Combination of monoclonal antibodies targeting type 2 inflammation for severe asthma and eosinophilic granulomatosis with polyangiitis.

Monoclonal antibodies targeting type 2 inflammation are promising treatments for eosinophilic-associated diseases. There is growing interest in the potential benefits of combining two biologics to treat patients with poorly controlled conditions. We present a case of a 54-year-old female patient affected with a relapsing-refractory ANCA myeloperoxidase positive eosinophilic granulomatosis with polyangiitis (EGPA), presenting with difficult-to-treat asthma and rhino-sinusitis manifestations. She failed several biologics, including omalizumab 300 mg, mepolizumab 100 mg, and benralizumab 30 mg every 8 weeks. A switch to dupilumab led to significant eosinophilia (7.69 × 109/L) as well as systemic symptoms, and a deterioration of asthma control. Therefore, a combination of dupilumab-benralizumab was started, leading to better nasal and ear outcomes, asthma control and decrease in blood eosinophils. During the 12-month treatment, no adverse effects were observed. We conducted an extensive literature search in MEDLINE for original articles published until August 1st, 2023 reporting the combination of anti-type 2 biologics. A total of 51 cases were retrieved from the literature. Omalizumab was the most frequently combined drugs (34 cases). Combination therapy led to reduction of asthma exacerbations and glucocorticoid intake, though was ineffective only for one EGPA patient. Only one patient on omalizumab-mepolizumab therapy reported a mild adverse reaction. Combination biologic therapies for conditions which share pathogenic pathways appears to be both safe and effective. This approach may benefit patients with uncontrolled conditions and counter side effects of biologics, like dupilumab-related hypereosinophilia.

Benralizumab for eosinophilic granulomatosis with polyangiitis: a retrospective, multicentre, cohort study.

BACKGROUND: Interleukin-5 (IL-5) inhibitors represent novel therapies for eosinophilic granulomatosis with polyangiitis (EGPA). This study assessed the effectiveness and safety of the IL-5 receptor inhibitor benralizumab in a European cohort of patients with EGPA. METHODS: This retrospective cohort study included patients with EGPA from 28 European referral centres of the European EGPA Study Group across six countries (Italy, France, UK, Russia, Spain, and Switzerland) who received benralizumab as any line of treatment between Jan 1, 2019, and Sep 30, 2022. We assessed the rates of complete response, defined as no disease activity (Birmingham Vasculitis Activity Score [BVAS] of 0) and a prednisone dose of up to 4 mg/day, in contrast to partial response, defined as a BVAS of 0 and a prednisone dose greater than 4 mg/day. Active disease manifestations, pulmonary function, variation in glucocorticoid dose, and safety outcomes were also assessed over a 12-month follow-up. FINDINGS: 121 patients with relapsing-refractory EGPA treated with benralizumab at the dose approved for eosinophilic asthma were included (64 [53%] women and 57 [47%] men; median age at the time of beginning benralizumab treatment 54·1 years [IQR 44·2-62·2]). Complete response was reported in 15 (12·4%, 95% CI 7·1-19·6) of 121 patients at month 3, 25 (28·7%, 19·5-39·4) of 87 patients at month 6, and 32 (46·4%, 34·3-58·8) of 69 patients at month 12; partial response was observed in an additional 43 (35·5%, 27·0-44·8) patients at month 3, 23 (26·4%, 17·6-37·0) at month 6, and 13 (18·8%, 10·4-30·1) at month 12. BVAS dropped from 3·0 (IQR 2·0-8·0) at baseline to 0·0 (0·0-2·0) at months 3 and 6, and to 0·0 (0·0-1·0) at month 12. The proportion of patients with systemic manifestations, active peripheral neurological disease, ear, nose, and throat involvement, and pulmonary involvement decreased, with an improvement in lung function tests. Six patients relapsed after having a complete response. The oral prednisone (or equivalent) dose decreased from 10·0 mg/day (5·0-12·5) at baseline to 5·0 mg/day (3·6-8·5) at month 3 (p<0·01), to 5·0 mg/day (2·5-6·3) at month 6, and to 2·5 mg/day (0·0-5·0) at month 12 (p<0·0001). 19 (16%) of 121 patients had adverse events and 16 (13%) discontinued benralizumab. INTERPRETATION: These data suggest that benralizumab could be an effective treatment for EGPA in real-life clinical practice. Further clinical trials are required to confirm the efficacy of benralizumab in patients with a higher baseline disease activity. FUNDING: None.

Dyspnea, effort and muscle pain during exercise in lung transplant recipients: an analysis of their association with cardiopulmonary function parameters using machine learning.

BACKGROUND: Despite improvement in lung function, most lung transplant (LTx) recipients show an unexpectedly reduced exercise capacity that could be explained by persisting peripheral muscle dysfunction of multifactorial origin. We analyzed the course of symptoms, including dyspnea, muscle effort and muscle pain and its relation with cardiac and pulmonary function parameters during an incremental exercise testing. METHODS: Twenty-four bilateral LTx recipients were evaluated in an observational cross-sectional study. Recruited patients underwent incremental cardio-pulmonary exercise testing (CPET). Arterial blood gases at rest and peak exercise were measured. Dyspnea, muscle effort and muscle pain were scored according to the Borg modified scale. Potential associations between the severity of symptoms and exercise testing parameters were analyzed using a Forest-Tree Machine Learning approach, which accomplishes for a ratio between number of observations and number of screened variables less than unit. RESULTS: Dyspnea score was significantly associated with maximum power output (WR, watts), and minute ventilation (VE, L/min) at peak exercise. In a controlled subgroup analysis, dyspnea score was a limiting symptom only in LTx recipients who reached the higher levels of WR (≥ 101 watts) and VE (≥ 53 L/min). Muscle effort score was significantly associated with breathing reserve as percent of maximal voluntary ventilation (BR%MVV). The lower the BR%MVV at peak exercise (< 32) the higher the muscle effort perception. Muscle pain score was significantly associated with VO2 peak, arterial [HCO3-] at rest, and VE/VCO2 slope. In a subgroup analysis, muscle pain was the limiting symptom in LTx recipients with a lower VO2 peak (< 15 mL/Kg/min) and a higher VE/VCO2 slope (≥ 32). CONCLUSIONS: The majority of our LTx recipients reported peripheral limitation as the prevalent reason for exercise termination. Muscle pain at peak exercise was strictly associated with basal and exercise-induced metabolic altered pathways. The onset of dyspnea (breathing effort) was associated with the intensity of ventilatory response to meet metabolic demands for increasing WR. Our study suggests that only an accurate assessment of symptoms combined with cardio-pulmonary parameters allows a correct interpretation of exercise limitation and a tailored exercise prescription. The role and mechanisms of muscle pain during exercise in LTx recipients requires further investigations.

Spontaneous pneumomediastinum complicating severe acute asthma exacerbation in adult patients.

Objectives: The real incidence of pneumomediastinum (PNM) in adult patients with severe acute asthma exacerbation continues to be unknown. The current study aims to investigate the occurrence of PNM in an adult population of patients presenting a severe asthma attack and to evaluate the risk factors associated to its development. Methods: The 45 consecutive subjects who were admitted to our Division between January 1, 2015 and December 31, 2016 for severe acute asthma exacerbation underwent a diagnostic protocol including a standard chest X-ray and continuous monitoring of arterial oxygen saturation (SaO2) during the first 24 hours following admission. The patients showing persistence or deterioration of oxyhemoglobin desaturation were prescribed a chest Computed Tomographic (CT) scan. Results: Five out of the 45 patients (11.1%) with severe acute asthma exacerbation were diagnosed with PNM, in one case on the basis of an X-ray image and in four on the basis of a chest CT scan. Data analysis showed that the PNM patients were younger [21 (17-21) vs 49.5 (20-73) yrs; p < 0.001] and more likely to show sensitization to Alternaria (2/5 vs 0/40; p = 0.0101) with respect to their non-PNM counterparts. The duration of hospital stay was similar in the two groups [8 (4-12) vs 7 (3-15) days; p = 0.6939]. Conclusions: PNM is a common clinical entity in young adults with severe acute asthma exacerbation, particularly in those with unsatisfactory response to initial medical therapy. Although generally benign, patients with suspected PNM should be closely monitored because of the risk of developing severe hypoxemia.

Fatal asthma; is it still an epidemic?

BACKGROUND: Asthma mortality has declined since the 1980s. Nevertheless the World Health Organization (WHO) identified asthma as responsible for 225.000 deaths worldwide in 2005, and 430.000 fatal cases are expected by 2030. Some unexpected and concentrated fatal asthma events all occurred between 2013 and 2015 in Veneto, a North Eastern region of Italy, which prompted a more in-depth investigation of characteristics and risk factors. METHODS: A web search including key words related to fatal asthma in Italy between 2013 and 2015 has been performed. Concerning the cases that occurred in Veneto, subjects' clinical records have been evaluated and details about concomitant weather conditions, pollutants and pollen count have been collected. RESULTS: Twenty-three cases of asthma deaths were found in Italy; 16 of them (69%) occurred in the Veneto Region. A prevalence of male and young age was observed. Most of patients were atopic, died in the night-time hours and during the weekends. The possible risk factors identified were the sensitization to alternaria, previous near fatal asthma attacks and the incorrect treatment of the disease. Weather condition did not appear to be related to the fatal exacerbations, whereas among the pollutants only ozone was detected over the accepted limits. Smoking habits, possible drug abuse and concomitant complementary therapies might be regarded as further risk factors. DISCUSSION: Although not free from potential biases, our web search and further investigations highlight an increasing asthma mortality trend, similarly to what other observatories report. The analysis of available clinical data suggests that the lack of treatment more than a severe asthma phenotype characterizes the fatal events. CONCLUSIONS: Asthma mortality still represents a critical issue in the management of the disease, particularly in youngsters. Once more the inadequate treatment and the lack of adherence seem to be not only related to the uncontrolled asthma but also to asthma mortality.

Noninvasive ventilation in the event of acute respiratory failure in patients with idiopathic pulmonary fibrosis.

BACKGROUND: Some patients with idiopathic pulmonary fibrosis (IPF) develop severe acute respiratory failure (ARF) requiring admission to an intensive care unit (ICU) and ventilatory support. A limited number of observational studies have reported that noninvasive ventilation (NIV) can be an effective treatment to support breathing and to prevent use of invasive mechanical ventilation in these patients. This study aimed to retrospectively investigate the clinical status and outcomes in IPF patients receiving NIV for ARF and to identify those clinical and laboratory characteristics, which could be considered risk factors for its failure. METHODS: This is a retrospective analysis of short-term outcomes in 18 IPF patients being administered NIV for ARF. This study was conducted in a 4-bed respiratory ICU (RICU) in a university hospital. Eighteen IPF patients who were administered NIV between January 1, 2005, and April 30, 2013, were included. The outcome measures are the need for endotracheal intubation despite NIV treatment and mortality rate during their RICU stay. The length of the patients' stay in the RICU and their survival rate following RICU admission were also evaluated. RESULTS: Noninvasive ventilation was successful in 8 patients and unsuccessful in 10 who required endotracheal intubation. All the patients in the NIV failure group died within 20.2±15.3 days of intubation. The patients in the NIV success group spent fewer days in the RICU (11.6±4.5 vs 24.6±13.7; P=.0146). The median survival time was significantly shorter for the patients in the NIV failure with respect to the success group (18.0 [95% confidence interval {CI}, 9.0-25.0] vs 90.0 [95% CI, 65.0-305.0] days; P<.0001); the survival rate at 90 days was, likewise, lower in the NIV failure group (0% vs 34%±19.5%). At admission, the patients in the failure group had significantly higher respiratory rate values (36.9±7.8 vs 30.5±3.3 breaths/min; P=.036), plasma N-terminal fragment of the prohormone of B-type natriuretic peptide (NT-proBNP) levels (4528.8±4012.8 vs 634.6±808.0 pg/mL; P=.023) and serum C-reactive protein values (72.0±50.0 vs 20.7±24.0 µg/mL; P=.0289) with respect to those in the success group. Noninvasive ventilation failure was correlated to the plasma NT-proBNP levels at RICU admission (P=.0326) with an odds ratio of 12.2 (95% CI, 1.2 to infinity) in the patients with abnormally high values (>900 pg/mL). CONCLUSIONS: The outcome of IPF patients who were administered NIV was quite poor. The use of NIV was, nevertheless, found to be associated with clinical benefits in selected IPF patients, preventing the need for intubation and reducing the rate of complications/death. Elevated plasma NT-proBNP levels at the time of ICU admission is a simple clinical marker for poor NIV outcome.