Author: Shi Honglei and Huang Kewu
Affiliation: Department of Respiratory and Critical Care Medicine, Beijing Chaoyang Hospital, Capital Medical University, Beijing Institute of Respiratory Diseases
引用本文: 史宏磊, 黄克武. 支气管哮喘诊治年度进展2023 [J] . 中华结核和呼吸杂志, 2024, 47(2) : 157-162. DOI: 10.3760/cma.j.cn112147-20231129-00348.
summary
Bronchial asthma (abbreviated asthma) is a common chronic airway inflammatory disease mediated by a variety of immune cells, cytokines and inflammatory mediators, which has obvious heterogeneity in clinical symptoms, severity and treatment effect, which brings great challenges to diagnosis and treatment. This article reviews the basic and clinical research literature on asthma published from October 1, 2022 to September 30, 2023, focusing on the pathogenesis, diagnosis, evaluation and treatment of asthma, aiming to provide more evidence for clinical diagnosis and treatment and provide new perspectives for future research.
Bronchial asthma (asthma) is a common chronic airway disease whose clinical manifestations include recurrent wheezing, shortness of breath, chest tightness, cough and other symptoms, which are associated with chronic airway inflammation, airway hyperresponsiveness, and variable airflow limitation. There is significant heterogeneity in clinical symptoms, severity, and treatment response to asthma [1, 2]. This article reviews the global asthma blockbuster studies published from October 1, 2022 to September 30, 2023, focusing on the pathogenesis, diagnosis, evaluation and treatment of asthma, aiming to provide more evidence for clinical diagnosis and treatment and provide new perspectives for future research.
1. New pathogenesis
The occurrence and progression of asthma involves a variety of pathophysiological mechanisms, and asthma is classified into T2 asthma and non-T2 asthma according to the airway inflammation caused by the immune response [3]. Recent studies have shown that antiviral immune responses and autoimmunity may be involved in the development of asthma. (1) Asthma and viral infections: In 2023, Vanderbilt University in the United States published a large prospective cohort study in healthy infants born at term in the United States in the Lancet [4]. The investigators determined the respiratory syncytial virus (RSV) infection status of infants in the first year of life, and then followed them prospectively for 5 consecutive years to collect information on recurrent wheezing and asthma in children, and found that children with no evidence of RSV infection in infancy had a lower prevalence of asthma at the age of 5 years than children with RSV infection in infancy. The results of this study suggest that RSV infection is related to asthma in children, but the mechanism of RSV involvement in asthma is not clear and needs to be further explored. It has been found that viral infections may be involved in the acute exacerbation of asthma through interleukin (IL)-33 and thymic stromal lymphopoietin (TSLP). IL-33 is present in the nucleus of airway epithelial cells and is an airway epithelial cell-derived cytokine that is released at the time of cell injury and can trigger severe asthma exacerbations, when the virus is infected, IL-33 is released and binds to ST2 receptors, activating downstream signaling pathways, resulting in an inflammatory response and increased airway hyperresponsiveness, and treatments targeting IL-33 may be effective for virus-induced asthma exacerbations. Ravanetti et al. [5] found that IL-33 inhibits the formation of dendritic cells in Th1 immune inflammation by inhibiting inhibition of innate and adaptive antiviral immunity, as well as inhibiting the expression of epithelial cells and dendritic cells IFN-b, thereby enhancing airway hyperresponsiveness and airway inflammation. IL-33 can also promote the extracellular trap net activity of airway neutrophils and inhibit the cytolytic antiviral activity, but does not affect the Th2 immune response, so it is speculated that targeted intervention of the IL-33/ST2 axis may have potential therapeutic value for virus-induced asthma exacerbations. In addition, Jackson et al. [6] cultured human T cells and type 2 innate lymphoid cells (ILC2) using the supernatant of rhinovirus-infected human bronchial epithelial cells (BECs), which strongly induced the expression of type 2 cytokines (IL-4, IL-5, IL-13), and this induction was completely dependent on IL-33. Tezepelumab, an anti-monoclonal antibody against TSLP, has been shown to reduce exacerbations in patients with asthma [7, 8], but the effect of blocking TSLP on host epithelial resistance and tolerance to viral infection is unclear. Sverrild et al. [9] found that tezelumab reduced airway epithelial inflammatory responses, including IL-33 and T2 cytokine expression, in patients with asthma who received tezelumumab before and after 12 weeks of treatment with trazelumab obtained their BEC by tracheoscopy, cultured in vitro and exposed to viral infection mimicking poly(I:C) or rhinovirus infection, and found that tezeluzumab reduced airway epithelial inflammatory responses, including IL-33 and T2 cytokine expression, further suggesting that viral infection may be associated with T2 asthma exacerbations. In addition, Tiotiu et al. [10] used the U-BIOPRED (Unbiased Biomarkers for the Prediction of Respiratory Diseases Outcomes) asthma cohort to explore the relationship between different mast cell activation and airway granulocyte inflammation in patients with severe asthma, and the results showed that mast cells can be induced to exhibit different transcriptional phenotypes associated with specific clinical phenotypes, IL-33/ The mast cell/neutrophil axis may play a role in the onset of non-T2 asthma, with IL-33-stimulated mast cell signaling associated with severe neutrophilic asthma, and IgE-activated mast cell signaling associated with eosinophilic phenotype [11]. Whether the induction of IL-33 by damaged epithelial cells after viral infection can lead to the development of non-T2 asthma through the IL-33/mast cell/neutrophil axis remains to be further explored. (2) Whether asthma and autoimmune autoimmune responses are involved in the pathogenesis of asthma is an interesting topic in the pathogenesis of asthma. In 2018, Mukherjee et al. [12] reported a "polyclonal" autoimmune event in patients with hormone-dependent asthma, namely sputum antieosinophil peroxidase (EPX) and IgG isoform antinuclear antibody positivity. In 2023, the research team published another prospective study [13], which collected sputum samples from patients with severe asthma from 2017 to 2020 to detect the expression of anti-macrophage receptor with collagenous structure (MARCO) in sputum, and evaluated the effect of high-titer anti-MARCO IgG on macrophage function through cell experiments. The discovery of autoimmune responses in the respiratory tract of patients with severe asthma and the possibility that anti-MARCO IgG antibodies may cause macrophage dysfunction and weaken host defenses, thereby increasing host susceptibility to airway infections, provides a new perspective on the pathogenesis of non-T2 asthma.
2. Asthma diagnosis
Guidelines recommend that the diagnosis of asthma be based primarily on clinical symptoms and objective evidence of variable airflow limitation [14]. However, in current clinical practice, bronchial provocation tests mainly rely on forced expiratory volume in the first second of spirometry (FEV1) as the primary outcome indicator, however, the FEV1 test has some limitations, such as high requirements for patients' ability to cooperate and insensitivity to small airway changes. Parker et al. [15] retrospectively analyzed the clinical data of 211 patients with asthma who underwent methacholine provocation and showed that 93 percent of patients diagnosed with a provocative concentration (PC40) that caused a 40 percent decrease in specific airway conductance (sGaw) were subsequently diagnosed with asthma, compared with a 20 percent decrease in FEV1 Only 66% of patients with asthma were subsequently diagnosed with asthma at PC20, suggesting that sGaw has a higher sensitivity for airway hyperresponsiveness than FEV1 and may help detect airway hyperresponsiveness in lower doses of methacholine provocation. Given the relative simplicity and ease of operation of the technique of sGaw measurement, it may be more suitable for patients who cannot tolerate pulmonary function tests. However, the criteria for the use of sGaw for a positive provocation test remain controversial, and the European Respiratory Society guidelines do not recommend sGaw as a diagnostic basis for asthma [14].
3. Asthma assessment
(1) Classification assessment of induced sputum cell count is the standard clinical method for classifying asthma airway inflammation. However, due to the induction of sputum specimens that could not be routinely obtained, Flinkman et al. [16] analyzed the clinical data of 203 asthma patients with 12 years of follow-up, and divided asthma patients into four types: eosinophil count (BEC, 0.30×109) and neutrophil count (4.40×109) as cut-off values. They found that patients with neutrophilic asthma had a higher body mass index, greater inhaled hormone use, more unscheduled visits, and more antibiotic use than those with oligocytic asthma; Patients with eosinophilic asthma are more likely to develop nasal polyps and have a faster decline in lung function. Patients with neutrophil, eosinophilic, and mixed asthma have a higher proportion of patients with moderate to severe asthma than with oligocytic asthma. (ii) Risk assessment of acute exacerbationsBleecker et al. [17] analyzed the relationship between BEC and clinical phenotype in 718 patients with severe asthma in two randomized controlled studies of severe asthma in SIROCCO and CALIMA, all of whom had BEC measured up to 6 times at weeks 0, 4, 8, 24, 40, and 48/56 in a one-year prospective study, and divided the patients into a low BEC group based on the results of BEC detection (80% of BEC multiple measurements The above measurements were less than 300 cells/μl), the high BEC group (more than 80% of the measurements were higher than 300 cells/μl in multiple BEC measurements), and the BEC variant group (less than 80% of the measurements were on the same side of 300 cells/μl in the multiple BEC measurements), and the study found that asthma patients in the high BEC group and the variant BEC group had a higher risk of acute exacerbations, The results of this study suggest that dynamic assessment of patient biomarker changes may have higher clinical guidance value in the risk assessment of asthma exacerbations. To gain insight into the longitudinal trajectories of patients who develop severe asthma and to analyze the correlation of different trajectories with asthma control measures and comorbidities. von Bülow et al. [18] conducted a 10-year retrospective analysis of 4 543 patients with severe asthma using data from the NORDSTAR research platform in Sweden and classified the severity of asthma treatment each year. The study used latent category analysis to identify four trajectories of severe asthma, which were labeled as "persistent severe asthma (8.6%)", "gradual onset severe asthma (20.7%)", "intermittent severe asthma (37.1%)", and "sudden severe asthma (33.6%)". Among them, patients with "persistent severe asthma" have a higher daily dose of inhaled hormones and a higher prevalence of osteoporosis, while patients with "gradual onset of severe asthma" and "sudden severe asthma" have comorbidities associated with T2 inflammation during the development of severe asthma. Therefore, identifying the different trajectories of severe asthma development can help to identify high-risk patients early and provide a basis for early intervention. The ATLANTIS (Assessment of Small Airways Involvement in Asthma) study [19] is a one-year observational study of patients with mild, moderate, and severe stable asthma enrolled in a medical database of 29 centers in 9 countries. To explore how to better assess the presence and severity of asthma small airway disease and its relationship to asthma control status. The study found that among the 773 asthma patients enrolled, persistent airflow limitation (PAL) was present not only in patients with severe asthma but also in 21% of patients with mild asthma[20], and further analysis found that patients with PAL showed more severe airflow limitation, higher BEC, and higher rates of systemic hormone and biologics use, and longitudinal analysis found that PAL was associated with a high risk of asthma exacerbations[21]. Increased intensity of treatment in patients with mild asthma who have persistent airflow limitation can help reduce the risk of exacerbations. (3) Assessment of comorbidities: Biological therapy is generally recommended for severe uncontrolled asthma (SUA), and routine bronchoscopy is not recommended for these patients unless there is a specific indication to rule out comorbidities. The problem is that it is unclear whether routine bronchoscopy will help to further identify the phenotype and internal type of SUA patients and how safe it will be before biologic therapy. A multicenter prospective study conducted in Spain in 100 patients with severely poorly controlled asthma, all undergoing bronchoscopy, found gastroesophageal reflux disease, vocal cord dysfunction in 5%, and tracheal abnormalities in 21%, of which eosinophilic infiltrates were detected on bronchial biopsy in 91% of patients, although overall eosinophilic infiltrates in the airway mucosa were associated with blood eosinophils, However, 5 patients with asthma with the T2 phenotype did not show eosinophilic infiltration on bronchial mucosal biopsy, and 3 non-T2 patients showed eosinophilic infiltrate on bronchial mucosal biopsy. Only 1 of all patients who underwent bronchoscopy had moderate bleeding. This study suggests that bronchoscopy prior to initiation of individualized biologic therapy for severe uncontrolled asthma can help rule out comorbidities that contribute to poorly controlled asthma, thereby reducing unnecessary escalation [22].
4. Biological agent therapy
(1) Comparison of the efficacy of different biological agents At present, there are four major categories of biological agents for the treatment of severe asthma, including anti-IgE monoclonal antibody [omalizumab (Omalizumab)], anti-IL-5/IL-5R monoclonal antibody [mepolizumab (Mepolizumab), benralizumab (benralizumab), reslizumab (Reslizumad)], anti-IL-4Rα monoclonal antibody [dupilumab], Anti-TSLP monoclonal antibody [tezepelumab]. In recent years, a number of clinical studies of biologics for the treatment of severe asthma have been published [8,23, 24, 25, 26, 27, 28, 29], as shown in Table 1.
Recently, Nopsopon et al. [30] systematically reviewed the results of 10 randomized controlled clinical trials of biologics for the treatment of severe asthma, and used Bayesian network meta-analysis to evaluate the effects of tezelumab, dupilumab, benralizumab, and mepolizumab in reducing severe asthma exacerbations, Indirect comparisons were made with differences in FEV1 and ACQ scores before bronchodilator improvement. The results showed that in the treatment of eosinophilic asthma, tezelumab, dupilumab and mepolizumab all had a more than 99% probability of reducing asthma exacerbations by 50%, but benralizumab only had a 66% probability of reducing asthma exacerbations by 50%. In addition, dupilumab or tezelumab performed better in improving lung function FEV1, but there was no significant difference between the four classes of biologics in terms of improvement in ACQ scores. Recently, Langton et al. [31] reported real-world differences in the clinical efficacy of mepolizumab and benralizumab in the treatment of severe asthmab using real-world clinical data from January 2017 to July 2020 in the treatment of severe asthma with mepolizumab and benralizumab in two large tertiary hospital critical asthma clinics in Australia (Monash Health Centre and Peninsula Health Centre) to compare data on clinical outcomes after at least 6 months of treatment with the biologics described above, Of the 204 patients with severe asthma included in the final analysis, 117 were treated with mepolizumab and 87 were treated with benralizumab. The results showed that after 6 months of treatment, the improvement in FEV1 was significantly higher in the benralizumab group than in the mepolizumab group, and this difference was more significant after 12 months of treatment. In addition, benralizumab improved the frequency of acute exacerbations by 64% more than mepolizumab (P=0.01), and although both treatments significantly reduced peripheral BEC at 6 and 12 months, benralizumab significantly reduced the magnitude of the reduction was significantly greater than that of mepolizumab [-260 (-400~-110) cells/μl, P=0.001]). As this study is a real-world observational study, it is not possible to compare the differences between the two treatment groups in some baseline clinical features that may affect treatment response, so the results of the study may be biased, and a head-to-head trial is needed to directly compare the differences in clinical efficacy of different biologics. In addition, the predictive value of biomarkers for treatment effect needs to be further explored in the future, and the population characteristics of good responders after receiving biologics treatment should be clarified. (ii) Indicators for predicting response to biologicsAlthough current biologically targeted therapies have brought many benefits to patients with severe asthma, not all patients have shown a good response to these treatments. In order to find biomarkers that can predict response to biologics in order to screen the target population at an early stage and reduce unnecessary medical burden, Moermans et al. [32] included 52 patients with severe asthma, collected baseline sputum samples from patients at the beginning of the study, and measured the proportion of type 2 inflammatory markers and cells. Subsequently, patients were treated with anti-IL-5 (51 with mepolizumab and 1 with remlizumab) and followed up for 1 year after treatment. The results showed that there were differences in the expression of inflammatory mediators in sputum between the remission group and the non-remission group, and the sputum eosinophil chemoattractant factor-1 (eotaxin-1), TSLP, IL-5, EPX and other type 2 inflammatory markers in the remission group were higher at baseline. Univariate regression analysis showed that sex, sputum neutrophil percentage, eotaxin-1, IL-5, and EPX were potential predictors of remission. The team also evaluated the role of baseline sputum BEC in identifying superresponders to mepolizumab and benralizumab therapy, and they found that patients with high BEC in sputum at baseline were more likely to be anti-IL-5/anti-IL-5R superresponders through a complete evaluation of 106 patients with severe eosinophilic asthma at baseline and after 24 weeks of treatment [33]. Unfortunately, the sample size of these two studies is relatively small, the selection of study participants may be biased, and the lack of comprehensive consideration of other confounding factors has not been able to determine a good cut-off value to guide response prediction. (3) New indicators for the evaluation of the efficacy of biologicsAt present, the evaluation of the efficacy of biologics mainly focuses on reducing the number of acute exacerbations, improving subjective symptom scores, reducing oral glucocorticoids, and improving FEV1. In a retrospective study from Cleveland [34] in the United States, 67 patients with severe eosinophilic asthma treated with mepolizumab were compared with 47 hyperresponders (overresponders achieved three dimensions of improvement, with at least two primary criteria met. Main criteria: no exacerbation, significant improvement in asthma control i.e., at least 2 times more than the minimum clinically important difference, discontinuation of oral corticosteroids; Secondary criteria: 75% reduction in acute exacerbations, well-controlled asthma, improvement in FEV1 ≥ 500 ml. ) and other patients in ACQ-6, ACQ-7, eosinophils, FEV1, and forced expiratory flow between 25% and 75% of vital capacity (FEF25%~75%). The results showed that after 6 and a half years of treatment with mepolizumab, there was no significant improvement in FEV1 overall, but in hyperresponders, FEF25%~75% increased significantly by 40%. For the evaluation of treatment response, the change of FEF25%~75% was more meaningful than the change of FEV1. Recently, several studies have evaluated the effects of biologics on the internal structure and physiological function of the airways. McIntosh et al. [35] used chest CT to assess mucus obstruction in the airways and MRI ventilation defect percentage (VDP) to assess asthma ventilatory dysfunction. The results of the study showed that on the 28th day of treatment with benralizumab, a significant improvement in VDP and ACQ-6 scores was observed in 5 patients with mucus plugs, ≥ and in mucus plugsNo significant improvement was observed in < five patients. Patients with worse ventilation and more mucus obstruction prior to treatment were more likely to have improved ACQ-6 scores after benralizumab injection. To further understand whether this 28-day early treatment response can persist in the long term, the team continued to perform pulmonary function tests, ACQ-6, CT, and MRI examinations 28 days, 1 year, and 2.5 years after starting benralizumab treatment for poorly controlled eosinophilic asthmab, and found that early improvement in VDP persisted after 2.5 years of treatment, and CT mucus score, total airway count, airway lumen area and wall thickness, ACQ score, and FEV1 [36]. This study suggests that non-invasive imaging techniques can help to further understand the impact of biologics on airway structure and function, and provide a new method for evaluating the efficacy of biologics. To date, the assessment of response to biologics has not been standardized and quantified, so the German expert consensus has proposed a scoring standard called BARS [37], which is based on annual exacerbations, daily oral corticosteroid (OCS) doses, and different levels of asthma control, respectively, using 2, 1, and 0 to score the scores of all criteria and dividing the scores of all criteria by the number of criteria to obtain a composite score. The cut-off value of the score ≥1.5 indicates good treatment effect, 0.5~1.33 indicates moderate, and <0.5 indicates insufficient response. Consensus recommends that the first treatment response assessment be performed 6 months after the start of treatment, and if the treatment response is inadequate, treatment discontinuation is recommended. In the case of moderate response to treatment, the decision should be made on an individual basis whether current biologic therapy should be continued or switched to another agent. If the patient responds well to treatment, a final evaluation is recommended 12 months after the start of treatment. Using data from the German adult severe asthma cohort, Milger et al. [38] validated the BARS scoring criteria, and found that among 210 patients with severe asthma, 33 received omalizumab, 40 received mepolizumab, 81 received benralizumab, 1 received derlizumab, and 56 received dupilumab, and after 1 year of treatment, the overall treatment effect was 61.4% good, 26.7% moderate, and 11.9% underresponded. However, the current data on the evaluation of response to biologics and the duration of medication are insufficient, so large-sample, multicenter, and long-term studies are still needed for further validation.
5. Summary and outlook
In the past year, progress has been made in both basic and clinical research in the field of asthma, providing new perspectives for the diagnosis and evaluation of asthma. In the treatment of severe asthma, there is a gradual increase in clinical evidence for the selection, response prediction and efficacy evaluation of biologics, but there is still a need for higher-quality clinical studies to provide reliable data support and gradually form clinical guidance.
References (abbreviated)