Tobacco Exposure and Efficacy of Biologic Therapy in Patients With Severe Asthma: A Nationwide Study From the Danish Severe Asthma Register.

BACKGROUND: Randomized trials of biologics in severe, uncontrolled asthma have excluded patients with a cumulative tobacco exposure of more than 10 pack-years. Therefore, our knowledge of the impact of smoking exposure on the clinical effects of biologics in severe asthma remains incomplete. However, because many patients with asthma are current or former smokers, investigating the potential impacts of tobacco exposure on the effects of biologic treatment is clinically important. OBJECTIVE: To investigate the impact of smoking history and tobacco exposure on the effectiveness of biologic therapy in real-life patients with severe asthma. METHODS: We used data from a complete nationwide cohort of patients with severe asthma who were receiving biologics, the Danish Severe Asthma Register. We divided patients according to smoking history and cumulative tobacco exposure and analyzed data at baseline and after 12 months of biologic treatment. RESULTS: A total of 724 bio-naive patients were identified in the Danish Severe Asthma Register, 398 of whom had never been smokers (55%), 316 were previous smokers (44%), and 10 were current smokers (1%). Within the group of current and former smokers, 37% had 1 to 9 pack-years of tobacco exposure, 26% had 10 to 19 pack-years, and 37% had 20 or more pack-years of tobacco exposure. Patients with tobacco exposure had similar reductions in the number of exacerbations, reductions in maintenance oral corticosteroid use, and improvements in asthma symptoms compared with patients with 0 pack-years. CONCLUSION: Former smoking history and lifetime tobacco exposure do not have an impact on the efficacy of biologics in patients with severe asthma.

Screening for impaired pulmonary function using peak expiratory flow: Performance of different interpretation strategies.

BACKGROUND: Spirometry is the gold standard for diagnosis of impaired pulmonary function, but is often unavailable in resource-constrained settings. Some authors have suggested using peak expiratory flow (PEF) to screen for impaired pulmonary function when spirometry is unavailable, but with no consensus on how to define abnormally low PEF. Strategies have included cutoffs based on absolute value of PEF, PEF in percent predicted, PEF Z-score, PEF × height-2, and gender-specific cutoffs of absolute PEF. The objective of this paper is to determine the PEF interpretation strategy with the highest predictive ability for low pulmonary function, with spirometry as the gold standard. METHODS: We analyzed data on individuals aged 40-79 years in the United States National Health and Nutrition Examination Survey 2007-2012. 6,144 individuals fulfilled inclusion criteria for the main analysis. For each PEF interpretation strategy, we calculated the area under the receiver operating curve (AUC) for the detection of low pulmonary function (defined by FEV1 Z-score < -1.645, < -2, < -2.5 or < -3). RESULTS: The AUC was substantially and statistically significantly higher for PEF in percent predicted and PEF Z-score than for absolute value and PEF × height-2, including after stratification by gender. There was no difference in AUC between PEF in percent predicted and PEF Z-score. CONCLUSION: If using PEF to screen adults aged 40 years or older for impaired pulmonary function defined by low FEV1 Z-score, basing cutoffs on PEF in percent predicted or PEF Z-score may result in improved predictive ability. As percent predicted is a mathematically simpler term than Z-score, it may be preferable to use cutoffs based on PEF in percent predicted.

A register-based study: cough - a frequent phenomenon in the adult population.

BACKGROUND: Chronic cough, more than 8 weeks, can either be without co-morbidity called unexplained chronic cough (UCC) or with co-morbidity called refractory chronic cough (RCC). Using datasets from the Danish National Prescription Registry (Prescription Registry) and Danish National Patient Registry (Patient Registry) we wanted to investigate the prevalence and factors of importance of cough in a Nationwide registry. MATERIAL AND METHODS: Inclusion criteria were patients 18-90 years with at least one final cough diagnosis (ICD-10 DR05/DR059) in Patient registry or patients who have redeemed ≥2 prescriptions for relevant cough-medication within a 90-day harvest in the Prescription registry from 2008 to 2017. To validate this study's chosen proxy on chronic cough an analysis of the Patient registry sub-population with a contact of ≥8 weeks and then final diagnosis code DR05/DR059 was also performed. The population was divided into UCC and RCC. RESULTS: Of the 104,216 patients from the Prescription registry, 52,727 were classified as having UCC and 51,489 were classified with RCC. From the Patient registry 34,260 were included, of whom 12,278 had UCC and 21,982 had RCC. Cough were frequently found among females (p < 0.0001). Both genders were around 2 years older in RCC than UCC (p < 0.0001) Spirometry was performed in 69 and 57%, X-ray in 73 and 58% and asthma challenge test performed in 13 and 5% (UCC and RCC, respectively, p < 0.0001). The frequency of co-morbidities such as heart failure, rheumatologic disease, pulmonary embolism, and diabetes was < 10%. CONCLUSION: Many patients suffer from chronic cough or cough requiring medications, with or without co-morbidity; frequently found among menopausal women. Most patients had a substantial work-up performed. The high frequency and the resources consuming work-up program call for systematic coding of disease, systematic patient evaluation and more specific treatment options. The study was approved (ID: no. P-2019-191).

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.

Fatigue Is a Major Symptom at COVID-19 Hospitalization Follow-Up.

Persistent symptoms after hospitalization with COVID-19 are common, but the frequency and severity of these symptoms are insufficiently understood. We aimed to describe symptoms and pulmonary function after hospitalization with COVID-19. Patients hospitalized with COVID-19 in Central Denmark Region were invited for follow-up 3 months after discharge. Clinical characteristics, patient reported outcomes (Fatigue Assessment Scale (FAS), anxiety and depression (HADS)), symptoms, pulmonary function test and 6-min walk test were collected. We included 218 patients (mean age 59.9 (95% CI: 58.2, 61.7), 59% males). Fatigue, dyspnea and impaired concentration were the most prevalent symptoms at follow-up. Using FAS, 47% reported mild-to-moderate fatigue and 18% severe fatigue. Mean HADS was 7.9 (95% CI: 6.9, 8.9). FAS was correlated to HADS (ß = 0.52 (95% CI: 0.44, 0.59, p < 0.001)). Mean DLCO was 80.4% (95% CI: 77.8, 83.0) and 45% had DLCO ˂ 80%. Mean DLCO was significantly reduced in patients treated in the ICU (70.46% (95% CI 65.13, 75.79)). The highest FAS and HADS were seen in patients with the shortest period of hospitalization (2.1 days (95% CI: 1.4, 2.7)) with no need for oxygen. In conclusion, fatigue is a common symptom after hospitalization for COVID-19 and ICU treatment is associated to decreased diffusion capacity.

Intralymphatic immunotherapy improves grass pollen allergic rhinoconjunctivitis: A 3-year randomized placebo-controlled trial.

BACKGROUND: Allergic rhinoconjunctivitis is a global health problem. Different allergen immunotherapy regimes are marketed but have low adherence because they are expensive, complex, and time-consuming. New allergen immunotherapy forms are needed. OBJECTIVE: In a 3-year follow-up double-blind randomized placebo-controlled trial, we aimed to investigate the effect of intralymphatic allergen immunotherapy (ILIT). METHODS: Patients with grass pollen rhinoconjunctivitis were treated with 3 ILIT injections and an ILIT booster 1 year later, 3 ILIT injections and a placebo booster, or 3 placebo injections and a placebo booster. Primary outcome was improvement in a combined symptom and medication score (cSMS). A novel evaluation tool with a linear regression model of cSMS and grass pollen counts was developed. Secondary outcomes were changes in grass specific immunoglobulins and skin and nasal provocation tests to grass pollen. RESULTS: A total of 36 patients were included. Log10-transformed cSMS was reduced by 0.30 (95% CI, 0.11-0.49; P = .002), equaling 48.5% (95% CI, 24.5%-62%), in the entire 3-year follow-up period, significant only in the first follow-up season but not in the second and third seasons. The regression model showed a 37% (P < .001) reduction in cSMS. The booster injection 1 year later had no additional effect. Secondary, repeated measures of IgE and IgG4 to grass showed significant between-group difference and within-group change in the ILIT groups. No change in provocation test results was found. CONCLUSIONS: ILIT gives a substantial reduction in grass pollen allergy symptoms and use of rescue medication, significant in the first season after treatment. A booster injection had no additional effect.

Oral corticosteroid sparing effects of anti-IL5/ anti-IL5 receptor treatment after 2 years of treatment.

INTRODUCTION: Clinical trials have shown oral corticosteroid (OCS) sparing effects of anti-IL5/anti-IL5-receptor treatments. The generalisability of these clinical trials may be limited, due to the rigid inclusion and exclusion criteria, and the short tapering duration. Real-world evidence is needed to bridge the gap between the clinical trials and the clinical practice. With this study we present real-life data on the OCS sparing effects of anti-IL5/anti-IL5-receptor treatments after 12 and 24 months of treatment. METHODS: Severe, eosinophilic asthma patients treated with mepolizumab, reslizumab or benralizumab for 24 months were included in this observational study. Data on OCS-dose, FEV1, ACT/ACQ score and blood eosinophils were obtained from the patients records before anti-IL5/anti-IL5-receptor treatment, and after 12 and 24 months of treatment. RESULTS: At baseline 75% of patients were on daily OCS. This number was reduced to 50% after one year of treatment, p < 0.001, and 28% after two years of treatment, p < 0.001. Within the group on daily OCS the median daily dose was reduced from 10 mg of Prednisolone at baseline (IQR 5-20) to 3.75 mg Prednisolone (IQR 0-10) after 12 months, and 0 mg Prednisolone (IQR 0-7.5) after 24 months, p < 0.001. CONCLUSIONS: The findings in this study add to the generalisability of the clinical studies, showing significant OCS sparing effects of anti-IL5/anti-IL5-receptor treatment in a real-life setting. Furthermore, these findings add to the understanding of the long-term effects of anti-IL5/anti-IL5-receptor treatment, showing an even further and persistent OCS reduction after two years of treatment.

Preparing an orthopedic department for COVID-19.

Background and purpose - The COVID-19 pandemic has disrupted healthcare services around the world. We (1) describe the organizational changes at a level 1 trauma center, (2) investigate how orthopedic healthcare professionals perceived the immense amount of information and educational activities, and (3) make recommendations on how an organization can prepare for disruptive situations such as the COVID-19 pandemic in the future. Methods - We conducted a retrospective survey on the organizational restructuring of the orthopedic department and the learning outcomes of a needs-driven educational program. The educational activities were evaluated by a non-validated, 7-item questionnaire. Results - The hospital established 5 COVID-19 clusters, which were planned to be activated in sequential order. The orthopedic ward comprised cluster 4, where orthopedic nursing staff were teamed up with internal medicine physicians, while the orthopedic team were redistributed to manage minor and major injuries in the emergency department (ED). The mean learning outcome of the educational activities was high-very high, i.e., 5.4 (SD 0.7; 7-point Likert scale). Consequently, the staff felt more confident to protect themselves and to treat COVID-19 patients. Interpretation - Using core clinical competencies of the staff, i.e., redistribution of the orthopedic team to the ED, while ED physicians could use their competencies treating COVID-19 patients, may be applicable in other centers. In-situ simulation is an efficient tool to enhance non-technical and technical skills and to facilitate organizational learning in regard to complying with unforeseen changes.

New-onset asthma in a bilateral lung transplant patient.

We present a case of new-onset asthma in a 35-year-old man who had undergone bilateral lung transplantation 11 years before due to idiopathic bronchiectasis and pulmonary hypertension. He presented with recurrent episodes of breathlessness, wheezing and coughing. Spirometry demonstrated severe airway obstruction. After treatment with systemic and inhaled corticosteroids and long-acting bronchodilators as well as short-acting beta-agonists as needed, his symptoms resolved and his spirometry normalised. A bronchial mannitol challenge test showed significant airway hyperresponsiveness and is thus consistent for a diagnosis of asthma. To our best knowledge, this is the first case of late new-onset asthma in a lung transplant recipient.

Increasing time interval and decreasing allergen dose interval improves ex vivo desensitization of human blood basophils.

BACKGROUND: Desensitization is a method for inducing temporary tolerance to allergen. The mechanism underlying desensitization is yet to be established. METHODS: Basophil granulocytes in whole blood from grass pollen allergic subjects were desensitized ex vivo by sequential addition of increasing allergen concentrations. At each step basophil activation (CD193 + CD63+ ) was monitored with and without (background activation) allergen challenge at optimal concentration. The sequential desensitization protocol was compared to two single-dose desensitization protocols with threshold and subthreshold allergen concentrations. Incubation intervals and allergen concentrations were varied in order to optimise the protocol. RESULTS: Sequential desensitization effectively reduced basophil response. The single-dose subthreshold protocol and single-dose threshold protocol did not reduce basophil activation with optimal allergen challenge from a mean 57.1 (95% CI: 32.7 - 81.5) to 50.4% (95% CI: 16.3 - 84.4; n = 5; P = 0.43) and 45.0% (95% CI: 23.1 - 66.9; P = 0.14) respectively, while the sequential desensitization protocol reduced activation to a mean 37.2% (95% CI: 16.3 - 58.1; P = 0.018). Reducing incubation time from 10 to 5 minutes increased mean background activation from 22.4 (95% CI: 11.7 - 33.1) to 30.0% (95% CI: 19.7 - 40.3; n = 5; P = 0.026). Increasing time intervals from 10 to 20 minutes reduced background activation from 30.9 (95% CI: 22.8 - 39.0) to 21.9% (95% CI: 16.0 - 27.7; n = 5; P = 0.020). Increasing allergen concentration intervals from 2-fold to 5- and 10-fold did not have significant effect on basophil activation. CONCLUSIONS: Sequential desensitization ex vivo effectively attenuates the basophil response to allergen. Increasing the time spent at each step improves desensitization. This protocol could be valuable for investigation the mechanism of desensitization. © 2016 International Clinical Cytometry Society.

Intralymphatic immunotherapy induces allergen specific plasmablasts and increases tolerance to skin prick testing in a pilot study.

BACKGROUND: Allergen Immunotherapy is a promising treatment of allergy. Seven patients with rhinoconjunctivitis to grass allergen were treated with intralymphatic immunotherapy (ILIT) to explore whether this treatment could be performed. Effect of treatment was assessed as change in symptom medication score, response in skin prick test and nasal allergen provocation. ILIT deposits allergen in an inguinal lymph node to elicit a strong immune stimulus. This allowed us to monitor appearance of allergen specific plasmablasts 7 days after allergen injection. FINDINGS: In an open trial of seven patients with a history of symptomatic allergic rhinoconjunctivitis due to grass pollen, three injections of allergen into inguinal lymph nodes were performed with monthly intervals. Allergen injections induced grass allergen specific plasmablasts expressing other isotypes than IgE after 7 days, induced a trend toward improvement in symptom and medication score and rhinoconjunctivitis-related quality of life during the grass pollen season 2013 and significantly raised the threshold in nasal allergen challenge and titrated skin prick testing. Mild side-effects were recorded after 3 of the 21 of injections (14 %). CONCLUSIONS: This pilot study shows that ILIT may induce allergen specific plasmablasts, and confirms an effect on provocation of mast cells in skin and nasal mucosa during the ensuing winter.

Pretreatment IgE sensitization patterns determine the molecular profile of the IgG4 response during updosing of subcutaneous immunotherapy with timothy grass pollen extract.

BACKGROUND: Allergen immunotherapy is an effective treatment of allergic rhinoconjunctivitis. Clinical efficacy is associated with improvement of basophil sensitivity and an increase in allergen-specific immunoglobulin concentration. OBJECTIVE: We sought to determine whether changes in allergen component-specific serum IgE and IgG4 levels during the updosing phase of subcutaneous immunotherapy (SCIT) are biomarkers of the immunologic changes that can lead to treatment efficacy. METHODS: Twenty-four subjects with grass pollen-induced allergic rhinoconjunctivitis were randomized 3:1 to receive SCIT (Alutard SQ) or to an open control group. IgE and IgG4 concentrations were determined for the major allergens Phl p 1 or Phl p 5 by using ImmunoCAP and for 8 grass pollen molecules by using Immuno Solid-phase Allergy Chip (ISAC) before treatment and after updosing. RESULTS: Levels of specific IgE against the dominant major allergens Phl p 1 and Phl p 5 increased from a mean of 23.0 to 48.8 kU/L (P = .01, n = 18) during the updosing phase in ImmunoCAP measurements but decreased from a median of 4.6 ISAC specific units (ISU) to 2.14 ISU (P < .0001, n = 102) when measured by using ISAC against 8 grass allergen components. The updosing phase induced a specific IgG4 level increase from a median of 0 ISU before treatment to 0.83 ISU after 12 weeks (P < .0001, n = 102) but only for allergen molecules to which pretreatment-specific IgE antibodies were detected (Spearman σ = 0.72, P < .0001, n = 102). CONCLUSION: Pretreatment allergen component-specific IgE appears to determine the induction of IgG4 in the updosing phase. Induced IgG4 seems to suppress IgE levels on ISAC, resulting in a marked decrease in ISAC-measured specific IgE levels after updosing of SCIT. Thus this decrease in ISAC IgE levels can be used to monitor the blocking effect of allergen-specific immunotherapy-induced non-IgE antibodies.