling. These findings have implications for the potentially injurious impact of long-term use of popular low-power e-cigarette pods on the human alveolar epithelium. Gene expression data might be an important endpoint for evaluating the potential harmful effects of vaping devices that do not cause overt toxicity.

Aerosolized vitamin E acetate causes oxidative injury in mice and in alveolar macrophages.

Although vitamin E acetate (VEA) is suspected to play a causal role in the development of electronic-cigarette, or vaping, product use-associated lung injury (EVALI), the underlying biological mechanisms of pulmonary injury are yet to be determined. In addition, no study has replicated the systemic inflammation observed in humans in a murine EVALI model, nor investigated potential additive toxicity of viral infection in the setting of exposure to vaping products. To identify the mechanisms driving VEA-related lung injury and test the hypothesis that viral infection causes additive lung injury in the presence of aerosolized VEA, we exposed mice to aerosolized VEA for extended times, followed by influenza infection in some experiments. We used mass spectrometry to evaluate the composition of aerosolized VEA condensate and the VEA deposition in murine or human alveolar macrophages. Extended vaping for 28 days versus 15 days did not worsen lung injury but caused systemic inflammation in the murine EVALI model. Vaping plus influenza increased lung water compared with virus alone. Murine alveolar macrophages exposed to vaped VEA hydrolyzed the VEA to vitamin E with evidence of oxidative stress in the alveolar space and systemic circulation. Aerosolized VEA also induced cell death and chemokine release and reduced efferocytotic function in human alveolar macrophages in vitro. These findings provide new insights into the biological mechanisms of VEA toxicity.

Rescue venovenous extracorporeal membrane oxygenation for the deterioration of acute respiratory distress syndrome in pediatric liver transplantation.

BACKGROUND: Twenty percent of pediatric patients with BA develop ACLF with increased mortality while awaiting LT. Respiratory complications are common in pediatric ACLF and are associated with increased morbidity and mortality. ARDS is the most severe manifestation of acute respiratory failure with considerable risk of mortality. METHODS: A 5-month-old girl with post-Kasai BA preoperatively experienced ARDS from RSV infection while awaiting LT. She developed decompensated liver failure with shock, acute kidney injury, coagulopathy, and pulmonary hemorrhage after several episodes of sepsis over the course of 1 month in the PICU. At this stage, RSV was not detected in the patient's tracheal aspirate by real-time polymerase chain reaction. She underwent living donor LT to manage her pre-existing critical state. Following reperfusion during LT, her pre-existing ARDS rapidly deteriorated, which was alleviated by intraoperative VV ECMO. RESULTS: Severe respiratory acidosis improved rapidly following ECMO, and LT was completed uneventfully. The patient was successfully weaned off ECMO on POD 3. CONCLUSIONS: This is the first pediatric case rescued by the intraoperative application of ECMO during LT. Our case and cumulative evidence suggest that VV ECMO can serve as rescue therapy for perioperative refractory respiratory failure in pediatric LT.

Population Pharmacokinetics and Pharmacodynamics of Meropenem in Critically Ill Pediatric Patients.

This study investigates the optimal meropenem (MEM) dosing regimen for critically ill pediatric patients, for which there is a lack of pharmacokinetic (PK) studies. We conducted a retrospective single-center PK and pharmacodynamic (PD) analysis of 34 pediatric intensive care unit patients who received MEM. Individual PK parameters were determined by a two-compartment analysis. The median (range) age and body weight were 1.4 (0.03 to 14.6) years and 8.9 (2.7 to 40.9) kg, respectively, and eight (23.5%) patients received continuous renal replacement therapy (CRRT), three of whom received extracorporeal membrane oxygenation. Renal function, the systemic inflammatory response syndrome (SIRS) score for the clearance (CL), and the use of CRRT for the central volume of distribution (Vc) were identified as significant covariates. The mean CL, Vc, and peripheral volume of distribution (Vp) were 0.45 liters/kg/h, 0.49 liters/kg, and 0.34 liters/kg, respectively. The mean population CL of MEM increased by 35% in patients with SIRS and Vc increased by 66% in patients on CRRT in the final model. Dosing simulations suggested that the standard dosing regimen provided insufficient PD exposures of a 100% free time above the MIC, and higher doses (40 to 80 mg/kg of body weight/dose every 8 h) with a prolonged 3-h infusion were required to ensure the appropriate PD exposures for patients with SIRS. Our PK model indicated that critically ill pediatric patients are at risk of subtherapeutic exposure under the standard dosing regimen of MEM. A larger, prospective investigation confirming the safety and efficacy of higher concentrations and prolonged infusion of MEM is necessary.

Extracellular Vesicles: A New Frontier for Research in Acute Respiratory Distress Syndrome.

Recent research on extracellular vesicles (EVs) has provided new insights into pathogenesis and potential therapeutic options for acute respiratory distress syndrome (ARDS). EVs are membrane-bound anuclear structures that carry important intercellular communication mechanisms, allowing targeted transfer of diverse biologic cargo, including protein, mRNA, and microRNA, among several different cell types. In this review, we discuss the important role EVs play in both inducing and attenuating inflammatory lung injury in ARDS as well as in sepsis, the most important clinical cause of ARDS. We discuss the translational challenges that need to be overcome before EVs can also be used as prognostic biomarkers in patients with ARDS and sepsis. We also consider how EVs may provide a platform for novel therapeutics in ARDS.

Dose-Dependent Pulmonary Toxicity of Aerosolized Vitamin E Acetate.

Electronic-cigarette, or vaping, product use-associated lung injury (EVALI) is a syndrome of acute respiratory failure characterized by monocytic and neutrophilic alveolar inflammation. Epidemiological and clinical evidence suggests a role of vitamin E acetate (VEA) in the development of EVALI, yet it remains unclear whether VEA has direct pulmonary toxicity. To test the hypotheses that aerosolized VEA causes lung injury in mice and directly injures human alveolar epithelial cells, we exposed adult mice and primary human alveolar epithelial type II (AT II) cells to an aerosol of VEA generated by a device designed for vaping oils. Outcome measures in mice included lung edema, BAL analysis, histology, and inflammatory cytokines; in vitro outcomes included cell death, cytokine release, cellular uptake of VEA, and gene-expression analysis. Comparison exposures in both models included the popular nicotine-containing JUUL aerosol. We discovered that VEA caused dose-dependent increases in lung water and BAL protein compared with control and JUUL-exposed mice in association with increased BAL neutrophils, oil-laden macrophages, multinucleated giant cells, and inflammatory cytokines. VEA aerosol was also toxic to AT II cells, causing increased cell death and the release of monocyte and neutrophil chemokines. VEA was directly absorbed by AT II cells, resulting in the differential gene expression of several inflammatory biological pathways. Given the epidemiological and clinical characteristics of the EVALI outbreak, these results suggest that VEA plays an important causal role.

Protective role of testis-specific peroxiredoxin 4 against cellular oxidative stress.

Peroxiredoxin (PRDX), a newly discovered antioxidant enzyme, has an important role in hydrogen peroxide reduction. Among six PRDX genes (PRDX1-6) in mammals, PRDX4 gene is alternatively spliced to produce the somatic cell form (PRDX4) and the testis specific form (PRDX4t). In our previous study, PRDX4 knockout mice displayed testicular atrophy with an increase in cell death due to oxidative stress. However, the antioxidant function of PRDX4t is unknown. In this study, we demonstrate that PRDX4t plays a protective role against oxidative stress in the mammalian cell line HEK293T. The PRDX4t-EGFP plasmid was transferred into HEK293T cells; protein expression was confirmed in the cytoplasm. To determine the protective role of PRDX4t in cells, we performed image-based analysis of PRDX4t-EGFP expressed cells exposed to UV irradiation and hydrogen peroxide using fluorescent probe CellROX. Our results suggested that PRDX4t-EGFP expressed cells had reduced levels of oxidative stress compared with cells that express only EGFP. This study highlights that PRDX4t plays an important role in cellular antioxidant defense.

Continuous Veno-Venous Hemodiafiltration and Plasma Exchange in Infantile Acute Liver Failure.

OBJECTIVES: The purpose of the current study was to assess our multidisciplinary approach consisting of early application of neurology-oriented intensive care, aggressive artificial liver support and liver transplantation at the appropriate time for infants with acute liver failure. DESIGN: Retrospective cohort study. SETTING: A tertiary pediatric medical center in Japan. PATIENTS: Seventeen infants younger than 12 months with acute liver failure who subsequently underwent liver transplantation between February 2006 and June 2011. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The patients varied from 1 to 11 months, with a median of 6 months. The median body weight was 8.0 kg (range, 2.7-10 kg). With respect to the encephalopathy grading before liver transplantation, four cases were categorized as grade II, seven cases were categorized as grade III, and five cases were categorized as grade IV. Continuous veno-venous hemodiafiltration and plasma exchange were applied to all the infants until liver transplantation. Bilirubin, ammonia, prothrombin time/international normalized ratio and creatinine decreased significantly after continuous veno-venous hemodiafiltration + plasma exchange (p < 0.001). The median value of catecholamine index changed from 10 to 0 (range, 0-20.6). Notably, among the 16 infants who underwent electroencephalography assessment, five did not show slow waves throughout their stay, and one who did so before treatment ceased to show any after treatment. The all patients underwent living-donor liver transplantation and were subsequently discharged from the PICU. The overall survival rate was 88% (15/17) with a median follow-up period of 28 months (range, 2-64 mo). Regarding the neurological outcomes of the survivors, 73% (11/15) had no neurological morbidities and 20% (3/15) had mild disabilities. CONCLUSIONS: Our multidisciplinary approach for infants with acute liver failure achieved favorable outcomes. Further investigations are needed to examine the efficacy of the artificial liver support.

Inadvertent Arterial Placement of a Peripherally Inserted Central Catheter in an Infant With Dilated Cardiomyopathy: A Case Report.

Peripherally inserted central catheter (PICC) placement under real-time ultrasound guidance has emerged as a favorable procedure in children as a method to efficiently obtain central access. Nevertheless, small infants with hemodynamic instability are at high risk of complications and extra precautions are necessary. We present a case of an inadvertent arterial placement of a PICC in a two-month-old infant with dilated cardiomyopathy and decompensated heart failure. Differentiation of arteries and veins under ultrasonographic evaluation may sometimes be difficult when the applied tourniquet pressure exceeds the patient's arterial blood pressure. In particular, arterial flow can be easily compromised by applying tourniquet pressure in small children with low blood pressure. A thorough understanding of the upper extremity vascular anatomy, basic scanning techniques, and meticulous preparation especially in small infants with hemodynamic instability are essential for maintaining the safety and efficacy of this procedure.

A Case of Acute Necrotizing Encephalopathy With Multiple Organ Failure Following COVID-19.

Neurological complications are frequent non-respiratory complications associated with coronavirus disease 2019 (COVID-19), and acute encephalopathy (AE) has been reported to occur in 2.2% of patients. Among many phenotypes of AEs, acute necrotizing encephalopathy (ANE) is associated with multiple organ failure (MOF), leading to severe neurological morbidity and mortality. A previously healthy seven-year-old girl presented with a one-day history of fever followed by 12 hours of vomiting and altered consciousness. On arrival, the patient was in shock. Blood tests revealed severe acute liver failure and kidney injury, accompanied by coagulopathy. The serum interleukin-6 levels were also elevated. PCR testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was positive. A head CT scan showed heterogeneous low-density areas in the bilateral thalamus, without brainstem involvement. She was diagnosed as ANE complicated with MOF (ANE severity score = 6). Intravenous methylprednisolone and therapeutic plasma exchange (TPE) were initiated with neurocritical care. After the introduction of TPE, hemodynamics improved rapidly, followed by gradual improvement in neurological manifestations. Upon follow-up after two months, no neurological or systemic sequelae were noted. Although further studies are needed, our case suggests that early immunomodulatory therapy and TPE may have contributed to the improvement in ANE and MOF associated with COVID-19.

Severe Pasteurella multocida Infection in a Neonate: A Case Report and Literature Review.

Pasteurella multocida is a well-known cause of skin and soft tissue infections resulting from animal bites. The patient was a newborn male with no perinatal abnormalities except for a cephalohematoma on the left parietal region. At 10 days of age, he had a bite wound to the cephalohematoma from an indoor dog. The wound was very mild and there was no bleeding. At 12 days of age, he visited a local hospital with a fever and poor feeding. At presentation, he was in septic shock and was transferred to the intensive care unit of the hospital. On day three of hospitalization, P. multocida was identified in the blood culture. On day four of hospitalization, CT of the head revealed multiple low-density lesions in the cerebral parenchyma, and aspiration of the cephalohematoma was performed. A culture of the aspirated fluid also grew P. multocida. On day five of hospitalization, the patient underwent drainage of the cephalohematoma. The patient developed hydrocephalus and worsening cerebral edema injuries, ultimately resulting in severe neurological sequelae. We summarized previous reports on P. multocida infections in children 60 days old or younger. Of the reported cases, neonates accounted for a majority of cases. In addition, nontraumatic exposure was more common than traumatic exposure. The patients requiring surgical intervention and those with neurological sequelae were all neonates. Neonatal P. multocida infection can cause severe systemic illness and neurological sequelae, even in the absence of traumatic exposure.

Successful management with urgent haploidentical-peripheral blood stem cell transplantation for a patient with severe aplastic anaemia who developed disseminated fungal infection following immunosuppressive therapy.

Urgent haploidentical haematopoietic cell transplantation may be considered in cases of severe aplastic anaemia (SAA) without a human leukocyte antigen-matched donor and suffering from severe infection. However, deciding on allogeneic transplantation in the setting of active systemic infection is challenging due to poor outcomes. This report presents a case of disseminated Magnusiomyces capitatus infection in a 5-year-old male who underwent immunosuppressive therapy for hepatitis-associated SAA. To address the critical situation, granulocyte transfusion was promptly administered from the patient's mother, followed by unmanipulated haploidentical peripheral blood stem cell transplantation from the patient's father with posttransplant cyclophosphamide, ultimately resulting in successful rescue.

Biological Effects of Corticosteroids on Pneumococcal Pneumonia in Mice and Humans.

Background: Streptococcus pneumoniae is the most common bacterial cause of community acquired pneumonia and the acute respiratory distress syndrome (ARDS). Some clinical trials have demonstrated a beneficial effect of corticosteroid therapy in community acquired pneumonia, COVID-19, and ARDS, but the mechanisms of this benefit remain unclear. The objective of this study was to investigate the effects of corticosteroids on the pulmonary biology of pneumococcal pneumonia in an observational cohort of mechanically ventilated patients and in a mouse model of bacterial pneumonia with Streptococcus pneumoniae. Methods: We studied gene expression with lower respiratory tract transcriptomes from a cohort of mechanically ventilated patients and in mice. We also carried out comprehensive physiologic, biochemical, and histological analyses in mice to identify the mechanisms of lung injury in Streptococcus pneumoniae with and without adjunctive steroid therapy. Results: Transcriptomic analysis identified pleiotropic effects of steroid therapy on the lower respiratory tract in critically ill patients with pneumococcal pneumonia, findings that were reproducible in mice. In mice with pneumonia, dexamethasone in combination with ceftriaxone reduced (1) pulmonary edema formation, (2) alveolar protein permeability, (3) proinflammatory cytokine release, (4) histopathologic lung injury score, and (5) hypoxemia but did not increase bacterial burden. Conclusions: The gene expression studies in patients and in the mice support the clinical relevance of the mouse studies, which replicate several features of pneumococcal pneumonia and steroid therapy in humans. In combination with appropriate antibiotic therapy in mice, treatment of pneumococcal pneumonia with steroid therapy reduced hypoxemia, pulmonary edema, lung permeability, and histologic criteria of lung injury, and also altered inflammatory responses at the protein and gene expression level. The results from these studies provide evidence for the mechanisms that may explain the beneficial effects of glucocorticoid therapy in patients with community acquired pneumonia from Streptococcus Pneumoniae.

Method to Alleviate Dilutional Coagulopathy Caused by Continuous Renal Replacement Therapy Introduction in a Low-Birth-Weight Neonate: A Case Report.

Continuous renal replacement therapy (CRRT) in neonates and children has recently been used to treat hyperammonemia and metabolic disorders. However, CRRT introduction in low-birth-weight neonates is still a challenge due to vascular access limitations, bleeding complications, and a lack of neonatal-specific devices. We present the case of a low-birth-weight neonate whose severe coagulopathy due to CRRT introduction with a red cell concentration-primed circuit was alleviated by priming the new circuit with blood from the current circuit. This male preterm infant (birth weight: 1,935 g) was admitted to the pediatric intensive care unit at two days old with metabolic acidosis and hyperammonemia, which required CRRT. Following CRRT introduction, he showed marked thrombocytopenia (platelet count: 305,000-59,000/µL) and coagulopathy (prothrombin time international normalized ratio (PT/INR) >10), necessitating platelet and fresh frozen plasma transfusions. Upon circuit exchange, we primed the new circuit with blood from the current circuit. This resulted in only a slight worsening of thrombocytopenia (platelet count: 56,000-32,000/µL) and almost no change in coagulation (PT/INR: 1.42-1.54). We also reviewed the literature regarding safe CRRT management in low-birth-weight neonates. Since there is no established method for the use of blood from the current circuit during circuit exchange, this should be addressed in future work.

SARS-CoV-2 infection of airway organoids reveals conserved use of Tetraspanin-8 by Ancestral, Delta, and Omicron variants.

Ancestral SARS coronavirus-2 (SARS-CoV-2) and variants of concern (VOC) caused a global pandemic with a spectrum of disease severity. The mechanistic explaining variations related to airway epithelium are relatively understudied. Here, we biobanked airway organoids (AO) by preserving stem cell function. We optimized viral infection with H1N1/PR8 and comprehensively characterized epithelial responses to SARS-CoV-2 infection in phenotypically stable AO from 20 different subjects. We discovered Tetraspanin-8 (TSPAN8) as a facilitator of SARS-CoV-2 infection. TSPAN8 facilitates SARS-CoV-2 infection rates independently of ACE2-Spike interaction. In head-to-head comparisons with Ancestral SARS-CoV-2, Delta and Omicron VOC displayed lower overall infection rates of AO but triggered changes in epithelial response. All variants shared highest tropism for ciliated and goblet cells. TSPAN8-blocking antibodies diminish SARS-CoV-2 infection and may spur novel avenues for COVID-19 therapy.

ARDS clinical practice guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D); we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D); we suggest against routinely implementing NO inhalation therapy (GRADE 2C); and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jrs.or.jp/publication/jrs_guidelines/). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

ARDS Clinical Practice Guideline 2021.

BACKGROUND: The joint committee of the Japanese Society of Intensive Care Medicine/Japanese Respiratory Society/Japanese Society of Respiratory Care Medicine on ARDS Clinical Practice Guideline has created and released the ARDS Clinical Practice Guideline 2021. METHODS: The 2016 edition of the Clinical Practice Guideline covered clinical questions (CQs) that targeted only adults, but the present guideline includes 15 CQs for children in addition to 46 CQs for adults. As with the previous edition, we used a systematic review method with the Grading of Recommendations Assessment Development and Evaluation (GRADE) system as well as a degree of recommendation determination method. We also conducted systematic reviews that used meta-analyses of diagnostic accuracy and network meta-analyses as a new method. RESULTS: Recommendations for adult patients with ARDS are described: we suggest against using serum C-reactive protein and procalcitonin levels to identify bacterial pneumonia as the underlying disease (GRADE 2D); we recommend limiting tidal volume to 4-8 mL/kg for mechanical ventilation (GRADE 1D); we recommend against managements targeting an excessively low SpO2 (PaO2) (GRADE 2D); we suggest against using transpulmonary pressure as a routine basis in positive end-expiratory pressure settings (GRADE 2B); we suggest implementing extracorporeal membrane oxygenation for those with severe ARDS (GRADE 2B); we suggest against using high-dose steroids (GRADE 2C); and we recommend using low-dose steroids (GRADE 1B). The recommendations for pediatric patients with ARDS are as follows: we suggest against using non-invasive respiratory support (non-invasive positive pressure ventilation/high-flow nasal cannula oxygen therapy) (GRADE 2D), we suggest placing pediatric patients with moderate ARDS in the prone position (GRADE 2D), we suggest against routinely implementing NO inhalation therapy (GRADE 2C), and we suggest against implementing daily sedation interruption for pediatric patients with respiratory failure (GRADE 2D). CONCLUSIONS: This article is a translated summary of the full version of the ARDS Clinical Practice Guideline 2021 published in Japanese (URL: https://www.jsicm.org/publication/guideline.html ). The original text, which was written for Japanese healthcare professionals, may include different perspectives from healthcare professionals of other countries.

SARS-CoV-2 infection studies in lung organoids identify TSPAN8 as novel mediator.

SARS coronavirus-2 (SARS-CoV-2) is causing a global pandemic with large variation in COVID-19 disease spectrum. SARS-CoV-2 infection requires host receptor ACE2 on lung epithelium, but epithelial underpinnings of variation are largely unknown. We capitalized on comprehensive organoid assays to report remarkable variation in SARS-CoV-2 infection rates of lung organoids from different subjects. Tropism is highest for TUBA- and MUC5AC-positive organoid cells, but levels of TUBA-, MUC5A-, or ACE2- positive cells do not predict infection rate. We identify surface molecule Tetraspanin 8 (TSPAN8) as novel mediator of SARS-CoV-2 infection, which is not downregulated by this specific virus. TSPAN8 levels, prior to infection, strongly correlate with infection rate and TSPAN8-blocking antibodies diminish SARS-CoV-2 infection. We propose TSPAN8 as novel functional biomarker and potential therapeutic target for COVID-19.