Chronic Pulmonary Symptoms Research Articles

Single-cell RNA sequencing reveals characteristics of myeloid cells in post-acute sequelae of SARS-CoV-2 patients with persistent respiratory symptoms.

Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complications in COVID-19 infection remains unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection (PASC) with persistent pulmonary symptoms. The dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing (scRNA-seq) to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from a participant naïve to SARS-CoV-2 (Control) (n=1) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC) (n=2). After integrating scRNA-seq data with a naïve participant from a published dataset, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14+/CD16+monocytes, and dendritic cells) was increased in PPASC (n=2) compared to controls (n=2). MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (VEGF, WNT, and SMAD) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. Further comparison of PPASC with scRNA-seq data with Severe COVID-19 (n=4) data demonstrated enrichment of fibrotic transcriptional signatures. In PPASC, we observed interactive VEGF ligand-receptor pairs among MLCs, and network modules in CD14+ (cluster 4) and CD16+ (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naïve samples. Analysis of a small scRNA-seq dataset demonstrated alterations in the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests a potential role in PPASC development.

Chronic Neurocognitive, Neuropsychological, and Pulmonary Symptoms in Outpatient and Inpatient Cohorts After COVID-19 Infection.

Neuropsychological symptoms associated with post-COVID-19 conditions may prevent patients from resuming normal activities at home or work. We report a retrospective, cross-sectional evaluation of neuropsychological and cardiopulmonary outcomes in 2 groups of patients: outpatients with mild enough infection to be spared from hospitalization and those who required inpatient admission. We hypothesized a dose-response model of post-COVID symptom severity in which persistent consequences would be more severe in those who experienced worse acute infections. In a dedicated COVID clinic, 321 patients were seen (33% outpatient, 67% inpatient). Outpatients skewed female, White, non-Hispanic, and younger. Outpatients had worse insomnia (measured with insomnia severity index) and were less able to resume their usual activities (EQ-5D-5L usual activities scale), despite inpatients experiencing worse cognition (Montreal Cognitive Assessment), having greater obesity (body mass index), decreased exercise tolerance (6-minute-walk distance), and more exertional oxygen desaturation. In both groups, insomnia worsened while cognition improved significantly with time from infection to testing while controlling for patient age; other variables did not. In logistic regression, female sex, higher MoCA score, EQ-5D-5L "usual activities" subscore, less oxygen desaturation with exertion, and longer time from infection remained as significant associations with outpatient status. Our study demonstrated that the functional sequelae of post-COVID-19 conditions in patients with mild acute disease have the potential to be as severe as that in patients who have recovered from severe illness.

Phenotypic alteration of low-density granulocytes in people with pulmonary post-acute sequalae of SARS-CoV-2 infection.

Low-density granulocytes (LDGs) are a distinct subset of neutrophils whose increased abundance is associated with the severity of COVID-19. However, the long-term effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on LDG levels and phenotypic alteration remain unexplored. Using participants naïve to SARS-CoV-2 (NP), infected with SARS-CoV-2 with no residual symptoms (NRS), and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC), we compared LDG levels and their phenotype by measuring the expression of markers for activation, maturation, and neutrophil extracellular trap (NET) formation using flow cytometry. The number of LDGs was elevated in PPASC compared to NP. Individuals infected with SARS-CoV-2 (NRS and PPASC) demonstrated increased CD10+ and CD16hi subset counts of LDGs compared to NP group. Further characterization of LDGs demonstrated that LDGs from COVID-19 convalescents (PPASC and NRS) displayed increased markers of NET forming ability and aggregation with platelets compared to LDGs from NP, but no differences were observed between PPASC and NRS. Our data from a small cohort study demonstrates that mature neutrophils with a heightened activation phenotype remain in circulation long after initial SARS-CoV-2 infection. Persistent elevation of markers for neutrophil activation and NET formation on LDGs, as well as an enhanced proclivity for platelet-neutrophil aggregation (PNA) formation in COVID-19 convalescent individuals may be associated with PPASC prognosis and development.

Chronic Cavitary Pulmonary Aspergillosis: An Unusual Cause of Chronic Cough, Pleuritic Chest Pain, and Hemoptysis in a 24-Year-Old Coal Mine Worker

Pulmonary Aspergillus infections are caused by the ubiquitous fungus mold when spores found in compost, dust, and plant material are inhaled. Manifestation of the disease is represented by a delicate balance between host and pathogen interactions, making Aspergillus infection more commonly observed in immunocompromised individuals. Chronic cavitary pulmonary aspergillosis (CCPA) is a subtype of pulmonary Aspergillosis associated with history of chronic or prior lung disease. Here we present the case of a non-immunocompromised 24-year-old male with a history of intermittent asthma with chronic pulmonary symptoms and finding of a lung mass on imaging. We describe the diagnostic challenge and surgical treatment of CCPA in medically refractory disease.

CT imaging features of paranasal sinuses in children with primary ciliary dyskinesia

Background Primary ciliary dyskinesia (PCD) causes impaired mucociliary clearance and results in chronic pulmonary and sinonasal symptoms. Objectives To study the CT imaging features of paranasal sinuses in children with PCD. Materials and methods 17 PCD patients ranged from 4 to 13 years, a mean age of 7.9 ± 3.3 years, were included in the final analysis. Patients with non-PCD chronic rhinosinusitis (CRS) who accepted maxillary balloon catheter dilation were included in the control group. Paranasal sinuses CT scans were scored according to the Lund–Mackay staging system. The correlation between age and Lund–Mackay score was analyzed. Results 100% (17/17) had rhinosinusitis, 52.9% (9/17) had lung consolidation, 64.7% (11/17) had atelectasis, 35.3% (6/17) had bronchiectasis, and 47.1% (8/17) had a history of neonatal respiratory distress. The mean Lund–Mackay score of PCD patients was 14.2 ± 3.1, that of non-PCD CRS patients was 14.6 ± 5.5, the difference was not significant (p = .79). There was a significant inverse correlation between age and Lund–Mackay score in PCD patients (r = −0.530, p = .029) but not in non-PCD CRS patients (r = −0.168, p = .519). Conclusion Radiographic severity of rhinosinusitis in PCD patients was similar to the control population but decreased with age. Significance First time to propose radiographic severity of rhinosinusitis in pediatric patients with PCD might decrease with age.

Primary Immunodeficiency Disorders in children with Non-Cystic Fibrosis Bronchiectasis.

Introduction. Primary immunodeficiency diseases (PID) are common in patients with non-cystic fibrosis bronchiectasis (NCFB). Our objective was to determine ratio/types of PID in NCFB. Methods. Seventy NCFB patients followed up in a two-year period were enrolled. Results. Median age was 14 years (min-max: 6-30). Male/female ratio was 39/31; parental consanguinity, 38.6%. Most patients with NCFB (84.28%) had their first pulmonary infection within the first year of their lives. Patients had their first pulmonary infection at a median age of 6 months (min-max: 0.5-84), were diagnosed with bronchiectasis at about 9 years (114 months, min-max: 2-276). PID, primary ciliary dyskinesia (PCD), bronchiolitis obliterans, rheumatic/autoimmune diseases, severe congenital heart disease and tuberculosis were evaluated as the most common causes of NCFB. About 40% of patients (n=16) had bronchial hyperreactivity (BH) and asthma. Twenty-nine patients (41.4%) had a PID, and nearly all (n=28) had primary antibody deficiency, including patients with combined T and B cell deficiency. PID and non-PID groups did not differ according to gender, parental consanguinity, age at first pneumonia, age of onset of chronic pulmonary symptoms, bronchiectasis, presence of gastroesophageal reflux disease (GERD), BH and asthma (p greater-than 0.05). Admission to immunology clinic was about 3 years later in PID compared with non-PID group (p less-than 0.001). Five patients got molecular diagnosis, X-linked agammaglobulinemia (n=2), LRBA deficiency (n=1), RASGRP1 deficiency (n=1), MHC Class II deficiency (n=1). They were given monthly IVIG and HSCT was performed for three patients. Conclusions. PID accounted for about 40% of NCFB. Early diagnosis/appropriate treatment have impact on clinical course of a PID patient. Thus, follow-up in also immunology clinics should be a routine for patients who experience pneumonia in the first year of their lives and those with NCFB.

Sinus Development and Pneumatization in a Primary Ciliary Dyskinesia Cohort.

BackgroundPrimary ciliary dyskinesia (PCD) is a genetically diverse disease which causes impaired mucociliary clearance, and results in pulmonary, otologic, and rhinologic disease in affected patients. Genetic mutations in multiple genes impair the ability of patients to clear mucous from the lungs, middle ear, and sinonasal cavity and lead to chronic pulmonary and sinonasal symptoms.MethodsWe identified 17 PCD patients who had available CT scans. Volumes for bilateral maxillary, sphenoid, and frontal sinuses were calculated. A control population of patients who had preoperative CT scans for endoscopic endonasal resection of skull base pathology without sinonasal cavity involvement was also identified.ResultsThe mean age of PCD was 33 and ranged from 13 to 54 years. Patients were age- and gender-matched to a control group that underwent resection of anterior skull-base tumors and had a mean age of 35 that ranged between 17–53 years old. The volumes for all thee sinus cavities were significantly smaller (p < 0.007) compared to the control population. The average Lund-Mackay score was 10.6 in the PCD cohort (range 6–16) in comparison to an average of 0.7 in the control cohort (range 0–2).ConclusionsOverall sinus volumes were smaller in patients with PCD compared to our control population. Future studies will be aimed at understanding defects in sinus development as a function of specific genetic mutations in PCD patients. Ultimately, a better understanding of the underlying pathophysiology of PCD will allow us to identify the optimal treatment practices for this unique patient group.

INCIDENTAL FINDING OF TRACHEAL BRONCHUS IN AN INTUBATED PATIENT PRESENTING WITH RIGHT LUNG ATELECTASIS

SESSION TITLE: Case Report Semifinalists 2 SESSION TYPE: Fellow Case Report Posters PRESENTED ON: 10/21/2019 02:30 PM - 03:15 PM INTRODUCTION: A long-standing atelectasis in an intubated patient with proper endotracheal positioning and prompt medical management warrants careful investigation. An under diagnosed congenital anomaly may be missed in these cases. CASE PRESENTATION: This is the case of a 1-year old male with Congenital Heart Disease, Tetralogy of Fallot, who had no pulmonary problems prior to the surgical correction of the cardiac lesion. The operation was well-tolerated by the patient. However, during the 1st post-operative day, the patient developed right lung atelectasis which remained unresolved despite aggressive pulmonary regimen. Bronchoscopy was done on the tenth day post-intubation which revealed fish-mouth shaped right main bronchus which may be a manifestation of a possible compression of an adjacent structure from the outside. Because of the persistence of the atelectasis and the bronchoscopic finding of a possible external compression of the right main bronchus, chest CT scan was done which revealed tracheal bronchus. DISCUSSION: Tracheal bronchus is an abnormal accessory bronchus arising usually from the right lateral wall of the trachea1. It is usually of no clinical significance, however may present as an aggravating factor in the development of post-operative complications. This congenital anomaly is usually discovered as an incidental finding, during a radiological investigation or bronchoscopy3. In the said patient, the tracheal bronchus was not detected in the serial chest radiographs taken. In a plain chest radiograph, the tracheal bronchus can easily be missed, as in the study of Zheng et.al. Out of the 396 patients, tracheal bronchus was detected in 1.8% of the patients who underwent bronchoschopy. The lesion was noted at the right side of the trachea in all the 7 patients. All these 7 patients’ chest radiographs did not manifest any sign of tracheal bronchus4. As in the case of our patient, the chest radiograph reading did not reveal any sign of pig bronchus. Furthermore, during the bronchoscopy done while the patient was intubated, the tracheal bronchus was also not appreciated, probably due to the positioning of the endotracheal tube obscuring the lumen of the accessory bronchus. Several of the studies conducted demonstrated the diagnosis of the bronchial anomaly through the use of chest CT scan. The use of multiplanar reconstruction, three-dimensional reconstruction and three-dimensional virtual bronchoscopy are very helpful in the diagnosis of this anomaly. CONCLUSIONS: Tracheal bronchus is a relatively under diagnosed condition in patients presenting with chronic pulmonary signs and symptoms. This congenital anomaly should be considered as a differential diagnosis for intubated patients presenting with long-standing atelectasis. A careful review of the plain radiograph, bronchoscopic findings, and chest CT scan results should be done in such cases. Reference #1: Wilmott, Deterding, Li, Ratjen, Sly, Zar, Bush. Kendig’s Disorders of the Respiratory Tract in Children. 9th edition, 2019. Reference #2: H. Ellis. Clinical Anatomy. 11th edition, 2006. Reference #3: G. Panzironi, V. Noce, R.M. Ammendola, A. Fiorelli, I. Carbone. European Journal of Radiology Open 2 (2015) 1-2. Tracheal Bronchus: High Resolution Computed Tomography diagnosis in a symptomatic patient DISCLOSURES: No relevant relationships by Karenne Somera, source=Web Response

Asymptomatic congenital lung malformations: Is nonoperative management a viable alternative?

IntroductionThe purpose of this study was to evaluate clinical outcomes in children with asymptomatic congenital lung malformations (CLM) who were initially managed nonoperatively. MethodsAn IRB-approved retrospective review was performed on all CLMs at a single tertiary care referral center (Jan 2006–Dec 2016, n=140). Asymptomatic cases that did not undergo elective resection were evaluated for subsequent CLM-related complications based on clinical records and a telephone quality of life survey. ResultsOut of 39 (27.9%) who were initially managed nonoperatively, 13 (33%) developed CLM-related symptoms and underwent surgical intervention at a median age of 6.8years (range, 0.7–19.8years). The most common indication for conversion to operative management was pneumonia (78%). Larger lesions, as measured by CT scan, were significantly associated with the need for subsequent surgical intervention (mean maximal diameter, 5.7 vs. 2.9cm; p=0.005). Based on survey data with a median follow up of 3.9years (range, 0.2–13.2years), 17% developed chronic pulmonary symptoms, including cough (11%) and asthma requiring bronchodilators (12%). ConclusionAlthough these data support nonoperative management as a viable alternative to surgical resection, at least one-third of CLM children eventually develop pneumonia or other pulmonary symptoms. Larger lesions are correlated with an increased risk for eventual surgical resection. Level of EvidenceLevel IV.

The Impact of mHealth Interventions: Systematic Review of Systematic Reviews.

BackgroundMobile phone usage has been rapidly increasing worldwide. mHealth could efficiently deliver high-quality health care, but the evidence supporting its current effectiveness is still mixed.ObjectiveWe performed a systematic review of systematic reviews to assess the impact or effectiveness of mobile health (mHealth) interventions in different health conditions and in the processes of health care service delivery.MethodsWe used a common search strategy of five major scientific databases, restricting the search by publication date, language, and parameters in methodology and content. Methodological quality was evaluated using the Measurement Tool to Assess Systematic Reviews (AMSTAR) checklist.ResultsThe searches resulted in a total of 10,689 articles. Of these, 23 systematic reviews (371 studies; more than 79,665 patients) were included. Seventeen reviews included studies performed in low- and middle-income countries. The studies used diverse mHealth interventions, most frequently text messaging (short message service, SMS) applied to different purposes (reminder, alert, education, motivation, prevention). Ten reviews were rated as low quality (AMSTAR score 0-4), seven were rated as moderate quality (AMSTAR score 5-8), and six were categorized as high quality (AMSTAR score 9-11). A beneficial impact of mHealth was observed in chronic disease management, showing improvement in symptoms and peak flow variability in asthma patients, reducing hospitalizations and improving forced expiratory volume in 1 second; improving chronic pulmonary diseases symptoms; improving heart failure symptoms, reducing deaths and hospitalization; improving glycemic control in diabetes patients; improving blood pressure in hypertensive patients; and reducing weight in overweight and obese patients. Studies also showed a positive impact of SMS reminders in improving attendance rates, with a similar impact to phone call reminders at reduced cost, and improved adherence to tuberculosis and human immunodeficiency virus therapy in some scenarios, with evidence of decrease of viral load.ConclusionsAlthough mHealth is growing in popularity, the evidence for efficacy is still limited. In general, the methodological quality of the studies included in the systematic reviews is low. For some fields, its impact is not evident, the results are mixed, or no long-term studies exist. Exceptions include the moderate quality evidence of improvement in asthma patients, attendance rates, and increased smoking abstinence rates. Most studies were performed in high-income countries, implying that mHealth is still at an early stage of development in low-income countries.

Exposure to Cooking Fumes and Acute Reversible Decrement in Lung Functional Capacity.

Background: Being exposed to cooking fumes, kitchen workers are occupationally at risk of multiple respiratory hazards. No conclusive evidence exists as to whether occupational exposure to these fumes is associated with acute and chronic pulmonary effects and symptoms of respiratory diseases. Objective: To quantify the exposure levels and evaluate possible chronic and acute pulmonary effects associated with exposure to cooking fumes. Methods: In this cross-sectional study, 60 kitchen workers exposed to cooking fumes and 60 unexposed employees were investigated. The prevalence of respiratory symptoms among these groups was determined through completion of a standard questionnaire. Pulmonary function parameters were also measured before and after participants' work shift. Moreover, air samples were collected and analyzed to quantify their aldehyde, particle, and volatile organic contents. Results: The mean airborne concentrations of formaldehyde, acetaldehyde, and acrolein was 0.45 (SD 0.41), 0.13 (0.1), and 1.56 (0.41) mg/m3, respectively. The mean atmospheric concentrations of PM1, PM2.5, PM7, PM10, and total volatile organic compounds (TVOCs) was 3.31 (2.6), 12.21 (5.9), 44.16 (16.6), 57 (21.55) µg/m3, and 1.31 (1.11) mg/m3, respectively. All respiratory symptoms were significantly (p<0.05) more prevalent in exposed group. No significant difference was noted between the pre-shift mean of spirometry parameters of exposed and unexposed group. However, exposed workers showed cross-shift decrease in most spirometry parameters, significantly lower than the pre-shift values and those of the comparison group. Conclusion: Exposure to cooking fumes is associated with a significant increase in the prevalence of respiratory symptoms as well as acute reversible decrease in lung functional capacity.

Efficacy of probiotic supplementation on quality of life and pulmonary symptoms due to sulfur mustard exposure: a randomized double-blind placebo-controlled trial

Objective: This study investigated the efficacy and safety of supplementation with probiotics in improving chronic pulmonary symptoms due to sulfur mustard (SM) exposure. Methods: In a randomized double-blind placebo-controlled study, 65 subjects suffering from chronic pulmonary complications of SM were assigned to one probiotic capsule (1 × 109 CFU containing seven strains of lactic acid-producing bacteria) every 12 h or an identical placebo for six weeks. Serum high-sensitivity C-reactive protein (CRP) concentrations, pulmonary function tests (FEV1, FEV1/FVC and MMEF 25–75%) and COPD assessment test (CAT) were assessed at baseline and at the end of trial. Results: The groups were comparable in baseline characteristics. There were significant improvements in FEV1/FVC in the probiotic but not in placebo group. CAT scores were decreased in both study groups. However, between-group comparison of changes in the assessed parameters reached statistical significance only for CAT score (p < 0.001). There was no report of adverse events during the course of trial. Conclusions: Findings of the present trial favor the efficacy of probiotic supplementation in improving the pulmonary symptoms of SM-exposed subjects.

Respiratory failure in adults due to foreign body aspiration: A case series

Introduction: Foreign body aspiration (FBA) is rare in adults and its clinical presentation can be very diverse. Acute symptoms as dyspnea and choking are often immediately linked to FBA. However, mild or even asymptomatic chronic pulmonary symptoms can be presented as a result of FBA. Physical examination is usually nonspecific. Chest X-ray is often normal or shows nonspecific findings. Treatment and definite diagnosis can be accomplished using rigid or flexible bronchoscopy. Case Series: We present two cases of foreign body aspiration. The first case was the aspiration of a broken tracheostomy tube leading to acute respiratory failure and the second case was the aspiration of a medication blister which initially presented as atypical chronic pulmonary symptoms but evolved to a medical emergency of acute respiratory failure. Conclusion: These two cases show the broad range of symptoms and findings associated with FBA. When patients present with nonspecific pulmonary findings, FBA should be included in the differential diagnosis. (This page in not part of the published article.) International Journal of Case Reports and Images, Vol. 7 No. 7, July 2016. ISSN – [0976-3198] Int J Case Rep Images 2016;7(7):422–426. www.ijcasereportsandimages.com Woittiez et al. 422 CASE REPORT OPEN ACCESS Respiratory failure in adults due to foreign body aspiration: A case series Lycke R. Woittiez, Elsbeth J. Wesselink, Marcel A. de Leeuw, Cornelis Slagt

Alpha- 1 Antitrypsin Deficiency in Children: Pulmonary Involvement

Introduction: α1-antitrypsin deficiency (α1-ATD) is one of the most common genetic disorders in white race, a usual cause of liver disease in children, and hepatopulmonary involvement in children and adult. The aim of this case description is presenting a child with early lung disease without liver parenchymal disorder. Case presentation: We describe a 13 year old boy because of exertional dyspnea, wheezing, productive cough and repeated hospital admission due to bronchopneumonia. There was no immune deficiency, sinusitis and allergic lung disease. There was no history of foreign body aspiration. Cystic fibrosis cause ruled out. Protein electrophoresis and serum level α1-AT evaluation documented α1-ATD. The patient was treated with conservative management. Conclusion: This article suggests that if a child presents with chronic pulmonary symptoms, possibility of α1-ATD should be considered and worked up.

A Novel Home-Based Patient Centered Eight-Week Pulmonary Rehabilitation Program for Asthma

L21 A Novel Home-Based Patient Centered Eight-Week Pulmonary Rehabilitation Program for Asthma Mark R. Windt, MD, Courtney Rice, MS, Sarah Regan, BS, Rebecca Chase, MS; Center for Asthma Allergy and Respiratory Disease, North Hampton, NH. RATIONALE: Because asthma and chronic obstructive pulmonary disease share symptoms such as dyspnea, diminished functional capacity and reduce quality-of-life, it would follow that pulmonary rehabilitation may also be effective in treating asthma. The ‘‘ATS/ERS statement on pulmonary rehabilitation’’ states that, while its effectiveness has only been clearly established for COPD, it ‘‘may be of value for all patients in whom respiratory symptoms are associated with diminished functional capacity or reduced HRQL’’. METHODS: Patients undergo an eight week, one session per week course which includes pre-and post-assessment, cardiovascular and strength training, respiratory muscle training, energy conservation, balance training, and nutritional education. Patients are given a detailed training syllabus, at home weekly assignments and are required to maintain daily datasheets. The exercise component is divided into exercise performed onsite and prescriptive training that the patient incorporates into his/her daily routine at home. RESULTS: Significant improvements (n5 16) were seen in body fat % (P 5 .003), waist circumference (P5 .049), 6 min. walk (P5 .001), gait speed (P 5 .001), inspiratory muscle training (P 5 .001), right leg balance (P 5 .032), sit to stand (P5.001), push-ups (P5.011) andBaecke questionnaire (P 5 .022). The asthma quality of life questionnaire did not show statistically significant improvement. CONCLUSIONS: Our study shows that assessment tools used in pulmonary rehabilitation are helpful in the comprehensive management of asthma and demonstrate improvement in functional capacity.

Effect of YM-40461, a novel surfactant secretagogue, on chronic obstructive pulmonary diseases and similar symptoms in guinea pigs.

YM-40461 (1-(2-dimethylaminoethyl)-1-(3,4,5-trimethoxyphenyl)urea, CAS 142912-85-4), is a novel surfactant secretagogue. The effect of YM-40461 on symptoms, e.g. change of airway functions and hypoxemia, were examined using guinea pigs with induced subacute bronchitis. Bronchitic guinea pigs exhibited basal lung resistance (RL) was 0.152 +/- 0.005 cm H2O/ml/s (normal: 0.130 +/- 0.002 cm H2O/ml/s) and basal lung compliance (CL) of 0.455 +/- 0.011 ml/cm H2O (normal: 0.509 +/- 0.009 ml/cm H2O). Although YM-40461 slightly improved the lung resistance in these animals, it improved significantly and dose-dependently the lung compliance (0.468 +/- 0.008 ml/cm H2O for 1 mg/kg, 0.477 +/- 0.008 for 3 mg/kg, 0.490 +/- 0.011 for 10 mg/kg, p < 0.05 at 10 mg/kg) compared to nontreated bronchitic guinea pigs. YM-40461 improved airway functions in bronchitic guinea pigs just as wall as the beta 2-adrenoceptor agonist salbutamol. Additionally, YM-40461 significantly reduced airway hyperreactivity in response to intravenously infused acetylcholine (ACh). Basal PaO2 was 83.1 +/- 0.7 cm H2O in healthy guinea pigs and 71.2 +/- 1.7 cm H2O in bronchitic guinea pigs, indicating hypoxemia. A dose of 10 mg/kg of YM-40461 relieved hypoxemia in these animals with the values returning to 81.8 +/- 1.9 cm H2O (p < 0.05). These results suggest that YM-40461 ameliorates chronic obstructive pulmonary disease (COPD)-like symptoms in bronchitis models due to increased surfactant in the airway.

Familial pulmonary fibrosis is the strongest risk factor for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a lethal lung disorder of unknown etiology. The disease is likely the result of complex interactions between genetic and environmental factors. Evidence suggests that certain environmental factors, such as cigarette smoking and metal dust exposures, or comorbidities like gastroesophageal reflux, and type 2 diabetes mellitus (DM2) may increase risk to develop IPF. Substantial uncertainty remains, however, regarding these and other putative risk factors for IPF. In this study we performed a case-control analysis including 100 patients with IPF and 263 controls matched for age sex and place of residence. We used a structured questionnaire to identify potential risk factors for IPF, including environmental and occupational exposures as well as the relevance of family history of pulmonary fibrosis. The multivariate analysis revealed that family history of pulmonary fibrosis [OR = 6.1, CI95% 2.3-15.9; p < 0.0001] was strongly associated with increased risk of IPF. Actually, 20% of the cases reported a parent or sibling with pulmonary fibrosis. Gastroesophageal reflux [OR = 2.9, CI: 1.3-6.6; p = 0.007], former cigarette smoking [OR = 2.5, CI: 1.4-4.6, p = 0.003], and past or current occupational exposure to dusts, smokes, gases or chemicals [OR = 2.8, CI: 1.5-5.5; p = 0.002] were also associated with the disease. Despite being a significant risk factor on univariate analysis DM2 was not significant in multivariate analysis. These findings indicate that family history of pulmonary fibrosis is a strong risk factor for IPF. Also, we confirmed that occupational exposures, gastroesophageal reflux and former smoking increase the risk for this disease.

Mevalonate Kinase Deficiency: A Survey of 50 Patients

The goal of this study was to describe the spectrum of clinical signs of mevalonate kinase deficiency (MKD). This was a retrospective French and Belgian study of patients identified on the basis of MKD gene mutations. Fifty patients from 38 different families were identified, including 1 asymptomatic patient. Symptoms began during the first 6 months of life in 30 patients (60%) and before the age of 5 years in 46 patients (92%). Symptoms consisted of febrile diarrhea and/or rash in 23 of 35 patients (66%). Febrile attacks were mostly associated with lymphadenopathy (71%), diarrhea (69%), joint pain (67%), skin lesions (67%), abdominal pain (63%), and splenomegaly (63%). In addition to febrile attacks, 27 patients presented with inflammatory bowel disease, erosive polyarthritis, Sjögren syndrome, and other chronic neurologic, renal, pulmonary, endocrine, cutaneous, hematologic, or ocular symptoms. Recurrent and/or severe infections were observed in 13 patients, hypogammaglobulinemia in 3 patients, and renal angiomyolipoma in 3 patients. Twenty-nine genomic mutations were identified; the p.Val377Ile mutation was the most frequently found (29 of 38 families). Three patients died of causes related to MKD. The disease remained highly active in 17 of the 31 surviving symptomatic patients followed up for >5 years, whereas disease activity decreased over time in the other 14 patients. Interleukin 1 antagonists were the most effective biological agents tested, leading to complete or partial remission in 9 of 11 patients. MKD is not only an autoinflammatory syndrome but also a multisystemic inflammatory disorder, a possible immunodeficiency disorder, and a condition that predisposes patients to the development of renal angiomyolipoma.

Clinical Features of Asthma in Children Differ with Regard to the Intensity of Distal Gastroesophageal Acid Reflux

Background. The prevalence of gastroesophageal reflux (GER) in children with asthma is higher than in healthy controls, but the nature and direction of this association is unclear. Objective. The aim of our study was to assess the relationship between esophageal acid exposure and the clinical features of asthma in children. Methods. In total, 66 children (mean age 122.8 months [SD 44.89 months]) with chronic pulmonary symptoms, fulfilling diagnostic criteria of persistent asthma, underwent 24-hour esophageal pH monitoring and answered a detailed questionnaire-based survey. The questionnaire topics included environmental factors, familial history, current and previous clinical symptoms, atopy, asthma severity, and medication. Results. Abnormal results of 24-hour esophageal pH monitoring were found in 28 out of 66 children (42.4%). Age, sex, severity of asthma, environmental factors, spirometry results, and the type of medication did not correlate with esophageal acid exposure. However, children with abnormal pH results developed asthma significantly earlier (asthma onset 3.63 years [SD 2.52 years] vs 5.77 years [SD 3.82 years]; p < .01). Nonatopic individuals had more intensive esophageal acid exposure than atopic ones (Boix-Ochoa score 28.19 [SD 18.26] vs 18.26 [SD 12.84]; p < .048). The intensity of GER was also significantly correlated with frequent or difficult-to-control nighttime asthma attacks. Conclusions. There are differences in clinical features of asthma in children with regard to the intensity of esophageal acid exposure. Symptoms of asthma in nonatopic individuals with early onset and difficult-to-control nighttime asthma attacks suggest the possibility of concomitant, clinically relevant GER.

Disseminated blastomycosis diagnosed by fine-needle aspiration of the thyroid

Blastomycosis is an uncommon disease caused by the dimorphic fungus Blastomyces dermatitidis. It can manifest as chronic pulmonary symptoms or disseminated disease. Only three previous cases of blastomycosis involving the thyroid have been reported, of which two were diagnosed by fine-needle aspiration. We present a case of disseminated blastomycosis initially diagnosed by thyroid fine-needle aspiration. Our case was a 47-year-old man with past medical history significant for diabetes, hyperlipidemia, and chronic pancreatitis who presented with a 2-week history of fever, chills, rigors, constipation, and 10 pound weight loss. Abdominal CT revealed chronic pancreatitis and a calcified mass in the pancreas. Chest CT revealed a single 1.5-2 cm thyroid mass and innumerably small 2-3 mm pulmonary nodule bilaterally. Fine-needle aspiration of the thyroid demonstrated 10-20 μm broad-based budding yeasts with thick-walled, refractile capsules amidst a background of granulomatous inflammation, and was diagnosed as a fungal infection consistent with blastomycosis. The patient was started on treatment with itraconazole based upon the FNA diagnosis. Concurrent lung biopsy demonstrated rare possible yeast forms on histology. A specimen from the lung was sent for culture, and was positive for B. dermatitidis, confirming the diagnosis. Disseminated blastomycosis rarely involves the thyroid. However, the thyroid is amenable to fine-needle aspiration. Fungal and mycobacterial cultures and special stains for fungal organisms should be requested on all thyroid fine-needle aspiration biopsies with granulomatous inflammation.