Complete response to anti-interleukin-5 biologics in a real-life setting:results from the nationwide Danish Severe Asthma Register

BACKGROUND: Phase III regulatory trials show that anti-interleukin (IL)-5 biologics efficiently reduce exacerbations and the use of maintenance oral corticosteroids (mOCS) in patients with severe eosinophilic asthma. However, patients eligible for these trials differ significantly compared with real-life severe asthma populations. Therefore, our aim was to explore efficacy in a real-life setting. The Danish Severe Asthma Register (DSAR) is a complete, nationwide register that comprises all Danish patients on biological therapy for severe asthma. METHODS: This prospective study identified patients in the DSAR who were complete responders to anti-IL-5 biologics after 1 year of treatment. A complete response was defined as resolution of the parameter setting the indication, i.e. recurrent exacerbations and/or use of mOCS. RESULTS: A total of 289 out of 502 (58%) patients were complete responders to anti-IL-5 biologics after 12 months. Complete responders had greater improvements in forced expiratory volume in 1 s and Asthma Control Questionnaire (ACQ) score compared with noncomplete responders (Δ 210 versus 30 mL; p<0.0001 and Δ −1.04 versus −0.68; p=0.016, respectively). A complete response was predicted by age at onset, less severe disease at baseline (i.e. no mOCS and lower ACQ score) and higher blood eosinophils. CONCLUSIONS: More than half of Danish patients treated with anti-IL-5 biologics for severe asthma achieve a complete response to treatment, thereby becoming free from asthma exacerbations and the need for mOCS. Complete responders also achieved superior effects on lung function and symptoms compared with noncomplete responders

Targeted AntiBiotics for Chronic pulmonary diseases (TARGET ABC):can targeted antibiotic therapy improve the prognosis of Pseudomonas aeruginosa-infected patients with chronic pulmonary obstructive disease, non-cystic fibrosis bronchiectasis, and asthma? A multicenter, randomized, controlled, open-label trial

BACKGROUND: Pseudomonas aeruginosa infection is seen in chronic pulmonary disease and is associated with exacerbations and poor long-term prognosis. However, evidence-based guidelines for the management and treatment of P. aeruginosa infection in chronic, non-cystic fibrosis (CF) pulmonary disease are lacking. The aim of this study is to investigate whether targeted antibiotic treatment against P. aeruginosa can reduce exacerbations and mortality in patients with chronic obstructive pulmonary disease (COPD), non-CF bronchiectasis, and asthma. METHODS: This study is an ongoing multicenter, randomized, controlled, open-label trial. A total of 150 patients with COPD, non-CF bronchiectasis or asthma, and P. aeruginosa-positive lower respiratory tract samples will be randomly assigned with a 1:1 ratio to either no antibiotic treatment or anti-pseudomonal antibiotic treatment with intravenous beta-lactam and oral ciprofloxacin for 14 days. The primary outcome, analyzed with two co-primary endpoints, is (i) time to prednisolone and/or antibiotic requiring exacerbation or death, in the primary or secondary health sector, within days 20–365 from study allocation and (ii) days alive and without exacerbation within days 20–365 from the study allocation. DISCUSSION: This trial will determine whether targeted antibiotics can benefit future patients with chronic, non-CF pulmonary disease and P. aeruginosa infection in terms of reduced morbidity and mortality, thus optimizing therapeutic approaches in this large group of chronic patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT03262142. Registered on August 25, 2017. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-022-06720-z

Surfactant protein D, Club cell protein 16, Pulmonary and activation-regulated chemokine, C-reactive protein, and Fibrinogen biomarker variation in chronic obstructive lung disease.

Chronic obstructive pulmonary disease (COPD) is a multifaceted condition that cannot be fully described by the severity of airway obstruction. The limitations of spirometry and clinical history have prompted researchers to investigate a multitude of surrogate biomarkers of disease for the assessment of patients, prediction of risk, and guidance of treatment. The aim of this review is to provide a comprehensive summary of observations for a selection of recently investigated pulmonary inflammatory biomarkers (Surfactant protein D (SP-D), Club cell protein 16 (CC-16), and Pulmonary and activation-regulated chemokine (PARC/CCL-18)) and systemic inflammatory biomarkers (C-reactive protein (CRP) and fibrinogen) with COPD. The relevance of these biomarkers for COPD is discussed in terms of their biological plausibility, their independent association to disease and hard clinical outcomes, their modification by interventions, and whether changes in clinical outcomes are reflected by changes in the biomarker

Enzyme-linked immunosorbent assay characterization of basal variation and heritability of systemic microfibrillar-associated protein 4.

BACKGROUND: Microfibrillar-associated protein 4 (MFAP4) is a systemic biomarker that is significantly elevated in samples from patients suffering from hepatic cirrhosis. The protein is generally localized to elastic fibers and other connective tissue fibers in the extracellular matrix (ECM), and variation in systemic MFAP4 (sMFAP4) has the potential to reflect diverse diseases with increased ECM turnover. Here, we aimed to validate an enzyme-linked immunosorbent assay (ELISA) for the measurement of sMFAP4 with an emphasis on the robustness of the assay. Moreover, we aimed to determine confounders influencing the basal sMFAP4 variability and the genetic contribution to the basal variation. METHODS: The sandwich ELISA was based on two monoclonal anti-MFAP4 antibodies and was optimized and calibrated with a standard of recombinant MFAP4. The importance of pre-analytical sample handling was evaluated regarding sample tube type, time, and temperature conditions. The mean value structure and variance structure was determined in a twin cohort including 1,417 Danish twins (age 18-67 years) by mixed-effect linear regression modeling. RESULTS: The practical working range of the sandwich ELISA was estimated to be 4-75 U/ml. The maximum intra- and inter-assay variation was estimated to be 8.7% and 6.6%, respectively. Sample handling and processing appeared to influence MFAP4 measurements only marginally. The average concentration of sMFAP4 in the serum was 18.9 ± 8.4 (SD) U/ml in the twin cohort (95% CI: 18.5-19.4, median sMFAP4 17.3 U/ml). The mean structure model was demonstrated to include waist-hip ratio, age, and cigarette smoking status in interactions with gender. A relatively low heritability of h(2) = 0.24 was found after applying a model including additive genetic factors and shared and non-shared environmental factors. CONCLUSIONS: The described ELISA provides robust measures of the liver fibrosis marker sMFAP4. The low heritability and the relatively limited basal variation suggest that increased sMFAP4 reflects disease-induced processes

Clinical response and remission in severe asthma patients treated with biologic therapies

BACKGROUND: The development of novel targeted biologic therapies for severe asthma has provided an opportunity to consider remission as a new treatment goal.RESEARCH QUESTION: How many severe asthma patients treated with biologic therapy achieve clinical remission, and what predicts response to treatment?STUDY DESIGN AND METHODS: The Danish Severe Asthma Registry is a nationwide register including all adult patients receiving biologic therapy for severe asthma in Denmark. We conducted an observational cohort study and defined "clinical response" to treatment after 12 months as ≥50% reduction in exacerbations, and/or a ≥50% reduction in maintenance oral corticosteroid dose, if required. "Clinical remission" was defined by cessation of exacerbations and maintenance OCS, as well as a normalization of lung function (FEV1%&gt;80%) and an Asthma Control Questionnaire-6 score ≤1.50 after 12 months of treatment.RESULTS: After 12 months of treatment of 501 biologically naïve patients, there were 104 (21%) patients with no response to treatment, whereas 397 (79%) had a clinical response. Among the latter, 97 (24%) fulfilled our criteria of clinical remission, corresponding to 19% in the entire population. Remission was predicted by shorter duration of disease and lower BMI in our entire population of all patients treated with biologic therapy.INTERPRETATION: Clinical response was achieved in most adult patients initiating biologic therapy and clinical remission was observed in 19% of the patients after 12 months of treatment. Further studies are required to assess the long-term outcome of achieving clinical remission on biologic therapy.</p

Microfibrillar-associated protein 4:A potential biomarker of chronic obstructive pulmonary disease

SummaryBackgroundMicrofibrillar-associated protein 4 (MFAP4) is a matricellular glycoprotein that co-localises with elastic fibres and is highly expressed in the lungs. The aim of this study was to test the hypothesis that plasma MFAP4 (pMFAP4) reflects clinical outcomes in chronic obstructive pulmonary disease (COPD).MethodspMFAP4 was measured by an AlphaLISA immunoassay in stable COPD (n = 69) at baseline and at follow-up until 24 months after inclusion and in acute exacerbations of COPD (AECOPD) (n = 14) at baseline and until 6 months after inclusion.ResultsThe majority of patients (89%) were in GOLD II and III. Multiple linear regressions showed positive associations between pMFAP4 and the Global initiative for Obstructive Lung Disease (GOLD) grade (p = 0.01), modified Medical Research Council score (p < 0.0001) and BODE index (p = 0.04). Negative associations were found with 6-min walking distance (p = 0.04) and bronchodilator-induced reversibility (p = 0.02). The pMFAP4 levels varied less than 25% between the baseline and a 3 month follow-up in 83% of the patients. The pMFAP4 levels appeared unaffected in the acute phase of severe AECOPD but rose to an increased stable level within one month after hospitalization.ConclusionIncreased pMFAP4 was associated to the severity in COPD and has the potential to serve as a stable disease biomarker. This observation warrants confirmation in a larger longitudinal COPD population

Localization of microfibrillar-associated protein 4 (MFAP4) in human tissues: clinical evaluation of serum MFAP4 and its association with various cardiovascular conditions.

Microfibrillar-associated protein 4 (MFAP4) is located in the extracellular matrix (ECM). We sought to identify tissues with high levels of MFAP4 mRNA and MFAP4 protein expression. Moreover, we aimed to evaluate the significance of MFAP4 as a marker of cardiovascular disease (CVD) and to correlate MFAP4 with other known ECM markers, such as fibulin-1, osteoprotegerin (OPG), and osteopontin (OPN). Quantitative real-time PCR demonstrated that MFAP4 mRNA was more highly expressed in the heart, lung, and intestine than in other elastic tissues. Immunohistochemical studies demonstrated high levels of MFAP4 protein mainly at sites rich in elastic fibers and within blood vessels in all tissues investigated. The AlphaLISA technique was used to determine serum MFAP4 levels in a clinical cohort of 172 patients consisting of 5 matched groups with varying degrees of CVD: 1: patients with ST elevation myocardial infarction (STEMI), 2: patients with non-STEMI, 3: patients destined for vascular surgery because of various atherosclerotic diseases (stable atherosclerotic disease), 4: apparently healthy individuals with documented coronary artery calcification (CAC-positive), and 5: apparently healthy individuals without signs of coronary artery calcification (CAC-negative). Serum MFAP4 levels were significantly lower in patients with stable atherosclerotic disease than CAC-negative individuals (p<0.05). Furthermore, lower serum MFAP4 levels were present in patients with stable atherosclerotic disease compared with STEMI and non-STEMI patients (p<0.05). In patients with stable atherosclerotic disease, positive correlations between MFAP4 and both fibulin-1 (ρ = 0.50; p = 0.0244) and OPG (ρ = 0.62; p = 0.0014) were found. Together, these results indicate that MFAP4 is mainly located in elastic fibers and is highly expressed in blood vessels. The present study suggests that serum MFAP4 varies in groups of patients with different cardiovascular conditions. Further studies are warranted to describe the role of serum MFAP4 as a biomarker of stable atherosclerotic disease

sMFAP4 estimates as a function of age or waist-hip ratio.

<p>Serum MFAP4 estimates based on the coefficients in the mean value structure shown in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0082383#pone-0082383-t003" target="_blank">Table 3</a>. <b>A</b>. The three graphs report sMFAP4 as a function of age and smoking status (smokers, non-smoking males, and non-smoking females). The mean values of the waist-hip ratio are used in the calculations (females 0.812, males 0.927, and all 0.867). <b>B</b>. The three graphs report sMFAP4 as a function of the waist-hip ratio and smoking status (smokers, non-smoking males, and non-smoking females). The mean values of age are used in the calculations (females 37.5, males 38.0, and all 37.7).</p

Gel permeation chromatography.

<p>Protein elution profiles are shown from the analytical Superose 6 10/300 GL column gel permeation chromatography. The smooth lines in all four graphs (A-D) show the profile of a standard protein mixture containing thyroglobulin (670 kDa), thyroglobulin monomer (335 kDa), IgG (158 kDa), ovalbumin (44 kDa), myoglobin (17 kDa), and vitamin B12 (1.35 kDa). The corresponding values on the right ordinate represent the UV absorbance measure (mAU). All samples were collected in 1-ml fractions analyzed by MFAP4 ELISA as described. The numbers on the left ordinate correspond to the estimated MFAP4 content in U/ml. <b>A</b>. Culture supernatant from CHO cells over-expressing recMFAP4 (filled circles) and a negative control of culture supernatant from CHO cells transfected with an empty construct (open circles). <b>B</b>. Normal human serum (filled triangles) and normal human serum depleted of MFAP4 (open triangles). <b>C</b>. MFAP4-depleted normal human serum reconstituted with recMFAP4 (filled squares). <b>D</b>. Affinity-chromatography purified human MFAP4 (filled rhombus).</p