Tezepelumab is effective in older patients with type 2 severe asthma, and baseline serum cytokine levels may be useful in predicting the efficacy of tezepelumab

Clinical characteristics in 545 patients with severe asthma on biological treatment during the COVID-19 outbreak

AB0796 The predictive role of interleikine 6 and 10 in impairment of mental health in patients with knee osteoarthritis and uncontrolled type 2 diabetes mellitus

We investigated the correlations between serum levels of selected proinflammatory, hematopoietic and angiogenic cytokines and soluble cytokine receptors with the clinico-pathological features and prognosis in soft tissue sarcoma patients. Serum levels of 9 cytokines (TNFalpha, IL-1ra, IL-6, IL-8, IL-10, M-CSF, G-CSF, VEGF, bFGF) and 4 free cytokine receptors (sIL-2R alpha, sIL-6R, TNFRI, TNFRII) were measured by means of an enzyme-linked immunoadsorbent assay kit in 156 soft tissue sarcoma patients before the treatment and in 50 healthy controls. Serum levels of 10 cytokines and cytokine receptors were also assayed during patients' follow-up after the treatment. Significantly elevated pretreatment serum levels of 11/13 cytokines and cytokine receptors were found in sarcoma patients, as compared to healthy controls. In 40.4% of patients 6 or more cytokines and cytokine receptors (most frequently: TNF RI, IL-6, IL-8) were elevated in parallel. Serum levels of IL-6, sIL-2R, VEGF, M-CSF and TNF RI correlated significantly with tumor size and serum levels of IL-8 and IL-6 were significantly higher in patients with Grade 2/3 vs. Grade 1 tumors. We did not observe any significant differences in cytokine serum levels between patients with primary and recurrent tumors and patients with and without distant metastases. Using univariate analysis, overall survival (OS) in all patients was affected by tumor size (<5 cm vs. 5-10 cm vs. >10 cm), tumor grade (G1 vs. G2/3), presence of metastases, pretreatment serum levels of 8 cytokines (IL-6, IL-8, IL-10, sIL-2R, TNF RI, TNF RII, M-CSF, VEGF) and the number of cytokines increased (0-1 vs. 2-5 vs. < or = 6). Elevated serum levels of IL-6, IL-8, IL-10 and sIL-2R alpha, high tumor grade and larger tumor size strongly correlated with shorter disease-free survival (DFS). Multivariate analysis identified G2/3 tumor grade (p = 0.001), the presence of metastases (p = 0.004), elevated IL-6 serum level (p = 0.02), elevated IL-8 serum level (p = 0.048) and the number of cytokine serum levels above upper cut-off values (p = 0.01) as the independent prognostic factors related to OS, and G2/3 tumor grade (p = 0.005) and increased IL-6 serum level (p = 0.035) as independent prognostic factors related to DFS. In a group of patients without metastases (M0) higher tumor grade, elevated serum level of IL-6 and TNF RII, and the number of elevated cytokine serum levels correlated independently with poor survival. We found a significant decrease of several cytokine serum levels in patients after treatment (IL-1ra, IL-6, IL-8, IL-10, TNF RII, M-CSF) [p < 0.05]. Persistently elevated serum level of IL-6 after the treatment has also shown negative prognostic significance for OS (univariate analysis). Serum levels of some proinflammatory, hematopoietic and angiogenic cytokines and cytokine receptors are elevated, frequently in parallel, in a large percentage of soft tissue sarcoma patients. Significant correlations of serum cytokine levels with tumor size and grade suggest that some of these cytokines may be directly or indirectly involved in the progression of soft tissue sarcomas. Serum assays of IL-6, IL-8 and TNF RII before or after the treatment may be useful in establishing soft tissue sarcoma patients prognosis.

Bronchial asthma is a major public health problem in the world. A considerable proportion of patients suffer from severe asthma, which is manifested by a decrease in the quality of life, an increase in the frequency of exacerbations, hospitalisations, and mortality. The ineffectiveness of conventional therapy in such patients contributes to the development of biological treatment methods with higher specificity, aimed at the pathogenetic links of the disease. The purpose of the study was to analyse the effectiveness of the treatment of severe bronchial asthma with monoclonal antibodies based on literature data. The study examines publications over the past 5 years that are available on the Internet. The following terms were used for the search: monoclonal antibodies, endotype, phenotype. Five monoclonal antibody biological agents targeting IgE, IL-5, IL-4, and IL-13, which are approved for use in patients with severe asthma, were analysed: omalizumab, mepolizumab, reslizumab, benralizumab, and dupilumab. The use of these medications has led to progress in the treatment of bronchial asthma. It was found that determining disease endotypes based on the assessment of biomarkers such as eosinophil count in blood and sputum, fractional exhaled nitric oxide, and serum periostin contributes to the greater effectiveness of biological therapy. It was investigated that monoclonal antibody treatment improves lung function, reduces exacerbation frequency, and decreases the need for additional medications. Many other biological agents, particularly those targeting key cytokines, are in the clinical development stage. Approved monoclonal antibodies targeting IgE, IL-5, and IL-4/IL13 demonstrate high efficacy in the treatment of severe bronchial asthma. The use of these agents in patients with severe asthma and high Th2 levels considerably improves lung function, symptom control, and reduces the frequency of disease exacerbations

Severe asthma in the US population and eligibility for mAb therapy

Asthma diagnosis and treatment: Filling in the information gaps

Severe asthma: definition and mechanisms.

Periodontitis is a local inflammatory disease that also has some systemic effects. We investigated the levels of interferon (IFN)-γ, tumor necrosis factor (TNF)-α, and interleukin (IL)-2, -4, -5, and -10 in the serum of patients with periodontitis in relation to the bacterial load in the dental plaques. Serum cytokine levels in patients with generalized periodontitis and healthy control groups were determined using the cytometric bead array kit. Bacterial load in the dental plaque was determined semiquantitatively by real-time polymerase chain reaction. The proportions of different lymphocyte subsets were determined in the peripheral blood of patients with periodontitis by flow cytometry. Finally, relationships between the bacterial load in the subgingival plaques of patients with periodontitis and levels of cytokines and counts of lymphocyte subsets were established. Serum levels of IFN-γ, TNF-α, and IL-10 were significantly increased, whereas those of IL-2 were significantly decreased in patients with periodontitis compared to healthy controls. Increased serum levels of IFN-γ and TNF-α in patients with periodontitis were associated with the enhanced dental plaque load with Aggregatibacter actinomycetemcomitans (previously Actinobacillus actinomycetemcomitans) and Porphyromonas gingivalis, respectively. Finally, as revealed by analysis of lymphocyte populations, the presence of A. actinomycetemcomitans and Trepomena denticola was associated with an increased population of CD3(-)/CD16(+) and CD3(+)/CD8(+) cells, respectively. Certain periodontal pathogens could be associated with an increased level of proinflammatory cytokines in the peripheral blood and thus increased risk of systemic diseases.

Abstracts

Background anti-IgE (Omalizumab) is one of the targeted therapies for severe bronchial asthma. Its real-life safety is still under scrutiny. The aim of the study was to evaluate the persistent efficacy and safety of Omalizumab as a long-term treatment of severe bronchial asthma. Patients and methods A prospective cohort study was conducted on 74 patients who had severe bronchial asthma eligible for Omalizumab subcutaneous treatment with a long-term regular follow-up to evaluate the long-term safety and efficacy of Omalizumab. Results This study was conducted on 74 patients who had severe bronchial asthma: 33 patients (44.6%) were males with a mean±SD (37.2 ± 4), and 41 females (55.4%) with a mean±SD (35.9 ± 6). Those patients were eligible for Omalizumab treatment with a long-term regular follow-up (from 7 to 10 years) to assess the long-term safety of Omalizumab. Omalizumab treatment has a significant improvement in the clinical condition of severe bronchial asthma as it decreased the number of patients who used oral steroids from 63 patients (before starting treatment) to 6 patients after 6 months of treatment, and 2 patients after 12 months of the dose. The use of tiotropium bromide had a significant decrease because the number of patients fell from 61 patients (before the start of treatment) to 13 patients after 6 months. It also reduced the number of acute exacerbations of bronchial asthma from 7 times per year (before the start of treatment) to 3 times after 6 months, and 2 times after 12 months of treatment. Patients’ pulmonary functions (FEV1, FEV1/ FVC, PEFR) improved significantly from (43.7 ± 9, 52.3 ± 11, 51.1 ± 4) before starting Omalizumab treatment to (64.1 ± 11,71.3 ± 13, 68.2 ± 7) after 6 months of usage; and to (69.4 ± 12, 73.3 ± 14, 72.1 ± 6) after 12 months of treatment. Long-term use of Omalizumab has less severe side effects as 70% of patients had injection site reactions in the form of local tenderness and swelling, 24.3% had a headache, 12% had nausea, 9.4% had myalgia, and 17.5% had a fever while the serious side effects as cancer, anaphylaxis or myocardial infarction has not recorded. All the side effects occurred in the first year of treatment. Conclusion Long term use of Omalizumab in severe bronchial asthma management has persistent efficacy and no serious side effects such as cancer, myocardial infarction or anaphylaxis and has only minimal side effects that occurred mostly in the first year of Omalizumab treatment, meaning that the physician cannot stop giving patients the medication.

Severe asthma with fungal sensitization is associated with worse small airway dysfunction but similar symptom control

Patients with severe refractory asthma represent a small subset of the asthmatic population (between 5% and 10% of all patients) but are the greatest burden to the health care system. New treatment approaches developed to manage some of the phenotypes of severe refractory asthma have included humanized monoclonal antibodies (hMabs). To review the evidence and ascertain whether hMabs provide clinical benefit to patients with severe refractory asthma. Studies that examined the efficacy of hMabs against immunoglobulin (Ig) E, tumour necrosis factor-alpha, interleukin (IL)-5, and IL-4⁄IL-13 in patients with severe refractory asthma were reviewed and summarized. Treatment with anti-IgE improved asthma control and reduced severe exacerbations in patients with severe asthma and elevated serum IgE levels. Treatments with hMabs that block tumour necrosis factor-alpha are unlikely to be useful in asthma treatment. In contrast, hMabs that block IL-5 have consistently shown benefit in reducing severe exacerbations in patients with severe refractory asthma with persistent eosinophilia. Finally, hMabs that block IL-13 may provide benefit in patients with elevated blood periostin levels. hMabs that block IgE are approved for the treatment of allergic asthma. It is likely that blocking IL-5 will also provide benefit in patients with severe asthma with persistent eosinophilia. These studies have emphasized the importance of careful phenotyping of patients with severe refractory asthma before embarking on treatment with hMabs.

Asthma Update

1UBC James Hogg Research Centre, Institute for Heart + Lung Health, Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada, 2The Prince Charles Hospital and The University of Queensland, Brisbane, Queensland, Australia, 3Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, and 4Department of Medicine, National University Hospital, Singapore, Singapore

Sellers & Messahel [1] in their paper report on seven patients (four of whom were children) with acute severe asthma managed in the conventional manner but who in addition received an immediate dose of intravenous salbutamol. They report good clinical response by these patients to intravenous salbutamol although two patients (one a child) eventually required intubation and assisted ventilation. From this experience, these authors suggest that the immediate use of intravenous salbutamol should be considered in every case of acute severe asthma and that if this had little clinical effect, a repeat dose of intravenous salbutamol should be immediately given, and in some cases several times over. The severe asthmatic is easily recognised, but creating an all-encompassing definition of asthma severity has been difficult [2]. There is no single investigation that defines asthma. This has resulted in much confusion in the literature with regards to asthma management. In many cases, what is considered moderate asthma in the southern hemisphere is commonly classified as severe elsewhere. The management of these patients is clearly very different and any attempt at comparison will result in confusion. Most countries now have national guidelines [3] that are in agreement, but we must remain careful in interpreting data that have classified asthma in a non-discriminate way as we are most likely comparing 'apples with oranges'. A recent meta-analysis on the use of intravenous β-agonists suffers from poor case definition as well and being poorly controlled for patient age. In addition, the study combines papers that use both β-agonists and aminophylline in treatment protocols that were so different as to be considered different approaches to management rather than equivalent therapies [4]. The paper by Sellers & Messahel again raises the perennial question of asthma definition and how they defined acute severe asthma in their report. In our original paper on the use of intravenous salbutamol in children [5], there was a difference between severe as defined in that paper, i.e. severe enough to come to the emergency department and not responding to the first dose of inhaled salbutamol, and that in the general asthma literature. Sellers & Messahel have defined severe asthma in the traditional way as used by PICU, these patients having refractory disease with significant respiratory failure mandating intensive care. Asthma is an inflammatory disease that is typified by airway hyper reactivity and obstruction, producing variable airway resistance with a reduction in air flow [5]. The initial management of an acute attack involves a stepwise approach, although in cases of life-threatening asthma immediate intravenous therapy is recommended [6]. Traditionally, intravenous therapy, particularly in children, has been left for the most severe cases. This is often considered after the use of frequent doses of inhaled bronchodilators has failed. In cases of severe asthma, any delay in clinical response may render airways bronchodilator unresponsive due to progression of the inflammatory process in these airways. We believe there is a window of opportunity during initial presentation with severe asthma to the emergency department where the airways may continue to be bronchodilator responsive. If intravenous therapy is used early as shown by Sellers et al., then clinical response should be rapid with more rapid stabilisation of the patient. The mainstay of treatment of acute asthma involves the frequent use of inhaled β-agonists, together with corticosteroids [6]. We have shown that inhaled β-agonists produce systemic plasma drug concentrations in the range 20–40 ng.ml−1, within 2 h of commencement of therapy. In many patients, but particularly in children, with severe asthma, inhaled therapy can be unreliable as this is dependent on delivery technique and tidal volume, both of which are highly variable [5, 7, 8]. In addition, these patients fail to improve because severe bronchospasm and mucus plugging prevents distal drug delivery by the aerosol route. In this case, a better initial alternative, particularly if asthma is severe, is to use the intravenous route. Intravenous β-agonist therapy can be highly effective in reversing bronchospasm, even in the presence of marked hypercapnia [9]. It has been shown that intravenous salbutamol was more effective than inhaled salbutamol in reversing airways obstruction. In addition, those patients receiving the intravenous preparation achieved earlier therapeutic level, more rapid clinical response and could be discharged earlier. With intravenous salbutamol, plasma levels similar to those achieved with inhaled therapy are reached with a 10-min infusion of salbutamol at a rate of 1.5 µg.kg−1.min−1[5, 7, 8]. We would ideally recommend in children that intravenous bronchodilator therapy be reserved for patients with acute severe asthma who are not responding to initial nebulised bronchodilators (Fig. 1). The tendency, however, to delay intravenous drug treatment in the most severe asthmatic patients has the potential to lead to a protracted clinical course. Sellers & Messahel suggest in their paper that if after initial intravenous bolus no clinical effect is observed, repeated boluses of intravenous salbutamol should be considered. This is probably safe provided the patient is carefully monitored in the presence of an intensive care physician. In our institution, we would use a short-term continuous intravenous salbutamol infusion, commencing this in the emergency department. Although widely used, uncertainty currently exists as to the correct dose that should be used of a continuous intravenous salbutamol infusion (CIS). We would consider an infusion of 5 µg.kg−1.min−1 of salbutamol for 2 h in those children with acute severe asthma who are clinically stable and on maximal medical therapy a reasonable approach (Fig. 1). This dosage is considered safe and has not been shown to be associated with serious side-effects. The physician would thereafter titrate intravenous salbutamol therapy according to the patient's clinical response with admission to PICU mandatory if ongoing CIS is needed or clinical deterioration is detected during the administration of this therapy in the emergency department. Our rationale for using CIS rather than repeated bolus doses of salbutamol is as follows. Over a 10-year period in our PICU, we have seen a two-fold increase in admissions for acute severe asthma. We have seen a three-fold increase in CIS use mirrored by a reduction in aminophylline use. Only a handful of patients were mechanically ventilated over this period but all received CIS. For those non-ventilated patients, CIS was ceased within 4–6 h after it had been commenced. This suggested to us that there is an opportunity to treat some of these patients effectively in the emergency department before being admitted to the PICU. We reported the use of CIS in Australian and New Zealand Emergency Departments (ANZ-ED). CIS has been used for the treatment of acute severe asthma in children in 85% of ANZ-ED [10]. A wide variation in dose of CIS was reported. The use of a continuous infusion rather than repeated boluses of intravenous salbutamol is our preferred option if the initial single bolus fails to provoke an adequate clinical response. Salbutamol has a long half-life of 2–4 h in adults. This is consistent with it being excreted renally and occupying extracellular space. There are limited data in children but there is no reason to suppose different pharmacokinetics. An infusion of 5 µg.kg−1.min−1 will achieve a plasma level of 110 ng.ml−1, and this level will then be maintained at a slower infusion of 1 µg.kg−1.min−1[11, 12]. Because in some patients salbutamol will have a shorter half-life, it would be prudent to allow overshoot, so we recommend continuing the infusion for 2 h. Overshoot will not result in toxicity as much higher levels are known to be well tolerated [13]. If the effect is inadequate, increasing the infusion to 2 µg. kg−1.min−1 preceded by a 1-h infusion at 10 µg.kg−1.min−1 will achieve a double plasma level. These infusion rates are a much higher dosing than suggested by Sellers & Messahel, in which up to six boluses amounts to the equivalent of no more than 30 min at 5 µg. kg−1.min−1. As suggested by Shann [11], salbutamol takes approximately four half-lives to reach a plateau concentration of drug. If salbutamol is given as a constant infusion without an appropriate loading dose, 10–20 h is required to reach a plateau concentration. In these cases, there will be either subtherapeutic levels at the beginning of therapy, excessive levels after several hours of therapy or both. In this respect, salbutamol and terbutaline require similar plasma concentrations to produce a given effect and are therefore equivalent drugs, although salbutamol has been the preferred β-agonist owing to its greater margin of safety when administered intravenously. The addition of ipratropium to β-agonist therapy offers a statistically significant, albeit modest, improvement in pulmonary function, as well as a reduction in the rate of hospital admissions. The use of inhaled ipratropium bromide in addition to intravenous salbutamol, frequent doses of inhaled salbutamol and corticosteroids as initial emergency department therapy have no clinical benefits for children with acute severe asthma [8]. Aminophylline has bronchodilator effects with an additional theoretical benefit of an inotropic effect on respiratory muscles [14]. A recent study in children suggests that aminophylline may be useful in reducing length of stay in hospital [15]. However, the window between therapeutic effect and toxicity is relatively narrow, and this can lead to serious side-effects. Given the potential for toxicity and the marginal benefit, we would not recommend this drug as a standard therapy for severe asthma but rather something to consider in refractory disease in the intensive care. Although magnesium sulphate has been reported to improve bronchospasm in the emergency department or in the ICU, there is currently insufficient clinical evidence to support its routine use in severe asthma [16]. Asthma deaths in hospital should be very rare and so should intubation. Over the last 3 years since we have adopted this approach in our emergency department and regional hospitals, we have not had the need to intubate a single patient admitted to our PICU with acute severe asthma. The need for intubation, however, should be on the basis of clinical signs of respiratory failure, i.e. genuine exhaustion. We would expect that with appropriate assessment of patients with acute severe asthma in the emergency department in addition to the correct use of intravenous salbutamol in these patients, we can avoid progression to respiratory exhaustion and hence intensive care interventions such as intubation. This should be reserved for those rare patients who are unresponsive to aggressive salbutamol therapy and therefore have refractory disease in addition to rapidly progressive respiratory exhaustion. We should therefore continue to use salbutamol in acute severe and life-threatening asthma because its appropriate use is both clinically very effective and has an extremely high margin of safety. Intravenous salbutamol for managing acute severe asthma in the emergency department has the potential to shorten the duration of an acute asthma attack, to reduce overall requirements for inhaled salbutamol and will result in earlier hospital discharge of these patients. We would like to remind the reader that salbutamol is called albuterol in USA. Salbutamol and albuterol are the same drug and we should not be confused by this difference in nomenclature nor get them mixed up when using these drugs clinically.