Correlation between Reduced FEF25-75% and a Positive Methacholine Challenge Test in Adults with Nonobstructive Baseline Spirometry

Rationale. FEF25-75% is routinely reported on spirometry and is thought to be a marker of small airway obstruction. It is reduced in children with asthma, but its significance in adults and especially those without asthma diagnosis remains unclear. Objective. To clarify whether in adults with a nonobstructive spirometry a reduced FEF25-75% is associated with a positive methacholine challenge test (MCT). Methods. Data was collected for all the patients who had a MCT done between April 2014 and January 2020 but had nonobstructive baseline spirometry. Logistic regression was utilized to estimate the log odds of a positive methacholine test as a function of FEF25-75% and also for age, gender, BMI, FEV1, and FEV1/FVC. Results. Out of 496 patients, 187 (38%) had a positive MCT. Baseline characteristics in two groups were similar except that patients with positive MCT were younger ( 32 ± 11.57 vs. 38 ± 13.25 years, respectively, p < 0.001 ). Mean FEF25-75% was lower in MCT positive ( 3.12 ± 0.99 L/s) vs. MCT negative ( 3.39 ± 0.97 L/s) patients, p = 0.003 . Logistic regression results suggest that MCT outcome is inversely related to FEF25-75%, age, and gender. Specifically, as FEF25-75% percentage of predicted value increases, the log odds of a positive MCT decrease ( odds ratio OR = 0.90 , 95% confidence intervals CI = 0.84 ‐ 0.96 , p = 0.002 ). Also, as age increases, the log odds of a positive MCT decrease ( OR = 0.95 , 95 % CI = 0.94 ‐ 0.97 , p < 0.001 ). Conclusions. Reduced FEF25-75% in adults with nonobstructive spirometry can predict a positive response to MCT in younger patients. However, this relationship becomes weaker with increasing age.

Methacholine Challenges: comparison of different tidal breathing challenge methods

Tidal breathing methacholine challenges are now recommended by guidelines, to avoid the bronchoprotective effects of deep inhalation. This study compared different tidal breathing methacholine challenge methods, assessed the agreement between tidal dosimetric and continuous output challenges, and challenge repeatability with different methods. 15 asthma patients performed dosimetric challenges and a continuous output breath actuated challenge, all at least 3 days apart. All subjects had a pre-bronchodilator forced expired volume in 1 s (FEV1) ≥65% predicted, and PD20 <1.2 mg. Of the dosimetric challenges, one method increased methacholine concentration (standard dosimetric challenge), and one adjusted nebuliser output time to increase dose (adjusted dosimetric challenge). The adjusted dosimetric and continuous output challenges were performed twice on separate days to assess for repeatability. All challenges were matched for dose at each dose step. The mean PD20 ratio of the standard dosimetric challenge to the adjusted dosimetric challenge was 0.90 (CI: 0.66–1.23; p=0.49), and intraclass correlation coefficient (ICC)=0.82. Repeated adjusted dosimetric challenges had an ICC=0.62 for PD20. Repeated continuous output challenges had an ICC =0.74 for PD20. The adjusted dosimetric and continuous output challenges correlated (r=0.69, p=0.0043; ICC: 0.65), but PD20 was higher for the adjusted dosimetric challenge (mean PD20 ratio=2.31; CI: 1.57–3.40; p=0.0004). Tidal dosimetric methacholine challenge using adjustment of nebuliser output produces results with good repeatability. The results of this adjusted dosimetric method differed from the continuous output method, underscoring that the results of different methacholine challenge methodologies may not be directly comparable.

New Insights Into the Regulation of TGF-β/Smad and MPK Signaling Pathway Gene Expression by Nasal Allergen and Methacholine Challenge Test in Asthma.

BackgroundAsthma is a heterogeneous chronic inflammatory disease of the bronchi, the course of which is significantly influenced by specific and non-specific extrinsic factors. The aim of this study was to evaluate the effect of these factors on changes in the mRNA expression of genes encoding the TGF-β (TGF-β1 and TGF-β3) - Smad (MPK1/3, Smad1/3/6/7) signaling pathway in asthmatic patients. Methods and ResultsSeventy-five subjects were included in the study, of whom 27 (nine men and 18 women) received an intranasal allergen provocation (specific factors) and 48 (17 men and 31 women) were administered a methacholine provocation (non-specific factors). ConclusionBoth examined types of challenges were found to contribute to changes in the relative expression of genes of the TGF-β (TGF-β1 and TGF-β3) - Smad (MPK1/3, Smad1/3/6/7) signaling pathway in asthmatic patients. A decrease was noted for the MAPK1, MAPK3, Smad3, Smad6 and Smad7 genes, while an increase of up to 2.5 times was observed for the TGF-β1 gene. Our findings suggest that intranasal allergen or bronchial methacholine challenge influences the mRNA expression of the TGF-β1- MPK1/3 and Smad3/6/7 genes.

Intrauterine Growth Restriction Promotes Postnatal Airway Hyperresponsiveness Independent of Allergic Disease

Introduction: Intrauterine growth restriction (IUGR) is associated with asthma. Murine models of IUGR have altered airway responsiveness in the absence of any inflammatory exposure. Given that a primary feature of asthma is airway inflammation, IUGR-affected individuals may develop more substantial respiratory impairment if subsequently exposed to an allergen. This study used a maternal hypoxia-induced mouse model of IUGR to determine the combined effects of IUGR and allergy on airway responsiveness.Methods: Pregnant BALB/c mice were housed under hypoxic conditions (10.5% O2) from gestational day (GD) 11-GD 17.5 (IUGR group; term = GD 21). Following hypoxic exposure, mice were returned to a normoxic environment (21% O2). A second group of pregnant mice were housed under normoxic conditions throughout pregnancy (Control). All offspring were sensitized to ovalbumin (OVA) and assigned to one of four treatment groups: Control – normoxic and saline challenge; IUGR – hypoxic and saline challenge; Allergy – normoxic and OVA challenge; and IUGR + Allergy – hypoxic and OVA challenge. At 8 weeks of age, and 24 h post-aerosol challenge, mice were tracheostomised for methacholine challenge and assessment of lung mechanics by the forced oscillation technique, and lungs subsequently fixed for morphometry.Results: IUGR offspring were lighter than Control at birth and in adulthood. Both Allergy and IUGR independently increased airway resistance after methacholine challenge. The IUGR group also exhibited an exaggerated increase in tissue damping and elastance after methacholine challenge compared with Control. However, there was no incremental effect on airway responsiveness in the combined IUGR + Allergy group. There was no impact of IUGR or Allergy on airway structure and no effect of sex on any outcome.Conclusion: IUGR and aeroallergen independently increased bronchoconstrictor response, but when combined the pathophysiology was not worsened. Findings suggest that an association between IUGR and asthma is mediated by baseline airway responsiveness rather than susceptibility to allergen.