Ultra-high-resolution computed tomography shows changes in the lungs related with airway hyperresponsiveness in a murine asthma model.

In vivo presentation of airway hyper-responsiveness (AHR) at the different time points of the allergic reaction is not clearly understood. The purpose of this study was to investigate how AHR manifests in the airway and the lung parenchyma in vivo following exposure to different stimuli and in the early and late phases of asthma after allergen exposure. Ovalbumin (OVA)-induced allergic asthma model was established using 6-week female BALB/c mice. Enhanced pause was measured with a non-invasive method to assess AHR. The dynamic changes of the airway and lung parenchyma were evaluated with ultra-high-resolution computed tomography (128 multi-detector, 1024 × 1024 matrix) for 10 h. While the methacholine challenge showed no grossly visible changes in the proximal airway and lung parenchyma despite provoking AHR, the OVA challenge induced significant immediate changes manifesting as peribronchial ground glass opacities, consolidations, air-trapping, and paradoxical proximal airway dilatations. After resolution of immediate response, multiple episodes of AHRs occurred with paradoxical proximal airway dilatation and peripheral air-trapping in late phase over a prolonged time period in vivo. Understanding of airflow limitation based on the structural changes of asthmatic airway would be helpful to make an appropriate drug delivery strategy for the treatment of asthma.

A Novel Approach for Investigating Upper Airway Hyperresponsiveness Using Micro-CT in Eosinophilic Upper Airway Inflammation such as Allergic Rhinitis Model.

Airway hyperresponsiveness (AHR) has been proposed as a feature of pathogenesis of eosinophilic upper airway inflammation such as allergic rhinitis (AR). The measurement system for upper AHR (UAHR) in rodents is poorly developed, although measurements of nasal resistance have been reported. Here we assessed UAHR by direct measurement of swelling of the nasal mucosa induced by intranasal methacholine (MCh) using micro-computed tomography (micro-CT). Micro-CT analysis was performed in both naïve and ovalbumin-induced AR mice following intranasal administration of MCh. The nasal cavity was segmented into two-dimensional horizontal and axial planes, and the data for nasal mucosa were acquired for the region of interest threshold. Then, a ratio between the nasal mucosa area and nasal cavity area was calculated as nasal mucosa index. Using our novel method, nasal cavity structure was clearly identified on micro-CT, and dose-dependent increased swelling of the nasal mucosa was observed upon MCh treatment. Moreover, the nasal mucosa index was significantly increased in AR mice compared to controls following MCh treatment, while ovalbumin administration did not affect swelling of the nasal mucosa in either group. This UAHR following MCh treatment was completely reversed by pretreatment with glucocorticoids. This novel approach using micro-CT for investigating UAHR reflects a precise assessment system for swelling of the nasal mucosa following MCh treatment; it not only sheds light on the mechanism of AR but also contributes to the development of new therapeutic drugs in AR patients.

Severe asthma phenotypes classified by site of airway involvement and remodeling via chest CT scan

Objectives: This study aimed to establish a system that can classify severe asthma on the basis of airway remodeling patterns visualized using computed tomography (CT) images and to evaluate the clinical characteristics of individual image-based subtypes. Methods: Chest CT images from severe asthma patients were retrospectively evaluated to classify phenotypes by site of airway involvement and remodeling. The association between radiologic subtypes and clinical characteristics was assessed. Results: Of 91 patients with severe asthma, 74 (81.3%) exhibited abnormal radiologic findings, including bronchial wall thickening (BT), mucus plugging (MP), and bronchiectasis (BE). The severity of BT and the extent of MP were independently associated with peripheral blood eosinophil count (P=.012, r2=0.112) and sputum eosinophil count (P=.022, r2=0.090), respectively. The large-to-medium airway remodeling type, which showed diffuse BT combined with MP and BE, accounted for 44% of patients and revealed higher peripheral blood eosinophil counts than other types. In the small airway remodeling type, which accounted for 6.6% of patients, we observed a higher rate of fixed airflow obstruction, along with a predominance of males and smokers and more frequent use of controller medication than other phenotypes. In 26% of patients with severe asthma, no prominent airway remodeling was observed (near-normal type); the near-normal type required oral corticosteroids less frequently than the large-to-medium airway and small airway remodeling types. Conclusions: Depending on the site of airway involvement and remodeling pattern, 3 different structural types can be distinguished in chest CT findings from patients with severe asthma. Remodeling in large-to-medium sized airways revealed an association with systemic eosinophilic inflammation in patients with severe asthma

Objetivos: Este estudio tuvo como objetivo establecer un sistema que pueda clasificar el asma grave en función de los patrones de remodelación de la vía aérea visualizados mediante imágenes de tomografía computarizada (TC) y para evaluar las características clínicas de los subtipos de pacientes basados en imágenes. Métodos: Las imágenes de tomografía computarizada del tórax de pacientes con asma grave se evaluaron retrospectivamente para clasificar fenotipos por sitio de afectación y remodelación de la vía aérea. También se evaluó la asociación entre los subtipos radiológicos y las características clínicas. Resultados: De 91 pacientes con asma severa, 74 (81,3%) exhibieron hallazgos radiológicos anormales, incluyendo engrosamiento de la pared bronquial (BT), taponamiento de moco (MP) o bronquiectasias (BE). La gravedad del BT y la puntuación de extensión de MP se asociaron de forma independiente con el recuento de eosinófilos en sangre periférica (p= 0,012, r2 = 0,112) y el recuento de eosinófilos en esputo (p= 0,022, r2 = 0,090), respectivamente. El tipo de remodelación de la vía respiratoria grande a mediana (tipo LA), que muestra una BT difusa combinada con MP y BE, representó el 44% del total de pacientes y presentó recuentos de eosinófilos en sangre periférica más altos que otros tipos. El tipo de remodelación de la vía aérea pequeña (tipo SA), que constituyó el 6,6% de los pacientes, mostró una mayor tasa de obstrucción del flujo de aire fijo, junto con el predominio de hombres y fumadores y un mayor uso de medicación controladora que otros fenotipos. En el 26% de los pacientes con asma grave, no se observó una remodelación prominente de la vía aérea (tipo casi normal, tipo NN). El tipo NN mostró menos requerimientos de esteroides orales en relación con los tipos LA y SA. Conclusiones: Se pueden distinguir tres tipos estructurales diferentes mediante los hallazgos de la TC de tórax, según el sitio de afectación de la vía aérea y el patrón de remodelación en los pulmones de pacientes con asma grave. La remodelación de las vías respiratorias de grandes a medianas reveló una asociación con la inflamación eosinofílica sistémica en el asma grave

Allergic fungal rhino sinusitis with granulomas: A new entity?

INTRODUCTION: Allergic fungal rhino sinusitis (AFS) is classically described as allergic manifestation to the fungal antigen present in sinuses with no evidence of invasion. Granulomas in histopathology, suspicious of invasion, are occasionally observed in AFS and the disease in these patients behaves like invasive fungal sinusitis even without histologic evidence of invasion. We retrospectively studied AFS patients to analyze whether AFS should be continued to be designated as an allergic entity. MATERIAL AND METHODS: AFS patients operated from January 2009 to July 2013 were retrospectively reviewed. Of the total 57 cases operated in last 4 years, nine showing presence of granuloma in histology were included in the AFS with granuloma Group (group 1) and the rest 48 were included in the AFS group (group 2). Both the groups were compared in terms of various parameters at presentation, treatment course and rate of recurrence. RESULTS: Group 1 had significantly high rates of orbital erosion (P = .000), with positive association of skull base erosion (P = .092) and high rates of telecanthus (P = .000), diplopia (P = .000), proptosis (P = .161) and facial pain. Recurrent surgery was needed in 8 of 9 patients in the group 1 as compared to 1 of 48 patients group 2. CONCLUSION: Granulomas suggests a more severe disease with a trend toward the invasive fungal sinusitis and alerts the clinician regarding the nature of progression. AFS seems to be a part of a continuous spectrum of fungal sinusitis rather than an allergic form as a distinct entity.

Longitudinal characterization of a model of chronic allergic lung inflammation in mice using imaging, functional and immunological methods.

The present study investigated the role that imaging could have for assessing lung inflammation in a mouse model of HDM (house dust mite)-provoked allergic inflammation. Inflammation is usually assessed using terminal procedures such as BAL (bronchoalveolar lavage) and histopathology; however, MRI (magnetic resonance imaging) and CT (computed tomography) methods have the potential to allow longitudinal, repeated study of individual animals. Female BALB/c mice were administered daily either saline, or a solution of mixed HDM proteins sufficient to deliver a dose of 12 or 25 µg total HDM protein±budesonide (1 mg/kg of body weight, during weeks 5-7) for 7 weeks. AHR (airway hyper-responsiveness) and IgE measurements were taken on weeks 3, 5 and 7. Following imaging sessions at weeks 3, 5 and 7 lungs were prepared for histology. BAL samples were taken at week 7 and lungs prepared for histology. MRI showed a gradual weekly increase in LTI (lung tissue intensity) in animals treated with HDM compared with control. The 25 µg HDM group showed a continual significant increase in LTI between weeks 3 and 7, the 12 µg HDM-treated group showed a similar rate of increase, and plateaued by week 5. A corresponding increase in AHR, cell counts and IgE were observed. CT showed significant increases in lung tissue density from week 1 of HDM exposure and this was maintained throughout the 7 weeks. Budesonide treatment reversed the increase in tissue density. MRI and CT therefore provide non-invasive sensitive methods for longitudinally assessing lung inflammation. Lung tissue changes could be compared directly with the classical functional and inflammatory readouts, allowing more accurate assessments to be made within each animal and providing a clinically translatable approach.

Airway distension during lung inflation in healthy and allergic-sensitised mice in vivo.

We evaluated the airway distention during lung inflation of varying size in healthy and allergic-sensitised mice in vivo. Computed tomography (CT) images of healthy and ovalbumin-treated mice were acquired using a synchrotron in vivo CT system when lung pressures was 0 and 20 cmH(2)O, and the morphometric distension (diameter, length, and volume) and the compliance of airway segments (to as small as ~150 µm internal diameter) were calculated. With respect to airway size, in healthy mice, the changes in airway diameter and compliance were larger in the small-airway group. In contrast, in allergic-sensitised mice, there were no significant differences in the changes in airway distension or compliance. Airway wall thickness in allergic-sensitised mice increased significantly in all airway groups, but the change was much larger in the small than in the large-airway group. Compared with healthy airways, the changes in diameter and airway compliance of the allergic-sensitised mice were significantly smaller in the small-airway group.

[Clomipramine hypersensitivity with predominantly pulmonary involvement]. / DRESS syndrome avec atteinte pulmonaire prédominante sous clomipramine.

Drug hypersensitivity (DRESS syndrome) is a rare disorder with diverse systemic and visceral manifestations. Pulmonary involvement is uncommon and is mainly characterized by eosinophilic infiltration. We report a case of DRESS syndrome induced by clomipramine with predominant pulmonary involvement.

The effects of inhaled house dust mite on airway barrier function and sensitivity to inhaled methacholine in mice.

Asthma is functionally characterized by increased airway sensitivity and reactivity. Multiple mechanisms are believed to underlie these functional disorders, including impairment of airway wall barrier function. One proposed mechanism of impaired barrier function is through the direct consequence of proteolytic properties of inhaled allergens, including house dust mite (HDM). Here, we have observed the direct effects of HDM on airway barrier function and response to nebulized or intravenous methacholine. HDM naïve BALB/c mice were anesthetized, exposed to intranasal or intratracheal HDM (15 or 100 µg), and allowed to recover for 30 min or 2 h before methacholine challenge. A separate group of mice was exposed to intratracheal poly-L-lysine (PLL; 100 µg) for a duration of 30 min. This group served as a positive control for the presence of impaired barrier function and airway hypersensitivity. Negative control mice received saline challenges. Outcomes included assessment of lung mechanics in response to nebulized or intravenous methacholine as well as clearance of intratracheally instilled technetium-labeled ((99m)Tc) DTPA to evaluate airway epithelial barrier function. We found that PLL produced a leftward shift in the dose-response curve following nebulized but not intravenous methacholine challenge. This was associated with a significantly faster clearance of (99m)Tc-DTPA, indicating impairment in airway barrier function. However, HDM exposure did not produce changes in these outcomes when compared with saline-exposed mice. These findings suggest that direct impact on airway barrier function does not appear to be a mechanism by which HDM produces altered airway sensitivity in airway disease.

Diagnostic value of nasal allergen challenge combined with radiography and ultrasonography in chronic maxillary sinus disease.

OBJECTIVE: To investigate the possible role of nasal allergy in chronic disease of the maxillary sinuses (CDMS) by means of nasal provocation test (NPT) with allergen combined with radiography and ultrasonography. DESIGN: Prospective clinical controlled study. SETTING: Academic referral center. PATIENTS: Seventy-one patients with CDMS and 16 control subjects with allergic rhinitis but no history of sinus disease. INTERVENTIONS: In the 71 patients, a total of 135 NPTs and 71 control challenges with phosphate-buffered saline were performed by rhinomanometry combined with radiography and ultrasonography. In the control patients, 16 positive NPTs were repeated and combined with radiography and ultrasonography. MAIN OUTCOME MEASURES: Number, type, and timing of nasal responses with accompanying changes on radiographs and ultrasonograms. RESULTS: Of the 71 patients, 67 developed 104 positive nasal responses of various types (P < .001), 89 of which were accompanied by significant changes on radiographs (P = .008), whereas 83 were also associated with significant changes on ultrasonograms (P = .007). No significant changes on the radiographs or the ultrasonograms were recorded during the 71 phosphate-buffered saline control tests in the patients with CDMS (P = .14 and .06, respectively) or during the 16 NPTs in control subjects (P = .15 and .12, respectively). The radiographic and ultrasonographic findings were significantly correlated (r = 0.81; P < .01). CONCLUSIONS: Nasal allergy may be involved in some patients with CDMS, resulting in appearance of a maxillary sinus response. Monitoring this response by means of serial ultrasonography and, if necessary, also by conventional radiography or computed tomography simultaneously with the nasal challenge with allergen seems to be a very useful diagnostic supplement allowing additional therapeutic measures focused on the nasal allergy.

Airway hyperresponsiveness in allergically inflamed mice: the role of airway closure.

RATIONALE: Allergically inflamed mice exhibit airway hyperresponsiveness to inhaled methacholine, which computer simulations of lung impedance suggest is due to enhanced lung derecruitment and which we sought to verify in the present study. METHODS: BALB/c mice were sensitized and challenged with ovalbumin to induce allergic inflammation; the control mice were sensitized but received no challenge. The mice were then challenged with inhaled methacholine and respiratory system impedance tracked for the following 10 minutes. Respiratory elastance (H) was estimated from each impedance measurement. One group of mice was ventilated with 100% O(2) during this procedure and another group was ventilated with air. After the procedure, the mice were killed and ventilated with pure N(2), after which the trachea was tied off and the lungs were imaged with micro-computed tomography (micro-CT). RESULTS: H was significantly higher in allergic mice than in control animals after methacholine challenge. The ratio of H at the end of the measurement period between allergic and nonallergic mice ventilated with O(2) was 1.36, indicating substantial derecruitment in the allergic animals. The ratio between lung volumes determined by micro-CT in the control and the allergic mice was also 1.36, indicative of a corresponding volume loss due to absorption atelectasis. Micro-CT images and histograms of Hounsfield units from the lungs also showed increased volume loss in the allergic mice compared with control animals after methacholine challenge. CONCLUSIONS: These results support the conclusion that airway closure is a major component of hyperresponsiveness in allergically inflamed mice.

Small airway changes in healthy and ovalbumin-treated mice during quasi-static lung inflation.

Previously, we developed a synchrotron radiation CT system to evaluate the morphometric changes (length and diameter, D) and small airway compliance (sC(aw)) of euthanized mice under quasi-static inflation [Sera, T., Uesugi, K., Yagi, N., 2005. Localized morphometric deformations of small airways and alveoli in intact mouse lungs under quasi-static inflation. Respir. Physiol. Neurobiol. 147, 51-63). Using this system, this study compared normal and asthmatic small airways. Ovalbumin-treated mice were used as an asthma model. Compared with the values at functional residual capacity, D of normal and asthmatic small airways (D<200microm) increased by 48% and 36% at the end of tidal inspiration. For larger airways (D>500microm), the increases were 23% and 20%, respectively. The ratio of the sC(aw) of asthmatic small airways to that of healthy small airways was 0.57, and the ratio was 0.70 for larger airways. The morphometric changes and sC(aw) in asthma model mice were significantly lower than those of healthy mice. The differences in sC(aw) between healthy and asthma model mice were greater for smaller airways.

Noninvasive mapping of regional response to segmental allergen challenge using magnetic resonance imaging and [F-18]fluorodeoxyglucose positron emission tomography.

Magnetic resonance (MR) and positron emission tomography (PET) imaging techniques were coregistered to demonstrate regional ventilation and inflammation in the lung for in vivo, noninvasive evaluation of regional lung function associated with allergic inflammation. Four Brown Norway rats were imaged pre- and post segmental allergen challenge using respiratory-gated He-3 magnetic resonance imaging (MRI) to visualize ventilation, T(1)-weighted proton MRI to depict inflammatory infiltrate, and [F-18]fluorodeoxyglucose-PET to detect regional glucose metabolism by inflammatory cells. Segmental allergen challenges were delivered and the pre- and postchallenge lung as well as the contralateral lung were compared. Coregistration of the imaging results demonstrated that regions of ventilation defects, inflammatory infiltrate, and increased glucose metabolism correlated well with the site of allergen challenge delivery and inflammatory cell recruitment, as confirmed by histology. This method demonstrates that fusion of functional and anatomic PET and MRI image data may be useful to elucidate the functional correlates of inflammatory processes in the lungs.

Furazolidone-induced pulmonary hypersensitivity.

OBJECTIVE: To report a case of pulmonary hypersensitivity associated with furazolidone use and review the literature on this topic. CASE SUMMARY: A 43-year-old white female presented with fever and dyspnea. She had recently completed a course of furazolidone 125 mg 4 times daily for 10 days for enteritis. Investigations revealed bibasilar interstitial infiltrates on chest X-ray, hypoxia, and 21% eosinophilia. Her fever, hypoxia, and dyspnea rapidly abated following discontinuation of furazolidone and administration of corticosteroids. DISCUSSION: Furazolidone is a bactericidal agent used to treat infectious enteropathies. It is chemically similar to nitrofurantoin, which is well known to cause pulmonary hypersensitivity reactions. Application of the Naranjo probability scale suggests that a furazolidone adverse reaction in this patient was probable. A MEDLINE search from 1966 to October 2004 revealed 2 previously reported cases suggestive of furazolidone pulmonary hypersensitivity. All published reports closely resemble each other and descriptions of nitrofurantoin-associated pulmonary hypersensitivity reactions. CONCLUSIONS: Furazolidone may induce pulmonary hypersensitivity reactions; clinicians should be aware of this potentially serious adverse effect.

Allergic fungal sinusitis: CT findings.

PURPOSE: To determine the computed tomographic (CT) findings in patients with allergic fungal sinusitis. MATERIALS AND METHODS: The authors retrospectively reviewed CT scans and surgical and histopathologic reports in 45 patients (27 male, 18 female; age range, 8-68 years) with allergic fungal sinusitis from multiple institutions. The median age (25 years) and demographics of the patients were determined. Two head and neck radiologists together evaluated the CT scans for the presence of intrasinus high-attenuation areas, extent of sinus involvement, bone expansion and thinning, bone erosion, and extension of disease into the adjacent soft tissues. RESULTS: Allergic fungal sinusitis was more common in male patients and in patients aged 20-30 years. All patients had increased intrasinus attenuation at non-contrast material-enhanced CT. Multiple sinus involvement occurred in 43 patients. Bilateral involvement was more common than unilateral disease. Forty-four patients had complete opacification of at least one of the involved sinuses; 43 of these patients had expansion of an involved sinus, 42 had remodeling and thinning of the bony sinus walls, and 41 had erosion of the sinus wall. CONCLUSION: Allergic fungal sinusitis is a distinct clinical entity with nonspecific symptoms that may be initially suggested by the CT findings. These findings should alert the clinician to the possibility of allergic fungal sinusitis and prompt other diagnostic studies to establish the diagnosis and treatment plan.

Radiological findings in the maxillary sinuses of symptomless young men.

The maxillary sinuses were examined radiologically by occipitomental projection (Waters' view) in 404 conscripts without any symptoms of sinusitis. Abnormalities were found in 188 (23.3%) of all 808 sinuses, the most common being mucosal thickening of > 6 mm (12.3% of the sinuses), cysts or polyps (7.2%), and completely opacified sinus (3.3%). Normal x-ray findings were more common in the conscripts examined during the summer months and mucosal thickening was more frequently encountered in winter than in summer. Nasal bacteria were studied in 100 cases. Findings of normal bacterial flora and of pathogenic bacteria were equally frequent among subjects with normal sinus x-ray (score 0 and 1) and subjects with severe abnormalities (scores 3-6), but mucosal cysts (score 2) was more often combined with pathogens in the nose. Mucosal thickening was more often observed in non-allergic than in allergic persons; thus allergy did not seem to increase radiological abnormalities. Of young men engaged in outdoor activities, about one fifth seem to have significant chronic mucous membrane abnormalities in the maxillary antra without clinical symptoms. In 1-2% of cases secretion is detected in the maxillary sinus indicating a subclinical sinusitis.

Early neutrophil but not eosinophil or platelet recruitment to the lungs of allergic horses following antigen exposure.

Previous studies have shown that bronchoalveolar lavage fluid from horses with allergic respiratory disease and showing clinical symptoms contains increased numbers of neutrophils. In some cases, the eosinophil count is also increased. In this study the time course of changes in lung function and the accumulation of radiolabelled leucocytes and platelets in the lungs of allergic and normal horses has been examined during a 7 hr allergen exposure. Antigen challenge had no effect on pleural pressure or the distribution of radiolabelled neutrophils, eosinophils or platelets in normal horses. In contrast, in 6/8 allergic horses, there was an increase in pleural pressure and neutrophil accumulation in the lungs, both of which were evident after 4-5 hr. However, during the 7 hr challenge period radiolabelled eosinophils were detected in the lungs of only 1/6 horses exhibiting an increase in pleural pressure and in 1/7 horses that failed to show a change in airway function despite a clinical history of allergic respiratory disease. Antigen challenge did not alter the distribution of radiolabelled platelets in the five allergic horses tested. These results demonstrate that increased pleural pressure is not accompanied by eosinophil or platelet accumulation in the lungs of horses with allergic respiratory disease following exposure to antigen. However, changes in airway function can be associated with neutrophil accumulation but can also take place in the absence of this cell recruitment. This raises the possibility that the presence of neutrophils in the lung is not a prerequisite for changes in lung function.

Fibrotic stage of allergic bronchopulmonary candidiasis.

Since its first description in 1952, ABPA has been recognized with increasing frequency. More recently fungi other than Aspergillus fumigatus, in particular Candida albicans, have been implicated in a similar disease process. The following case report illustrates the possibility of finding a fibrotic stage 5 ABPM caused by C albicans.