Use of a vibrating mesh nebulizer for allergen challenge.

BACKGROUND: Allergen inhalation tests are a valuable research tool. The allergen dose producing an early asthmatic response (EAR) can be predicted from methacholine responsiveness and allergen skin test endpoint (STE). The Wright® jet nebulizer, which is both inefficient and increasingly difficult to obtain, has been used historically. We assessed the Solo® vibrating mesh nebulizer as an alternative for allergen and methacholine challenges. METHODS: Eighteen mild atopic asthmatics completed the study. Doubling concentration allergen prick skin tests were performed to determine the STE in allergen units/mL. The Wright® protocol was used to measure the methacholine provocation dose causing a 20% forced expired volume in one second (FEV1) fall (PD20) (µg) and the allergen PD20 (units). The Solo® protocol (0.5 mL nebulized to completion, tidal breathing inhalation) was used to determine both methacholine PD20 and allergen PD20. The nebulizer order was randomized and separated by ≥ 2 weeks. RESULTS: All data were log transformed. The allergen PD20, predicted from the methacholine PD20 and the STE, was within 2 doubling doses of the PD20 measured with the Wright® and 2.64 doubling doses of that measured with Solo®. The Wright® allergen PD20 correlated with the Wright® methacholine PD20 (r = 0.74) and the STE (r = 0.78) and more strongly with the product of the two (Wright® methacholine PD20 × STE, r = 0.91, p < 0.00001). The Solo® allergen PD20 showed similar relationships with the Solo® methacholine PD20 (r = 0.61), the STE (r = 0.75) and the product of the two (Solo® methacholine PD20 × STE, r = 0.83, p < 0.00002). The Wright® and the Solo® methacholine geometric mean PD20s were not significantly different (49.3 and 54.5 µg respectively, p = 0.62). The Wright® allergen PD20 was slightly but significantly lower than the Solo® allergen PD20 (geometric means 6.7 and 10.5 units respectively, p = 0.003). CONCLUSION: The Solo® allergen PD20 showed the same relationship with methacholine responsiveness and STE as did the Wright®. The Solo® allergen PD20 was slightly but significantly higher than the Wright® allergen PD20. The Solo® vibrating mesh nebulizer was well tolerated and is an acceptable alternative for allergen challenge.Trial registration clinicaltrials.gov: NCT03491358.

Reversible bilateral phrenic nerve paralysis.

Bilateral phrenic nerve paralysis is a rare potentially life-threatening condition which is usually due to trauma (including surgery) or neurologic disease. We present a patient with apparent rapid onset bilateral phrenic nerve paralysis whose primary symptom was severe positional (supine) dyspnea with profound supine oxygen desaturation. Nerve conduction study abnormalities of the phrenic nerves and some left brachial plexus nerves suggested a diagnosis of ALS. He was treated with supportive night time ventilatory assistance (BiPAP) and over 4 years his condition recovered essentially completely. In retrospect the most likely diagnosis was a rare brachial plexopathy referred to as neuralgic amyotrophy.

ERS technical standard on bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing.

Recently, this international task force reported the general considerations for bronchial challenge testing and the performance of the methacholine challenge test, a "direct" airway challenge test. Here, the task force provides an updated description of the pathophysiology and the methods to conduct indirect challenge tests. Because indirect challenge tests trigger airway narrowing through the activation of endogenous pathways that are involved in asthma, indirect challenge tests tend to be specific for asthma and reveal much about the biology of asthma, but may be less sensitive than direct tests for the detection of airway hyperresponsiveness. We provide recommendations for the conduct and interpretation of hyperpnoea challenge tests such as dry air exercise challenge and eucapnic voluntary hyperpnoea that provide a single strong stimulus for airway narrowing. This technical standard expands the recommendations to additional indirect tests such as hypertonic saline, mannitol and adenosine challenge that are incremental tests, but still retain characteristics of other indirect challenges. Assessment of airway hyperresponsiveness, with direct and indirect tests, are valuable tools to understand and to monitor airway function and to characterise the underlying asthma phenotype to guide therapy. The tests should be interpreted within the context of the clinical features of asthma.

Environmental Causes of Asthma.

Environmental factors which cause asthma are those that induce airway inflammation with eosinophils (more common) or neutrophils along with airway hyperresponsiveness (AHR). The most common of these (indeed the most common cause of asthma) are IgE-mediated inhalant allergen exposures. Allergen-induced AHR and inflammation are both associated with the allergen-induced late asthmatic response (LAR). Although allergens were previously recognized only as causes of symptoms and bronchoconstriction in asthmatics, we now appreciate them as causes of the fundamental pathophysiologic features of asthma. Low-molecular-weight chemical sensitizers, causes of occupational asthma, also cause asthma in a manner analogous to allergen. Acute irritant-induced asthma (reactive airways dysfunction syndrome) following a very heavy irritant exposure and chronic irritant-induced asthma following repeated high exposures can also induce persistent or permanent changes (inflammation and AHR) consistent with asthma. Textile dust exposure produces a different form of airway disease (byssinosis) which is less frequently observed currently. Environmental exposure to tobacco smoke facilitates the development of asthma in children. Personal smoking and environmental air pollution have an inconsistent and likely generally small effect in causing asthma.

Methacholine Challenge Testing: A Novel Method for Measuring PD20.

BACKGROUND: New guidelines for methacholine challenge testing recommend reporting the test outcome as dose rather than concentration. Jet nebulizers have historically been used for methacholine challenge testing, but much of the weight loss, often (incorrectly) referred to as aerosol output, is actually evaporation. The Wright nebulizer is well characterized and still widely used, but its availability is unclear, and it is nondisposable. We developed a novel method using a vibrating mesh nebulizer (Solo). This method was compared with the standard 2-min tidal breathing method using the Wright nebulizer. Repeatability within and between nebulizers was also tested. METHODS: Fifteen patients with mild asthma completed four methacholine challenges (two with the Solo vibrating mesh nebulizer and two with the Wright jet nebulizer). Challenges with the same nebulizer were 24 h apart, and challenges between nebulizers were separated by 1 week. Standard 2-min tidal breathing methods were used with the Wright nebulizer. For the Solo nebulizer, the tidal breathing method was modified by nebulizing to completion 0.5 mL of doubling concentrations of methacholine at 5-min intervals. RESULTS: Geometric mean methacholine doses required to cause a 20% fall in FEV1 were similar (96 vs 110 µg; P > .05); methacholine concentrations that caused a 20% fall in FEV1 were significantly lower with the vibrating mesh nebulizer (0.48 vs 4.4 mg/mL; P < .001). Repeatability of methacholine doses required to cause a 20% fall in FEV1 within and between nebulizers was excellent (intraclass correlation coefficient > 0.92). CONCLUSIONS: We have developed a novel, simple, repeatable method for conducting methacholine challenges using new nebulizer technology. Importantly, the method meets recommendations set out in the new guidelines. TRIAL REGISTRY: ClinicalTrials.gov; No.: 02965482; URL: www.clinicaltrials.gov.

Lung function and respiratory symptoms in a randomized smoking cessation trial of electronic cigarettes.

Quitting smoking is the most important step smokers can take to improve their health. Nonetheless, there is little information on long-term improvements in lung function and/or respiratory symptoms after smoking cessation. Here we illustrate long-term changes in spirometric indices as well as in respiratory symptoms in smokers invited to quit or reduce their cigarette consumption by switching to electronic cigarettes (ECs). Prospective evaluation of cigarette consumption, spirometry and symptoms was performed in a 1-year randomized controlled trial of smokers receiving EC containing 2.4%, 1.8% or 0% nicotine. Spirometric data are presented on the basis of participants' pooled continuous smoking phenotype classification (Quitters, Reducers, Failures), whereas respiratory symptoms on the basis of their point prevalence-smoking phenotype. Smoking phenotype classification (Quitters, Reducers, Failures) had no significant effect on spirometric indices (FEV1, FVC and FEV1/FVC) with the exception of FEF25-75%, which significantly (P =0.034) increased over the time among Quitters; their FEF25-75% (% predicted) improving from (means±S.D.) 85.7±15.6% at baseline (BL) to 100.8±14.6%. High prevalence of cough/phlegm (43.1%) and shortness of breath (SoB; 34.8%) was reported at BL with substantial reduction in their frequency at subsequent follow-up visits. These symptoms virtually disappeared very quickly in both quitters and reducers. Smokers invited to switch to ECs who completely abstained from smoking showed steady progressive improvements in their FEF25-75% Normalization of peripheral airways function was associated with improvement in respiratory symptoms, adding to the notion that abstaining from smoking can reverse tobacco harm in the lung.

Allergen inhalation challenge, refractoriness and the effects of ibuprofen.

BACKGROUND: Bronchoprovocation challenges use direct or indirect acting stimuli to induce airflow obstruction. Indirect stimuli either non-allergic/non-IgE mediated (e.g. exercise, mannitol) or allergic/IgE mediated (i.e. allergen) trigger mast cells to release bronchoconstricting mediators (e.g. cysteinyl leukotrienes, histamine). Performing repeat challenges within a short timeframe (e.g. 3 h) with non-allergic indirect stimuli results in a diminished, refractory response to the second challenge that is inhibited by non-steroidal anti-inflammatory medications. Cross refractoriness occurs between indirect stimuli. It follows that repeat bronchoprovocation with allergen might exhibit refractoriness that might be altered by ibuprofen. We assessed the response to a second allergen challenge performed 24 h after an initial allergen challenge to determine if the response is refractory. If refractoriness developed, the study aimed to determine whether a single dose of ibuprofen would alter the refractory response to the second allergen challenge. In the absence of a refractory response, the study design allowed for the assessment of the effect of ibuprofen on allergen challenge outcomes, including indices of airway inflammation. METHODS: Thirteen mild atopic asthmatics were enrolled in a randomized, double-blind, placebo controlled, cross-over study. Ibuprofen (400 mg) or placebo was administered 1 h prior to the first of two allergen challenges, performed 24 h apart. Blood and sputum eosinophils, airway responsiveness to methacholine and levels of fractional exhaled nitric oxide were assessed before and 7 h after each allergen challenge. All data were log transformed and differences in geometric means were analyzed by paired t-tests. RESULTS: After placebo, early asthmatic responses for the two challenges were not significantly different (p = 0.82). A single 400 mg dose of ibuprofen decreased both the early (p = 0.03; n = 12) and late asthmatic responses (p = 0.03; n = 3). CONCLUSION: Allergen challenges conducted 24 h apart do not exhibit refractoriness. Single dose ibuprofen inhibits early and late asthmatic responses to allergen bronchoprovocation. Ibuprofen should be withheld for at least 24 h prior to investigations utilizing allergen bronchoprovocation. Trial registration clinicaltrials.gov #NCT02327234.

Pulmonary fibrosis in dyskeratosis congenita: report of 2 cases.

Dyskeratosis congenita (DC) is a disorder of poor telomere maintenance and is related to 1 or more mutations that involve the vertebrate telomerase RNA component. Most affected patients develop mucocutaneous manifestations and cytopenias in the peripheral blood between 5 and 15 years of age. DC patients may also develop pulmonary complications including fibrotic interstitial lung disease and pulmonary vascular abnormalities. The radiologic and pathologic features of pulmonary fibrosis associated with DC are poorly defined. Herein, we report 2 new DC cases and suggest that the radiologic and histopathologic findings may resemble usual interstitial pneumonia but may not neatly fit into the current classification of interstitial lung disease.

Past, present and future uses of methacholine testing.

Methacholine challenge testing is a valuable diagnostic and research tool used by clinicians to assist in the diagnosis of asthma, and by researchers to understand disease pathophysiology and assess novel therapeutic efficacy. The use of methacholine challenge in asthma relates to its direct effect on airway smooth muscle (i.e., bronchoconstriction) as a measure of airway hyperresponsiveness, a cardinal feature of asthma. Airway hyperresponsiveness has been documented in other airway disorders, including chronic obstructive pulmonary disease, cystic fibrosis and allergic rhinitis; however, there is little clinical application of methacholine challenge in these conditions as a diagnostic or disease management tool. The authors will review the aspects of methacholine challenge testing, as they relate to asthma, and point out its usefulness in clinical research. A brief review of past (historical) uses and speculation as to the future uses of methacholine challenge will also be discussed.

Normal expiratory flow rate and lung volumes in patients with combined emphysema and interstitial lung disease: a case series and literature review.

Pulmonary function tests in patients with idiopathic pulmonary fibrosis characteristically show a restrictive pattern including small lung volumes and increased expiratory flow rates resulting from a reduction in pulmonary compliance due to diffuse fibrosis. Conversely, an obstructive pattern with hyperinflation results in emphysema by loss of elastic recoil, expiratory collapse of the peripheral airways and air trapping. When the diseases coexist, pulmonary volumes are compensated, and a smaller than expected reduction or even normal lung volumes can be found. The present report describes 10 patients with progressive breathlessness, three of whom experienced severe limitation in their quality of life. All patients showed lung interstitial involvement and emphysema on computed tomography scan of the chest. The 10 patients showed normal spirometry and lung volumes with severe compromise of gas exchange. Normal lung volumes do not exclude diagnosis of idiopathic pulmonary fibrosis in patients with concomitant emphysema. The relatively preserved lung volumes may underestimate the severity of idiopathic pulmonary fibrosis and attenuate its effects on lung function parameters.

Familial interstitial pulmonary fibrosis: a large family with atypical clinical features.

A large kindred of familial pulmonary fibrosis is reported. Six members from the first two generations of this particular kindred were described more than 40 years previously; six more individuals from the third and fourth generations have also been evaluated. The proband, now 23 years of age, has mild disease; the other 11 documented affected family members all died from their disease at an average age of 37 years (range 25 to 50 years). The pathology was that of usual interstitial pneumonia, as is typical in idiopathic pulmonary fibrosis. However, the initial radiographic pattern in many of these individuals was upper lobe and nodular and, along with the young age, was atypical for idiopathic pulmonary fibrosis. Several genetic abnormalities have been associated with familial pulmonary fibrosis. The present study examined the genes coding for surfactant protein-C, ATPbinding cassette protein A3 and telomerase, and found no abnormalities.

Direct challenge tests: Airway hyperresponsiveness in asthma: its measurement and clinical significance.

Direct bronchoprovocation challenges (eg, methacholine), which act directly on a specific airway smooth muscle receptor, are the most commonly performed challenge tests. Cut points have been arbitrarily selected to give high sensitivity and negative predictive values. In subjects with clinically current symptoms (within a few days) who inhale methacholine without deep inhalations, a normal methacholine test (provocative concentration causing a 20% fall in FEV(1) [PC(20)] > 16 mg/mL) rules out (current) asthma with reasonable certainty. A positive test in the moderate or greater range (PC(20) < 1 mg/mL) has high specificity and positive predictive value, comparable to the indirect challenges. Values between these levels are consistent with, but not diagnostic of, asthma. The positive predictive value (for clinical asthma) will increase the closer the PC(20) is to 1 mg/mL, the higher the pretest probability is for asthma and the more the methacholine-induced symptoms resemble the naturally occurring symptoms. Direct challenges are more sensitive and less specific than indirect challenges (exercise, adenosine monophosphate, mannitol, etc).

Diagnostic and therapeutic value of airway challenges in asthma.

Airway challenges are of value in the assessment of asthma. Direct challenges (histamine and methacholine) are highly sensitive for clinically current symptomatic asthma and particularly useful to exclude current asthma when they are negative. Indirect challenges (exercise, eucapnic voluntary hyperventilation, adenosine monophosphate, hypertonic saline, mannitol) are more specific but very insensitive for clinical asthma. They are of particular value to confirm asthma and to differentiate asthma from other airway diseases, such as chronic airflow limitation. The indirect stimuli are the challenges of choice for evaluating exercise-induced bronchoconstriction.

ELR-CXC chemokine receptor antagonism targets inflammatory responses at multiple levels.

The ELR-CXC chemokines play important roles in neutrophilic inflammation. We report in this study that a fully human ELR-CXC chemokine antagonist that we have generated, CXCL8((3-72))K11R/G31P (G31P), has potent anti-inflammatory effects that arise through its actions at multiple levels. G31P inhibited CXCL8-induced chemotactic responses and intracellular Ca(2+) flux in CXCR1-transfected HEK cells and neutrophils, and responses of neutrophils to CXCR2-exclusive ligands. G31P desensitized heterologous G protein-coupled receptors on neutrophils, 52-86% reducing their Ca(2+) flux and chemotactic responses to leukotriene B(4), C5a, and the bacterial tripeptide fMLP. G31P also 60-90% blocked neutrophil chemotactic responses to mediators present in 10 of 12 sputum samples from cystic fibrosis or bronchiectasis subjects with bacterial pneumonia. Moreover, whereas A549 bronchial epithelial cells (which expressed CXCR1) secreted approximately 29,000 pg/ml CXCL8 in response to in vitro endotoxin challenge, G31P reduced this response by up to 98%, presumably by interrupting an autocrine inflammatory loop. The anti-inflammatory effects of G31P extended also to reversing the antiapoptotic influence of ELR-CXC chemokines on neutrophils. That these effects were relevant in vivo was confirmed in a guinea pig model of airway endotoxemia, wherein the human form of G31P >95% blocked neutrophil infiltration into and activation within the airways, as determined by airway levels of the neutrophil primary, secondary, and tertiary granule markers myeloperoxidase, lactoferrin, and matrix metalloproteinase-9, respectively, and the epithelial cell marker matrix metalloproteinase-2. These data suggest that the beneficial effects of ELR-CXC chemokine antagonism arise through effects that occur at multiple levels, including epithelial cells, neutrophils, and alternate G protein-coupled receptors.

Nitrofurantoin-associated bronchiolitis obliterans organizing pneumonia: report of a case.

Bronchiolitis obliterans organizing pneumonia due to nitrofurantoin has rarely been reported and is associated with poor outcomes. A case of nitrofurantoin-associated bronchiolitis obliterans organizing pneumonia responsive to drug withdrawal and corticosteroids is presented.

Regional variations in risk factors for asthma in school children.

BACKGROUND: The authors have previously reported an increased prevalence of asthma in Estevan, Saskatchewan (21.4%) compared with Swift Current, Saskatchewan (16.2%). OBJECTIVE: To determine the association between asthma and personal and indoor environmental risk factors in these communities. METHODS: A population-based cross-sectional study was conducted in January 2000. A questionnaire was distributed to school children in grades 1 to 6 for completion by a parent. Multivariate logistic regression was used to examine associations between various risk factors and physician-diagnosed asthma. RESULTS: Asthma was associated with respiratory allergy (adjusted OR [adjOR]=8.85, 95% CI 6.79 to 11.54), early respiratory illness (adjOR=2.81, 95% CI 1.96 to 4.03) and family history of asthma (adjOR=2.37, 95% CI 1.67 to 3.36). Several environmental factors varied with asthma by town. In Estevan, asthma was associated with home mould or dampness (adjOR=1.82, 95% CI 1.23 to 2.69) and was inversely associated with air conditioning (adjOR=0.56, 95% CI 0.37 to 0.85). The risk of asthma was increased if the child had previous exposure to environmental tobacco smoke from the mother in both communities (Swift Current: OR=1.87, 95% CI 1.06 to 3.30; Estevan: OR=2.00, 95% CI 1.17 to 3.43), and there was an inverse association with current exposure to environmental tobacco smoke from the mother in Estevan (OR=0.64, 95% CI 0.40 to 1.00). When multivariate analyses were stratified by sex, the relationship between home mould or dampness and asthma was most prominent in girls in Estevan. CONCLUSIONS: Despite a similar regional location, different risk factors for asthma were identified in each community. Local environmental factors are important to consider when interpreting findings and planning asthma care.

Nonspecific interstitial pneumonia and usual interstitial pneumonia with mutation in surfactant protein C in familial pulmonary fibrosis.

Nonspecific interstitial pneumonia, a recently described form of idiopathic interstitial pneumonia, is characterized by uniform involvement of the alveolar septae with interstitial inflammation and variable amounts of fibrosis. Histological observations differentiate nonspecific interstitial pneumonia from usual interstitial pneumonia and clinically, patients with a nonspecific interstitial pneumonia pattern show better prognosis than those with usual interstitial pneumonia. We have genetically analyzed a family with a history of usual interstitial pneumonia. Most of the patients presented as adults and their biopsies showed a pattern consistent with usual interstitial pneumonia. However, three family members presented in early childhood and their biopsies revealed a nonspecific interstitial pneumonia pattern. The inheritance pattern of usual interstitial pneumonia is consistent with autosomal dominant inheritance with variable expression. DNA sequence analyses of the surfactant protein C gene in children with nonspecific interstitial pneumonia and adults with usual interstitial pneumonia exhibit a common heterozygous mutation located in exon 5. The mutation causes a Leu188 to Gln188 change in the carboxy-terminal region of prosurfactant protein C, possibly affecting peptide processing. These observations suggest that individuals with this particular mutation in surfactant protein C gene might be at increased risk of interstitial lung disease of variety of types.