Impulse oscillometry bronchodilator response in preschool children.

BACKGROUND: In preschoolers, performing an acceptable spirometry and measuring bronchodilator response (BDR) is challenging; in this context, impulse oscillometry (IOS) represents a valid alternative. However, more studies on the standardization of BDR for IOS in young children are required. OBJECTIVE: The objective of the study was to identify optimal thresholds to define a positive BDR test with IOS in preschoolers with suspected asthma. METHODS: Children aged 3-6 years with suspected asthma and their lung function investigated with both IOS and spirometry pre- and post-BDR were retrospectively analyzed. The spirometric BDR was defined as positive when the change of FEV1 was ≥12% or ≥200 mL. The oscillometric BDR was defined as positive in case of change of at least -40% in R5, +50% in X5, and -80% in AX. RESULTS: Among 72 patients, 36 (age 5.2 ± 1 years; 64% boys) were selected for the subsequent analysis according to ATS/ERS quality criteria of measurements; specifically, 19 patients did not meet IOS and 36 did not meet spirometry criteria. The spirometric BDR was found positive in seven subjects (19.4%); conversely, a positive oscillometric BDR was identified in four patients (11.1%). No patient presented a positive BDR response with both methods. In IOS, the mean decrease in R5 and AX was 19.9% ± 10% and 44% ± 22.1%, and the mean increase in X5 was 23.3% ± 17.8%, respectively. A decrease in R5 of 25.7% (AUC 0.77, p = .03) and an increase in X5 of 25.7% (AUC 0.75, p = .04) showed the best combination of sensitivity and specificity to detect an increase of FEV1 ≥ 12% and/or ≥200 mL. CONCLUSION: The IOS represents a valid alternative to spirometry to measure BDR in preschool children and should be the gold standard in this age group. We are considering a decrease of 26% in R5 and an increase of 26% in X5 as diagnostic threshold for BDR.

Are Questionnaires Helpful To Predict Exercise-Induced Bronchoconstriction (EIB) And Exercise-Induced Laryngeal Obstruction (EILO)?

OBJECTIVE: Exercise induced laryngeal obstruction (EILO) is an important differential diagnosis to exercise induced bronchoconstriction (EIB) and diagnosed via continuous laryngoscopy while exercising (CLE). However, availability of CLE is limited to specialized centres. And without CLE EILO is often misdiagnosed as EIB. Therefore it is essential to carefully preselect potential EILO candidates. Aim of this study was to investigate whether two short questionnaires -Asthma Control Test (ACT) and Dyspnea Index (DI) evaluating upper airway-related dyspnea- can differentiate between EIB and EILO. METHODS: Patients with dyspnea while exercising were analysed with an exercise challenge in the cold chamber (ECC) to diagnose EIB in visit 1 (V1), as appropriate a CLE in visit 2 (V2, 4-6 weeks after V1) and ACT and DI in V1 and V2. EIB patients were treated with asthma medication after V1. RESULTS: Complete dataset of 36 subjects were gathered. The ACT showed lower values in V2 in EILO compared to EIB patients. A lack of improvement in ACT in V2 after asthma medication of EIB patients is suspicious for additional EILO diagnosis. The DI showed higher values in V1 in EILO compared to EIB patients. A score≥30 can predict a positive CLE reaction. CONCLUSION: ACT and DI are valuable tools in preselecting CLE candidates to assure timely diagnostic despite limited diagnostic capabilities.

Severe bronchial hyperresponsiveness along with house dust mite allergy indicates persistence of asthma in young children.

BACKGROUND: Significant risk factors for persistence of asthma later in life are family history of allergies, early allergic sensitization and bronchial hyperresponsiveness (BHR). The evolution of BHR in young children without allergic sensitization and with house dust mite allergy (HDM) was investigated. METHODS: In this retrospective analysis, electronic charts of 4850 young children with asthma and wheezy bronchitis between 2005 and 2018 were reviewed in order to study all patients ≤6 years with BHR assessed by methacholine provocation tests (MCT) at least once (n = 1175). Patients with more than two follow-up measurements were divided in group 1 (no allergic sensitization; n = 110) and group 2 (HDM allergy; n = 88). Additionally, skin prick test, exhaled nitrite oxide (eNO), and asthma treatment were analyzed. RESULTS: Forty-seven patients of group 1 aged median 4.3 years and 48 patients of group 2 aged median 4.7 years showed initially severe BHR <0.1 mg. At follow-up, patients with HDM were more likely to show persistence of severe BHR than non-sensitized patients (severe BHR group 1: n = 5 (10.6%) vs. group 2: n = 21 (43.8%), p < .001). In addition, 89.4% of group 1 had mild to moderate or no BHR, compared to only 56.2% of group 2. There was a significant difference in eN0 (median group 1: 9 ppb vs. group 2: 26 ppb, p < .001), at last follow-up. Age, sex, and asthma therapy had no effect on BHR. CONCLUSION: In young children without sensitization BHR normalizes, whereas HDM allergy indicates a persistence of asthma beyond infancy.

Randomized controlled phase 2 trial of hydroxychloroquine in childhood interstitial lung disease.

BACKGROUND: No results of controlled trials are available for any of the few treatments offered to children with interstitial lung diseases (chILD). We evaluated hydroxychloroquine (HCQ) in a phase 2, prospective, multicentre, 1:1-randomized, double-blind, placebo-controlled, parallel-group/crossover trial. HCQ (START arm) or placebo were given for 4 weeks. Then all subjects received HCQ for another 4 weeks. In the STOP arm subjects already taking HCQ were randomized to 12 weeks of HCQ or placebo (= withdrawal of HCQ). Then all subjects stopped treatment and were observed for another 12 weeks. RESULTS: 26 subjects were included in the START arm, 9 in the STOP arm, of these four subjects participated in both arms. The primary endpoint, presence or absence of a response to treatment, assessed as oxygenation (calculated from a change in transcutaneous O2-saturation of ≥ 5%, respiratory rate ≥ 20% or level of respiratory support), did not differ between placebo and HCQ groups. Secondary endpoints including change of O2-saturation ≥ 3%, health related quality of life, pulmonary function and 6-min-walk-test distance, were not different between groups. Finally combining all placebo and all HCQ treatment periods did not identify significant treatment effects. Overall effect sizes were small. HCQ was well tolerated, adverse events were not different between placebo and HCQ. CONCLUSIONS: Acknowledging important shortcomings of the study, including a small study population, the treatment duration, lack of outcomes like lung function testing below age of 6 years, the small effect size of HCQ treatment observed requires careful reassessments of prescriptions in everyday practice (EudraCT-Nr.: 2013-003714-40, www.clinicaltrialsregister.eu , registered 02.07.2013). Registration The study was registered on 2 July 2013 (Eudra-CT Number: 2013-003714-40), whereas the approval by BfArM was received 24.11.2014, followed by the approval by the lead EC of the University Hospital Munich on 20.01.2015. At clinicaltrials.gov the trial was additionally registered on November 8, 2015 (NCT02615938).

Evaluating Children and Adolescents with Suspected Exercise Induced Asthma: Real Life Data.

OBJECTIVE: Exercise-induced bronchoconstriction (EIB) occurs frequently in children and adolescents and may be a sign of insufficient asthma control. EIB is often evaluated by respiratory symptoms, spirometry, eNO measurement and methacholine testing (MCT) instead of time consuming exercise test. Aim of this study was to analyse the amount of patients for which an exercise challenge in a cold chamber (ECC) was needed for a clear EIB diagnosis, to characterize EIB phenotypes and the incidence of exercise induced laryngeal obstruction (EILO) in a large cohort of patients with EIB. METHODS: A retrospective analysis was performed in 595 children and adolescents (mean age 12.1 years) with suspected EIB from January 2014 to December 2018. Complete data sets of skin prick test, spirometry, eNO and MCT were available from 336 patients. RESULTS: An ECC to confirm the EIB diagnosis was performed in 125 (37.2%) of patients. Three EIB phenotypes were detected: group 1: EIB without allergic sensitization (n=159); group 2: EIB with other than house dust mite (HDM) sensitization (n=87) and group 3: EIB with HDM sensitization (n=90). MCT and eNO showed significant differences between the subgroups: An eNO>46 ppb and/or a MCT<0.1 mg was found in 23.9% vs. 50.6% vs. 57.8% in group 1-3, respectively. Significantly more patients suffered from EILO in group 1 compared to group 2 and 3 (n=13 vs. n=1). CONCLUSION: EIB without sensitization is as often as EIB with sensitization. In patients without sensitization, EILO has to be considered as a possible cause of symptoms during exercise.

EAACI position paper on the clinical use of the bronchial allergen challenge: Unmet needs and research priorities.

Allergic asthma (AA) is a common asthma phenotype, and its diagnosis requires both the demonstration of IgE-sensitization to aeroallergens and the causative role of this sensitization as a major driver of asthma symptoms. Therefore, a bronchial allergen challenge (BAC) would be occasionally required to identify AA patients among atopic asthmatics. Nevertheless, BAC is usually considered a research tool only, with existing protocols being tailored to mild asthmatics and research needs (eg long washout period for inhaled corticosteroids). Consequently, existing BAC protocols are not designed to be performed in moderate-to-severe asthmatics or in clinical practice. The correct diagnosis of AA might help select patients for immunomodulatory therapies. Allergen sublingual immunotherapy is now registered and recommended for controlled or partially controlled patients with house dust mite-driven AA and with FEV1 ≥ 70%. Allergen avoidance is costly and difficult to implement for the management of AA, so the proper selection of patients is also beneficial. In this position paper, the EAACI Task Force proposes a methodology for clinical BAC that would need to be validated in future studies. The clinical implementation of BAC could ultimately translate into a better phenotyping of asthmatics in real life, and into a more accurate selection of patients for long-term and costly management pathways.

Herb-induced liver injury (HILI) with 12,068 worldwide cases published with causality assessments by Roussel Uclaf Causality Assessment Method (RUCAM): an overview.

Herbal products including herbal medicines are worldwide used in large amounts for treating minor ailments and for disease prevention. However, efficacy of most herbal products has rarely been well documented through randomized controlled trials in line with evidence-based medicine concepts, which could be used to estimate the benefit/risk ratio. Instead, much better documented are adverse reactions such as liver injury associated with the consumption of some herbal products, so called herb-induced liver injury (HILI), which represents a clinical challenge. In order to establish HILI as valid diagnosis, the use of a diagnostic algorithms such as Roussel Uclaf Causality Assessment Method (RUCAM) is widely recommended, although physicians in some countries are reluctant to use RUCAM for their HILI cases. This review on worldwide HILI and RUCAM, developed as part of the artificial intelligence ideas, reveals that China is the leading country with 24 publications on HILI cases that were all assessed for causality using RUCAM, followed by Korea with 15 reports, Germany with 9 reports, the US with 7 reports, and Spain with 6 reports, whereas the remaining countries provided less than 4 reports. The total number of assessed HILI cases is 12,068 worldwide derived from 80 publications but in each report HILI case numbers were variable in a range from 1 up to 6,971. This figure compares with 46,266 cases of drug-induced liver injury (DILI) published worldwide from 2014 to early 2019 also assessed for causality by RUCAM. The original version of RUCAM was validated and established in 1993 and updated in 2016 that should be used in future HILI cases. RUCAM is an objective, structured, and validated method, specifically designed for liver injury. It is a scoring system including case data elements to be assessed and scored individually to provide a final score in five causality gradings. Among the 11,404/12,068 HILI (94.5%) cases assessable for evaluation, causality gradings were highly probable in 4.2%, probable in 15.5%, possible in 70.3%, and unlikely or excluded in 10.0%. To improve the future reporting of RUCAM based HILI cases, recommendations include the strict adherence to instructions outlined in the updated RUCAM and, in particular, to follow prospective data collection on the cases to ensure completeness of case data. In conclusion, RUCAM can well be used to assess causality in suspected HILI cases, and additional efforts are now required to increase the quality of the reported cases.

Cannabinoid Activity-Is There a Causal Connection to Spasmolysis in Clinical Studies?

Cannabinoid drugs are registered for postoperative nausea and emesis, Tourette syndrome and tumor-related anorexia, but are also used for spasticity and pain relief, among other conditions. Clinical studies for spasmolysis have been equivocal and even conclusions from meta-analyses were not consistent. This may be due to uncertainty in diagnostic criteria as well as a lack of direct spasmolytic activity (direct causality). In this review we used the Hill criteria to investigate whether a temporal association is causal or spurious. METHODS: A systematic literature search was performed to identify all clinical trials of cannabinoids for spasticity. Studies were evaluated for dose dependency and time association; all studies together were analyzed for reproducibility, coherence, analogy and mechanistic consistency. A Funnel plot was done for all studies to identify selection or publication bias. RESULTS: Twenty-seven studies were included in this meta-analysis. The spasmolytic activity (effect strength) was weak, with a nonsignificant small effect in most studies and a large effect only in a few studies ("enriched" studies, low patient numbers). No dose dependency was seen and plotting effect size vs. daily dose resulted in a slope of 0.004. Most studies titrated the cannabinoid to the optimum dose, e.g., 20 mg/d THC. The effect decreased with longer treatment duration (3-4 months). The spasmolytic effect is consistent for different European countries but not always within a country, nor is the effect specific for an etiology (multiple sclerosis, spinal cord injury, others). For other criteria like plausibility, coherence or analogous effects, no data exist to support or refute them. In most studies, adverse effects were frequently reported indicating a therapeutic effect only at high doses with relevant side effects. CONCLUSIONS: Current data do not support a specific spasmolytic effect; a general decrease in CNS activity analogous to benzodiazepines appears more likely. Whether individual patients or specific subgroups benefit from cannabinoids is unclear. Further studies should compare cannabinoids with other, nonspecific spasmolytic drugs like benzodiazepines.

Inadequate treatment in internships: a comparison between medical and other students.

Aims: Inadequate treatment is one of the factors interfering with a successful social and working life. Among students, it can impair their health and learning progress. In the field of medicine the problem of inadequate treatment seems widespread. This study examines wether inadequate treatment in internships differs between medicine and other academic disciplines. Method: Using a questionnaire, the frequency, forms and severity of inadequate treatment among students were compared between the disciplines of medicine, civil engineering and teaching. Results: 69,3% of medical students reported inadequate treatment during their internships, about twice as many as students of other disciplines. The ratios of verbal, non-verbal and organisational inadequate treatment were similar between the different academic disciplines. However, medical students executed tasks without receiving sufficient safety precautions or training significantly more often (sevenfold) than students of other disciplines. In total however, the experienced incidents of inadequate treatment were seen as similarly severe across the different academic fields. Conclusion: Inadequate treatment of students during internships is a larger problem in medicine than in civil engineering or teaching, particularly concerning the performance of unsafe tasks. With regard to the health of students and patients, inadequate treatment in the medical education should be tackled. Previous studies suggest that this goal can be achieved only through longtime extensive measures on the level of students, lecturers, faculty and teaching hospitals.

Tiotropium as an Add-on Treatment Option for Severe Uncontrolled Asthma in Preschool Patients.

BACKGROUND: Toddlers with asthma suffer disproportionally more than school-aged children from exacerbations with emergency visits and hospital admissions despite inhaled corticosteroid (ICS) treatment. A recent trial for children ≤5 years showed tolerability of tiotropium and potential to reduce asthma-related events. METHODS: We conducted a retrospective analysis of electronic outpatient records (2017‒2019) of children <6 years treated with ICS plus long-acting ß2-agonists (LABAs) plus tiotropium as an add-on for uncontrolled severe asthma. The primary endpoint was a comparison of systemic corticosteroid (SCS) prescriptions 6 months before and after ICS/LABA/tiotropium start. Secondary endpoints included physician visits, hospitalisations and antibiotic prescriptions. We compared outcomes with children without asthma matched for age, sex, season and screening date. RESULTS: Compared with a mean 2.42 (95% CI: 1.75, 3.36) SCS courses per patient within 6 months prior to ICS/LABA/tiotropium, 0.74 (95% CI: 0.25, 1.08) SCS courses per patient were prescribed within 6 months after starting ICS/LABA/tiotropium (P<0.001). Physician visits dropped from 9.23 (95% CI: 7.15, 12.72) to 5.76 (95% CI: 3.10, 7.70) per patient (P<0.01). Nineteen hospitalisations were recorded 6 months before ICS/LABA/tiotropium compared with one hospitalisation after (P<0.01). A mean 1.79 antibiotic courses (95% CI: 1.22, 2.23) per patient were prescribed before ICS/LABA/tiotropium compared with 0.74 (95% CI: 0.22, 1.00) after ICS/LABA/tiotropium (P<0.001). Hospitalisation rates for patients at observation end were not statistically different from healthy controls before/after matching. INTERPRETATION: Our retrospective study showed that adding tiotropium to ICS/LABA is a new treatment option for patients with severe preschool asthma; however, larger confirmatory studies are needed.

[German Family Practitioners' Attitude toward the Legal and Economic Framework of their Professional Work]. / Die Einstellung deutscher Hausärzte zu rechtlichen und wirtschaftlichen Rahmenbedingungen ihrer Tätigkeit.

Advances in medical technology, demographic developments and changes in society's understanding of health and illness are altering the requirements in modern family medicine. In parallel, the privately financed secondary health care market is growing. The practice of family medicine is shaped by the regulatory environment of the Code of Social Law (economical, reasonable, necessary, practicable) but now increasingly by the economic orientation of the secondary health care market and by legal questions as well. To capture the implications of these developments, German family practitioners were surveyed about the resultant attitudes and consequences. A total of 500 family doctors took part in an online survey regarding the medical practice. The questionnaire was developed and pre-tested on the basis of semi-structured interviews. It contained items related to the implications of the secondary health care market as well as questions about commercial and legal consequences. Except for the sex of participants, the sample was representative of the overall distribution of family practitioners in Germany. Every second doctor practicing family medicine dislikes private payment for health care services; 75% perceived negatively the influence of non-medical actors in the public health sector on medical measures. Only 8% of the participants agreed with the statement that integration of innovative care concepts through digitalization improved patient care while 37% rejected it; 41% of those surveyed advocated stronger legal monitoring due to the increasingly negative influence of privatization. However, approximately two-thirds of the participants felt that current legislation, including the passage of the Anti-Corruption Law of 2016, was inadequate. The confidence of family doctors in legal prosecution for medical criminal acts was minimal. The self-image of family medicine will change through stronger integration among the commercial and legal aspects, which will be necessary for modern family medicine. A critical discussion regarding the possible effects of a competitive orientation must closely accompany any innovative care. In addition to the risk of the economization of practices, combining the classical health care system with the secondary health care market also offers opportunities to improve the quality of medical care.

Hospitalization, Asthma Phenotypes, and Readmission Rates in Pre-school Asthma.

Objective: Children with pre-school asthma suffer disproportionally more often from severe asthma exacerbations with emergency visits and hospital admissions compared to school children. Despite this high disease burden, there are only a few reports looking at this particular severe asthma cohort. Similarly, there is little real-life research on the distribution of asthma phenotypes and personalized treatment at discharge in this age group. Patients and Methods: Retrospective analysis of the electronic charts of all children aged 1-5 years with asthma hospitalizations (ICD J45) at the Frankfurt University between 2008 and 2017. An acute severe asthma exacerbation was defined as dyspnea, oxygen demand, and/or systemic steroid therapy. Age, gender, duration of hospitalization, asthma phenotype, treatment, and readmission rate were analyzed. Results: Of 572 patients, 205 met the definition of acute severe asthma. The phenotypic characterization showed 56.1% had allergic asthma, 15.2% eosinophilic asthma and 28.7% non-allergic asthma. Of these patients, 71.7% were discharged with inhaled corticosteroids (ICS) or ICS + long-acting-beta-agonists (LABA), 15.1% with leukotriene antagonists (LTRA) and 7.3% salbutamol on demand. The rate of emergency presentations (emergency department and readmission) within 12 months after discharge was high (n = 42; 20.5%). No phenotype tailored treatment was detectable. Neither the number of eosinophils (>300/µl) nor the treatment at discharge had an effect on emergency visits and readmission rate. Conclusion: Despite protective therapy with ICS, ICS + LABA, or LTRA, the readmission rate was high. Thus, current care and treatment strategies should be reevaluated continuously, in order to better control asthma in pre-school children and prevent hospitalization.

Comparison of bronchial and nasal allergen provocation in children and adolescents with bronchial asthma and house dust mite sensitization.

BACKGROUND: Bronchial allergen provocation (BAP) is an established tool for the diagnosis of allergy in patients with asthma, but its use is limited by the potential risk of severe asthmatic reactions. Nasal provocation testing (NPT) may be an alternative safe method and does not require sophisticated equipment. OBJECTIVE: The aim of this prospective study was to evaluate the concordance of both methods in patients with asthma and house dust mite (HDM) sensitization. METHODS: A total of 112 patients with HDM sensitization underwent BAP and had the following parameters analysed: decrease in FEV1, exhaled NO, and total and specific IgE. Within 12 weeks, NPT with HDM was performed in 74 patients with a median age of 9 years (range, 5-16 years). The results were evaluated using the Lebel score which quantifies major symptoms like rhinorrhea, nasal obstruction, sneezes and minor symptoms, such as pruritus, conjunctivitis and pharyngitis. RESULTS: Fifty-seven of 74 patients had an early asthmatic reaction, of which 41 were identified using the Lebel score. The Lebel score had a sensitivity of 71.9% and a positive predictive value (PPV) of 89.1%. In addition, an eNO ≥ 10 ppb (AUC 0.78), a specific IgE Dermatophagoïdes pteronyssinus ≥ 25.6 kU/L (AUC 0.76) and a specific IgE Dermatophagoïdes farinae ≥ 6.6 kU/L (AUC 0.78) were good predictors of an early asthmatic reaction. CONCLUSION: A sequential use of NPT prior to BAP is justified to establish the relevance of HDM allergy. In patients with a negative NPT, BAP is still recommended to rule out a HDM-induced asthmatic reaction.

Prospective comparison of a nonmodified and a modified mite extract for immunotherapy in children and adolescents.

Aim: This prospective study compares nonmodified and modified house dust mite extracts for allergen immunotherapy (AIT) in pediatric patients with allergic asthma. Materials & methods: Total 95 patients underwent bronchial allergen provocation (BAP). AIT was recommended to 62 patients. Complete datasets of 54 subjects were obtained. Primary aim was the comparison of treatment success defined by BAP between two extracts after 1 year. Secondary parameters were laboratory parameters and clinical symptoms. Results: Significant improvement (p < 0.001) was measured by BAP in both treatment groups. No change was seen in the controls. Both extracts exerted comparable effects on all parameters. Conclusion: After 1 year of AIT, the extracts were equally efficient, with significant improvements in 70.0% (nonmodified) and 72.2% (modified) of patients.

Predictors and reproducibility of exercise-induced bronchoconstriction in cold air.

BACKGROUND: Physical activity is an important part of life, and hence exercise-induced bronchoconstriction (EIB) can reduce the quality of life. A standardized test is needed to diagnose EIB. The American Thoracic Society (ATS) guidelines recommend an exercise challenge in combination with dry air. We investigated the feasibility of a new, ATS guidelines conform exercise challenge in a cold chamber (ECC) to detect EIB. The aim of this study was to investigate the surrogate marker reaction to methacholine, ECC and exercise challenge in ambient temperature for the prediction of a positive reaction and to re-evaluate the reproducibility of the response to an ECC. METHODS: Seventy-eight subjects aged 6 to 40 years with suspected EIB were recruited for the study. The subjects performed one methacholine challenge, two ECCs, and one exercise challenge at an ambient temperature. To define the sensitivity and specificity of the predictor, a receiver-operating characteristic curve was plotted. The repeatability was evaluated using the method described by Bland and Altman (95% Limits of agreement). RESULTS: The following cut-off values showed the best combination of sensitivity and specificity: the provocation dose causing a 20% decrease in the forced expiratory volume in 1 s (PD20FEV1) of methacholine: 1.36 mg (AUC 0.69, p < 0.05), the maximal decrease in FEV1 during the ECC: 8.5% (AUC 0.78, p < 0.001) and exercise challenges at ambient temperatures: FEV1 5.2% (AUC 0.64, p = 0.13). The median decline in FEV1 was 14.5% (0.0-64.2) during the first ECC and 10.7% (0.0-52.5) during the second ECC. In the comparison of both ECCs, the Spearman rank correlation of the FEV1 decrease was r = 0.58 (p < 0.001). The 95% limits of agreement (95% LOAs) for the FEV1 decrease were - 17.7 to 26.4%. CONCLUSIONS: The surrogate markers PD20FEV1 of methacholine and maximal decrease in FEV1 during ECC can predict a positive reaction in another ECC, whereas the maximal FEV1 decrease in an exercise challenge at an ambient temperature was not predictive. Compared with previous studies, we can achieve a similar reproducibility with an ECC. CLINICAL TRIAL REGISTRATION: NCT02026492 (retrospectively registered 03/Jan/2014).

Correlation of spirometry and body plethysmography during exercise-induced bronchial obstruction.

BACKGROUND: The exercise challenge is the gold standard for diagnosing exercise-induced bronchoconstriction (EIB). Airway obstructions appear up to 30 min after the challenge, with a maximum decrease in spirometry and a maximum increase in airway resistance. There is evidence that changes in body plethysmography parameters are more sensitive to the exercise challenge and precede those in spirometry. PURPOSE: To compare changes in body plethysmography and spirometry parameters after exercise challenges and to verify the cut-off values of sReff in EIB. PROCEDURES: In 82 subjects with suspected EIB, a total of 473 lung function tests were measured at baseline and at 5, 10, 15, and 30 min after exercise challenges at different stages of bronchial obstruction. FINDINGS: The maximum changes in the body plethysmography parameter sReff significantly preceded the maximum changes in the spirometry parameter FEV1 (sReff: 12.2 min ±8.8, FEV1: 15.2 min ±9.3, p < 0.005). The parameters of sReff and FEV1 had a strong negative correlation (r = -0.63, p < 0.0001) with a nonlinear, polynomial relationship. Furthermore, sReff and Reff had a strong linear correlation (r = 0.86, p < 0.001), and Reff and Rtot had a perfect linear correlation (r = 0.99, p < 0.001). Based on baseline values and on quantile regression, an increase of 0.25 kPa s in sReff was defined as significant. Using this cut-off value, FEV1 and sReff almost equally detected EIB. CONCLUSION: The changes in sReff were more sensitive and better indicated lung impairment than did the changes in FEV1, which underestimated the degree of hyperinflation.

Diagnostic Biomarkers in Liver Injury by Drugs, Herbs, and Alcohol: Tricky Dilemma after EMA Correctly and Officially Retracted Letter of Support.

Liver injuries caused by the use of exogenous compounds such as drugs, herbs, and alcohol are commonly well diagnosed using laboratory tests, toxin analyses, or eventually reactive intermediates generated during metabolic degradation of the respective chemical in the liver and subject to covalent binding by target proteins. Conditions are somewhat different for idiosyncratic drug induced liver injury (DILI), for which metabolic intermediates as diagnostic aids are rarely available. Although the diagnosis of idiosyncratic DILI can well be established using the validated, liver specific, structured, and quantitative RUCAM (Roussel Uclaf Causality Assessment Method), there is an ongoing search for new diagnostic biomarkers that could assist in and also confirm RUCAM-based DILI diagnoses. With respect to idiosyncratic DILI and following previous regulatory letters of recommendations, selected biomarkers reached the clinical focus, including microRNA-122, microRNA-192, cytokeratin analogues, glutamate dehydrogenase, total HMGB-1 (High Mobility Group Box), and hyperacetylated HMGB-1 proteins. However, the new parameters total HMGB-1, and even more so the acetylated HMGB-1, came under critical scientific fire after misconduct at one of the collaborating partner centers, leading the EMA to recommend no longer the exploratory hyperacetylated HMGB1 isoform biomarkers in clinical studies. The overall promising nature of the recommended biomarkers was considered by EMA as highly dependent on the outstanding results of the now incriminated biomarker hyperacetylated HMGB-1. The EMA therefore correctly decided to officially retract its Letter of Support affecting all biomarkers listed above. New biomarkers are now under heavy scrutiny that will require re-evaluations prior to newly adapted recommendations. With Integrin beta 3 (ITGB3), however, a new diagnostic biomarker may emerge, possibly being drug specific but tested in only 16 patients; due to substantial remaining uncertainties, final recommendations would be premature. In conclusion, most of the currently recommended new biomarkers have lost regulatory support due to scientific misconduct, requiring now innovative approaches and re-evaluation before they can be assimilated into clinical practice.