Laryngeal dysplasia: a 10-year review of rates of progression to invasive carcinoma and treatment-specific outcomes in a regional ENT department in Northern Ireland.

BACKGROUND: Laryngeal dysplasia represents a complex pre-malignant condition characterised by a spectrum of mucosal changes, with a reported malignant transformation rate from dysplasia to invasive carcinoma of 14.0 per cent. OBJECTIVE: To identify whether increasing glottic dysplasia severity is associated with higher local malignant transformation rates or adverse clinical outcomes. METHODS: This retrospective cohort study identified 125 patients with any histopathological grade of glottic dysplasia over a 10-year period who were followed up for a standardised 10-year period. RESULTS: The malignant transformation rate was 21.8 per cent over 10 years, demonstrating a statistically significant greater risk with increasing dysplasia severity. The mean time to transformation was 52 months, with time to transformation statistically associated with increasing dysplasia severity. Rapid progression to carcinoma within 12 months occurred in 40 per cent of cases, and 58 per cent of subsequently diagnosed laryngeal squamous cell carcinomas were tumour stage T1. CONCLUSION: Laryngeal dysplasia carries a significant malignant potential, appearing greatest within 12 months of diagnosis and with increasing severity of dysplasia.

Defective monocyte-derived macrophage phagocytosis is associated with exacerbation frequency in COPD.

BACKGROUND: Lower airway bacterial colonisation (LABC) in COPD patients is associated with increased exacerbation frequency and faster lung function decline. Defective macrophage phagocytosis in COPD drives inflammation, but how defective macrophage function contributes to exacerbations is not clear. This study investigated the association between macrophage phagocytosis and exacerbation frequency, LABC and clinical parameters. METHODS: Monocyte-derived macrophages (MDM) were generated from 92 stable COPD patients, and at the onset of exacerbation in 39 patients. Macrophages were exposed to fluorescently labelled Haemophilus influenzae or Streptococcus pneumoniae for 4 h, then phagocytosis measured by fluorimetry and cytokine release by ELISA. Sputum bacterial colonisation was measured by PCR. RESULTS: Phagocytosis of H. influenzae was negatively correlated with exacerbation frequency (r = 0.440, p < 0.01), and was significantly reduced in frequent vs. infrequent exacerbators (1.9 × 103 RFU vs. 2.5 × 103 RFU, p < 0.01). There was no correlation for S. pneumoniae. There was no association between phagocytosis of either bacteria with age, lung function, smoking history or treatment with inhaled corticosteroids, or long-acting bronchodilators. Phagocytosis was not altered during an exacerbation, or in the 2 weeks post-exacerbation. In response to phagocytosis, MDM from exacerbating patients showed increased release of CXCL-8 (p < 0.001) and TNFα (p < 0.01) compared to stable state. CONCLUSION: Impaired COPD macrophage phagocytosis of H. influenzae, but not S. pneumoniae is associated with exacerbation frequency, resulting in pro-inflammatory macrophages that may contribute to disease progression. Targeting these frequent exacerbators with drugs that improve macrophage phagocytosis may prove beneficial.

Changes in cold-related mortalities between 1995 and 2016 in South East England.

OBJECTIVE: The aim of the study was to examine trends in cold-related mortalities between 1995 and 2016. STUDY DESIGN: This is a longitudinal mortality study. METHODS: For men and women aged 65-74 years or those older than 85 years in South East England, the relationship between daily mortality (deaths per million population) and outdoor temperatures below 18 °C, with allowance for influenza epidemics, was assessed by linear regression on an annual basis. The regression coefficients were expressed as a percentage of the mortality at 18 °C to adjust for changes in mortality through health care. Trends in 'specific' cold-related mortalities were then examined over two periods, 1977-1994 and 1995-2016. RESULTS: In contrast to the early period, annual trends in cold-related specific mortalities showed no decline between 1995 and 2016. 'Specific' cold-related mortality of women, but not men, in the age group older than 85 years showed a significant increase over the 1995-2016 period, which was different from the trend over the earlier period (P < 0.01). CONCLUSION: Despite state-funded benefits to help alleviate fuel poverty and public health advice, very elderly women appear to be at increasing risk of cold-related mortality-greater help may be necessary.

Gut microbiota utilize immunoglobulin A for mucosal colonization.

The immune system responds vigorously to microbial infection while permitting lifelong colonization by the microbiome. Mechanisms that facilitate the establishment and stability of the gut microbiota remain poorly described. We found that a regulatory system in the prominent human commensal Bacteroides fragilis modulates its surface architecture to invite binding of immunoglobulin A (IgA) in mice. Specific immune recognition facilitated bacterial adherence to cultured intestinal epithelial cells and intimate association with the gut mucosal surface in vivo. The IgA response was required for B. fragilis (and other commensal species) to occupy a defined mucosal niche that mediates stable colonization of the gut through exclusion of exogenous competitors. Therefore, in addition to its role in pathogen clearance, we propose that IgA responses can be co-opted by the microbiome to engender robust host-microbial symbiosis.

Misspecification of at-risk periods and distributional assumptions in estimating COPD exacerbation rates: The resultant bias in treatment effect estimation.

In trials comparing the rate of chronic obstructive pulmonary disease exacerbation between treatment arms, the rate is typically calculated on the basis of the whole of each patient's follow-up period. However, the true time a patient is at risk should exclude periods in which an exacerbation episode is occurring, because a patient cannot be at risk of another exacerbation episode until recovered. We used data from two chronic obstructive pulmonary disease randomized controlled trials and compared treatment effect estimates and confidence intervals when using two different definitions of the at-risk period. Using a simulation study we examined the bias in the estimated treatment effect and the coverage of the confidence interval, using these two definitions of the at-risk period. We investigated how the sample size required for a given power changes on the basis of the definition of at-risk period used. Our results showed that treatment efficacy is underestimated when the at-risk period does not take account of exacerbation duration, and the power to detect a statistically significant result is slightly diminished. Correspondingly, using the correct at-risk period, some modest savings in required sample size can be achieved. Using the proposed at-risk period that excludes recovery times requires formal definitions of the beginning and end of an exacerbation episode, and we recommend these be always predefined in a trial protocol.

Use of home oxygen for children in England and Wales.

BACKGROUND: With the introduction of a standardised ordering system in February 2006, the opportunity arose to collect data on children requiring home oxygen in England and Wales. The authors' aim was to determine the incidence and patterns of home oxygen prescribing. METHODS: A paediatric home oxygen clinical network and the Children's Home Oxygen Record Database were established. During a 3-year period (February 2006 to January 2009), prescribers were requested to submit copies of the Home Oxygen Order Forms. In addition, anonymised point prevalence data on all patients currently receiving home oxygen in June 2007 were obtained from the four provider companies. RESULTS: Children's Home Oxygen Record Database--Forms were analysed for 888 children <16 years (58% boys) with a median age of 4.1 months; 656 (74%) were <1 year. 541 (68%) had a diagnosis of chronic neonatal lung disease; 53 (7%), neurodisability; and 49 (6%), cardiac disease. Order forms were often incomplete, and prescribing practice was variable. Provider's cross-sectional survey--There were 3338 children <16 years, representing 4% of all patients on home oxygen. Median age was 3.1 years with a peak at 6 months. The prevalence for paediatric home oxygen use in England and Wales was 0.33 per 1000, with a peak of 1.08 per 1000 for those <1 year. Marked regional variation was noted. CONCLUSIONS: This is the first national dataset available for children prescribed home oxygen in England and Wales. The study emphasises the need for a coordinated approach to home oxygen prescribing and justifies the recent publication of evidence-based guidelines.

Predictive accuracy of patient-reported exacerbation frequency in COPD.

Chronic obstructive pulmonary disease (COPD) exacerbation frequency is important for clinical risk assessment and trial recruitment. In order to accurately establish exacerbation frequency, patients need to be followed for 1 yr, although this is not always practical. 1) Patient recall of exacerbation number during the year prior to recruitment to the London COPD cohort was compared with the number of exacerbations recorded on diary cards during the subsequent year; and 2) patient recall of their exacerbation number after 1 yr of follow-up was compared with documented exacerbations over the same year. A total of 267 patients (forced expiratory volume in 1 s 1.14 L) recorded worsening of respiratory symptoms on daily diary cards for 1 yr. Exacerbations were defined according to previously validated criteria. There was no difference between the exacerbation number recalled by patients prior to recruitment and the number detected during the first year (median 2.0 (interquartile range 1.0-4.0) and 2.0 (1.0-4.0); expected agreement 76.4%; agreement 84.6%; κ = 0.3469). There was no difference between the number of exacerbations remembered by patients and the number recorded on diary cards over the same 1-yr period (2.0 (1.0-4.0) for both groups; expected agreement 74.9%; actual agreement 93.3%; κ = 0.6146). Patients remember the number of exacerbations they have in a year. Accuracy is increased when comparing the same 1-yr period. Patient recall is sufficiently robust for stratification into frequent and infrequent exacerbator groups for subsequent years.

Relationship between depression and exacerbations in COPD.

Chronic obstructive pulmonary disease is associated with exacerbations. Some patients are prone to frequent exacerbations and these individuals have a worse quality of life, greater limitation of their daily activity and faster disease progression than patients with less frequent exacerbations. A prospective study in a well-characterised cohort was performed and it was assessed whether depression, as determined by the Centre for Epidemiologic Studies Depression Scale, was related to exacerbation frequency, systemic inflammation and various social factors. The associations of any increase in depressive symptoms at exacerbation were also investigated. Frequent exacerbators had a significantly higher median (interquartile range) baseline depression score than infrequent exacerbators (17.0 (7.0-25.0) and 12.0 (6.0-18.0), respectively). Depressed patients spend significantly less time outdoors and had significantly worse quality of life as measured by the St George's Respiratory Questionnaire. Depression increased significantly in patients from baseline to exacerbation (12.5 (5.0-19.0) and 19.5 (12.0-28.0) respectively). The present study is the first to show a relationship between depression and exacerbation frequency in patients with chronic obstructive pulmonary disease. The finding that frequent exacerbators are more depressed than infrequent exacerbators is relevant, as exacerbation frequency is an important outcome measure in chronic obstructive pulmonary disease.

Effect of tiotropium on sputum and serum inflammatory markers and exacerbations in COPD.

Chronic obstructive pulmonary disease (COPD) patients experiencing frequent exacerbations demonstrate increased stable-state airway inflammation. Tiotropium has been shown to reduce exacerbation frequency, but its effect on airway inflammation is unknown. The aim of the present study was to investigate the effect of tiotropium on sputum inflammatory markers and exacerbation frequency. Patients (n = 142) were randomised to receive tiotropium or placebo in addition to their usual medication for 1 yr. Sputum and serum cytokines were assayed by ELISA and exacerbation frequency calculated using a symptom-based diary. There was no difference in the area under the curve for sputum interleukin (IL)-6 or myeloperoxidase between the groups, but sputum IL-8 level was increased in the tiotropium arm. There was no difference between start and end of study in serum IL-6 or C-reactive protein level. Tiotropium was associated with a 52% reduction in exacerbation frequency (1.17 versus 2.46 exacerbations.yr(-1)). Of patients on tiotropium, 43% experienced at least one exacerbation, compared with 64% on placebo. The total number of exacerbation days was reduced compared with placebo (17.3 versus 34.5 days). Tiotropium reduces exacerbation frequency in chronic obstructive pulmonary disease, but this effect does not appear to be due to a reduction in airway or systemic inflammation.

Loss-of-function mutations in the Nav1.7 gene underlie congenital indifference to pain in multiple human populations.

Congenital indifference to pain (CIP) is a rare condition in which patients have severely impaired pain perception, but are otherwise essentially normal. We identified and collected DNA from individuals from nine families of seven different nationalities in which the affected individuals meet the diagnostic criteria for CIP. Using homozygosity mapping and haplotype sharing methods, we narrowed the CIP locus to chromosome 2q24-q31, a region known to contain a cluster of voltage-gated sodium channel genes. From these prioritized candidate sodium channels, we identified 10 mutations in the SCN9A gene encoding the sodium channel protein Nav1.7. The mutations completely co-segregated with the disease phenotype, and nine of these SCN9A mutations resulted in truncation and loss-of-function of the Nav1.7 channel. These genetic data further support the evidence that Nav1.7 plays an essential role in mediating pain in humans, and that SCN9A mutations identified in multiple different populations underlie CIP.

Inflammatory changes, recovery and recurrence at COPD exacerbation.

Chronic obstructive pulmonary disease (COPD) exacerbations are associated with increased airway and systemic inflammation, though relationships between exacerbation recovery, recurrent exacerbation and inflammation have not been previously reported. In the present study, inflammatory changes at COPD exacerbations were related to clinical nonrecovery and recurrent exacerbations within 50 days. Serum interleukin (IL)-6, C-reactive protein (CRP), sputum IL-6 and IL-8 were measured in 73 COPD patients when stable, at exacerbation and at 7, 14 and 35 days post-exacerbation. In 23% of patients, symptoms did not recover to baseline by day 35. These patients had persistently higher levels of serum CRP during the recovery period. A total of 22% of the patients who had recurrent exacerbations within 50 days had significantly higher levels of serum CRP at day 14, compared with those without recurrences: 8.8 mg.L(-1) versus 3.4 mg.L(-1). Frequent exacerbators had a smaller reduction in systemic inflammation between exacerbation onset and day 35 compared with infrequent exacerbators. Nonrecovery of symptoms at chronic obstructive pulmonary disease exacerbation is associated with persistently heightened systemic inflammation. The time course of systemic inflammation following exacerbation is different between frequent and infrequent exacerbators. A high serum C-reactive protein concentration 14 days after an index exacerbation may be used as a predictor of recurrent exacerbations within 50 days.

Is there objective evidence that septal surgery improves nasal airflow?

OBJECTIVE: To identify any prospective, controlled trials providing objective evidence of a reduction in nasal airway resistance following nasal septal surgery, and to undertake a meta-analysis of available data. METHODS: A systematic review with meta-analysis of data was undertaken. A systematic review of the literature using a defined search strategy was conducted to identify papers that used objective methods of airway assessment to evaluate the benefit of septal surgery. Accepted techniques for objective airway assessment included acoustic rhinometry, active anterior rhinomanometry and peak nasal inspiratory airflow. Papers were included based on pre-defined criteria, which included standardization of techniques as outlined in the guidelines of the 1984 committee report on the standardization of rhinomanometry. RESULTS: We identified 942 articles, of which 13 were prospective studies evaluating the objective benefit of nasal septal surgery. Only three of these studies conformed to the inclusion criteria. A meta-analysis on these papers was performed using the Mantel-Haenszel method, and this demonstrated an overall reduction in nasal airway resistance following septal surgery for nasal obstruction (p=0.018). CONCLUSIONS: The majority of studies evaluating the objective benefit of septal surgery did not conform to the recommendations of the committee report on the standardization of rhinomanometry. Only three prospective controlled trials, with pooled data from 141 cases, were identified for meta-analysis. The conclusions that can be drawn concerning objective improvement in airway function following nasal septal surgery are therefore limited. More long-term studies, adhering to standardized techniques, are needed to provide more convincing data.

Antibody-mediated Hsp70 protein therapy.

Intracellular Hsp70 provides cytoprotection against a variety of stressful stimuli, and an effective means of increasing intracellular Hsp70 levels could prove beneficial in the prevention and treatment of a variety of human diseases. A novel protein transduction domain consisting of the single chain Fv fragment of an anti-DNA antibody known to penetrate into living cells and tissues, mAb 3E10, has recently been used to deliver functional proteins to cells. The ability of the single chain Fv fragment to deliver Hsp70 into living cells was tested by generating an Fv-Hsp70 fusion protein. Fv-Hsp70 was produced as a secreted protein in both COS-7 cells and the methylotropic yeast strain Pichia pastoris and was shown capable of penetrating into COS-7 cells and primary rat cortical neurons. Pre-treatment with Fv-Hsp70 protected both COS-7 cells and primary rat cortical neurons against subsequent exposure to hydrogen peroxide. These results provide the first evidence that the Fv fragment of mAb 3E10 is capable of delivering proteins to neurons and indicate its potential in the development of Hsp70 protein therapy.

COPD exacerbations .1: Epidemiology.

The epidemiology of exacerbations of chronic obstructive pulmonary disease (COPD) is reviewed with particular reference to the definition, frequency, time course, natural history and seasonality, and their relationship with decline in lung function, disease severity and mortality. The importance of distinguishing between recurrent and relapsed exacerbations is discussed.

Effects of exacerbations and seasonality on exhaled nitric oxide in COPD.

Exhaled nitric oxide (eNO) appears to be associated with airway inflammation seen in chronic obstructive pulmonary disease (COPD). The present authors studied the effects of exacerbation, season, temperature and pollution on eNO. eNO was measured seasonally and at exacerbations in 79 outpatients suffering from COPD (mean forced expiratory volume in one second=42%). The effects of exacerbation symptoms, physiological and environmental parameters were analysed. Stable eNO levels were correlated positively with arterial oxygen tension. Median levels were found to be lower in smokers (5.3 ppb) than in ex- or nonsmokers (6.8 ppb). Levels were higher during October to December (6.9 ppb) than in April to June (4.6 ppb). Levels were also higher during 68 exacerbations in 38 patients (7.4 ppb) than in stable conditions (5.4 ppb), independent of the effects of smoking. The rise in eNO was greater in exacerbations that were associated with colds, a sore throat or dyspnoea combined with a cold. In conclusion, exhaled nitric oxide levels were higher in colder weather and in the autumn, perhaps related to the increased prevalence of viral infection at this time of year. The levels were lower in more severe chronic obstructive pulmonary disease. Exhaled nitric oxide levels were raised at the onset of exacerbation, particularly in the presence of a cold.

MMP-9, TIMP-1 and inflammatory cells in sputum from COPD patients during exacerbation.

BACKGROUND: Irreversible airflow obstruction in Chronic Obstructive Pulmonary Disease (COPD) is thought to result from airway remodelling associated with aberrant inflammation. Patients who experience frequent episodes of acute deterioration in symptoms and lung function, termed exacerbations, experience a faster decline in their lung function, and thus over time greater disease severity However the mechanisms by which these episodes may contribute to decreased lung function are poorly understood. This study has prospectively examined changes in sputum levels of inflammatory cells, MMP-9 and TIMP-1 during exacerbations comparing with paired samples taken prior to exacerbation. METHODS: Nineteen COPD patients ((median, [IQR]) age 69 [63 to 74], forced expiratory volume in one second (FEV1) 1.0 [0.9 to 1.2], FEV1% predicted 37.6 [27.3 to 46.2]) provided sputa at exacerbation. Of these, 12 were paired with a samples collected when the patient was stable, a median 4 months [2 to 8 months] beforehand. RESULTS: MMP-9 levels increased from 10.5 microg/g [1.2 to 21.1] prior to exacerbation to 17.1 microg/g [9.3 to 48.7] during exacerbation (P < 0.01). TIMP-1 levels decreased from 3.5 microg/g [0.6 to 7.8] to 1.5 microg/g [0.3 to 4.9] (P = 0.16). MMP-9/TIMP-1 Molar ratio significantly increased from 0.6 [0.2 to 1.1] to 3.6 [2.0 to 25.3] (P < 0.05). Neutrophil, eosinophil and lymphocyte counts all showed significant increase during exacerbation compared to before (P < 0.05). Macrophage numbers remained level. MMP-9 levels during exacerbation showed highly significant correlation with both neutrophil and lymphocyte counts (Rho = 0.7, P < 0.01). CONCLUSION: During exacerbation, increased inflammatory burden coincides with an imbalance of the proteinase MMP-9 and its cognate inhibitor TIMP-1. This may suggest a pathway connecting frequent exacerbations with lung function decline.

Effects of exacerbations and seasonality on exhaled nitric oxide in COPD

Exhaled nitric oxide (eNO) appears to be associated with airway inflammation seen in chronic obstructive pulmonary disease (COPD). The present authors studied the effects of exacerbation, season, temperature and pollution on eNO. eNO was measured seasonally and at exacerbations in 79 outpatients suffering from COPD (mean forced expiratory volume in one second = 42%). The effects of exacerbation symptoms, physiological and environmental parameters were analysed. Stable eNO levels were correlated positively with arterial oxygen tension. Median levels were found to be lower in smokers (5.3 ppb) than in ex- or nonsmokers (6.8 ppb). Levels were higher during October to December (6.9 ppb) than in April to June (4.6 ppb). Levels were also higher during 68 exacerbations in 38 patients (7.4 ppb) than in stable conditions (5.4 ppb), independent of the effects of smoking. The rise in eNO was greater in exacerbations that were associated with colds, a sore throat or dyspnoea combined with a cold. In conclusion, exhaled nitric oxide levels were higher in colder weather and in the autumn, perhaps related to the increased prevalence of viral infection at this time of year. The levels were lower in more severe chronic obstructive pulmonary disease. Exhaled nitric oxide levels were raised at the onset of exacerbation, particularly in the presence of a cold.

Epidemiological relationships between the common cold and exacerbation frequency in COPD.

Higher exacerbation incidence rates in chronic obstructive pulmonary disease (COPD) are associated with more rapid decline in lung function and poorer quality of life, yet the mechanisms determining susceptibility to exacerbation remain ill-defined. The same viruses responsible for common colds are frequently isolated during exacerbations. The current authors hypothesised that exacerbation frequency may be associated with an increased frequency of colds, and investigated whether increased exacerbation frequency was associated with increased acquisition of colds, or a greater likelihood of exacerbation once a cold has been acquired. A total of 150 patients with COPD completed diary cards recording peak expiratory flow, and respiratory and coryzal symptoms for a median 1,047 days. Annual cold and exacerbation incidence rates (cold and exacerbation frequency) were calculated, and the relationships between these variables were investigated. This analysis is based on 1,005 colds and 1,493 exacerbations. Frequent exacerbators (i.e. those whose exacerbation frequency was greater than the median) experienced significantly more colds than infrequent exacerbators (1.73 versus 0.94.yr(-1)). The likelihood of exacerbation during a cold was unaffected by exacerbation frequency. Patients experiencing frequent colds had a significantly higher exposure to cigarette smoke (46 versus 33 pack-yrs). Exacerbation frequency in chronic obstructive pulmonary disease is associated with an increased frequency of acquiring the common cold, rather than an increased propensity to exacerbation once a cold has been acquired.

A comparison of visual analogue and numerical rating scale formats for the Lung Cancer Symptom Scale (LCSS): does format affect patient ratings of symptoms and quality of life?

PROBLEM AND PURPOSE: The Lung Cancer Symptom Scale (LCSS), a site-specific health-related quality of life measure for patients with lung cancer, was originally developed using a Visual Analogue Scale (VAS) format. However, the VAS format is not readily compatible with data management and software programs using scanning. The primary aim of this study was to evaluate the convergence of ratings obtained with a Numerical Rating Scale (NRS), with an 11-pt response category format, to those obtained with a VAS format. The intent was to determine the degree of agreement between two formats to generalize the existing psychometric properties for the original measure to the new presentation. DESIGN/SETTING: This methodological study evaluated the feasibility, reliability, and validity of a NRS format for the LCSS. The study was conducted at two cancer centers in New York City. PATIENTS/PROCEDURES: Sixty-eight patients with non-small cell lung cancer (NSCLC) completed both versions of the LCSS along with demographic and feasibility questions on a single occasion. The VAS form was administered first, followed by the NRS form to prevent bias. The intraclass correlation coefficient (ICC), Lin's concordance correlation coefficient (CCC), and Bland-Altman plots were used to evaluate agreement and to characterize bias. RESULTS: Cronbach's alpha for the NRS format total score was 0.89 for the 68 patients with NSCLC. Agreement was excellent, with both the ICC and CCC > or = 0.90 for the two summary scores (total score and average symptom burden index) for the LCSS. Only five of the nine individual items showed this level of strict agreement. An agreement criterion of > or = 0.80 (representing excellent) was observed for seven of the nine individual items (all but appetite loss and hemoptysis). Mean differences tended to be slightly lower for the VAS format compared to the NRS format (more so for the appetite and hemoptysis items), with evidence of scale shift for the same two items. The summary measures showed good concordance as measured by the ICC and CCC, but did display mean differences (VAS - NRS) of -2.7 and -3.1, respectively. CONCLUSIONS: Overall, the NRS format for the LCSS suitable for scanning has good feasibility, reliability (internal consistency), and convergent validity. The complete set of concordance evaluation measures supports the reproducibility of VAS scores by NRS scores, particularly for the two summary scores.