Respiratory Distress Research Articles

Stage IV renal cell carcinoma achieves pathologic complete response after two ipilimumab plus nivolumab courses despite severe immune-related adverse events: a case report

BackgroundIpilimumab (Ipi) plus nivolumab (Nivo) is the recommended first-line treatment for renal cell carcinoma (RCC). This report describes a case where pancreatic metastases disappeared after only two courses of Ipi + Nivo therapy. The primary tumor was cured by surgery, and a pathological Complete Response (pCR) was observed despite multiple serious immune-related Adverse Events (irAEs).Case presentationA 54-year-old woman with RCC and pancreatic metastasis at stage IV, diagnosed with intermediate risk according to the International Metastatic RCC Database Consortium classification, underwent initiation of Ipi + Nivo therapy. On day 26, she developed hyperthyroidism accompanied by tachycardia, leading to the commencement of metoprolol tartrate treatment. Following the resolution of tachycardia, a second course of Ipi + Nivo therapy was administered on day 50. By day 70, the patient exhibited Grade 3 hepatic dysfunction, followed by the onset of hypothyroidism on day 75, necessitating treatment with steroids and levothyroxine. After positive treatment, a Grade 3 skin disorder emerged on day 87 while tapering steroids, prompting treatment with methylprednisolone (mPSL) pulse therapy. The skin disorder responded to steroids, allowing for tapering. However, on day 113, a recurrence of Grade 3 skin disorder occurred, necessitating another mPSL pulse. The patient responded well to treatment, exhibiting improvement in her condition. On day 131, she presented at the hospital with complaints of respiratory distress, prompting a Computed Tomography (CT) scan that revealed interstitial pneumonia. By day 272, subsequent CT imaging showed the disappearance of pancreatic metastasis and shrinkage of the primary tumor. On day 294, she underwent a laparoscopic left nephrectomy. Pathological analysis confirmed a pCR in the primary tumor, indicating successful eradication of RCC through surgical intervention.ConclusionsThis case report presents a scenario where multiple severe irAEs appeared in a patient, yet metastases disappeared after only two courses of Ipi + Nivo therapy. The patient was ultimately cured by surgery and achieved a pCR. This case highlights that despite the occurrence of severe irAEs during RCC treatment with Ipi + Nivo therapy, they can be managed appropriately to maximize the therapeutic effects of checkpoint inhibitors.

Recurrent hyponatremia in neonate: a case of renal salt wasting syndrome

BackgroundRenal salt wasting (RSW) is primarily seen with central nervous disorders and is characterized by hyponatremia, elevated urinary sodium excretion, increased urine output, and hypovolemia. Although there have been reports of RSW in children, it has not been reported in newborns.Case presentationA term (38 weeks 2 days) female weighing 2060 g, born via normal vaginal delivery, to a primi-gravida mother, was admitted to our neonatal intensive care unit. At birth, the baby was non-vigorous, had aspirated meconium, and required bag-and-mask ventilation following which the baby cried. The child was put on CPAP and inotropes for respiratory distress and shock, respectively, along with first-line antibiotics. Over the next few days, the child was weaned off CPAP, inotropes were stopped, and feeds were started. On postnatal day (PND) 8, the baby developed repeated episodes of seizures requiring two-antiepileptics followed by midazolam infusion, had shock requiring inotropes, and also had a tense anterior fontanelle with altered sensorium and tone changes, for which mannitol and 3% saline were given. Antibiotics were upgraded, and neuroimaging (MRI) revealed left basal-ganglia bleed with intraventricular extension and cerebral venous thrombosis. The baby showed gradual clinical improvement with the above measures and was restarted on feeds. However, from PND-19 onwards the baby had repeated episodes of hyponatremia requiring 3% saline infusions, progressive weight loss, and polyuria. Considering RSW, urine sodium was done which was high (110 mmol/L). For polyuria and weight loss, feed volume was increased, whereas, for hyponatremia, table salt was added to the expressed breast milk (1 gm × tds). Subsequently, all the serum sodium values remained within normal limits, and the baby started gaining weight and was discharged on similar advice (PND 38). On further follow-up, table salt was gradually decreased in the feeds and was stopped after 1 month of discharge with normal serum sodium values.ConclusionManagement of recurrent hyponatremia in a neonate is challenging. Despite its rarity, RSW in newborns should be considered a differential.

High-flow nasal cannula oxygen therapy is equally effective to noninvasive ventilation for mild-moderate acute respiratory distress syndrome in patients with acute pancreatitis: A single-center, retrospective cohort study.

The use of high-flow nasal cannula (HFNC) oxygen therapy is gaining popularity for the treatment of acute hypoxic respiratory failure. However, limited evidence exists regarding the effectiveness of HFNC for acute respiratory distress syndrome (ARDS) in patients with acute pancreatitis (AP). This retrospective analysis focused on AP patients with mild-moderate ARDS, who were treated with either HFNC or noninvasive ventilation (NIV) in the emergency medicine department, from January 2020 to December 2022. The primary endpoint was treatment failure, defined as either invasive ventilation or a switch to any other study treatment (NIV for patients in the NFNC group and vice versa). A total of 146 patients with AP (68 in the HFNC group and 78 in the NIV group) were included in this study. The treatment failure rate in the HFNC group was 17.6% and 19.2% in the NIV group - a risk difference of -1.6% (95% CI, -11.3 to 14.0%; P = 0.806). The most common causes of failure in the HFNC group were aggravation of respiratory distress and hypoxemia. However, in the NIV group, the most common reasons for failure were treatment intolerance and exacerbation of respiratory distress. Treatment intolerance in the HFNC group was significantly lower than that in the NIV group (16.7% vs 60.0%, 95% CI -66.8 to -6.2; P = 0.023). Multivariate logistic regression analysis showed that body mass index (≥28), acute physiology and chronic health evaluation II score (≥15), partial arterial oxygen tension/fraction of inspired oxygen (≤200), and respiratory rate (≥32/min) at 1 hour were independent predictors of HFNC failure. In AP patients with mild-moderate ARDS, the usage of HFNC did not lead to a higher rate of treatment failure when compared to NIV. HFNC is an ideal choice of respiratory support for patients with NIV intolerance, but clinical application should pay attention to the influencing factors of its treatment failure.

Rhabdomyolysis – A Rare Presentation of COVID-19

Abstract COVID-19 pandemic presented a great global health-care challenge. The spectrum of illness comprises pulmonary and extrapulmonary manifestations including hepatic, renal, and neurological complications. Our patient is a young male who presented with fever, severe myalgia, and respiratory distress. After a thorough clinical examination and laboratory investigations, the diagnosis of COVID-19 pneumonia and associated rhabdomyolysis was made. He developed acute renal failure for which intravenous hydration was given. He also required renal replacement therapy. He was successfully treated and discharged with complete remission of symptoms. We did a literature search for similar cases and have discussed the potential mechanisms implied for these complications.

Role of Lung Ultrasonography in Acute Respiratory Distress in Pediatric Age Group: A Prospective Single-Centre Study

Role of Lung Ultrasonography in Acute Respiratory Distress in Pediatric Age Group: A Prospective Single-Centre Study

COVID-19 and mechanical ventilation

Mechanical ventilation (MV) is used to treat patients with severe coronavirus disease 2019 (COVID-19). This severe respiratory illness, typically develops 8 days after symptom onset and when it does not respond to non‐invasive respiratory support, it requires advanced respiratory support, including high concentrations of inspired oxygen and mechanical ventilation. Such therapies are also required for the acute respiratory distress syndrome (ARDS), which has been widely studied over several decade. Obesity as a disease causes a restrictive lung disease and is a sufficient predisposing factor for difficult ventilation. Higher BMI patients are more likely to be young, with single organ failure, less chronic comorbidity but with increased severity of hypoxemia at presentation. Severe respiratory failure from coronavirus disease 2019 pneumonia not responding to non‐invasive respiratory support requires mechanical ventilation. Although ventilation can be a life‐saving therapy, it can cause further lung injury if airway pressure and flow and their timing are not tailored to the respiratory system mechanics of the individual patient. The phenomenon of “hard lung” is observed as the ventilation of the intubated patient is very arduous and recruitment requires a lot of effort. Coronavirus disease 2019-induced acute respiratory distress syndrome is more severe in morbidly obese patients. This relationship between BMI and mortality was investigated by several observational studies, but the relationship was not universally observed. Some studies found increased BMI was associated with an increased risk of requiring intubation and ventilation, but with no clear relationship with mortality. The combination is quite difficult as these patients oppose the ventilator. Our objective was to determine the association between MV for treatment of COVID-19.

Efficacy and Safety of High PEEP NIV in COVID-19 Patients.

To investigate the efficacy and safety of non-invasive ventilation (NIV) with high PEEP levels application in patients with COVID-19-related acute respiratory distress syndrome (ARDS). This is a retrospective cohort study with data collected from 95 patients who were administered NIV as part of their treatment in the COVID-19 intensive care unit (ICU) at University Hospital Centre Zagreb between October 2021 and February 2022. The definite outcome was NIV failure. High PEEP NIV was applied in all 95 patients; 54 (56.84%) patients could be kept solely on NIV, while 41 (43.16%) patients required intubation. ICU mortality of patients solely on NIV was 3.70%, while total ICU mortality was 35.79%. The most significant difference in the dynamic of respiratory parameters between 2 patient groups was visible on Day 3 of ICU stay: By that day, patients kept solely on NIV required significantly lower PEEP levels and had better improvement in PaO2, P/F ratio, and HACOR score. High PEEP applied by NIV was a safe option for the initial respiratory treatment of all patients, despite the severity of ARDS. For some patients, it was also shown to be the only necessary form of oxygen supplementation.

A Case of Conservatively Managed Thymic Enlargement Secondary to Haemorrhage in a Newborn

Thymic haemorrhage is rare in neonates. We report a case of a newborn infant with respiratory distress, who had findings of a widened mediastinum and enlarged thymic shadow on chest radiography. Ultrasound and magnetic resonance imaging studies demonstrated a heterogenous lobulated anterior mediastinal mass proven on biopsy to represent an intrathymic haemorrhage. To the best of our knowledge, this was the only case reported in the literature to have not required any invasive ventilator support or blood products. It is therefore important to illustrate that this unusual pathology can respond well to conservative as well as more aggressive management strategies.

Biological effects of corticosteroids on pneumococcal pneumonia in Mice—translational significance

BackgroundStreptococcus 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.MethodsWe 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.ResultsIn 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.ConclusionsIn 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.

Duration of Invasive Mechanical Ventilation before Veno-Venous ExtraCorporeal Membrane Oxygenation for Covid-19 related Acute Respiratory Distress Syndrome: The experience of a tertiary care center

BackgroundVeno-Venous Extracorporeal Membrane Oxygenation (VV-ECMO) is an efficient ventilatory support in patients with refractory Covid-19-related Acute Respiratory Distress Syndrome (ARDS), however the duration of invasive mechanical ventilation (IMV) before ECMO initiation as a contraindication is still controversial. The aim of this study was to investigate the impact of prolonged IMV prior to VV-ECMO in patients suffering from refractory Covid-19-related ARDS. MethodsThis single-center retrospective study included all patients treated with VV-ECMO for refractory Covid-19-related ARDS between January 1, 2020 and May 31, 2022. The impact of IMV duration was investigated by comparing patients on VV-ECMO during the 7 days (and 10 days) following IMV with those assisted after 7 days (and 10 days). The primary endpoint was in-hospital mortality. ResultsSixty-four patients were hospitalized in the ICU for Covid-19-related refractory ARDS requiring VV-ECMO. Global in-hospital mortality was 55 %. Median duration of IMV was 4 [2; 8] days before VV-ECMO initiation. There was no significant difference in in-hospital mortality between patients assisted with IMV pre-VV-ECMO for a duration of ≤7 days (≤10 days) and those assisted after 7 days (and 10 days) ((p = 0.59 and p = 0.45). ConclusionThis study suggests that patients assisted with VV-ECMO after prolonged IMV had the same prognosis than those assisted earlier in refractory Covid-19-related ARDS. Therefore, prolonged mechanical ventilation of more than 7–10 days should not contraindicate VV-ECMO support. An individual approach is necessary to balance the risks and benefits of ECMO in this population.

Prediction models for COVID-19 disease outcomes

ABSTRACT SARS-CoV-2 has caused over 6.9 million deaths and continues to produce lasting health consequences. COVID-19 manifests broadly from no symptoms to death. In a retrospective cross-sectional study, we developed personalized risk assessment models that predict clinical outcomes for individuals with COVID-19 and inform targeted interventions. We sequenced viruses from SARS-CoV-2-positive nasopharyngeal swab samples between July 2020 and July 2022 from 4450 individuals in Missouri and retrieved associated disease courses, clinical history, and urban-rural classification. We integrated this data to develop machine learning-based predictive models to predict hospitalization, ICU admission, and long COVID. The mean age was 38.3 years (standard deviation = 21.4) with 55.2% (N = 2453) females and 44.8% (N = 1994) males (not reported, N = 4). Our analyses revealed a comprehensive set of predictors for each outcome, encompassing human, environment, and virus genome-wide genetic markers. Immunosuppression, cardiovascular disease, older age, cardiac, gastrointestinal, and constitutional symptoms, rural residence, and specific amino acid substitutions were associated with hospitalization. ICU admission was associated with acute respiratory distress syndrome, ventilation, bacterial co-infection, rural residence, and non-wild type SARS-CoV-2 variants. Finally, long COVID was associated with hospital admission, ventilation, and female sex. Overall, we developed risk assessment models that offer the capability to identify patients with COVID-19 necessitating enhanced monitoring or early interventions. Of importance, we demonstrate the value of including key elements of virus, host, and environmental factors to predict patient outcomes, serving as a valuable platform in the field of personalized medicine with the potential for adaptation to other infectious diseases.

Disruption of pulmonary microvascular endothelial barrier by dysregulated claudin-8 and claudin-4: uncovered mechanisms in porcine reproductive and respiratory syndrome virus infection

The pulmonary endothelium is a dynamic and metabolically active monolayer of endothelial cells. Dysfunction of the pulmonary endothelial barrier plays a crucial role in the acute lung injury (ALI) and acute respiratory distress syndrome (ARDS), frequently observed in the context of viral pneumonia. Dysregulation of tight junction proteins can lead to the disruption of the endothelial barrier and subsequent leakage. Here, the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) served as an ideal model for studying ALI and ARDS. The alveolar lavage fluid of pigs infected with HP-PRRSV, and the supernatant of HP-PRRSV infected pulmonary alveolar macrophages were respectively collected to treat the pulmonary microvascular endothelial cells (PMVECs) in Transwell culture system to explore the mechanism of pulmonary microvascular endothelial barrier leakage caused by viral infection. Cytokine screening, addition and blocking experiments revealed that proinflammatory cytokines IL-1β and TNF-α, secreted by HP-PRRSV-infected macrophages, disrupt the pulmonary microvascular endothelial barrier by downregulating claudin-8 and upregulating claudin-4 synergistically. Additionally, three transcription factors interleukin enhancer binding factor 2 (ILF2), general transcription factor III C subunit 2 (GTF3C2), and thyroid hormone receptor-associated protein 3 (THRAP3), were identified to accumulate in the nucleus of PMVECs, regulating the transcription of claudin-8 and claudin-4. Meanwhile, the upregulation of ssc-miR-185 was found to suppress claudin-8 expression via post-transcriptional inhibition. This study not only reveals the molecular mechanisms by which HP-PRRSV infection causes endothelial barrier leakage in acute lung injury, but also provides novel insights into the function and regulation of tight junctions in vascular homeostasis.

Determining Extracorporeal Membrane Oxygenation Outcomes in Obese Patients with ARDS

Extracorporeal membrane oxygenation (ECMO) is crucial for managing acute respiratory distress syndrome (ARDS) refractory to conventional therapy, but its impact on obese ARDS patients remains inadequately understood due to relative contraindications per the Extracorporeal Life Support Organization (ELSO) guidelines. This study aimed to analyze the association between obesity and ECMO outcomes in ARDS patients. Using five years of National Inpatient Sample data (2016–2020), we identified ARDS patients through ICD-10 codes, classifying those with a BMI > 30 as obese. Univariate and multivariate analyses were performed to assess mortality, rates of left ventricular assist devices, and tracheostomy differences between obese and non-obese patients, with secondary outcomes examining the impact of obesity on length of stay (LOS) and total hospitalization charges (TOTCHG). Among 3,219 ARDS patients requiring ECMO, 8.2% were obese. While initial univariate analysis showed a non-significant 43% lower mortality odd in obese patients, adjusting for confounders revealed a statistically significant 46% lower odd of mortality compared to non-obese patients (adjusted odds ratio 0.54, 95% confidence interval 0.3-0.94, p 0.032). LOS and TOTCHG did not significantly differ between the two groups, nor did the rates of LVAD or tracheostomy. These findings suggest that obesity may confer a survival advantage in ARDS patients undergoing ECMO, potentially due to factors such as nutritional reserves and the obesity paradox observed in critical illnesses. Therefore, BMI alone should not preclude obese patients from ECMO treatment, emphasizing the need for further research to inform clinical decision-making in this population.

COVID-19 influenced gut dysbiosis, post-acute sequelae, immune regulation, and therapeutic regimens.

The novel coronavirus disease 2019 (COVID-19) pandemic outbreak caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has garnered unprecedented global attention. It caused over 2.47 million deaths through various syndromes such as acute respiratory distress, hypercoagulability, and multiple organ failure. The viral invasion proceeds through the ACE2 receptor, expressed in multiple cell types, and in some patients caused serious damage to tissues, organs, immune cells, and the microbes that colonize the gastrointestinal tract (GIT). Some patients who survived the SARS-CoV-2 infection have developed months of persistent long-COVID-19 symptoms or post-acute sequelae of COVID-19 (PASC). Diagnosis of these patients has revealed multiple biological effects, none of which are mutually exclusive. However, the severity of COVID-19 also depends on numerous comorbidities such as obesity, age, diabetes, and hypertension and care must be taken with respect to other multiple morbidities, such as host immunity. Gut microbiota in relation to SARS-CoV-2 immunopathology is considered to evolve COVID-19 progression via mechanisms of biochemical metabolism, exacerbation of inflammation, intestinal mucosal secretion, cytokine storm, and immunity regulation. Therefore, modulation of gut microbiome equilibrium through food supplements and probiotics remains a hot topic of current research and debate. In this review, we discuss the biological complications of the physio-pathological effects of COVID-19 infection, GIT immune response, and therapeutic pharmacological strategies. We also summarize the therapeutic targets of probiotics, their limitations, and the efficacy of preclinical and clinical drugs to effectively inhibit the spread of SARS-CoV-2.

Clinical Characteristics and Outcomes of Disseminated Strongyloidiasis in the United States-A Multicenter Network Analysis.

Human strongyloidiasis is a potentially life-threatening parasitic disease among immunocompromised hosts. We aim to determine the factors and mortality associated with disseminated strongyloidiasis. We conducted a U.S.-based multicenter retrospective cohort study to determine 90-day clinical outcomes for people diagnosed with Strongyloides infection in the TriNetX patient database. We identified adult patients with the International Classification of Diseases (10th revision, clinical modification) code for Strongyloides infection (B78) or a positive Strongyloides IgG antibody test and captured outcomes at 90 days. We identified 5,434 patients with strongyloidiasis, of whom 48 had disseminated strongyloidiasis for 0.9% prevalence of disseminated disease. Systemic connective tissue disorders, pulmonary eosinophilia, liver cirrhosis, blood disorders (monoclonal gammopathy, aplastic anemia, and lymphoid malignancy), malnutrition, alcohol use disorder, and transplantation status were frequent in patients with disseminated disease. Mortality was significantly higher in people with disseminated disease at 30 days (21%). The 90-day risk of hospitalization, bacteremia, and acute respiratory distress syndrome (ARDS) was higher in those with disseminated infection. People with disseminated strongyloidiasis had a heightened risk of hospitalization, bacteremia, acute respiratory distress syndrome, and mortality. The population at risk for severe strongyloidiasis infection is evolving, reflecting conditions in which glucocorticoids or additional immunosuppressive medications are commonly used for treatment.

Fetal large tubular oesophageal duplication cyst: A case report

AbstractIntroductionOesophageal duplication cyst (EDC) is a rare congenital anomaly representing, after neuronal tumours, the second most common cause of posterior mass in children, with a prevalence of approximately 1/22,500 live births. Cervical cysts are very rare, and their antenatal detection is fairly uncommon.MethodsWe report the case of an isolated large mediastinal and cervical tubular EDC diagnosed prenatally in the third trimester.ResultsAfter birth, the baby became symptomatic developing respiratory distress due to the enlargement of the cyst and she underwent excision of the mass. The post‐operative evolution was very good.ConclusionOur purpose was to raise awareness of the ultrasonographic features of this condition, thus improving the rate of prenatal diagnosis and offering the parents a proper counselling regarding the prognosis and the need for a further multidisciplinary approach after birth.

Identifying novel clinical phenotypes of acute respiratory distress syndrome using trajectories of daily fluid balance: a secondary analysis of randomized controlled trials

BackgroundPreviously identified phenotypes of acute respiratory distress syndrome (ARDS) could not reveal the dynamic change of phenotypes over time. We aimed to identify novel clinical phenotypes in ARDS using trajectories of fluid balance, to test whether phenotypes respond differently to different treatment, and to develop a simplified model for phenotype identification.MethodsFACTT (conservative vs liberal fluid management) trial was classified as a development cohort, joint latent class mixed models (JLCMMs) were employed to identify trajectories of fluid balance. Heterogeneity of treatment effect (HTE) for fluid management strategy across phenotypes was investigated. We also constructed a parsimonious probabilistic model using baseline data to predict the fluid trajectories in the development cohort. The trajectory groups and the probabilistic model were externally validated in EDEN (initial trophic vs full enteral feeding) trial.ResultsUsing JLCMM, we identified two trajectory groups in the development cohort: Class 1 (n = 758, 76.4% of the cohort) had an early positive fluid balance, but achieved negative fluid balance rapidly, and Class 2 (n = 234, 24.6% of the cohort) was characterized by persistent positive fluid balance. Compared to Class 1 patients, patients in Class 2 had significantly higher 60-day mortality (53.5% vs. 17.8%, p < 0.001), and fewer ventilator-free days (0 vs. 20, p < 0.001). A significant HTE between phenotypes and fluid management strategies was observed in the FACTT. An 8-variables model was derived for phenotype assignment.ConclusionsWe identified and validated two novel clinical trajectories for ARDS patients, with both prognostic and predictive enrichment. The trajectories of ARDS can be identified with simple classifier models.

Acceptability of the Venting Wisely pathway for use in critically ill adults with hypoxaemic respiratory failure and acute respiratory distress syndrome (ARDS): a qualitative study protocol

IntroductionHypoxaemic respiratory failure (HRF) affects nearly 15% of critically ill adults admitted to an intensive care unit (ICU). An evidence-based, stakeholder-informed multidisciplinary care pathway (Venting Wisely) was created to standardise...

Loss of neutrophil Shp1 produces hemorrhagic and lethal acute lung injury.

The acute respiratory distress syndrome (ARDS) is associated with significant morbidity and mortality and neutrophils are critical to its pathogenesis. Neutrophil activation is closely regulated by inhibitory tyrosine phosphatases including Src homology region 2 domain containing phosphatase-1 (Shp1). Here, we report that loss of neutrophil Shp1 in mice produced hyperinflammation and lethal pulmonary hemorrhage in sterile inflammation and pathogen-induced models of acute lung injury (ALI) through a Syk kinase-dependent mechanism. We observed large intravascular neutrophil clusters, perivascular inflammation, and excessive neutrophil extracellular traps in neutrophil-specific Shp1 knockout mice suggesting an underlying mechanism for the observed pulmonary hemorrhage. Targeted immunomodulation through the administration of a Shp1 activator (SC43) reduced agonist-induced reactive oxygen species in vitro and ameliorated ALI-induced alveolar neutrophilia and NETs in vivo. We propose that the pharmacologic activation of Shp1 has the potential to fine-tune neutrophil hyperinflammation that is central to the pathogenesis of ARDS.

The utility value of ROX index and modified ROX index in determining the efficiency of HFNC in children admitted with respiratory distress

Background: The ROX index is defined as the ratio of SpO2/FiO2 to respiratory rate. The modified ROX index or ROX-HR index is defined as the ratio of ROX index/heart rate×100. The aim of the study was to determine the utility of the ROX index and the modified ROX index as predictors of initiation and efficiency of HFNC in children admitted with respiratory distress. Methods: This prospective observational study included 133 children with respiratory distress, who received HFNC. The ROX index, and modified ROX index were measured, and outcomes were recorded. Results: Total number of study subjects were 133. Statistically significant increase was seen in ROX index and modified ROX index at follow up (p value&lt;0.05). Interpretation of the area under the ROC curve showed that the performance of ROX index and modified ROX index at ‘0’ hour was outstanding. ROX Index and modified ROX Index at a Cut-off of ≤4.7959 and ≤2.5579 respectively at initiation i. e.; at ‘0’ hour predicted HFNC requirement. In prediction of HFNC requirement ROX index at ‘0’ hour had a sensitivity, specificity, positive predictive value, and negative predictive value of 88.24%, 87.84%, 93%, and 80.2% respectively, and modified ROX index had 78.68%, 93.24%, 95.5%, and 70.4% respectively. Low ROX and modified ROX indices at ‘0’ hour predicted prolonged ICU and hospital stays, as well as extended HFNC duration. Conclusions: Both ROX index, and modified ROX index were good predictors of HFNC requirement.