Effect of differing doses of inhaled budesonide on markers of airway inflammation in patients with mild asthma

BACKGROUND: It is desirable to prescribe the minimal effective dose of inhaled steroids to control asthma. To ensure that inflammation is suppressed whilst using the lowest possible dose, a sensitive and specific method for assessing airway inflammation is needed. METHODS: The usefulness of exhaled nitric oxide (NO), sputum eosinophils, and methacholine airway responsiveness (PC20) for monitoring airway inflammatory changes following four weeks of treatment with an inhaled corticosteroid (budesonide via Turbohaler) were compared. Mild stable steroid naive asthmatic subjects were randomised into two double blind, placebo controlled studies. The first was a parallel group study involving three groups receiving either 100 micrograms/day budesonide (n = 8), 400 micrograms/day budesonide (n = 7), or a matched placebo (n = 6). The second was a crossover study involving 10 subjects randomised to receive 1600 micrograms budesonide or placebo. The groups were matched with respect to age, PC20, baseline FEV1 (% predicted), exhaled NO, and sputum eosinophilia. RESULTS: There were significant improvements in FEV1 following 400 micrograms and 1600 micrograms budesonide (11.3% and 6.5%, respectively, p < 0.05). This was accompanied by significant reductions in eosinophil numbers in induced sputum (0.7 and 0.9 fold, p < 0.05). However, levels of exhaled NO were reduced following each budesonide dose while PC20 was improved only with 1600 micrograms budesonide. These results suggest that exhaled NO and PC20 may not reflect the control of airway inflammation as accurately as the number of eosinophils in sputum. There were dose dependent changes in exhaled NO, sputum eosinophils, and PC20 to inhaled budesonide but a plateau response of exhaled NO was found at a dose of 400 micrograms daily. CONCLUSION: Monitoring the number of eosinophils in induced sputum may be the most accurate guide to establish the minimum dose of inhaled steroids needed to control inflammation. This, however, requires further studies involving a larger number of patients.     

Respiratory symptoms in patients with treated hypothyroidism and inflammatory bowel disease

BACKGROUND: Patients with idiopathic chronic cough and unexplained airflow obstruction in non-smokers have been shown to have an increased prevalence of hypothyroidism and other organ specific autoimmune disorders. Whether patients with hypothyroidism have an increased prevalence of respiratory symptoms is unknown. METHODS: The prevalence of respiratory symptoms was assessed in 124 patients with treated hypothyroidism recruited from primary and secondary care, 64 outpatients with inflammatory bowel disease, and 1346 control adults recruited randomly from the electoral register in a case-control study. Respiratory symptoms and smoking history were assessed by a respiratory symptom questionnaire. RESULTS: After adjustment for age, sex and smoking, symptoms of breathlessness and sputum production were more prevalent in both patient populations than in controls (odds ratios for hypothyroidism and inflammatory bowel disease; breathlessness: 3.1 (95% CI 2.1 to 4.6) and 3.4 (95% CI 2.0 to 6.0), respectively; sputum production: 2.7 (95% CI 1.6 to 4.5) and 2.5 (95% CI 1.2 to 5.0), respectively). Cough during the day and night was significantly more prevalent in patients with hypothyroidism (1.8 (95% CI 1.2 to 2.9)) and approached significance in those with inflammatory bowel disease (1.8 (95% CI 1.0 to 3.4)). Wheeze and nocturnal cough were no more prevalent in either disease population than in controls. CONCLUSION: There is a significantly increased prevalence of respiratory symptoms in patients with hypothyroidism or inflammatory bowel disease compared with controls recruited from the general population. Further work is required to determine whether similar differences are seen in comparison with hospital based controls. These findings support the hypothesis that there is a link between autoimmune hypothyroidism and respiratory disease.     

Airway function at one year: association with premorbid airway function, wheezing, and maternal smoking

BACKGROUND: Impaired growth and development of the respiratory system during fetal and early postnatal life may have important implications for lung development and later lung health. The aim of this study was to examine the association of diminished premorbid airway function, prior wheezing, and maternal smoking with airway function at 1 year of age. METHODS: Respiratory function was measured at the end of the first year in 100 of 108 healthy term infants (93%) in whom similar measurements had been undertaken prior to any respiratory illness at 8 weeks. Physician diagnosed wheezing episodes were identified retrospectively from medical records. RESULTS: At 1 year specific airway conductance during end expiration (sGawEE; /s/kPa) was significantly diminished in those infants with prior wheezing (95% CI wheeze/no wheeze -0.76 to -0.14), mothers who smoked (95% CI smoke/no smoke -0.81 to -0.27), a family history of asthma (95% CI family history/no family history -0.62 to 0.00), or diminished premorbid sGawEE (95% CI -0.13 to -0.43/s/kPa per unit reduction sGawEE at 8 weeks). In a multivariate model only maternal smoking and diminished premorbid sGawEE were independently associated with diminished sGawEE at 1 year. CONCLUSIONS: Diminished airway function at the end of the first year appears to be mediated by impaired airway development during early life as well as by exposure to maternal smoking. These findings are consistent with the hypothesis that, at a population level, diminished premorbid airway function provides the link between wheezing lower respiratory illness and diminished airway function at 1 year. Maternal smoking remains an important and avoidable cause of impaired airway development and function in infancy.     

Relationship between airway dysbiosis,inflammation and lung function in adults with cystic fibrosis

Airway dysbiosis has been associated with lung disease severity in patients with cystic fibrosis (CF). However, the relationship between dysbiosis, airway inflammation and lung function impairement remains poorly understood. The aim of this study was therefore to determine how the structure of the sputum microbiota, airway inflammation markers and spirometry are related in patients with CF.Sputum samples were collected from 106 CF patients between 12 and 72 years. These were analyzed by 16S rRNA gene amplicon sequencing. Moreover, levels of pro-inflammatory cytokines (IL-1β, IL-8, IL-6 and TNF-α) and Neutrophil elastase (NE) were determined. The relationship between the microbiota, inflammation markers and forced expiratory volume in one second percent predicted (FEV₁% predicted) was evaluated by multi-parameter analysis.The microbiota α-diversity correlated inverse with inflammation markers IL-1β, IL-8, TNF-α, NE and positively with FEV₁% predicted. Patients could be divided into 7 clusters based on their microbiota structure. The most diverse cluster was defined by oropharyngeal-like flora (OF) while the others were characterized by the dominance of a single pathogen. Patients with the diverse OF microbiota cluster had lower sputum inflammatory markers and higher FEV₁% predicted compared to patients with a pathogen-dominated microbiota including Pseudomonas aeruginosa.Our results suggest that the diversity of the airway microbiota is an important biomarker of the severity of airway inflammation linking dysbiosis to lung function decline in patients with CF.     

Non-invasive markers of airway inflammation as predictors of oral steroid responsiveness in asthma

BACKGROUND: Sputum eosinophil counts and exhaled nitric oxide (NO) levels are increased in asthma and both measurements fall in response to corticosteroids. METHODS: Exhaled NO levels and sputum eosinophil counts were assessed as non-invasive markers of the response to an oral steroid in 37 patients (19 women) with stable chronic asthma (mean (SD) age 48.6 (12.2) years, asthma duration 25. 9 (17.3) years, and baseline forced expiratory volume in one second (FEV(1)) 76.3 (21.9)% predicted). Spirometric tests, with reversibility to a beta agonist (2.5 mg nebulised salbutamol), and induced sputum (using nebulised 3% saline) were performed at recruitment and following treatment with 30 mg prednisolone/day for 14 days. RESULTS: Baseline NO levels correlated with the percentage improvement in FEV(1) from baseline to the post-steroid, post-bronchodilator value (r(s) = 0.47, p = 0.003), with an NO level of >10 ppb at baseline having a positive predictive value of 83% for an improvement in FEV(1) of > or =15% (sensitivity 59%, specificity 90%). Sputum eosinophilia (> or =4%) had a positive predictive value of 68% (sensitivity 54%, specificity 76%) for an increase in FEV(1) of > or =15%. A combination of sputum eosinophilia and increased NO levels resulted in a positive predictive value of 72% and a negative predictive value of 79% (sensitivity 76%, specificity 75%). CONCLUSION: Exhaled NO levels and sputum eosinophilia may be useful in predicting the response to a trial of oral steroid in asthma.     

Airway management with dexmedetomidine for difficult airway

BACKGROUND : Dexmedetomidine has the advantage of producing sedation accompanying patient's cooperation without respiratory depression. We managed the airways of 10 cases with suspected difficult tracheal intubation under sedation with dexmedetomidine. METHODS : A dexmedetomidine loading dose of lmcg x kg(-1) IV was administered over 10 minutes and with supplementation until satisfactory sedation was obtained, followed by infusion of 0.2-0.7mcg x kg(-1) x hr(-1). During loading dose administration, the upper airway was anesthetized topically. RESULTS : Five cases were intubated fiberscopically, and 3 obstructive sleep apnea syndrome (OSAS) cases received direct laryngoscopy to exclude "cannot intubate, cannot ventilate (CICV)". One case with a large laryngeal tumor had tracheostomy, and another case with recurred pharyngeal cancer was intubated through the permanent tracheotomy site. All the cases were well sedated (Ramsay sedation scale 2-4) and cooperative during the procedure. No respiratory depression nor airway obstruction occurred even in the OSAS cases. In one case hypertension and elevated heart rate were noted transiently during loading dose administration. Another case had postinduction hypotension treated with a small dose of vasopressor. All cases had no uncomfortable recall. CONCLUSIONS : Dexmedetomidine is a safe and effective sedative for awake difficult airway management, for example, fiberscopic intubation, tracheostomy and direct laryngoscopy, though some attention must be paid to circulatory changes.     

Associations between nutritional markers and inflammation in hemodialysis patients

The purpose of this study is to evaluate associations between clinical, laboratory, demographic, and nutritional markers with inflammatory state and malnutrition in hemodialysis (HD) patients. Fifty-two patients on regular HD were evaluated by clinical, demographic, laboratory, and nutritional parameters (food intake, anthropometric measurements, bioelectric impedance, subjective global assessment—SGA and appetite characteristics). Inflammation (serum C-reactive protein ≥ 0.9 mg/dl) was present in 13 (25%) and malnutrition (SGA) in 16 (30.7%) patients. Body mass index (BMI), total lymphocytes count, and phase angle were negative and independently associated with malnutrition. Values of BMI ≥ 25 kg/m2 were associated with diabetes, positively associated with adipose tissue percentage (BIA) and negatively associated with diastolic blood pressure. Phase angle was positively associated with hematocrit, total lymphocytes count and serum creatinine, and was negatively associated with age. A negative and independent association between muscle mass percentage (BIA) and inflammation was observed. These results suggested that inflammatory state induces muscle mass depletion, while high BMI is associated with diabetes and with lower diastolic blood pressure, a recognized cardiovascular risk factor in uremic patients. Phase angle and SGA were associated with traditional nutritional markers, reinforcing their validity for HD patients.     

Acute-phase markers of inflammation and glomerular structure in patients with type 2 diabetes

Type 2 diabetes is frequently associated with an inflammatory status; the relationships between low-grade inflammation and diabetic nephropathy are still unclear. The aim of this study was to evaluate the relationships between acute-phase markers of inflammation, glomerular structure, and albumin excretion rate (AER) in type 2 diabetes. In 74 patients with type 2 diabetes (23 normoalbuminuric, 30 microalbuminuric, and 21 proteinuric) fibrinogen, serum amyloid A protein (SAA), C-reactive protein (CRP), and IL-6 were determined. AER was measured on three 24-h urine collections; GFR was measured by 51Cr EDTA plasma clearance. A kidney biopsy was performed, and mesangial fractional volume [Vv(mes/glom)] and glomerular basement membrane (GBM) width were estimated by electron microscopic morphometric analysis. CRP, fibrinogen, SAA, and IL-6 differed among groups, with proteinuric patients having the highest levels. SAA and fibrinogen correlated with AER (P < 0.03 and P < 0.001, respectively). GBM width and Vv(mes/glom) increased from normoalbuminuric to proteinuric patients [P < 0.005 normoalbuminuric and microalbuminuric versus proteinuric for GBM, P < 0.01 normoalbuminuric versus proteinuric for Vv(mes/glom)]. In patients with increased GBM width (> 396 nm), CRP, SAA, and IL-6 were higher than in patients with normal GBM width (P < 0.003, P < 0.004, and P < 0.0004, respectively). GBM width was directly correlated with fibrinogen (r = 0.33, P < 0.002) and IL-6 (r = 0.25 P < 0.05). In conclusion, this study demonstrates that acute-phase markers of inflammation are associated with nephropathy status and GBM thickening, suggesting a role for inflammation in the pathogenesis of diabetic glomerulopathy.     

Ongoing airway inflammation in patients with COPD who do not currently smoke

BACKGROUND: Inflammatory changes in the airways in chronic obstructive pulmonary disease (COPD) are largely attributed to smoking, yet they may be present even if patients do not currently smoke. The differences in inflammatory cells and the factors contributing to these differences were examined in the airways of patients with COPD who do not currently smoke. METHODS: Eighteen non-atopic subjects with COPD (14 men) of mean (SD) age 62 (8) years and forced expiratory volume in one second (FEV(1)) 59 (13)% predicted and 11 non-atopic healthy subjects (eight men) of mean (SD) age 58 (8) years, FEV(1) 104 (11)% predicted were studied. Sputum induction and bronchoscopy with bronchoalveolar lavage (BAL) and biopsies were performed. RESULTS: Patients with COPD had more mucosal EG2+ cells (eosinophils) (median (range) 40 (0-190) versus 5 (0-40) cells/mm(2), p = 0.049) and CD68+ cells (1115 (330-2920) versus 590 (450-1580) cells/mm(2), p = 0.03), and a tendency towards more CD4+ but not CD8+ lymphocytes than healthy controls. Furthermore, patients with COPD had higher percentages of sputum neutrophils (77 (29-94) versus 36 (18-60)%, p = 0.001) and eosinophils (1.2 (0-8.5) versus 0.2 (0-3.1)%, p = 0.008), BAL fluid eosinophils (0.4 (0-1.7) versus 0.2 (0-0.5)%, p = 0.03), and higher concentrations of sputum eosinophilic cationic protein (ECP) (838 (115-23 760) versus 121 (35-218) ng/ml, p<0.001). Concentrations of ECP expressed per eosinophil were not higher. Patients with COPD with high mucosal EG2+ cell numbers also had high mucosal CD4+ cell numbers. Sputum eosinophilia was associated with a decrease in FEV(1)/VC and BAL fluid eosinophilia with a decrease in mucosal NP57+ cells (neutrophils). CONCLUSIONS: Subjects with COPD who do not currently smoke have increased numbers of inflammatory cells. Eosinophils are increased in number in the airways in COPD but do not seem to be activated. The increased eosinophil numbers are probably due to recruitment as a result of ongoing inflammation. Macrophages and lymphocytes may play a part in this inflammation.     

Clinical significance of inflammation markers in abdominal sepsis patients

Possibilities of using C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6), lactoferrin (LF) and sorption ability of erythrocytes (SAE) as markers of the severity, prognosis and criteria of effectiveness of treatment were studied in 334 patients with abdominal sepsis. The investigation of the sepsis marker dynamics has shown that fast kinetics of CRP and PCT makes it impossible to assess the prognosis and effectiveness of treatment using these markers. IL-6, LF and SAE are the only ones to be used for this purpose.     

Relationship between airway inflammation and the frequency of exacerbations in patients with smoking related COPD

BACKGROUND: Patients with more frequent exacerbations of chronic obstructive pulmonary disease (COPD) may have increased bronchial inflammation. Airway inflammation was measured in patients who had been thoroughly investigated with full pulmonary function testing, thoracic HRCT scanning, and sputum microbiology to examine further the relationship between exacerbation frequency and bronchial inflammation. METHODS: Airway inflammation (spontaneous sputum sol phase myeloperoxidase (MPO), elastase, leukotriene (LT)B(4), interleukin (IL)-8, secretory leukoprotenase inhibitor (SLPI), protein leakage) and serum levels of C reactive protein (CRP) were compared in 40 patients with stable, smoking related COPD, divided into those with frequent (> or =3/year) or infrequent (< or =2/year) exacerbations according to the number of primary care consultations during the preceding year. The comparisons were repeated after excluding eight otherwise clinically indistinguishable patients who had tubular bronchiectasis on the HRCT scan. RESULTS: Patients with frequent (n=12) and infrequent (n=28) exacerbations were indistinguishable in terms of their clinical, pulmonary function, and sputum characteristics, CRP concentrations, and all of their bronchial inflammatory parameters (p>0.05). The patients without evidence of tubular bronchiectasis (n=32) were equally well matched but the sputum concentrations of SLPI were significantly lower in the frequent exacerbators (n=8) in this subset analysis (p<0.05). CONCLUSIONS: There are several clinical features that directly influence bronchial inflammation in COPD. When these were carefully controlled for, patients with more frequent reported exacerbations had lower sputum concentrations of SLPI. This important antiproteinase is also known to possess antibacterial and antiviral activity. Further studies are required into the nature of recurrent exacerbations and, in particular, the regulation and role of SLPI in affected individuals.     

Brief review: Airway rescue with insertion of laryngeal mask airway devices with patients in the prone position

Purpose

Unintentional extubation of the trachea while the anesthetized patient is in the prone position is a potentially life-threatening situation that is usually managed by turning the patient supine for emergent re-intubation. However, this approach may delay definitive airway management and lead to irreversible complications. This review evaluates the efficacy of insertion of a laryngeal mask airway device (LMAD) with the patient in the prone position as a rescue method in airway management for unintentional tracheal extubation.

Principal findings

We searched MEDLINE and EMBASE databases in the English language for the period 1980 to October 2009 in order to identify observational studies and case reports describing insertion of the LMAD with the patient in the prone position. We found 12 such articles (n = 526 patients) consisting of four retrospective studies, one prospective cohort with a control group, one non-controlled prospective study, and six case reports. On the first attempt, the LMAD was inserted successfully in 87.5-100% of the patients involved in the included reports. On the second attempt, the LMAD was inserted successfully in all patients, with or without laryngoscopy. Ventilation was maintained successfully in the lungs of 83.3-100% of the patients involved in the reported articles. Following insertion of the LMAD with patients in the prone position, the most common complications reported were sore throat, bleeding, bradycardia, and laryngospasm.

Conclusions

Cumulative experience from published reports suggests the feasibility of placing the LMAD with the patient in the prone position in the elective setting; however, the evidence is lacking regarding the use of this method for emergency management of unintended tracheal extubation with the patient in the prone position.     

Airway protection with the ProSeal laryngeal mask airway.

The ProSeal laryngeal mask airway is a new laryngeal mask device that has a modified cuff and a drainage tube. We describe a case where the ProSeal laryngeal mask successfully channelled regurgitated fluid away from the respiratory tract.