Long-term outcome of COVID-19 patients treated with helmet noninvasive ventilation vs. high-flow nasal oxygen: a randomized trial

Background: Long-term outcomes of patients treated with helmet noninvasive ventilation (NIV) are unknown: safety concerns regarding the risk of patient self-inflicted lung injury and delayed intubation exist when NIV is applied in hypoxemic patients. We assessed the 6-month outcome of patients who received helmet NIV or high-flow nasal oxygen for COVID-19 hypoxemic respiratory failure. Methods: In this prespecified analysis of a randomized trial of helmet NIV versus high-flow nasal oxygen (HENIVOT), clinical status, physical performance (6-min-walking-test and 30-s chair stand test), respiratory function and quality of life (EuroQoL five dimensions five levels questionnaire, EuroQoL VAS, SF36 and Post-Traumatic Stress Disorder Checklist for the DSM) were evaluated 6 months after the enrollment. Results: Among 80 patients who were alive, 71 (89%) completed the follow-up: 35 had received helmet NIV, 36 high-flow oxygen. There was no inter-group difference in any item concerning vital signs (N = 4), physical performance (N = 18), respiratory function (N = 27), quality of life (N = 21) and laboratory tests (N = 15). Arthralgia was significantly lower in the helmet group (16% vs. 55%, p = 0.002). Fifty-two percent of patients in helmet group vs. 63% of patients in high-flow group had diffusing capacity of the lungs for carbon monoxide < 80% of predicted (p = 0.44); 13% vs. 22% had forced vital capacity < 80% of predicted (p = 0.51). Both groups reported similar degree of pain (p = 0.81) and anxiety (p = 0.81) at the EQ-5D-5L test; the EQ-VAS score was similar in the two groups (p = 0.27). Compared to patients who successfully avoided invasive mechanical ventilation (54/71, 76%), intubated patients (17/71, 24%) had significantly worse pulmonary function (median diffusing capacity of the lungs for carbon monoxide 66% [Interquartile range: 47–77] of predicted vs. 80% [71–88], p = 0.005) and decreased quality of life (EQ-VAS: 70 [53–70] vs. 80 [70–83], p = 0.01). Conclusions: In patients with COVID-19 hypoxemic respiratory failure, treatment with helmet NIV or high-flow oxygen yielded similar quality of life and functional outcome at 6 months. The need for invasive mechanical ventilation was associated with worse outcomes. These data indicate that helmet NIV, as applied in the HENIVOT trial, can be safely used in hypoxemic patients. Trial registration Registered on clinicaltrials.gov NCT04502576 on August 6, 202

Are Hsp70 protein expression and genetic polymorphism implicated in multiple sclerosis inflammation?

Genetic and environmental factors contribute to disease Multiple Sclerosis (MS) susceptibility, the most prevalent neurological pathology affecting young individuals in Western countries. We focused our attention on HSP70-2, an inducible chaperon induced under stress conditions. Genotype analysis of HSP70-2 (+1267 A/G) polymorphism revealed a significant association between the minor allele G and presence of MS (OR:1.31, 95% CI: 1.02-1.69, P=0.039). In addition, Hsp70-2 protein content in vitro from PBMC was significantly lower in MS patients with GG genotype compared to AA genotype, indicating an implication of the G allele of HSP70-2 gene polymorphism in the development of MS

Response to oxidative stress of peripheral blood mononuclear cells from multiple sclerosis patients and healthy controls

The complex scenario of multiple sclerosis (MS) pathology involves several mechanisms, including oxidative stress response. The heat shock proteins (HSPs) are important for the protection of the cells; however, their role in MS is not clear. The present research is focused on the response of peripheral blood mononuclear cells (PBMCs) to oxidative stress and to the involvement of HSP70-2 (a protein coded by the HSPA1B gene, located in the MHC class III). To this aim, we challenged PBMCs from MS patients and healthy controls with hydrogen peroxide. Specifically, PBMCs mitochondrial activity, HSP70-2 protein expression and the production of intracellular reactive oxygen species were assessed. These parameters were also related to the HSP70-2 rs1061581 polymorphism, which is linked to the risk of developing MS. Moreover, mitochondrial activity and HSP70-2 protein levels were also related to disease severity. Overall, our results indicate that PBMCs, from both MS patients and healthy controls, may display a similar response towards an oxidative insult; within this context, HSP70-2 does not seem to be central in the protection of PBMCs. Nevertheless, the HSP70-2 rs1061581 polymorphism is related to ROS levels and appears to have a role in the different expression of HSP70-2 under oxidative stimulus

Unraveling a new player in multiple sclerosis pathogenesis: The RNA-binding protein HuR.

BACKGROUND: ELAV-like proteins are a small family of RNA-binding proteins that are fundamental players in post-transcriptional mechanisms and are involved in the pathogenesis of neurologic and psychiatric disorders. HuR, the ubiquitously expressed member of the family, is also implicated in sustaining inflammation and inflammatory diseases, supporting the production of pro-inflammatory cytokines. Inflammation plays a central role in Multiple Sclerosis (MS), which represents the most common cause of permanent physical disability in young adults. MS is a chronic autoimmune disease affecting the Central Nervous System, with a complex aetiology involving genetic, environmental and epigenetic factors. No data are available on the potential entanglement of HuR in MS pathogenesis in patients. In the present work, we aimed at exploring HuR protein levels in peripheral blood mononuclear cells (PBMCs) from MS patients, compared to healthy controls. To further elucidate the possible involvement of HuR in MS, we also investigated the relationship between this specific RNA-binding protein and HSP70-2 protein, also considering the HSP70-2 rs1061581 polymorphism, given that HSP70-2 mRNA has been reported as a HuR target and this specific polymorphism to be associated with MS risk. METHODS: Alleles and genotypes for HSP70-2 rs1061581 polymorphism were assessed, by using a Polymerase Chain Reaction-Restriction Fragment Length Polymorphism, followed by digestion with restriction enzyme, in MS patients and healthy controls. PBMCs from a subgroup of patients and controls were used to evaluate HuR and HSP70-2 protein content by Western blot. RESULTS: PBMCs from 52 MS patients had a lower HuR and higher HSP70-2 protein content compared to 43 healthy controls. An increase of 100 units of HuR significantly decreased the risk of developing MS by 9.8% (OR: 0.902, 95% CI: 0.83-0.98), controlling for HSP70-2 protein expression, HSP70-2 rs1061581 genotype, age and sex. Moreover, holding HuR levels, an increase of 100 units of HSP70-2 protein significantly increased the MS risk by 18.1% (OR: 1.181, 95% CI: 1.03-1.36) and the genetic susceptibility of developing MS for HSP70-2 rs1061581 GG carriers is confirmed. Of interest, MS patients with a moderate to severe form of MS (MSSS ≥ 3) showed a trend towards a reduction of HuR protein levels compared to patients with mild disease severity (MSSS < 3). CONCLUSIONS: HuR protein levels are reduced in MS patients compared to healthy subjects, and the protein amount may continue to decline with disease progression, suggesting a putative role of this RNA-binding protein. Moreover, our results suggest that MS pathology may have disrupted the link between HuR and its target transcript HSP70-2. It will be important to further explore the exact role of HuR in MS, considering the complex interplay with other RNA-binding factors and target mRNAs

Effect of Helmet Noninvasive Ventilation vs High-Flow Nasal Oxygen on Days Free of Respiratory Support in Patients with COVID-19 and Moderate to Severe Hypoxemic Respiratory Failure: The HENIVOT Randomized Clinical Trial

Importance: High-flow nasal oxygen is recommended as initial treatment for acute hypoxemic respiratory failure and is widely applied in patients with COVID-19. Objective: To assess whether helmet noninvasive ventilation can increase the days free of respiratory support in patients with COVID-19 compared with high-flow nasal oxygen alone. Design, Setting, and Participants: Multicenter randomized clinical trial in 4 intensive care units (ICUs) in Italy between October and December 2020, end of follow-up February 11, 2021, including 109 patients with COVID-19 and moderate to severe hypoxemic respiratory failure (ratio of partial pressure of arterial oxygen to fraction of inspired oxygen =200). Interventions: Participants were randomly assigned to receive continuous treatment with helmet noninvasive ventilation (positive end-expiratory pressure, 10-12 cm H2O; pressure support, 10-12 cm H2O) for at least 48 hours eventually followed by high-flow nasal oxygen (n = 54) or high-flow oxygen alone (60 L/min) (n = 55). Main Outcomes and Measures: The primary outcome was the number of days free of respiratory support within 28 days after enrollment. Secondary outcomes included the proportion of patients who required endotracheal intubation within 28 days from study enrollment, the number of days free of invasive mechanical ventilation at day 28, the number of days free of invasive mechanical ventilation at day 60, in-ICU mortality, in-hospital mortality, 28-day mortality, 60-day mortality, ICU length of stay, and hospital length of stay. Results: Among 110 patients who were randomized, 109 (99%) completed the trial (median age, 65 years [interquartile range {IQR}, 55-70]; 21 women [19%]). The median days free of respiratory support within 28 days after randomization were 20 (IQR, 0-25) in the helmet group and 18 (IQR, 0-22) in the high-flow nasal oxygen group, a difference that was not statistically significant (mean difference, 2 days [95% CI, -2 to 6]; P =.26). Of 9 prespecified secondary outcomes reported, 7 showed no significant difference. The rate of endotracheal intubation was significantly lower in the helmet group than in the high-flow nasal oxygen group (30% vs 51%; difference, -21% [95% CI, -38% to -3%]; P =.03). The median number of days free of invasive mechanical ventilation within 28 days was significantly higher in the helmet group than in the high-flow nasal oxygen group (28 [IQR, 13-28] vs 25 [IQR 4-28]; mean difference, 3 days [95% CI, 0-7]; P =.04). The rate of in-hospital mortality was 24% in the helmet group and 25% in the high-flow nasal oxygen group (absolute difference, -1% [95% CI, -17% to 15%]; P &gt;.99). Conclusions and Relevance: Among patients with COVID-19 and moderate to severe hypoxemia, treatment with helmet noninvasive ventilation, compared with high-flow nasal oxygen, resulted in no significant difference in the number of days free of respiratory support within 28 days. Further research is warranted to determine effects on other outcomes, including the need for endotracheal intubation