Positive Vasoreactivity Testing in Pulmonary Arterial Hypertension: Therapeutic Consequences, Treatment Patterns, and Outcomes in the Modern Management Era.

BACKGROUND: Among patients with pulmonary arterial hypertension (PAH), acute vasoreactivity testing during right heart catheterization may identify acute vasoresponders, for whom treatment with high-dose calcium channel blockers (CCBs) is recommended. However, long-term outcomes in the current era remain largely unknown. We sought to evaluate the implications of acute vasoreactivity response for long-term response to CCBs and other outcomes. METHODS: Patients diagnosed with PAH between January 1999 and December 2018 at 15 pulmonary hypertension centers were included and analyzed retrospectively. In accordance with current guidelines, acute vasoreactivity response was defined by a decrease of mean pulmonary artery pressure by ≥10 mm Hg to reach <40 mm Hg, without a decrease in cardiac output. Long-term response to CCBs was defined as alive with unchanged initial CCB therapy with or without other initial PAH therapy and World Health Organization functional class I/II and/or low European Society of Cardiology/European Respiratory Society risk status at 12 months after initiation of CCBs. Patients were followed for up to 5 years; clinical measures, outcome, and subsequent treatment patterns were captured. RESULTS: Of 3702 patients undergoing right heart catheterization for PAH diagnosis, 2051 had idiopathic, heritable, or drug-induced PAH, of whom 1904 (92.8%) underwent acute vasoreactivity testing. A total of 162 patients fulfilled acute vasoreactivity response criteria and received an initial CCB alone (n=123) or in combination with another PAH therapy (n=39). The median follow-up time was 60.0 months (interquartile range, 30.8-60.0), during which overall survival was 86.7%. At 12 months, 53.2% remained on CCB monotherapy, 14.7% on initial CCB plus another initial PAH therapy, and the remaining patients had the CCB withdrawn and/or PAH therapy added. CCB long-term response was found in 54.3% of patients. Five-year survival was 98.5% in long-term responders versus 73.0% in nonresponders. In addition to established vasodilator responder criteria, pulmonary artery compliance at acute vasoreactivity testing, low risk status and NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels at early follow-up correlated with long-term response and predicted survival. CONCLUSIONS: Our data display heterogeneity within the group of vasoresponders, with a large subset failing to show a sustained satisfactory clinical response to CCBs. This highlights the necessity for comprehensive reassessment during early follow-up. The use of pulmonary artery compliance in addition to current measures may better identify those likely to have a good long-term response.

Long-term multicenter comparison shows equivalent efficacy of monoclonal antibodies in severe asthma therapy.

BACKGROUND: Monoclonal antibodies (biologics) drastically changed severe asthma therapy. Mepolizumab (anti-interleukin (IL) 5), benralizumab (anti-IL5 receptor alpha), and dupilumab (anti-IL4/13) are the most used biologics in this context. While all biologics are efficient individually, the choice of biologic is complicated by insufficient data on their comparative long-term treatment efficacy. Here, we compare the real-life efficacy of these biologics in asthma therapy over 12 months. METHODS: 280 severe asthma patients treated with mepolizumab (129/280, 46%), benralizumab (83/280, 30%) or dupilumab (68/280, 24%) for one year were analyzed retrospectively. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels as well as responder status measured by the recently published "Biologic Asthma Response Score" (BARS). RESULTS: All biologics led to significant improvements in PF, ACT and OCS dose. Only Mepolizumab and Benralizumab significantly decreased the exacerbation rate, while only Mepolizumab and Dupilumab significantly decreased FeNO. Responder rates measured by BARS were high across all groups: roughly half of all patients achieved full response and most of the remainder achieved at least partial responder status. Overall, outcomes were similar between groups after both 6 and 12 months. CONCLUSIONS: All biologics showed great efficacy in individual parameters and high responder rates measured by BARS without a clinically relevant advantage for any antibody. Response was usually achieved after 6 months and retained at 12 months, emphasizing the utility of early response assessment.

Clinical decision making is improved by BioFire Pneumonia Plus in suspected lower respiratory tract infection after lung transplantation: Results of the prospective DBATE-IT study.

BACKGROUND: Lower respiratory tract infections (LRTIs) are a significant cause of morbidity and mortality in lung transplant (LTx) recipients. Timely and precise pathogen detection is vital to successful treatment. Multiplex PCR kits with short turnover times like the BioFire Pneumonia Plus (BFPPp) (manufactured by bioMérieux) may be a valuable addition to conventional tests. METHODS: We performed a prospective observational cohort study in 60 LTx recipients with suspected LRTI. All patients received BFPPp testing of bronchoalveolar lavage fluid in addition to conventional tests including microbiological cultures and conventional diagnostics for respiratory viruses. Primary outcome was time-to-test-result; secondary outcomes included time-to-clinical-decision and BFPPp test accuracy compared to conventional tests. RESULTS: BFPPp provided results faster than conventional tests (2.3 h [2-2.8] vs. 23.4 h [21-62], p < 0.001), allowing for faster clinical decisions (2.8 [2.2-44] vs. virology 28.1 h [23.1-70.6] and microbiology 32.6 h [4.6-70.9], both p < 0.001). Based on all available diagnostic modalities, 26 (43%) patients were diagnosed with viral LRTI, nine (15 %) with non-viral LRTI, and five (8 %) with combined viral and non-viral LRTI. These diagnoses were established by BFPPp in 92%, 78%, and 100%, respectively. The remaining 20 patients (33 %) received a diagnosis other than LRTI. Preliminary therapies based on BFPPp results were upheld in 90% of cases. There were six treatment modifications based on pathogen-isolation by conventional testing missed by BFPPp, including three due to fungal pathogens not covered by the BFPPp. CONCLUSION: BFPPp offered faster test results compared to conventional tests with good concordance. The absence of fungal pathogens from the panel is a potential weakness in a severely immunosuppressed population.

[A cross-sectional study in three German hospitals regarding oxygen therapy characteristics]. / Eine Querschnittsuntersuchung zur Qualität der Sauerstofftherapie in drei deutschen Krankenhäusern.

BACKGROUND: Oxygen (O2) therapy is one of the most commonly applied medications in German hospitals and rescue services. Both hypoxemia and hyperoxemia can be associated with complications. There is currently a lack of reliable data on the use, documentation and surveillance of O2-therapy in German hospitals. METHODS: We conducted a cross-sectional study on the use of O2 in three hospitals in Hannover, Germany. RESULTS: Of 343 patients included in this study, 20 % received O2 therapy. Twenty-nine percent of patients receiving O2 were at increased risk for hypercapnia. A standard operating procedure (SOP) for O2 therapy was available in only 68 % of patients. In 22 % patients the applied O2-therapy was appropriate in the context of the documented vital parameters. A complete documentation of vital parameters was conducted in only 30 % of all patients and 41 % of patients receiving O2-therapy. A surveillance of O2-therapy using capillary or arterial blood gas analysis was performed in 76 % of patients. Here, 64 % of patients showed normoxemia, 17 % showed hyperoxemia and 19 % of patients showed hypoxemia. The only identifiable predictor for an adequate O2-therapy was a previous invasive ventilation. DISCUSSION: Our data point towards and inadequate prescription, application and documentation of O2 therapy. The recently released German S3-guideline should be used to increase awareness among physicians and nursing staff regarding the use of O2-therapy to improve O2 therapy and consequently patient safety.

Characteristics and clinical implications of pleural effusions after lung transplantation: A retrospective analysis of 195 thoracocenteses in 113 patients.

Despite advances in lung transplantation (LTx), morbidity, and mortality are high. We hypothesized that pleural effusions requiring thoracocentesis lead to poor outcomes after LTx. We performed a single-center retrospective analysis of thoracocenteses after initial hospital discharge in LTx patients between March 2008 and September 2020 to identify risk factors, etiologies, and outcomes. Of the 1223 patients included, 113 patients (9.2%) required a total of 195 thoracocenteses. The cumulative incidence of thoracocentesis was 10.6% at 1 year and 14.2% at 5 years after transplantation. We observed a bimodal distribution of pleural effusion onset with a threshold at 6 months. Late-onset effusions were mostly of malignant or cardiac origin. We observed a high rate of nonspecific effusions (41.5%) irrespective of the timepoint post-transplantation. Patients with late-onset effusions had significantly lower survival compared to a matched controlled group (HR 2.43; 95% CI (1.27-4.62). All pulmonary function parameters were significantly decreased in patients requiring thoracocentesis compared to matched controls. Male sex and re-transplantation were risk factors for pleural effusions. In conclusion, pleural effusions requiring thoracocentesis occur frequently in LTx patients and lead to a reduced long-term allograft function. Late-onset effusions are associated with a lower survival.

Video Consultation During the COVID-19 Pandemic: A Single Center's Experience with Lung Transplant Recipients.

Background: The coronavirus disease 2019 (COVID-19) pandemic has disrupted health care systems worldwide. This is due to both to the reallocation of resources toward COVID-19 patients as well as concern for the risk of nosocomial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure. The interruption of routine care is especially problematic for patients with chronic conditions requiring regular follow-up, such as lung transplant (LTx) recipients. Introduction: New methods such as telemedicine are needed to bridge the gap in follow-up care caused by the pandemic. Materials and Methods: A retrospective analysis of video consultations (VCs) in comparison with on-site visits (OSVs) was performed during a 6-week period in an LTx center in Germany. VC included a structured work-up questionnaire and vital sign documentation. Results: During the 6-week study period, 75 VCs were performed for 53 patients and 75 OSVs by 51 patients occurred. By the end of our study period, 77% of physician-patient contacts occurred through VC. Physician-patient consultations were reduced by 47% compared with the equivalent time frame in 2019. In 62% of cases, VC resulted in a concrete clinical decision. One COVID-19 patient in home quarantine was admitted due to respiratory failure detected by VC. Patient satisfaction with VC was high. Discussion: Implementation of VC helped to reduce the need for OSV and thus the risk of SARS-CoV-2 exposure in our patient cohort. This technology can be adopted to provide care for a wide range of chronic illnesses. Conclusions: VC can preserve access to specialist care while reducing SARS-CoV-2 exposure for patients with chronic illnesses during the pandemic.

Relationship Between the Response to Antibody Therapy and Symptoms of Depression and Anxiety Disorders in Patients with Severe Asthma.

Purpose: Asthma is associated with a high prevalence of psychopathological disorders, especially depressive disorders or anxiety. In patients with uncontrolled severe asthma, monoclonal antibody (mAb)-therapy positively influenced control of mental disorders. Therefore, we evaluated the impact of antibody therapy on the burden of these mental diseases depending on responder status. Patients and Methods: Data were collected retrospectively in patients with uncontrolled severe asthma (n = 82) prior to mAb-therapy ("baseline") (omalizumab, dupilumab, benralizumab or mepolizumab). Symptoms of Major Depressive Disorder (MDD) or General Anxiety Disorder (GAD) were detected at baseline using the Hospital Anxiety and Depression Scale (HADS), as well as general sociodemographic data and lung function parameters. At 6-month (±3 month) follow-up, the burden of psychopathological symptoms under mAb-therapy was assessed using the Patient Health Questionnaire-2 (PHQ-2) and Generalized Anxiety Disorder Scale-2 (GAD-2). Response status was classified using the Biologics Asthma Response Score (BARS), assessing exacerbations, oral corticosteroid usage and asthma control test (ACT) score. Predictors for non-response to mAb-therapy were identified using linear regression analysis. Results: Patients with severe asthma suffered from symptoms of MDD/GAD more often compared to the general population, with a higher prevalence among mAb therapy non-responders. mAb-responders exhibited a declining burden of MDD, better quality of life (QoL), less exacerbations, better lung function and better disease control compared to non-responders. A history of symptoms of depression was identified as a predictor for non-response to mAb-therapy. Conclusion: Asthma symptoms and psychological problems are linked and more prevalent in our cohort of severe asthma patients than in the general population. Patients with signs of MDD/GAD before mAb-therapy show less mAb therapy response suggesting a negative impact of prior psychological problems on treatment response. In some patients, the score on MDD/GAD was caused by severe asthma - here symptoms decreased after effective treatment.

Graphic narrative based informed consent for bronchoscopy improves satisfaction in patients after lung-transplantation: A randomized controlled trial.

OBJECTIVE: This study investigated the effects of supplementing standard informed consent (IC) with a graphic narrative on patient satisfaction, periprocedural anxiety and experience. METHODS: Patients due to undergo first conscious surveillance bronchoscopy following lung transplantation were randomized to receive IC with (intervention group) or without (control group) a graphic narrative illustrating the procedure. The primary endpoint was overall patient satisfaction with the IC. Key secondary endpoints were change in state anxiety level, as measured by State Trait Anxiety Inventory, and a questionnaire assessing satisfaction with IC and adverse experience during bronchoscopy (judged by patient and examiners). RESULTS: Sixty patients were randomized, and 59 patients were included in the analysis (30 intervention-group; 29 control-group). Overall patient satisfaction was higher in the intervention group 9.5 (25Q-75Q: 8.6-9.8) vs. 8.6 (25Q-75Q: 8.1-9.2), p = 0.028). Change in state anxiety level (before vs after informed consent) was similar between the groups. There were no significant differences in adverse experience during bronchoscopy. CONCLUSION: Addition of a graphic narrative illustrating bronchoscopy improved patient satisfaction with IC but did not influence anxiety before and adverse experience during the procedure. PRACTICE IMPLICATIONS: Supplementing the IC process with a procedure-specific graphic narrative may be a simple tool to improve patient satisfaction.

[A cross-sectional study in three German hospitals regarding oxygen therapy characteristics]. / Eine Querschnittsuntersuchung zur Qualität der Sauerstofftherapie in drei deutschen Krankenhäusern.

BACKGROUND: Oxygen (O2) therapy is one of the most commonly applied medications in German hospitals and rescue services. Both hypoxemia and hyperoxemia can be associated with complications. There is currently a lack of reliable data on the use, documentation and surveillance of O2-therapy in German hospitals. METHODS: We conducted a cross-sectional study on the use of O2 in three hospitals in Hannover, Germany. RESULTS: Of 343 patients included in this study, 20 % received O2 therapy. Twenty-nine percent of patients receiving O2 were at increased risk for hypercapnia. A standard operating procedure (SOP) for O2 therapy was available in only 68 % of patients. In 22 % patients the applied O2-therapy was appropriate in the context of the documented vital parameters. A complete documentation of vital parameters was conducted in only 30 % of all patients and 41 % of patients receiving O2-therapy. A surveillance of O2-therapy using capillary or arterial blood gas analysis was performed in 76 % of patients. Here, 64 % of patients showed normoxemia, 17 % showed hyperoxemia and 19 % of patients showed hypoxemia. The only identifiable predictor for an adequate O2-therapy was a previous invasive ventilation. DISCUSSION: Our data point towards and inadequate prescription, application and documentation of O2 therapy. The recently released German S3-guideline should be used to increase awareness among physicians and nursing staff regarding the use of O2-therapy to improve O2 therapy and consequently patient safety.

Overall Response to Anti-IL-5/Anti-IL5-Rα Treatment in Severe Asthma Does Not Depend on Initial Bronchodilator Responsiveness.

BACKGROUND: Positive bronchodilator responsiveness (BDR) (change in forced expiratory volume in 1 second [ΔFEV1] ≥ +200 mL and ≥ +12%) after inhalation of a short-acting beta-2 agonist has been an inclusion criterion in licensing trials of anti-interleukin 5/anti-interleukin 5 receptor alpha (anti-IL-5/anti-IL-5Rα) biologics in severe asthma. However, in clinical practice, patients with severe uncontrolled asthma frequently show a negative BDR. OBJECTIVE: To investigate whether the response to anti-IL5/anti-IL5Rα therapies differs between patients with positive and negative BDR at baseline. METHODS: Retrospective multicenter analysis of treatment outcomes in patients with severe asthma receiving anti-IL-5/anti-IL-5Rα stratified for baseline BDR. RESULTS: Of 133 patients included, 37 had a positive and 96 had a negative BDR at baseline. Following anti-IL-5/anti-IL-5Rα treatment, FEV1 improved significantly in both groups compared with baseline (P < .0001), with no significant difference between patients with positive and negative BDR (ΔFEV1 +493 mL vs +306 mL; P = .06). Forced vital capacity (FVC) increased (ΔFVC: +85 mL vs +650 mL; P < .01) and residual volume (RV) decreased (ΔRV +113 mL vs -307 mL; P < .01) significantly in patients with negative BDR. Median annualized exacerbations (0 vs 0; P = .7), reduction of exacerbation rate (Δexacerbations 0 vs -2; P = .07), continuous oral corticosteroids (OCS) use (Δpatients on OCS -35% vs -39%; P = .99) and improvement of Asthma Control Test (ACT) score (ΔACT 6 vs 5; P = .7) were similar in both groups. Multivariate logistic regression analysis showed no significant correlations of positive versus negative BDR with response parameters. CONCLUSIONS: Both groups improved following treatment with similar responses concerning reduction of OCS therapy, exacerbations, and improvement of symptom control. Pulmonary function also improved in both groups during anti-IL-5/anti-IL-5Rα treatment, with differences in response patterns noted.

Real-World Multicenter Experience with Mepolizumab and Benralizumab in the Treatment of Uncontrolled Severe Eosinophilic Asthma Over 12 Months.

PURPOSE: Treatment of severe eosinophilic asthma (SEA) has been revolutionized by the development of monoclonal antibodies targeting underlying immunological pathways of eosinophilic asthma. Two of the most frequently used antibodies in clinical practice are mepolizumab, targeting interleukin (IL) 5 and benralizumab, targeting the IL5 receptor alpha. The comparative treatment efficacy of these antibodies remains unclear, particularly regarding long-term outcomes. PATIENTS AND METHODS: In this multicenter, retrospective study, we included 123 patients treated with mepolizumab and 64 patients treated with benralizumab for 12 months at one of three study sites in Germany. Data were collected at baseline and after 6 and 12 months of therapy. Endpoints were changes in pulmonary function (PF), exacerbation rate, oral corticosteroid (OCS) use and dose, asthma control test (ACT) score and fractional exhaled nitric oxide (FeNO) levels. RESULTS: Both mepolizumab and benralizumab led to significant improvements in PF with an increase in median forced expiratory volume (FEV1) after 12 months from 59% to 74% for mepolizumab and 63% to 72% for benralizumab. Treatment also led to significant improvements in ACT scores after 12 months (mepolizumab: 13 [interquartile range (IQR) 9-17] to 19 [IQR 15-23]; benralizumab: 12 [IQR 9-16] to 22 [IQR 16-25]) as well as a reduction of mean OCS dose (mepolizumab 8 mg [IQR 5-12.5 mg] median prednisolone equivalent at baseline to 5 mg [IQR 3-7.5 mg]; benralizumab 7.5 mg [IQR 5-15 mg] to 5 mg [IQR 2-10 mg]). The exacerbation rates were reduced significantly, irrespective of the treatment. Overall, changes were similar after 6 and 12 months of therapy. CONCLUSION: Both mepolizumab and benralizumab are highly effective in the long-term treatment of SEA, with no clinically relevant differences in outcomes after 12 months of therapy. In both groups, improvements were similar after 6 and 12 months of therapy, underlining the feasibility of early treatment evaluation.

Dupilumab Improves Asthma Control and Lung Function in Patients with Insufficient Outcome During Previous Antibody Therapy.

BACKGROUND: Biological treatments directed against IgE and IL-5 have largely improved outcomes for patients with severe type 2-high asthma. However, a fraction of patients with severe asthma show insufficient treatment outcome under anti-IgE and anti-IL-5/IL-5 receptor α antibodies. OBJECTIVE: To evaluate whether switching to dupilumab was of benefit in patients with insufficient outcome under previous anti-IgE or anti-IL-5/IL-5 receptor α therapy. METHODS: We retrospectively analyzed 38 patients who were switched to dupilumab from a previous anti-IgE or anti-IL-5/IL-5 receptor α medication because of insufficient outcome. We defined response criteria after 3 to 6 months as an improvement in at least 1 of the following criteria without deterioration in the other criteria, comparing values under dupilumab with values under previous antibody therapy: (1) increase of 3 or more in Asthma Control Test score, (2) 50% or more reduction in oral corticosteroid dose, and (3) FEV1 improvement greater than or equal to 150 mL, and classified patients as responders and nonresponders. RESULTS: Switch to dupilumab led to a response in 76% of patients. In the total cohort, Asthma Control Test score increased by a mean of 2.9 (P < .0001), whereas exacerbations decreased significantly (P < .0001) and number of oral corticosteroid-dependent patients decreased from 15 to 12. Mean FEV1 improved by 305 mL (P < .0001). Median fractional exhaled nitric oxide decreased by -30 ppb (P < .0001), whereas eosinophil counts increased by 0.17 G/L (P < .01). There were no significant differences in clinical characteristics between responders and nonresponders to dupilumab. However, patients with increased fractional exhaled nitric oxide (≥25 ppb) during previous antibody therapy were more often responders than patients with low fractional exhaled nitric oxide (<25 ppb) (P < .05). CONCLUSIONS: Altogether, we show that a switch to dupilumab in patients with insufficient outcome under previous biological therapy was effective in most patients.

Strategic Anti-SARS-CoV-2 Serology Testing in a Low Prevalence Setting: The COVID-19 Contact (CoCo) Study in Healthcare Professionals.

BACKGROUND: Serology testing is explored for epidemiological research and to inform individuals after suspected infection. During the coronavirus disease 2019 (COVID-19) pandemic, frontline healthcare professionals (HCP) may be at particular risk for infection. No longitudinal data on functional seroconversion in HCP in regions with low COVID-19 prevalence and low pre-test probability exist. METHODS: In a large German university hospital, we performed weekly questionnaire assessments and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) measurements with various commercial tests, a novel surrogate virus neutralisation test, and a neutralisation assay using live SARS-CoV-2. RESULTS: From baseline to week 6, 1080 screening measurements for anti-SARS CoV-2 (S1) IgG from 217 frontline HCP (65% female) were performed. Overall, 75.6% of HCP reported at least one symptom of respiratory infection. Self-perceived infection probability declined over time (from mean 20.1% at baseline to 12.4% in week 6, p < 0.001). In sera of convalescent patients with PCR-confirmed COVID-19, we measured high anti-SARS-CoV-2 IgG levels, obtained highly concordant results from enzyme-linked immunosorbent assays (ELISA) using e.g. the spike 1 (S1) protein domain and the nucleocapsid protein (NCP) as targets, and confirmed antiviral neutralisation. However, in HCP the cumulative incidence for anti-SARS-CoV-2 (S1) IgG was 1.86% for positive and 0.93% for equivocal positive results over the study period of 6 weeks. Except for one HCP, none of the eight initial positive results were confirmed by alternative serology tests or showed in vitro neutralisation against live SARS-CoV-2. The only true seroconversion occurred without symptoms and mounted strong functional humoral immunity. Thus, the confirmed cumulative incidence for neutralizing anti-SARS-CoV-2 IgG was 0.47%. CONCLUSION: When assessing anti-SARS-CoV-2 immune status in individuals with low pre-test probability, we suggest confirming positive results from single measurements by alternative serology tests or functional assays. Our data highlight the need for a methodical serology screening approach in regions with low SARS-CoV-2 infection rates. TRIAL REGISTRATION: The study is registered at DRKS00021152.