Very Rapid Improvement in Extended Nitric Oxide Parameters Is Associated With Clinical and Functional Improvement in Patients With Chronic Rhinosinusitis With Nasal Polyps Treated With Dupilumab.

BACKGROUND AND OBJECTIVE: Dupilumab, an anti-IL-4 receptor a monoclonal antibody, was recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate-to-severe asthma. Onset of its clinical effects is rapid. CRSwNP is characterized by extended type 2 inflammatory involvement that can be assessed using extended nitric oxide analysis. We investigated whether dupilumab was associated with a rapid improvement in extended nitric oxide parameters, lung function, and clinical outcomes in patients with CRSwNP. METHODS: Consecutive patients with CRSwNP and an indication for dupilumab were evaluated for extended nitric oxide analysis (exhaled, FeNO; bronchial, JawNO; alveolar, CalvNO; nasal, nNO) and lung function 15 and 30 days after initiation of treatment and for clinical outcomes (nasal polyps score [NPS], quality of life questionnaires, visual analog scale [VAS] for the main symptoms, and the Asthma Control Test [ACT]) 30 days after initiation of treatment. RESULTS: We enrolled 33 patients. All extended nitric oxide and lung function parameters improved significantly after 15 days of treatment, remaining stable at 30 days. Scores on the NPS, VAS for the main RSwNP symptoms, quality of life questionnaires, and the ACT improved significantly 30 days after initiation of treatment. CONCLUSION: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway areas. This is associated with improved lung function and clinical parameters in patients with CRSwNP.

Very rapid improvement of extended nitric oxide parameters, associated with clinical and functional betterment, in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) treated with Dupilumab.

BACKGROUND AND OBJECTIVE: Background: Dupilumab, an anti-IL-4 receptor alpha monoclonal antibody, has been recently approved for the treatment of chronic rhinosinusitis with nasal polyps (CRSwNP) and moderate to severe asthma, demonstrating a rapid onset of clinical effects. CRSwNP is characterized by an extended type-2 inflammatory involvement that can be assessed by extended nitric oxide analysis. Objective: In this study we investigated whether Dupilumab is associated with a rapid improvement in extended nitric oxide parameters, lung function and clinical outcomes in patients with CRSwNP. METHODS: : Consecutive patients with CRSwNP and indication to be treated with Dupilumab were evaluated for extended nitric oxide analysis (exhaled, FENO; bronchial, JawNO and alveolar, CalvNO components; nasal, nNO) and lung function 15 and 30 days after treatment initiation, and for clinical outcomes (nasal polyps score, NPS; quality of life questionnaires; visual analogue scales, VAS, for main symptoms, asthma control test, ACT) after 30 days of treatment initiation. RESULTS: 33 patients were enrolled. All extended nitric oxide and lung function parameters significantly improved after 15 days of treatment remaining stable at 30 days. NPS, VAS for main CRSwNP symptoms, quality of life questionnaires and ACT significantly improved after 30 days of treatment initiation. CONCLUSION: Dupilumab is associated with very rapid improvement in type 2 inflammation in all airway districts and this is associated with improved lung function and clinical parameters in patients with CRSwNP.

Comorbid allergic rhinitis and asthma: important clinical considerations.

INTRODUCTION: The numerous links between allergic rhinitis and asthma have been extensively explored in the last two decades, gaining great concern within the scientific community. These two conditions frequently coexist in the same patient and share numerous pathogenetic and pathophysiological mechanisms. AREAS COVERED: We reviewed major pathophysiological, epidemiological, and clinical links between allergic rhinitis and asthma. We also provided a comprehensive discussion of allergic rhinitis treatment according to current guidelines, with a particular focus on the relevance of allergic rhinitis therapies in patients with comorbid asthma. EXPERT OPINION: We believe that there are several unmet needs for our patients, however, there are promising advances forecasted for the future. Although allergic rhinitis is a recognized risk factor for asthma, a proper asthma detection and prevention plan in allergic rhinitis patients is not available. Allergen immunotherapy (AIT) represents a promising preventive strategy and may deserve an earlier positioning in allergic rhinitis management. A multidisciplinary approach should characterize the journey of patients with respiratory allergies, with an adequate referral to specialized Allergy/Asthma centers. Molecular Allergy Diagnosis may provide support for optimal AIT use. Finally, a possible evolution of biological treatment can be envisaged, mainly if biosimilars decrease such therapies' costs.

Predictors of intubation in COVID-19 patients treated with out-of-ICU continuous positive airway pressure.

BACKGROUND: As delayed intubation may worsen the outcome of coronavirus disease 2019 (COVID-19) patients treated with continuous positive airway pressure (CPAP), we sought to determine COVID-specific early predictors of CPAP failure. METHODS: In this observational retrospective multicentre study, we included all COVID-19 patients treated with out-of-ICU CPAP, candidates for intubation in case of CPAP failure. From these patients, we collected demographic and clinical data. RESULTS: A total of 397 COVID-19 patients were treated with CPAP for respiratory failure, with the therapeutic goal of providing intubation in case of CPAP failure. Univariable analysis showed that, age, lactate dehydrogenase (LDH) and white cell counts were all significantly lower in patients with successful CPAP treatment compared to those failing it and undergoing subsequent intubation. The percentage changes between baseline and CPAP application in the ratio of partial pressure arterial oxygen (PaO2) and fraction of inspired oxygen (FiO2), PaO2, respiratory rate and ROX index were higher in patients experiencing successful CPAP compared to those failing it. FiO2 and male gender were also significantly associated with intubation. Multivariable analysis adjusting for age, gender, Charlson comorbidity index, percentage change in PaO2/FiO2 or PaO2 and FiO2 separately, lactate, white blood cell count, LDH and C-reactive protein levels led to an area under the curve of 0.818 and confirmed that age, LDH and percentage increase in PaO2/FiO2 are predictors of intubation. CONCLUSIONS: In COVID-19 patients requiring CPAP, age, LDH and percentage change in PaO2/FiO2 after starting CPAP are predictors of intubation.

Venous thromboembolism in critically ill patients affected by ARDS related to COVID-19 in Northern-West Italy.

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is an emerging infectious disease that was first reported in Wuhan, China, and has subsequently spread worldwide. An association between increased venous thromboembolism in patients with pneumonia-related to COVID-19 has not yet been well described. PATIENTS AND METHODS: We aimed to illustrate cases of pulmonary thromboembolism in patients with acute respiratory distress syndrome related to COVID-19 treated in our intensive care unit. The medical records of patients affected by COVID-19 with acute respiratory distress syndrome in our institute from 1/3/2020 to 31/3/2020 were retrospectively reviewed. RESULTS: Our center registered a high prevalence of thromboembolic events among 62 patients affected by acute respiratory distress syndrome related to COVID-19 despite a regular antithrombotic prophylaxis. Out of these, 32 patients were transferred to other hospitals, and 30 were treated in our center. Venous thromboembolism was registered in 12 (19.3%) cases. In particular, 11 diagnoses of pulmonary embolism and 1 diagnosis of deep vein thrombosis were formulated. We described a case series of venous thromboembolism in nine patients treated in our Intensive Care Unit (ICU). Main pulmonary arteries were always involved in these patients. None of them died. CONCLUSIONS: In conclusion, critically ill patients with ARDS related to COVID-19 may have an increased risk of VTE that could be a leading cause of mortality. These patients require a high index of clinical suspicion and an accurate diagnostic approach, in order to immediately start an appropriate anticoagulant treatment.

Oxidative stress in critical care and vitamins supplement therapy: "a beneficial care enhancing".

OBJECTIVE: Critical illnesses are a significant public health issue because of their high rate of mortality, the increasing use of the Intensive Care Units and the resulting healthcare cost that is about 80 billion of dollars per year. Their mortality is about 12% whereas sepsis mortality reaches 30-40%. The only instruments currently used against sepsis are early diagnosis and antibiotic therapies, but the mortality rate can also be decreased through an improvement of the patient's nutrition. The aim of this paper is to summarize the effects of vitamins A, B, C and E on the balance between pro-oxidants and anti-oxidants in the critical care setting to confirm "a beneficial care enhancing". MATERIALS AND METHODS: The peer-reviewed articles analyzed were selected from PubMed databases using the keywords "critical care", "intensive care", "critical illness", "sepsis", "nutritional deficiency", "vitamins", "oxidative stress", "infection", and "surgery". Among the 654 papers identified, 160 articles were selected after title and abstract examination, removal of duplicates and of the studies on pediatric population. Finally, only the 92 articles relating to vitamins A, C, E and the B complex were analyzed. RESULTS: The use of vitamins decreased morbidity and mortality in perioperative period and critically ill patients, especially in ICU. Among the most encouraging results, we found that the use of vitamins, both as monotherapy and in vitamins combinations, play a crucial role in the redox balance. Vitamins, especially vitamins A, C, E and the B complex, could help prevent oxidative damage through the breakdown of the oxidizing chemical chain reaction. CONCLUSIONS: Even if the results of the studies are sometimes discordant or inconclusive, the current opinion is that the supplementation of one or more of these vitamins in critically ill patients may improve their clinical outcome, positively affecting the morbidity and the mortality. Further, randomized studies are required to deeply understand the potentiality of a vitamin supplementation therapy and develop homogeneous and standardized protocols to be adopted in every critical care scenario.

Targeting FGFR pathway in breast cancer.

Developments in breast cancer biology over the last years have permitted deconstructing the molecular profile of the most relevant breast cancer subtypes. This has led to an increase in therapeutic options, including more effective personalized therapy for breast cancer and substantial improvements in patient outcomes. Although currently there are only a few targeted therapies approved for metastatic breast cancer, the discovery of druggable kinase gene alterations has radically changed cancer treatment by providing novel and successfully actionable drug targets. Fibroblast growth factors and their receptors (FGFRs) participate in different physiologic processes and also play an essential role in cancer cell proliferation, survival, differentiation, migration, and apoptosis. This article summarizes the main molecular alterations of FGFRs, as well as the available preclinical and clinical data with FGFR inhibitors in breast cancer, and discusses new opportunities for the clinical development of these agents in patients with breast cancer.

Respiratory failure due to upper airway obstruction in children: use of the helmet as bridge interface.

Upper airway obstruction (UAO) can cause severe respiratory distress in young children by increasing inspiratory muscle load and decreasing alveolar ventilation, ultimately resulting in hypercapnia and hypoxemia which have long term negative cardiovascular effects. Although non-invasive continuous positive airway pressure (CPAP) improves gas exchange in these patients, use of conventional interfaces (nasal mask, nasal pillow and facial mask) may cause significant discomfort and lead to CPAP intolerance. We report five cases of children affected by UAO who experienced CPAP intolerance via application of conventional interfaces. Alternatively, we acutely applied helmet-CPAP which resulted in improved breathing pattern and gas exchange. Thereafter, patients received training with respect to a nasal CPAP interface, allowing successful long term treatment. In conclusion, these five clinical cases demonstrate that helmet-CPAP can be used acutely in children with UAO if compliance to conventional modalities is problematic, allowing for sufficient time to achieve compliance to nasal-CPAP.

Recommendations for anesthesia and perioperative management of patients with neuromuscular disorders.

Patients with neuromuscular disorders are at high risk of intraoperative and postoperative complications. General anesthesia in these patients may exacerbate respiratory and cardiovascular failure due to a marked sensitivity to several anesthetic drugs. Moreover, succinylcholine and halogenated agents can trigger life-threatening reactions, such as malignant hyperthermia, rhabdomyolysis and severe hyperkalemia. Therefore, regional anesthesia should be used whenever possible. If general anesthesia is unavoidable, special precautions must be taken. In particular, for patients at increased risk of respiratory complications (i.e., postoperative atelectasis, acute respiratory failure, nosocomial infections), noninvasive ventilation associated with aggressive airway clearance techniques can successfully treat upper airway obstruction, hypoventilation and airway secretion retention, avoiding prolonged intubation and tracheotomy. Anesthesia and perioperative management of patients with neuromuscular disorders are described in this article. To grade the strength of recommendations and the quality of evidence we adopted the GRADE approach. In case of low-quality evidence, these recommendations represent the collective opinion of the expert panel.

Long-term home ventilation of children in Italy: a national survey.

BACKGROUND: Improved technology, as well as professional and parental awareness, enable many ventilator-dependent children to live at home. However, the profile of this growing population, the quality and adequacy of home care, and patients' needs still require thorough assessment. OBJECTIVES: To define the characteristics of Italian children receiving long-term home mechanical ventilation (HMV) in Italy. METHODS: A detailed questionnaire was sent to 302 National Health Service hospitals potentially involved in the care of HVM in children (aged <17 years). Information was collected on patient characteristics, type of ventilation, and home respiratory care. RESULTS: A total of 362 HMV children was identified. The prevalence was 4.2 per 100,000 (95% CI: 3.8-4.6), median age was 8 years (interquartile range 4-14), median age at starting mechanical ventilation was 4 years (1-11), and 56% were male. The most frequent diagnostic categories were neuromuscular disorders (49%), lung and upper respiratory tract diseases (18%), hypoxic (ischemic) encephalopathy (13%), and abnormal ventilation control (12%). Medical professionals with nurses (for 62% of children) and physiotherapists (20%) participated in the patients' discharge from hospital, though parents were the primary care giver, and in 47% of cases, the sole care giver. Invasive ventilation was used in 41% and was significantly related to young age, southern regional residence, longer time spent under mechanical ventilation, neuromuscular disorders, or hypoxic (ischemic) encephalopathy. CONCLUSIONS: Care and technical assistance of long-term HMV children need assessment, planning, and resources. A wide variability in pattern of HMV was found throughout Italy. An Italian national ventilation program, as well as a national registry, could be useful in improving the care of these often critically ill children.

Invasive and non-invasive long-term mechanical ventilation in Italian children.

BACKGROUND: To date, few studies have been published regarding the number of children in Italy who require long-term mechanical ventilation (LTV) and their underlying diagnoses, ventilatory needs and hospital discharge rate. METHODS: A preliminary national postal survey was conducted and identified 535 children from 57 centers. Detailed data were then obtained for 378 children from 30 centers. RESULTS: The estimated prevalence in Italy of this population was 4.3/100000. The majority of children (72.2%) were followed in pediatric units. The primary physicians who cared for these patients were either pediatric intensivists or pediatric pulmonologists. Neurological patients (78.2% of cases) represented the principal disorder category. 57.2% of the patients were non-invasively ventilated, with a nasal mask being the most common interface (85% of cases). The presence of clinical symptoms that were associated with abnormal findings on diagnostic testing was the primary indication for ventilatory support, whereas weaning failure was the primary indication for tracheotomy. Invasive ventilation was significantly related to younger age, longer daily hours on ventilation and cerebral palsy. Ventilatory modes with guaranteed minimal tidal volume were more often used in patients with tracheotomy. Despite their age, illness severity and need for technological care, 98% of the study population were successfully home discharged. CONCLUSION: Managing pediatric home LTV requires tremendous effort on the part of the patient's family and places a significant strain on community financial resources. In particular, neurological patients require more health care than patients in other categories. To further improve the quality of care for these patients, it is essential to establish a dedicated national database.

Respiratory management of acute respiratory failure in neuromuscular diseases.

Neuromuscular diseases (NMD) can affect all major respiratory muscles, leading to the development of respiratory failure, which is the most common cause of morbidity and mortality in patients affected by those conditions. Based on the clinical onset of acute respiratory failure (ARF), NMD can be classified into two main categories: 1) slowly progressive NMD with acute exacerbations of chronic respiratory failure, and 2) rapidly progressive NMD with acute episodes of respiratory failure. The most common slowly progressive NMDs, such as motor neuron diseases and inherited myopathies, account for the majority of NMD patients developing chronic neuromuscular respiratory failure at risk of acute exacerbations. Conversely, rapidly progressive NMDs, such as Guillain-Barré syndrome and myasthenic crises, are characterized by a sudden onset of ARF, usually in patients with previously normal respiratory function. The patho-physiological mechanisms responsible for ARF in NMD and the variety and complexity of specific challenges presented by the two main categories of NMD will be analyzed in this review, with the aim of providing clinically relevant suggestions for adequate respiratory management of these patients.

The hemostatic balance after plasma-exchange transfusion in myasthenia Gravis.

BACKGROUND: To study the effects of plasma-exchange on removal and recovery of haemostatic factors and inhibitors using albumin or PPS as replacement fluid. DESIGN: Prospective, noninterventional study. SETTING: Medical intensive care unit of a university hospital. PATIENTS: The study included 11 consecutive patients with Myasthenia Gravis, whose haemostatic parameters were normal before plasma-exchange. INTERVENTIONS: Plasma coagulative factors and inhibitors were studied before at the end of and 24 hours after each exchange. RESULTS: Immediately after exchange plasma coagulation factors and inhibitors evaluated were reduced, except for factor VIII; 24 hours later only fibrinogen was significantly decreased; D-Dimer was not found increased; the platelets, after exchange, were at normal levels. CONCLUSIONS: Our data show a parallel lowering of haemostatic factors and inhibitors after plasmapheresis using material devoid of coagulation factors as replacement, this explains the absence of hemorrhagic or thrombotic complications. So we think that careful monitoring of coagulation during plasma-exchange is not useful.