Severe Airway Disease Research Articles

Herpes Simplex Virus Type 1 Infection Facilitates Invasion of Staphylococcus aureus into the Nasal Mucosa and Nasal Polyp Tissue

Background Staphylococcus aureus (S. aureus) plays an important role in the pathogenesis of severe chronic airway disease, such as nasal polyps. However the mechanisms underlying the initiation of damage and/or invasion of the nasal mucosa by S. aureus are not clearly understood. The aim of this study was to investigate the interaction between S. aureus and herpes simplex virus type 1 (HSV1) in the invasion of the nasal mucosa and nasal polyp tissue.Methodology/Principal FindingsInferior turbinate and nasal polyp samples were cultured and infected with either HSV1 alone, S. aureus alone or a combination of both. Both in turbinate mucosa and nasal polyp tissue, HSV1, with or without S. aureus incubation, led to focal infection of outer epithelial cells within 48 h, and loss or damage of the epithelium and invasion of HSV1 into the lamina propria within 72 h. After pre-infection with HSV1 for 24 h or 48 h, S. aureus was able to pass the basement membrane and invade the mucosa. Epithelial damage scores were significantly higher for HSV1 and S. aureus co-infected explants compared with control explants or S. aureus only-infected explants, and significantly correlated with HSV1-invasion scores. The epithelial damage scores of nasal polyp tissues were significantly higher than those of inferior turbinate tissues upon HSV1 infection. Consequently, invasion scores of HSV1 of nasal polyp tissues were significantly higher than those of inferior turbinate mucosa in the HSV1 and co-infection groups, and invasion scores of S. aureus of nasal polyp tissues were significantly higher than those of inferior turbinate tissues in the co-infection group.Conclusions/SignificanceHSV1 may lead to a significant damage of the nasal epithelium and consequently may facilitate invasion of S. aureus into the nasal mucosa. Nasal polyp tissue is more susceptible to the invasion of HSV1 and epithelial damage by HSV1 compared with inferior turbinate mucosa.

The effects of laparoscopic Nissen fundoplication on patients with severe gastroesophageal reflux disease and steroid-dependent asthma

BackgroundAn association between severe reactive airway disease (RAD) and gastroesophageal reflux disease (GERD) in children has been previously noted, but the relationship has not been well characterized. This study reports our experience with laparoscopic Nissen fundoplication and its effect on the pulmonary status of children with severe steroid-dependent RAD. MethodsBetween January 1993 and June 2011, 235 patients with severe steroid-dependent RAD and medically refractory GERD underwent laparoscopic Nissen fundoplication. Clinical response, ability to wean oral and inhaled steroids, and changes in pulmonary function testing were tracked during the postoperative period. ResultsOf 235 patients, 215 (91%) noted significant subjective improvement in their respiratory symptoms by the first postoperative visit at 2 weeks. Eighty percent was successfully weaned off their oral steroids within the first 2 postoperative months. Ninety-five percent reported a decrease in their inhaler use. Twenty-four percent of patients studied had a documented increase in their forced expiratory volume in the initial postoperative period. There were no intraoperative complications and no postoperative respiratory tract infections. ConclusionChildren with steroid-dependent RAD and documented GERD refractory to medical management show improvement in their respiratory status after laparoscopic Nissen fundoplication. Many can be weaned off of their oral and inhaled steroids postoperatively.

P133 Lung clearance index is a reproducible and sensitive measure of airways disease in bronchiectasis

IntroductionLung clearance index (LCI) is a measure of ventilation in homogeneity derived from multiple breath washout (MBW). Although FEV1 is commonly used to assess severity of airway disease and response...

TLR4 signalling in pulmonary stromal cells is critical for inflammation and immunity in the airways

Inflammation of the airways, which is often associated with life-threatening infection by Gram-negative bacteria or presence of endotoxin in the bioaerosol, is still a major cause of severe airway diseases. Moreover, inhaled endotoxin may play an important role in the development and progression of airway inflammation in asthma. Pathologic changes induced by endotoxin inhalation include bronchospasm, airflow obstruction, recruitment of inflammatory cells, injury of the alveolar epithelium, and disruption of pulmonary capillary integrity leading to protein rich fluid leak in the alveolar space. Mammalian Toll-like receptors (TLRs) are important signalling receptors in innate host defense. Among these receptors, TLR4 plays a critical role in the response to endotoxin.Lungs are a complex compartmentalized organ with separate barriers, namely the alveolar-capillary barrier, the microvascular endothelium, and the alveolar epithelium. An emerging theme in the field of lung immunology is that structural cells (SCs) of the airways such as epithelial cells (ECs), endothelial cells, fibroblasts and other stromal cells produce activating cytokines that determine the quantity and quality of the lung immune response. This review focuses on the role of TLR4 in the innate and adaptive immune functions of the pulmonary SCs.

Negative Pressure Pulmonary Edema Following Bronchospasm

Negative pressure pulmonary edema (NPPE) is an important cause of noncardiogenic pulmonary edema but is rarely reported in the setting of bronchospasm. A 43-year-old woman with severe reactive airway disease suffered an episode of severe bronchospasm after endotracheal extubation following an otherwise uneventful general anesthetic. Subsequently, she developed clinical and radiographic signs of pulmonary edema in the absence of other symptoms of acute left-sided heart failure, leading to the diagnosis of noncardiogenic pulmonary edema. She received noninvasive positive pressure ventilation for a few hours, after which her clinical and radiologic signs and symptoms of pulmonary edema were greatly improved. This clinical scenario strongly suggests NPPE. We submit that it is possible to create NPPE by generating highly negative intrathoracic pressures in the setting of severe bronchospasm.

Les rhinites chroniques difficiles

Chronic rhinitis, chronic non-mechanical damage to the nasal structures, has been defined and classified by the French ENT and Cervico-Facial Surgical Association and the French Allergology Association as well as by the recommendations of the ARIA (Allergic Rhinitis and its Impact on Asthma). Difficult chronic rhinitis is allergic or non-allergic rhinitis for which a specific etiological diagnosis remains difficult and that is poorly controlled by the usual treatments. The concept of severe chronic upper airway disease (SCUAD) was thus defined. The objective of this review is to provide an identification sheet for each of the many types of rhinitis and to specify their treatment. The description of these different categories of rhinitis shows that it is mainly the clinical characteristics, with consideration given to the context, terrain and symptoms, that make it possible to classify them and to establish a diagnosis by elimination.

68Ga PET/CT Ventilation–Perfusion Imaging for Pulmonary Embolism: A Pilot Study with Comparison to Conventional Scintigraphy

Ventilation-perfusion (V/Q) scintigraphy is established for regional assessment of lung function in a variety of diseases, including pulmonary embolism (PE). PET/CT may further improve the accuracy and utility of V/Q imaging because of its superior technical characteristics. This pilot study assessed the feasibility of performing V/Q PET/CT and compared diagnostic utility with conventional V/Q imaging in patients with clinical suspicion of PE. Ten patients undergoing conventional V/Q imaging were prospectively recruited. PET/CT V/Q imaging was performed after inhalation of (68)Ga-carbon nanoparticles ("Galligas") and administration of (68)Ga-macroaggregated albumin. Blinded to the results of the other study, SPECT/CT (n = 9) or SPECT (n = 1) images and PET/CT images were graded by a predefined scoring system for scan quality. The number of matched or unmatched defects and diagnosis were also measured and compared with a final diagnosis. PET image quality was equivalent or superior to SPECT in all patients, with more homogeneous radiotracer distribution for both ventilation and perfusion studies (P < 0.01). Based on conventional V/Q imaging, the diagnosis was acute PE in 2 patients and no PE in 7 patients, and the imaging results were nondiagnostic in 1 patient. The PET/CT diagnosis was concordant in 8 patients, and these studies demonstrated a similar number and distribution of matched and unmatched defects. In 1 discordant case, a patient with a SPECT/CT study that was nondiagnostic because of severe airway disease showed no PE on PET/CT. In another, the diagnosis of PE established on SPECT/CT was not reported on PET/CT 2 d later, possibly because of interval clot lysis or migration. This intraindividual comparative study demonstrated that V/Q PET/CT with (68)Ga-labeled radiotracers can be performed in clinical practice. Compared with conventional V/Q imaging, advantages include higher-resolution, fully tomographic images with potentially better regional quantitation of lung function. The short half-life of (68)Ga also enables more flexible acquisition protocols with the option of performing ventilation studies selectively on patients with abnormal perfusion. On the basis of our results, further studies are indicated to assess whether V/Q PET/CT can improve diagnostic algorithms for patients with suspected PE.

Family History Is a Risk Factor for COPD

Studies have shown that family history is a risk factor for COPD, but have not accounted for family history of smoking. Therefore, we sought to identify the effects of family history of smoking and family history of COPD on COPD susceptibility. We compared 821 patients with COPD to 776 control smokers from the Genetic Epidemiology of COPD (COPDGene) Study. Questionnaires captured parental histories of smoking and COPD, as well as childhood environmental tobacco smoke (ETS) exposure. Socioeconomic status was defined by educational achievement. Parental history of smoking (85.5% case patients, 82.9% control subjects) was more common than parental history of COPD (43.0% case patients, 30.8% control subjects). In a logistic regression model, parental history of COPD (OR, 1.73; P < .0001) and educational level (OR, 0.48 for some college vs no college; P < .0001) were significant predictors of COPD, but parental history of smoking and childhood ETS exposure were not significant. The population-attributable risk from COPD family history was 18.6%. Patients with COPD with a parental history had more severe disease, with lower lung function, worse quality of life, and more frequent exacerbations. There were nonsignificant trends for more severe emphysema and airway disease on quantitative chest CT scans. Family history of COPD is a strong risk factor for COPD, independent of family history of smoking, personal lifetime smoking, or childhood ETS exposure. Although further studies are required to identify genetic variants that influence COPD susceptibility, clinicians should question all smokers, especially those with known or suspected COPD, regarding COPD family history.

Cutting edge technologies in respiratory research: Lung function testing

Pulmonary function testing is part of routine clinical practice in respiratory medicine. It is based around spirometry, which will remain the central measurement of lung function given its prognostic significance and its integral role in defining severity of airways disease. However, there is an increasing body of evidence from studies using new methods of lung function measurement which are providing new insights into pathophysiology of disease. This body of data is forming a basis for their future clinical role, once the economics of producing the relevant devices becomes attractive. The forced oscillation technique and multiple breath nitrogen washout are currently the most commonly used of the newer lung function techniques, which are refinements of long-established techniques. Optical coherence tomography, optical reflection, electrical impedance and vibration response imaging have arisen by development of novel devices. The recent use of these techniques is reviewed.

Air pollution and airway disease

Epidemiological and toxicological research continues to support a link between urban air pollution and an increased incidence and/or severity of airway disease. Detrimental effects of ozone (O(3)), nitrogen dioxide (NO(2)) and particulate matter (PM), as well as traffic-related pollution as a whole, on respiratory symptoms and function are well documented. Not only do we have strong epidemiological evidence of a relationship between air pollution and exacerbation of asthma and respiratory morbidity and mortality in patients with chronic obstructive pulmonary disease (COPD), but recent studies, particularly in urban areas, have suggested a role for pollutants in the development of both asthma and COPD. Similarly, while prevalence and severity of atopic conditions appear to be more common in urban compared with rural communities, evidence is emerging that traffic-related pollutants may contribute to the development of allergy. Furthermore, numerous epidemiological and experimental studies suggest an association between exposure to NO(2) , O(3) , PM and combustion products of biomass fuels and an increased susceptibility to and morbidity from respiratory infection. Given the considerable contribution that traffic emissions make to urban air pollution researchers have sought to characterize the relative toxicity of traffic-related PM pollutants. Recent advances in mechanisms implicated in the association of air pollutants and airway disease include epigenetic alteration of genes by combustion-related pollutants and how polymorphisms in genes involved in antioxidant pathways and airway inflammation can modify responses to air pollution exposures. Other interesting epidemiological observations related to increased host susceptibility include a possible link between chronic PM exposure during childhood and vulnerability to COPD in adulthood, and that infants subjected to higher prenatal levels of air pollution may be at greater risk of developing respiratory conditions. While the characterization of pollutant components and sources promise to guide pollution control strategies, the identification of susceptible subpopulations will be necessary if targeted therapy/prevention of pollution-induced respiratory diseases is to be developed.

Stereotactic ablative radiotherapy for stage I NSCLC: Recent advances and controversies.

Stereotactic ablative radiotherapy (SABR) is a technique that has rapidly entered routine care for early-stage peripheral non-small cell lung cancer in many countries in the last decade. The adoption of SABR was partly stimulated by advances in the so-called 'image guided' radiotherapy delivery. In the last 2 years, a growing body of publications has reported on clinical outcomes, acute and late radiological changes after SABR, and sub-acute and late toxicity. The local control rates in many publications have exceeded 90% when tumors of up to 5 cm have been treated, with corresponding regional nodal failure rates of approximately 10%. However, these results are not universal: lower control rates reported by some authors serve to emphasize the importance of quality assurance in all steps of SABR treatment planning and delivery. High-grade toxicity is uncommon when so-called 'risk-adapted' fractionation schemes are applied; an approach which involves the use of lower daily doses and more fractions when critical normal organs are in the proximity of the tumor volume. This review will address the new data available on a number of controversial topics such as the treatment of patients without a tissue diagnosis of malignancy, data on SABR outcomes in patients with severe chronic obstructive airways disease, use of a classification system for late radiological changes post-SABR, late treatment-related toxicity, and the evidence to support a need for expert multi-disciplinary teams in the follow-up of such patients.

Correlations of sleep disorders with severity of obstructive airway disease in mustard gas-injured patients

Mustard gas has serious adverse effects on several organs and functions in humans. In this study, we analyzed potential correlations between obstructive airway disease and sleep disorders in Iranian mustard gas-injured patients. We enrolled 30 male mustard gas-injured veterans and civilians from the Chemical Warfare Exposure Clinic at Baqiyatallah Hospital, Tehran. All the subjects underwent comprehensive polysomnographic and spirometric evaluations for diagnosis of sleep disorders. Patients were categorized into three groups according to the severity of their obstructive airway disease based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria: group 1 (GOLD I and II), group 2 (GOLD III), and group 3 (GOLD IV). Patients with less severe obstructive airway disease had significantly higher rate of hypopnea (p = 0.05) and AHI (p = 0.05). The number of REM events was significantly higher in patients with less severe airway disease (p = 0.028). Stage 1 sleep among patients with higher FEV1 significantly constituted a higher proportion of sleep, and stage 4 sleep was significantly longer in patients with higher DLCO (p = 0.043, both). We found that sleep parameters in SM-exposed patients have some relations with spirometric parameters. Future studies with large patient populations are needed for confirmation of our results, and therapeutic interventions are needed to evaluate endeavors we can do to enhance health and quality of life in our mustard gas-injured population.

Plastic bronchitis: Resolution after heart transplantation

Plastic bronchitis (PB) is a rare cause of obstructive airway disease in patients who have undergone partially corrective surgery for congenital heart disease (CHD). The etiology of plastic bronchitis in such patients is ill-defined, and treatment is ineffective. We report resolution of PB and severe obstructive airway disease after heart transplantation in a patient with CHD.

Stereotactic radiation therapy: changing treatment paradigms for stage I nonsmall cell lung cancer

To review recent developments in stereotactic body radiation therapy (SBRT) for stage I nonsmall cell lung cancer (NSCLC). In stage I tumors measuring up to 5 cm in diameter, SBRT can achieve local tumor control rates of up to 97%. SBRT has a favorable toxicity profile and has been safely applied in elderly patients, after previous pneumonectomy, or with severe chronic obstructive airways disease. Population studies indicate that the introduction of SBRT was associated with increased treatment rates for elderly patients and improved overall survival. In patients with stage I NSCLC who do not undergo surgery, SBRT achieves superior survival as compared to treatment using conventionally fractionated radiotherapy. The role of SBRT in operable patients remains to be defined within randomized trials. In patients identified to be at high risk for surgical complications, SBRT appears to provide an effective alternative with low risks of hospitalization and 30-day mortality. Future treatment algorithms should include individualized assessment of surgical risks, and the consideration of SBRT for high-risk patients, in order to develop a personalized treatment approach.

Extracorporeal membrane oxygenation for respiratory failure: past, present and future

Extracorporeal membrane oxygenation for respiratory failure: past, present and future

A new subunit vaccine based on nucleoprotein nanoparticles confers partial clinical and virological protection in calves against bovine respiratory syncytial virus

Human and bovine respiratory syncytial viruses (HRSV and BRSV) are two closely related, worldwide prevalent viruses that are the leading cause of severe airway disease in children and calves, respectively. Efficacy of commercial bovine vaccines needs improvement and no human vaccine is licensed yet. We reported that nasal vaccination with the HRSV nucleoprotein produced as recombinant ring-shaped nanoparticles (NSRS) protects mice against a viral challenge with HRSV. The aim of this work was to evaluate this new vaccine that uses a conserved viral antigen, in calves, natural hosts for BRSV. Calves, free of colostral or natural anti-BRSV antibodies, were vaccinated with NSRS either intramuscularly, or both intramuscularly and intranasally using Montanide™ ISA71 and IMS4132 as adjuvants and challenged with BRSV. All vaccinated calves developed anti-N antibodies in blood and nasal secretions and N-specific cellular immunity in local lymph nodes. Clinical monitoring post-challenge demonstrated moderate respiratory pathology with local lung tissue consolidations for the non-vaccinated calves that were significantly reduced in the vaccinated calves. Vaccinated calves had lower viral loads than the non-vaccinated control calves. Thus NSRS vaccination in calves provided cross-protective immunity against BRSV infection without adverse inflammatory reaction.

Tissue-Engineered Tracheal Transplantation

Regenerative medicine offers new tools with which to tackle disorders for which there is currently no good therapeutic option. The trachea is an ideal organ in which to explore the clinical potential of tissue engineering because severe large airway disease is poorly managed by conventional treatments, and the success of a graft is determined only by its ability to conduct air lifelong: that is, whether it can become a sustainable biological conduit. We define the component parts of tissue engineering and review the experimental methods used to produce airway implants to date, including a recent successful, first-in-man experience.

Highly sensitive C-reactive protein levels in Iranian patients with pulmonary complication of sulfur mustard poisoning and its correlation with severity of airway diseases

Sulfur mustard (SM) is a chemical warfare agent that can cause serious pulmonary complications. This study was designed to determine serum highly sensitive C-reactive protein (hs-CRP) and evaluate its correlation with lung function parameters in patients with chronic obstructive pulmonary disease (COPD) due to SM poisoning. Fifty consecutive SM patients with stable COPD and a mean age 46.3 +/- 9.18 years were enrolled in this cross sectional study. Thirty healthy men were selected as controls. Lung function parameters were evaluated. Serum hs-CRP by immunoturbidometry assay was measured in both the patients and controls. In the case group, the mean forced expiratory volume in one second (FEV1) was 2.14 +/- 0.76 L (58.98% +/- 17.51% predicted). The mean serum hs-CRP was 9.4 +/- 6.78 SD and 3.9 +/- 1.92 SD mg/L in the cases and controls, respectively, with significant statistical differences (p < .001). There was negative correlation between the serum hs-CRP and FEV1 levels (p = .01). The serum hs-CRP levels were also correlated with Global Initiative for Chronic Obstructive Lung disease (GOLD) stages (r = .45, p < .001). Our findings suggest that the serum hs-CRP level is increased in SM patients with COPD and may have a direct correlation with disease severity. It may then be used as a marker for the severity of COPD in patients with SM poisoning.

Efficacité de l’association budésonide/formotérol dans le trouble ventilatoire obstructif survenant après allogreffe de cellules souches hématopoïétiques

État des connaissancesLa survenue d’un trouble ventilatoire obstructif au décours d’une allogreffe de cellules souches hématopoïétiques est attribuée à une réaction de greffon contre l’hôte pulmonaire et menace le pronostic des patients. La prise en charge thérapeutique consiste habituellement en une intensification du traitement immunosuppresseur systémique. Cette attitude non validée entraîne de nombreuses complications, notamment infectieuses, encourageant l’évaluation de traitements plus ciblés. Nous avons récemment rapporté de façon rétrospective notre expérience de l’efficacité du budésonide/ formotérol inhalés dans cette pathologie.MéthodesIl s’agit d’une étude prospective, multicentrique, randomisée, en double aveugle contre placebo qui évaluera l’efficacité de l’association budésonide/formotérol (400/12 µg 2 inhalations matin et soir) chez des patients ayant développé un trouble ventilatoire obstructif modéré à sévère après allogreffe de cellules souches hématopoïétiques. Le critère d’évaluation principal sera la variation absolue du VEMS après 1 mois de traitement. Les critères d’évaluation secondaires seront basés sur l’évolution de la symptomatologie clinique et de la fonction respiratoire après 6 mois de traitement.Résultats attendusL’hypothèse émise est que le traitement inhalé de budésonide/formotérol améliore de façon significative la fonction et les symptômes respiratoires dès le premier mois de traitement dans le groupe de patients étudié.

Unmet needs in severe chronic upper airway disease (SCUAD)

Although the majority of patients with chronic upper airway diseases have controlled symptoms during treatment, many patients have severe chronic upper airway diseases (SCUADs). SCUAD defines those patients whose symptoms are inadequately controlled despite adequate (ie, effective, safe, and acceptable) pharmacologic treatment based on guidelines. These patients have impaired quality of life, social functioning, sleep, and school/work performance. Severe uncontrolled allergic rhinitis, nonallergic rhinitis, chronic rhinosinusitis, aspirin-exacerbated respiratory diseases, or occupational airway diseases are defined as SCUADs. Pediatric SCUADs are still unclear. In developing countries SCUADs exist, but risk factors can differ from those seen in developed countries. Comorbidities are common in patients with SCUADs and might increase their severity. The present document is the position of a group of experts considering that SCUADs should be considered differently from mild chronic upper airway diseases. It reviews the state of the art, highlighting gaps in our knowledge, and proposes several areas for a better understanding, prevention, and management of SCUADs. This document can also serve to optimize the pharmacoeconomic evaluation of SCUADs by means of comparison with mild chronic upper airway diseases.