Development of polymer-based nanoparticles for zileuton delivery to the lung: PMeOx and PMeOzi surface chemistry reduces interactions with mucins.

In this paper, two amphiphilic graft copolymers were synthesized by grafting polylactic acid (PLA) as hydrophobic chain and poly(2-methyl-2-oxazoline) (PMeOx) or poly(2-methyl-2-oxazine) (PMeOzi) as hydrophilic chain, respectively, to a backbone of α,ß-poly(N-2-hydroxyethyl)-D,L-aspartamide (PHEA). These original graft copolymers were used to prepare nanoparticles delivering Zileuton in inhalation therapy. Among various tested methods, direct nanoprecipitation proved to be the best technique to prepare nanoparticles with the smallest dimensions, the narrowest dimensional distribution and a spherical shape. To overcome the size limitations for administration by inhalation, the nano-into-micro strategy was applied, encapsulating the nanoparticles in water-soluble mannitol-based microparticles by spray-drying. This process has allowed to produce spherical microparticles with the proper size for optimal lung deposition, and, once in contact with fluids mimicking the lung district, able to dissolve and release non-aggregated nanoparticles, potentially able to spread through the mucus, releasing about 70% of the drug payload in 24 h.

A case of endobronchial actinomycosis as a challenging cause of lung atelectasis.

BACKGROUND: Primary endobronchial actinomycosis is exceptionally uncommon and can be misdiagnosed as unresolving pneumonia, endobronchial lipoma, bronchogenic carcinoma or foreign body. Predisposing factors are immunosuppressive conditions, chronic lung diseases, poor oral hygiene or foreign body aspiration. CASE PRESENTATION: We reported a case of 88-year old woman with a 4 days history of mild exertional dyspnea, productive cough with purulent sputum and fever up to 37.8 °C, who developed left sided endobronchial actinomycosis in absence of any pre-existent risk conditions; endobronchial de-obstruction and specific antibiotic treatment were performed with success, achieving a full resolution of the disease, with bronchoscopy playing a key role in the diagnosticand therapeutic pathways. CONCLUSIONS: This case raises the necessity for increased awareness in the management of endobronchial lesions and in cases of suspected endobronchial actinomycosis; bronchoscopy plays a key role in the diagnostic and therapeutic process; prompt recognition of this entity can expedite proper treatment and recovery.

Prevalence and risk factors of small airway dysfunction, and association with smoking, in China: findings from a national cross-sectional study.

BACKGROUND: Small airway dysfunction is a common but neglected respiratory abnormality. Little is known about its prevalence, risk factors, and prognostic factors in China or anywhere else in the world. We aimed to estimate the prevalence of small airway dysfunction using spirometry before and after bronchodilation, both overall and in specific population subgroups; assess its association with a range of lifestyle and environmental factors (particularly smoking); and estimate the burden of small airway dysfunction in China. METHODS: From June, 2012, to May, 2015, the nationally representative China Pulmonary Health study invited 57 779 adults to participate using a multistage stratified sampling method from ten provinces (or equivalent), and 50 479 patients with valid lung function testing results were included in the analysis. We diagnosed small airway dysfunction on the basis of at least two of the following three indicators of lung function being less than 65% of predicted: maximal mid-expiratory flow, forced expiratory flow (FEF) 50%, and FEF 75%. Small airway dysfunction was further categorised into pre-small airway dysfunction (defined as having normal FEV1 and FEV1/forced vital capacity [FVC] ratio before bronchodilator inhalation), and post-small airway dysfunction (defined as having normal FEV1 and FEV1/FVC ratio both before and after bronchodilator inhalation). Logistic regression yielded adjusted odds ratios (ORs) for small airway dysfunction associated with smoking and other lifestyle and environmental factors. We further estimated the total number of cases of small airway dysfunction in China by applying present study findings to national census data. FINDINGS: Overall the prevalence of small airway dysfunction was 43·5% (95% CI 40·7-46·3), pre-small airway dysfunction was 25·5% (23·6-27·5), and post-small airway dysfunction was 11·3% (10·3-12·5). After multifactor regression analysis, the risk of small airway dysfunction was significantly associated with age, gender, urbanisation, education level, cigarette smoking, passive smoking, biomass use, exposure to high particulate matter with a diameter less than 2·5 µm (PM2·5) concentrations, history of chronic cough during childhood, history of childhood pneumonia or bronchitis, parental history of respiratory diseases, and increase of body-mass index (BMI) by 5 kg/m2. The ORs for small airway dysfunction and pre-small airway dysfunction were similar, whereas larger effect sizes were generally seen for post-small airway dysfunction than for either small airway dysfunction or pre-small airway dysfunction. For post-small airway dysfunction, cigarette smoking, exposure to PM2·5, and increase of BMI by 5 kg/m2 were significantly associated with increased risk, among preventable risk factors. There was also a dose-response association between cigarette smoking and post-small airway dysfunction among men, but not among women. We estimate that, in 2015, 426 (95% CI 411-468) million adults had small airway dysfunction, 253 (238-278) million had pre-small airway dysfunction, and 111 (104-126) million had post-small airway dysfunction in China. INTERPRETATION: In China, spirometry-defined small airway dysfunction is highly prevalent, with cigarette smoking being a major modifiable risk factor, along with PM2·5 exposure and increase of BMI by 5 kg/m2. Our findings emphasise the urgent need to develop and implement effective primary and secondary prevention strategies to reduce the burden of this condition in the general population. FUNDING: Ministry of Science and Technology of China; National Natural Science Foundation of China; National Health Commission of China.

Drastic healing process after pembrolizumab monotherapy in a case of advanced squamous cell carcinoma with severe bronchial stenosis observed over a two-year period using continuous bronchoscopy: A case report.

Programmed cell death-1 immune checkpoint inhibitor (ICI) antibody has proven to be effective in advanced non-small cell lung cancer (NSCLC) patients positive for programmed cell death-1 ligand-1. However, there are currently no reports which evaluate drug efficacy by continuous bronchoscopic observation. A 75-year-old man with complete right atelectasis was diagnosed with squamous cell carcinoma (SCC) of the right lower lobe (tumor proportion score: TPS 90%, cT4N3M0, stage 3C). For first-line chemotherapy, carboplatin and nab-paclitaxel were effective for the primary lesion and the right lung atelectasis improved. However, due to repeated febrile neutropenia with pneumonia, treatment was modified to pembrolizumab monotherapy. Bronchoscopic rebiopsy prior to second-line treatment revealed high TPS, with a severe stenosis in the right main bronchus. After three courses of pembrolizumab, the right main bronchus opened completely, and no signs of malignancy were observed. Bronchoscopic narrow-band and autofluorescence imaging also confirmed a complete endobronchial response. Subsequent bronchoscopic observation two years after the initial diagnosis showed a complete and continued response to treatment. ICIs can result in a drastic bronchoscopic response. In this case, the healing process was notable with minimal scarring, and resulted in continued locally bronchoscopic and complete pathological response to treatment compared to previous cytotoxic chemotherapy.

Invasive Tracheobronchial Aspergillosis with Bronchial Ulcers Complicated by Nontuberculous Mycobacterial Disease.

Invasive tracheobronchial aspergillosis (ITBA) complicated by nontuberculous mycobacteria (NTM) is rare. An 88-year-old man was admitted for hemoptysis. Bronchoscopy revealed bronchial ulcers, and a tissue biopsy showed Aspergillus fumigatus. He was diagnosed with ITBA, which improved with voriconazole. During treatment, infiltrative shadows appeared in his lungs, and bronchoscopy was performed once again. A non-necrotic epithelioid granuloma and Mycobacterium intracellulare were detected in the biopsy specimen. He was diagnosed with NTM disease. It is important to note that tracheobronchial ulcers may cause hemoptysis and to identify the etiology and treat it appropriately when multiple bacteria are found.

Immunotherapy-Induced Airway Disease: A New Pattern of Lung Toxicity of Immune Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) have been shown to improve overall and progression-free survival in various cancers but have been associated with various immune-related adverse events (IRAEs), including interstitial lung disease, especially organizing pneumonia. We report 2 cases of isolated severe airway disease attributable to ICIs, a rarely reported pattern of lung toxicity. The first patient received nivolumab with or without ipilimumab in a randomized double-blind trial for locoregional metastatic melanoma. The second patient was treated with nivolumab for lung adenocarcinoma. An IRAE was suspected in both cases due to a temporal relationship between ICI initiation and symptom onset. ICIs were stopped, and high-dose prednisone, inhaled corticosteroids, and bronchodilators were administered, allowing a rapid clinical and functional improvement in Patient 1. In Patient 2, despite prolonged high-dose prednisone, only a stabilization of forced expiratory volume in 1 s could be achieved, and the disease course was complicated by respiratory infections resulting in further loss of lung function. The patient died 1 year later due to progression of metastatic disease. These 2 cases suggest that pulmonary IRAEs secondary to ICIs may present as isolated bronchitis or bronchiolitis, with variable outcomes following ICI withdrawal and systemic corticosteroids.

Multidrug resistant lymph node fistula tracheobronchial tuberculosis: A case report.

RATIONALE: The patient in this case report has been diagnosed with multidrug resistant lymph node fistula tracheobronchial tuberculosis (TBTB). The PubMed was searched using the keywords "Tuberculosis, Multidrug-Resistant", "Tuberculosis", and "Bronchial Fistula", and the results yielded no similar case reports. Therefore, this report helps us to explore more on the causes of multidrug resistance and formation of lymph node fistula, as well as associated treatment strategies. PATIENT CONCERNS: A 15-year old Tibetan girl who was previously treated in the local Hospital for Infectious Diseases for repeated TBTB demonstrated poor treatment outcomes, and so was further diagnosed in our hospital. After standard treatments, the cough and expectoration of the girl showed improvement, and mycobacterium culture showed negative results. Thoracic CT showed local compression of the right bronchus, and disappearance of stenosis. Bronchoscopy showed that the fistula was closed and healed. DIAGNOSES: Multidrug resistant lymph node fistula TBTB. INTERVENTIONS: Antituberculosis drugs such as pyrazinamide (0.75 g/time, twice per day), moxifloxacin (0.4 g per day), protionamide enteric-coated tablets (0.2 g/time, 3 times per day), pasiniazide tablets (0.3 g/time, 3 times per day), and capreomycin (0.75 g per day) were orally administered. The treatment included an 8-month intensive treatment phase and a 12-month consolidation phase. Bronchoscopic local injection combined with cryotherapy was also conducted. OUTCOMES: Bronchoscopy showed that the fistula was closed and healed, mycobacterium culture showed negative results, and thoracic CT showed local compression of the right bronchus, disappearance of stenosis after treatment. LESSONS: (1) This girl had a history of long-term oral intake of antituberculosis drugs, but the treatment effectiveness remained poor. Therefore, resistance to tuberculosis can be considered, and also mycobacterium culture and drug sensitivity tests should be considered. After these, the treatment strategies should be adjusted accordingly.(2) TBTB should be further classified by analyzing under the bronchoscope to decide the best treatment strategy accordingly.

A 76-Year-Old Woman With Incidental Right Middle Lobe Atelectasis.

CASE PRESENTATION: A 76-year-old nonsmoking woman visiting from Honduras for the last 6 months with no known medical history originally presented to the ED complaining of abdominal pain. While in the ED, an incidental right middle lobe collapse was found on CT abdomen scan. Review of systems was positive for a chronic productive cough with white sputum for 3 years. She denied association with fevers, chills, night sweats, hemoptysis, appetite changes, or weight loss.

Hilar asymmetry in endobronchial tuberculosis patients: An often-overlooked clue.

BACKGROUND: Endobronchial tuberculosis (EBTB) is a challenging diagnosis because of its varied clinical and radiological manifestations. Hilar asymmetry on chest radiograph (CXR) may be found in patient with EBTB but is often overlooked, which may lead to delayed diagnosis. CASE REPORT: We present five cases with EBTB. Clinicians failed to identify unilateral hilar abnormalities on CXR, and these patients were treated initially for pharyngitis, bronchitis, or pneumonia with no improvement. Subsequently, they visited the pulmonary clinic and bronchoscopy revealed endobronchial lesions and microbial/histopathological evidence of tuberculous infection consistent with EBTB. Anti-tuberculosis therapy resulted in complete clinical resolution in four of the five patients; one patient had persistent bronchial stenosis. CONCLUSION: Hilar asymmetry on CXR may occur with EBTB and may suggest this diagnosis in the appropriate clinical setting. Bronchoscopy has an important role in establishing the final diagnosis.

Bronchoscopic local steroid spray to prevent bronchial tuberculosis-induced cicatricial bronchial stenosis: A case series.

RATONALE: Cicatricial bronchial stenosis or obstruction occurring in the healing process of endobronchial tuberculosis (ET) is a problematic complication of tuberculous airway lesions. Prevention by internal medical treatment is desired. PATIENT CONCERNS: This case series describes four patients who diagnosed ET with Type IIIb (protruding ulcer-type) based on Arai's classification of bronchoscopic findings of bronchial tuberculosis. DIAGNOSES: Endobronchial tuberculosis. INTERVENTIONS: A local steroid spray was applied bronchoscopically to active protruding ulcer-type lesions (which are likely to cause cicatricial stenosis) that extended in the transverse direction and occupied one-half or more of the circumference on bronchoscopy. OUTCOMES: Cicatricial stenosis was prevented in two of four patients. Treatment was discontinued in athird patient because tolerance could not be achieved, although the patient's condition had improved. In the fourth patient, treatment was switched to systemic steroid administration because of a problem with tolerance and the broad range of the lesion; however, stenosis remained. LESSONS: Local steroid spray-applied bronchoscopically to bronchial tuberculosis lesions in the ulcer formation and granulation periods may help prevent stenosis.

Nebulized heparin and N-acetylcysteine for smoke inhalational injury: A case report.

RATIONALE: Every year, ∼40,000 people suffer burn-related injuries in the United States. Despite recent advances, the odds of dying from exposure to fire, flames, or smoke are one in ∼1500. Smoke inhalation causes injury to the airways via a complex physiological process, and the treatment is mainly supportive. Many recent interventions aim to decrease the formation of fibrin casts, the main cause of airway damage in these patients. Among these, treatment with a combination of nebulized heparin and N-acetylcysteine (NAC) has shown benefit. PATIENT CONCERNS: We describe the case of a 58-year-old man who presented after smoke inhalation during a fire. Soot was found in the nostrils when he was admitted to our hospital, and after he began coughing up carbonaceous material, he was electively intubated and placed on volume assist control ventilation. DIAGNOSIS: Bronchoscopy on the first day of intensive care confirmed the injury from smoke inhalation and revealed mucosal edema and soot involving the tracheobronchial tree. INTERVENTIONS AND OUTCOMES: Inhaled unfractionated heparin of 10,000 IU in 3 mL of 0.9% normal saline alternating every 2 hours with 3 mL of 20% NAC was started 48 hours after admission and continued for 7 days. Bronchoscopy on the fifth day of intensive care showed significant improvement in airway edema and a resolution of soot. LESSONS: On the basis of our experience with this case and limited literature, we posit that nebulized heparin and NAC may be of benefit in patients with inhalational smoke-induced lung injury and mild-to-severe lung injury scores.

Endobronchial Tuberculosis Simulating Carcinoid Tumor.

Diagnosing endobronchial tuberculosis (EBTB) can be difficult due to the lack of specific signs and symptoms that differentiate it from other respiratory diseases, such as lung tumors. We hereby report a case of a very rare presentation of tuberculosis (TB) in a patient who presented with a dry cough and significant weight loss for 3 months. Chest X-ray and CT scan of the chest showed partial atelectasis and a segmental collapse of the right upper lobe and tumor-like arising from its bronchus along with a large right para-tracheal mediastinal lymphadenopathy, mimicking a metastatic (N2) disease. Fiber-optic bronchoscopy revealed a fleshy, highly vascularized mass occluding the right upper lobe bronchus, and thus the initial diagnosis of carcinoid tumor was made. Mediastinoscopy and biopsy of these mediastinal lymph nodes showed caseating chronic granulomatous inflammation consistent with TB, which changed the diagnosis to EBTB. The patient was treated with first-line anti-tuberculous drugs that led to a full resolution in terms of symptoms, radiological findings and complete disappearance of the endobronchial mass by bronchoscopy. To the best of authors' knowledge, there are no other similar cases in presentation and management in the literature.

Report of 12 cases with tracheobronchial mucormycosis and a review.

OBJECTIVES: Tracheobronchial mucormycosis is a rare and invasive pulmonary mucormycosis involving the tracheobronchial tree. DATA SOURCE: At a 3500-bed tertiary care center. STUDY SELECTION: This was a retroactive study of 12 cases of tracheobronchial mucormycosis diagnosed in our hospital, and 48 cases that were previously reported in the English literature. RESULTS: Rhizopus was the predominant species of pathogen (66.7%). Primary bronchus was the most frequently involved location (38.2%), and upper lobes (51% of cases) were a predilection. Obstructive necrosis and mucosal necrosis were the most common pathological forms (40% and 34.5%, respectively). Fever (59.3%), cough (59.3%), dyspnea (40.7%) and hemoptysis (30.5%) were the most common symptoms. 51.4% patients had rales, 40% had moist rales and 28.6% had negative physical findings. Ninety-five percent patients had immunosuppressive diseases. Diabetes mellitus (66.7%), diabetes ketoacidosis (21.7%), corticosteroid therapy (20%) and kidney insufficiency (18.3%) were the most common predisposing factors. 13.2% had neutropenia which was mostly among the non-diabetic patients (P = .006). Endobronchial lesion of 23.2% had imaging reports with 33.9% exhibiting single mass. Pathological diagnosis of 76.7% used the transbronchial biopsy. The most frequent antifungal therapies were intravenous amphotericin B (79.7%), surgery (33.3%) and surgery combined with amphotericin B therapy (28.3%). Overall in-hospital mortality was 52.5%, with hemoptysis (P = .017), dyspnea at presentation (P = .022) and angioinvasion (P = .03) as independent risk prognostic factors. In contrast, surgery (P = .003) was an independent protection prognostic factor. CONCLUSIONS: Tracheobronchial mucormycosis is a rare but severe disease with high mortality because of its nonspecific clinical presentations and variable predisposing factors.

[Endobronchial tuberculosis]. / La tuberculose endobronchique.

BACKGROUND/AIM: The endobronchial tuberculosis (EBTB) is an uncommon type of tuberculosis. The respiratory symptoms in EBTB are usually nonspecific and misleading. The aim of the study is to determine the clinical features and diagnostic aspects of EBTB. PATIENTS AND METHODS: Twenty-eight cases of endobronchial tuberculosis collected from January 2009 to October 2015. RESULTS: EBTB was found in 16 females and 12 males. The mean age was 48 years. The history of tuberculosis and tuberculosis contagion were not found in any case. The respiratory symptoms were dominated by cough and dyspnea. Hemoptysis was found in 7 cases. The chest X-ray showed associated pulmonary lesions in 26 cases. Bronchoscopy finded an endobronchial granular lesion in 15 cases, a tumorous pattern in 7 cases; a thickening spurs in 4 cases and ganglio-bronchial fistula in two cases. Bronchial biopsies had found a caseo-follicular tuberculosis in 27 cases. Pleural biopsy confirmed associated pleural tuberculosis in one case. The research of Koch bacillus in the sputum was positive in 13 cases and culture in 6 cases. The antituberculosis treatment was started in all patients and an oral corticosteroids treatment was associated in 5 cases. The evolution was good in 26 cases. CONCLUSION: This study showed clinical, radiological and endoscopic bronchial tuberculosis polymorphism making its diagnosis difficult and the importance of a bacteriological and/or histological confirmation.

Concurrent central nervous system and endobronchial tuberculosis mimicking a metastatic lung cancer.

BACKGROUND AND AIMS: Early diagnosis and treatment of central nervous system tuberculosis are important because of high mortality and morbidity. Airways must be carefully evaluated in differential diagnosis. METHODS: We present a rare case of intracranial-endobronchial tuberculosis mimicking lung cancer with brain metastasis. RESULTS: A vegetative mass lesion, confirmed as necrotic granulomatous inflammation, originating from the entrance of the right upper lobe entry, was coagulated and extracted by argon plasma coagulation and cryotherapy to prevent permanent upper lobe atelectasis. Mycobacterium tuberculosis complex was detected in bronchoscopic material. A four-drug initial anti-tuberculous treatment regimen was given in 2 months. The upper lobe atelectasis was resolved at the fourth month of therapy despite upper lobar bronchus patency. The patient was doing well and completed the two-drug maintenance therapy of 7 months with complete resolution. CONCLUSION: In such cases, tissue diagnosis should be achieved as early as possible and anti-tuberculous treatment was commenced along with advanced interventional techniques.

Pharmacological Management of Bronchorrhea in Malignant Disease: A Systematic Literature Review.

CONTEXT: Malignant respiratory tract tumors can lead to massive fluid production, known as bronchorrhea. This symptom can be very distressing itself, and it can lead to or aggravate other symptoms such as dyspnea and cough. Pharmacological treatment options have been reported in the literature. However, no systematic evaluation of their effectiveness has been conducted so far. OBJECTIVES: To systematically identify, appraise, and evaluate the effectiveness of symptomatic pharmacological treatment of bronchorrhea in malignant disease in palliative care. METHODS: A systematic literature review in Medline, Embase, and the Cochrane Database, as well as citation tracking, hand searches of selected journals, and reference lists of retrieved articles, was performed. For the purpose of this review, only symptomatic treatments were considered. RESULTS: No controlled clinical studies could be identified. Twenty of 48 retrieved references were analyzed in detail. These 20 case reports and case series dealt with the symptomatic pharmacological management of bronchorrhea in malignant disease; the other 28 had to be excluded for various reasons. The majority of patients suffered from bronchioloalveolar carcinoma. Reported treatments comprise corticosteroids, macrolide antibiotics, inhaled indomethacin, octreotide, and tyrosine-kinase inhibitors. For some drugs, significant clinical impact on distressing symptoms associated with bronchorrhea was reported. CONCLUSION: There are only very limited data on the pharmacological management of bronchorrhea in malignant disease. Because of the distressing nature of the symptom, a pragmatic management strategy is essential. This can include promising treatment options reported in the literature but should also take into account availability, individual tolerability, and costs. Further research is needed.

Colchicine Treatment for Tracheobronchial Amyloidosis.

Tracheobronchial amyloidosis is an infrequent disease characterized by the deposition of proteinaceous material in the tracheobronchial tree. The disease generally has a high morbidity and variable mortality in the years following diagnosis. There is no consensus on the optimal treatment. We report a case of a 63-year-old woman who presented with a diffuse tracheobronchial amyloidosis associated with laryngeal involvement, which required a percutaneous tracheostomy due to high-grade subglottic stenosis, with no evidence of systemic amyloidosis. After treatment exclusively with colchicine, she had a complete resolution of the stenotic area, with a very good response from the tracheobronchial amyloidosis disease, with only minor yellow plaques persisting. The patient has remained asymptomatic in the next 4 years of follow-up, with no evidence of endoscopic progression. This is the first documented case of this kind of response of tracheobronchial amyloidosis to colchicine treatment alone. A review of the available literature is presented.