Exhaled Breath Profiles Before, During and After Exacerbation of COPD: A Prospective Follow-Up Study.

Many patients with chronic obstructive lung disease (COPD) experience exacerbations. The diagnosis of an exacerbation is solely based on symptoms. We hypothesized that exhaled breath profiles, measured by Gas Chromatography-Mass Spectrometry (GC-MS) or electronic nose (eNose), are different between stable disease and exacerbations and may have the potential to serve as biomarkers for COPD exacerbations. In this prospective follow-up study, breath samples were taken during stable COPD, during a subsequent exacerbation and after recovery. Samples were analyzed by GC-MS and eNose. CCQ symptom scores were associated with univariate outcomes of GC-MS and eNose using analysis of covariance (ANCOVA). After multivariate modeling by Principal Component Analysis (PCA), paired student t-tests were performed. Sixty-eight patients were included, 31 had an exacerbation and 16 patients had breath sampled at all three time points. Significant differences were found in breathprints taken during exacerbation as compared to baseline and recovery for both GC-MS and eNose. Breath profiles obtained by GC-MS as well as by eNose showed a correct classification of 71% (10/14) for baseline vs exacerbation and of 78% (11/14) for exacerbation vs recovery. These results provide proof of principle that exhaled breath can serve as a noninvasive biomarker for the diagnosis of COPD exacerbations.

[Myositis: more than a muscle disease]. / Myositis is meer dan een spierziekte.

Idiopathic inflammatory myopathy (IIM), commonly referred to as "myositis", is a rare but treatable auto-immune disease that is often misdiagnosed or diagnosed after significant delay. Using three clinical case reports as introductory examples, an overview is given - and pitfalls are discussed - of the diagnosis and treatment of myositis. Disease features are often extra-muscular in nature, may vary considerably between patients, and are frequently non-specific. Myositis-related morbidity is high and myositis can be fatal, mainly due to cancer and interstitial lung disease. As such, we stress the importance of early recognition of this severe disease and timely referral of a patient with a (suspected) IIM to a multidisciplinary team for optimal diagnosis and disease management.

Trigger-happy resident memory CD4+ T cells inhabit the human lungs.

Resident memory T cells (TRM) reside in the lung epithelium and mediate protective immunity against respiratory pathogens. Although lung CD8+ TRM have been extensively characterized, the properties of CD4+ TRM remain unclear. Here we determined the transcriptional signature of CD4+ TRM, identified by the expression of CD103, retrieved from human lung resection material. Various tissue homing molecules were specifically upregulated on CD4+ TRM, whereas expression of tissue egress and lymph node homing molecules were low. CD103+ TRM expressed low levels of T-bet, only a small portion expressed Eomesodermin (Eomes), and although the mRNA levels for Hobit were increased, protein expression was absent. On the other hand, the CD103+ TRM showed a Notch signature. CD4+CD103+ TRM constitutively expressed high transcript levels of numerous cytotoxic mediators that was functionally reflected by a fast recall response, magnitude of cytokine production, and a high degree of polyfunctionality. Interestingly, the superior cytokine production appears to be because of an accessible interferon-γ (IFNγ) locus and was partially because of rapid translation of preformed mRNA. Our studies provide a molecular understanding of the maintenance and potential function of CD4+ TRM in the human lung. Understanding the specific properties of CD4+ TRM is required to rationally improve vaccine design.

Management of community-acquired pneumonia in adults: 2016 guideline update from the Dutch Working Party on Antibiotic Policy (SWAB) and Dutch Association of Chest Physicians (NVALT).

The Dutch Working Party on Antibiotic Policy in collaboration with the Dutch Association of Chest Physicians, the Dutch Society for Intensive Care and the Dutch College of General Practitioners have updated their evidence-based guidelines on the diagnosis and treatment of community-acquired pneumonia (CAP) in adults who present to the hospital. This 2016 update focuses on new data on the aetiological and radiological diagnosis of CAP, severity classification methods, initial antibiotic treatment in patients with severe CAP and the role of adjunctive corticosteroids. Other parts overlap with the 2011 guideline. Apart from the Q fever outbreak in the Netherlands (2007-2010) no other shifts in the most common causative agents of CAP or in their resistance patterns were observed in the last five years. Low-dose CT scanning may ultimately replace the conventional chest X-ray; however, at present, there is insufficient evidence to advocate the use of CT scanning as the new standard in patients evaluated for CAP. A pneumococcal urine antigen test is now recommended for all patients presenting with severe CAP; a positive test result can help streamline therapy once clinical stability has been reached and no other pathogens have been detected. Coverage for atypical microorganisms is no longer recommended in empirical treatment of severe CAP in the non-intensive care setting. For these patients (with CURB-65 score >2 or Pneumonia Severity Index score of 5) empirical therapy with a 2nd/3rd generation cephalosporin is recommended, because of the relatively high incidence of Gram-negative bacteria, and to a lesser extent S. aureus. Corticosteroids are not recommended as adjunctive therapy for CAP.

Anti-IgE and other new immunomodulation-based therapies for allergic asthma.

Understanding of the cellular and molecular mechanisms in asthma has lead to the recognition of a number of potential therapeutic targets, a few of which have been evaluated in clinical studies. Parenteral administrations of both anti-IL-5 and IL-12 inhibit eosinophil recruitment to the airways, but display a lack of clinical efficacy. Interrupting the IL-4 pathway thus far has also shown disappointing results in clinical studies. Omalizumab is the first anti-IgE monoclonal antibody developed for the treatment of moderate to severe asthmatics to receive FDA approval. In a number of clinical trials treatment with omalizumab was associated with moderate improvements in a number of relevant endpoints, including the rate of occurrence of disease exacerbations. Newer DNA-based therapeutic strategies including DNA vaccination and the antisense oligonucleotides show promise but thus far have only been tested in animal models.

Revised SWAB guidelines for antimicrobial therapy of community-acquired pneumonia.

The Dutch Working Party on Antibiotic Policy (SWAB) develops evidence-based guidelines, aimed at optimalisation of antibiotic use and limitation of the spread of antimicrobial resistance. A revision of the SWAB guideline for the treatment of community-acquired pneumonia (CAP), published in 1998, was considered necessary because of changes in resistance patterns and new insights into the epidemiology, diagnostics and treatment of CAP. In contrast to the former version, this guideline is transmural and has been drawn up according to the recommendations for evidence-based guideline development by a multidisciplinary committee consisting of experts from all relevant professional societies. The 'severity of disease' exhibited by the patient with pneumonia on admission is considered important for the choice of the optimum empirical treatment strategy. Severely ill patients are treated empirically with a drug directed against multiple potential pathogens, including Legionella spp. Classification according to 'severity of disease' can be accomplished with a validated scoring system (Pneumonia Severity Index or CURB-65 score) or pragmatically, based on the site of treatment: an outpatient setting, a clinical ward or an intensive care unit. The Legionella urine antigen test plays an important role in decisions on the choice of initial antibiotic treatment.

Abnormal radiological findings and a decreased carbon monoxide transfer factor can persist long after the acute phase of Legionella pneumophila pneumonia.

Pulmonary abnormalities may persist long after the acute phase of legionnaires disease (LD). In a cohort of 122 survivors of an outbreak of LD, 57% were still experiencing an increased number of symptoms associated with dyspnea at a mean of 16 months after recovery from acute-phase LD. For 86 of these patients, additional evaluation involving high-resolution computed tomography (HRCT) of the lung revealed pulmonary abnormalities in 21 (24%); abnormal HRCT findings generally presented as discrete and multiple radiodensities. Residual pulmonary abnormalities were associated with a mean reduction of 20% in the gas transport capacity of the lung. This latter sign could not be used to explain the increased symptoms of dyspnea reported by patients. Receipt of mechanical ventilation during the acute phase of LD, delayed initiation of adequate antibiotic therapy, and chronic obstructive pulmonary disease were identified as risk factors for the persistence of lung abnormalities.

Quantification of theophylline-induced eosinopenia and hypokalaemia in healthy volunteers.

The relationship between theophylline pharmacokinetics and its eosinopenic and hypokalaemic effects were studied in 6 healthy volunteers after an oral dose of theophylline 250 mg. The mean peak theophylline concentration (Cmax) of 8.33 +/- 2.16 mg/L occurred 1.02 +/- 0.26 h after ingestion. The delay between the Cmax and the subsequent eosinopenic or hypokalaemic nadirs was 4.52 +/- 1.73 and 3.65 +/- 1.32 h, respectively. The time courses of theophylline and its effects were linked by a sigmoid Emax effect model. The maximal eosinopenic and hypokalaemic effects (Emax) of the drug were 83 +/- 25.8% and 16 +/- 9.7% of the possible, respectively. The theophylline concentrations causing 50% of the Emax (EC50) were 5.06 +/- 1.84 and 5.04 +/- 2.09 mg/L, respectively. The data obtained with our methodology indicate that, in humans, theophylline induced eosinopenia could be mediated through a receptor and/or postreceptor mechanism unrelated to the mechanism of theophylline induced bronchodilation. We conclude that therapeutic theophylline plasma concentrations have a profound effect on the redistribution of blood eosinophils.

Hypokalaemia in healthy volunteers after single and multiple doses of formoterol or salbutamol.

A specific beta(2)-adrenoceptor-mediated effect, hypokalaemia, was studied in healthy volunteers after single as well as multiple dosages of the long-acting agonist formoterol and the short-acting agent salbutamol. The purpose of the study was to test with simple methodologies if rapidly induced tachyphylaxis for this well known systemic effect can be shown and if it will then be more pronounced for the long-acting compound. Hypokalaemia induced by inhalation of, respectively, 72microg formoterol and 1200microg of salbutamol was studied before and after 1 week of medication. Potassium-time curves were described by a biexponential equation and also analysed with a deconvolution technique. Both drugs induced a statistically significant hypokalaemia, the duration of this effect being considerably shorter for salbutamol than for formoterol (p < 0.05 with both methods of analysis). After multiple doses for 1 week, both maximal hypokalaemia and the area under the curve of the hypokalaemic effect had decreased after inhalation of formoterol (p < 0.05) but not after inhalation of salbutamol.It was concluded that plasma potassium as an effect measurement can be used to study in a simple but reproducible way differences of pharmacological interest between various beta(2)-adrenoceptor agonists.

[Pneumococcal vaccination in adults]. / Pneumokokkenvaccinatie van volwassenen.

Pneumococcal pneumonia and bacteraemia are an important cause of morbidity and mortality, especially in a number of risk groups. On the basis of data from available literature, there is no convincing evidence that vaccination of such risk groups, including all people over 65, with a polyvalent vaccine of pneumococcal capsular polysaccharides in addition to influenza vaccination offers any additional protection against the risk of acquiring pneumococcal pneumonia. There is adequate evidence that pneumococcal vaccination does protect against invasive infections and that in this respect vaccination of all elderly persons could be cost-effective. However, there are insufficient data on whether pneumococcal vaccination provides additional protection against invasive infections in people already receiving influenza vaccination. Therefore a well-considered assessment of the cost-effectiveness of applying such a strategy in the Netherlands is not yet possible. Vaccination of (imminent) immuno-compromised persons is only effective and of value if an adequate antibody response can be expected. There is as yet no proven advantage of vaccination with a conjugate vaccine in adults.

SWAB/NVALT (Dutch Working Party on Antibiotic Policy and Dutch Association of Chest Physicians) guidelines on the management of community-acquired pneumonia in adults.

The Dutch Working Party on Antibiotic Policy (SWAB) and the Dutch Association of Chest Physicians (NVALT) convened a joint committee to develop evidence-based guidelines on the diagnosis and treatment of community acquired pneumonia (CAP). The guidelines are intended for adult patients with CAP who present at the hospital and are treated as outpatients as well as for hospitalised patients up to 72 hours after admission. Areas covered include current patterns of epidemiology and antibiotic resistance of causative agents of CAP in the Netherlands, the possibility to predict the causative agent of CAP on the basis of clinical data at first presentation, risk factors associated with specific pathogens, the importance of the severity of disease upon presentation for choice of initial treatment, the role of rapid diagnostic tests in treatment decisions, the optimal initial empiric treatment and treatment when a specific pathogen has been identified, the timeframe in which the first dose of antibiotics should be given, optimal duration of antibiotic treatment and antibiotic switch from the intravenous to the oral route. Additional recommendations are made on the role of radiological investigations in the diagnostic work-up of patients with a clinical suspicion of CAP, on the potential benefit of adjunctive immunotherapy, and on the policy for patients with parapneumonic effusions.

Long-term effects of budesonide on inflammatory status in COPD.

A beneficial effect of long-term corticosteroid treatment in patients with COPD may be linked to suppressing inflammation, in particular neutrophilic inflammation. Effects on neutrophilic and eosinophilic inflammation and on lung function of long-term inhaled budesonide treatment (800 microg daily, 6 months, double-blind, randomised, cross-over versus placebo) were studied and compared to the effects of 3 weeks oral prednisolone (30 mg daily) in 19 patients with COPD (mean age 63 y, FEV(1) 65% of predicted). Neither treatment influenced neutrophilic inflammation. Inhaled budesonide compared to placebo significantly reduced sputum % eosinophils at 3 months (-42%, p = 0.036), but not significantly at 6 months (-31%, p = 0.78). Eosinophil count per g sputum was decreased with 30% at 3 months (p = 0.09) and with 9% at 6 months (p = 0.78). FEV(1) was slightly higher after 6 months budesonide (+2.5% predicted, p = 0.09). Prednisolone significantly reduced sputum % eosinophils (-87%, p = 0.007), but did not affect eosinophil count per g sputum and did not improve FEV(1) (-0.6% predicted, p = 0.40). A higher baseline FEV(1) (%) correlated with effects of budesonide on FEV(1) (p < 0.001), effects on sputum interleukin-8 and eosinophil cationic protein (both p < 0.05) and tended to correlate with effects on sputum % eosinophils (p = 0.056). Baseline inflammatory data and effects of prednisolone did not correlate with effects of budesonide. Effects of inhaled budesonide in COPD are not restricted to patients with severe disease and may be linked to a suppression of eosinophilic inflammation. Investigating effects of prednisolone has no predictive value for long-term treatment.

The shrinking lung syndrome in systemic lupus erythematosus: improvement with corticosteroid therapy.

Respiratory manifestations of systemic lupus erythematosus (SLE) are frequent. The 'shrinking lung syndrome' (SLS) represents a rare complication of SLE. The pathogenesis and therapy of the SLS remains controversial. We report a series of five consecutive cases with the SLS of which we provide a detailed description of the extent and dynamics of the response to corticosteroid therapy.

Quantification of metoprolol beta 2-adrenoceptor antagonism in asthmatic patients by pharmacokinetic-pharmacodynamic modelling.

An integrated pharmacokinetic-pharmacodynamic model was used to quantify the beta 2-blocking activity of metoprolol in seven asthmatic patients. The patients received a subcutaneous dose of terbutaline on two consecutive days. On day 1 they were pretreated with placebo and on day 2 with metoprolol 150 mg orally. Beta 2-adrenoceptor mediated changes of plasma potassium and FEV1 were related to plasma concentrations of terbutaline and racemic metoprolol. Metoprolol activity was measured as the competitive (blocking) interaction of racemic metoprolol on the terbutaline response. Plasma concentrations and effects were monitored over 7 h following terbutaline administration. Despite the relative beta 1-selectivity of metoprolol, the effects of terbutaline were considerably attenuated. The mean (racemic) metoprolol concentration that corresponds to 50% maximum metoprolol receptor occupancy (IC50) for the effects on FEV1 and hypokalemia were, respectively, 17 (+/- 8) and 22 (+/- 12) ng/ml and were not statistically discernible. We conclude that individual integrated pharmacokinetic-pharmacodynamic modelling of the concentration-effect relations of agonist and antagonist is a feasible and direct method of quantifying beta 2-blocker effects in asthmatic patients. In stable asthma patients receiving therapeutic doses of metoprolol, the terbutaline plasma concentration needs to be increased two- to four-fold to obtain the same effect on FEV1. Plasma potassium may be considered an appropriate alternative parameter to predict the effect on FEV1.

Pharmacodynamic modelling of the drug-induced downregulation of a beta 2-adrenoceptor mediated response and lack of restoration of receptor function after a single high dose of prednisone.

Changes in beta 2-adrenoceptor function by chronic dosing of beta 2-mimetics and the possible influence of a single dose of prednisone have been studied as changes over time in the concentration-effect relationship of the beta 2-adrenoceptor agonist terbutaline. Hypokalaemia was used as the specific beta 2-adrenoceptor mediated effect. 8 healthy volunteers were given subcutaneous terbutaline 0.01 mg.kg-1 BW on 3 occasions over a 10-day experimental protocol: 1 Control experiment on Day 1; 2 After 7 days of oral terbutaline 5 mg t.i.d. (Day 8); and 3 After 8 days on oral terbutaline and 12 h after prednisone 100 mg orally (Day 10). The time course of the terbutaline concentrations and hypokalaemia was related using a pharmacokinetic-pharmacodynamic model. A sigmoid and a threshold Emax model were used to relate drug concentrations to effects. The oral terbutaline treatment caused a 35% increase in the distribution volume of SC terbutaline. After one week on oral terbutaline the concentration-effect relationship was shifted to the right and was steeper, with a higher EC50 of terbutaline and higher values for the apparent threshold concentration. These observations are compatible with a decrease in receptor numbers after 7 days of terbutaline in a system characterised by the presence of spare receptors. The data after prednisone pretreatment showed an apparent decline in the baseline plasma potassium concentrations that could be included in the Emax model. There was no change in the concentration-effect relationship 12 hours after prednisone.

Analysis of 6-mercaptopurine in human plasma with a high-performance liquid chromatographic method including post-column derivatization and fluorimetric detection.

A relatively simple assay with improved reliability and sensitivity for measuring levels of 6-mercaptopurine in human plasma is presented. After extraction of the compound and the added internal standard with phenyl mercury acetate, samples were separated by ion-pair reversed-phase high-performance liquid chromatography. On-line the analytes were oxidized to fluorescent products and detected in a flow-fluorimeter. The within-day coefficient of variation was 3.8% at a concentration of 25 ng/ml. The lower detection limit was 2 ng/ml when 1.0 ml of plasma was used. Mercaptopurine concentration versus time curves of two subjects after a single oral dose of azathioprine are shown.

Debrisoquine phenotype and the pharmacokinetics and beta-2 receptor pharmacodynamics of metoprolol and its enantiomers.

The metabolism of the cardioselective beta-blocker metoprolol is under genetic control of the debrisoquine/sparteine type. The two metabolic phenotypes, extensive (EM) and poor metabolizers (PM), show different stereoselective metabolism, resulting in apparently higher beta-1 adrenoceptor antagonistic potency of racemic metoprolol in EMs. We investigated if the latter also applies to the beta-2 adrenoceptor antagonism by metoprolol. The drug effect studied was the antagonism by metoprolol of terbutaline-induced hypokalemia. By using pharmacokinetic pharmacodynamic modeling the pharmacodynamics of racemic metoprolol and the active S-isomer, were quantitated in EMs and PMs in terms of IC50 values, representing metoprolol plasma concentrations resulting in half-maximum receptor occupancy. Six EMs received 0.5 mg of terbutaline s.c. on two different occasions: 1) 1 hr after administration of a placebo and 2) 1 hr after 150 mg of metoprolol p.o. Five PMs were studied according to the same protocol, except for a higher terbutaline dose (0.75 mg) on day 2. Blood samples for the analysis of plasma potassium, terbutaline, metoprolol (racemic, R- and S-isomer), and alpha-hydroxymetoprolol concentrations were taken at regular time intervals, during 8 hr after metoprolol. In PMs, metoprolol increased the terbutaline area under the plasma concentration vs. time curve (+67%). Higher metoprolol/alpha-hydroxymetoprolol ratios in PMs were predictive for higher R-/S-isomer ratios of unchanged drug. There was a difference in metoprolol potency with higher racemic metoprolol IC50 values in PMs (72 +/- 7 ng.ml-1) than EMs (42 +/- 8 ng.ml-1, P less than .001).(ABSTRACT TRUNCATED AT 250 WORDS)

A comparison of salmeterol and formoterol in attenuating airway responses to short-acting beta2-agonists.

In vitro data suggest that salmeterol, contrary to formoterol, can partly antagonise the effect of short-acting beta(2)-agonist rescue medication. To explore whether this occurs in vivo, we compared the effects of increasing doses (200-3200 microg) of fenoterol on the recovery of methacholine induced bronchoconstriction as well as PD(20) methacholine in 23 asthmatic patients, during two-week treatment periods with placebo, and standard doses of salmeterol or formoterol in a double blind, double-dummy, crossover study. Salmeterol showed a slightly higher propensity for the development of bronchodilator tolerance. The recovery of methacholine induced bronchoconstriction was more complete during regular use of formoterol relative to salmeterol. During regular use of both long-acting beta(2)-agonists the bronchoprotective efficacy of fenoterol was attenuated, but this was more pronounced during salmeterol than during formoterol. The mean maximum increase in PD(20) metacholine after the highest dose of fenoterol was 3.97 DD during placebo, 2.47 DD during formoterol (p<0.001) and 1.81 DD during salmeterol treatment (p<0.001). We conclude that in asthmatic patients the efficacy of short-acting beta(2)-adrenoceptor agonists can be significantly attenuated during regular use of long-acting beta(2)-agonists. In this respect, differences were observed between salmeterol and formoterol that may represent the expression of partial antagonism by salmeterol.