Thomas Köhnlein

Non-invasive positive pressure ventilation for the treatment of severe stable chronic obstructive pulmonary disease: a prospective, multicentre, randomised, controlled clinical trial

BACKGROUND Evidence is weak for the ability of long-term non-invasive positive pressure ventilation (NPPV) to improve survival in patients with stable hypercapnic chronic obstructive pulmonary disease (COPD). Previous prospective studies did not target a reduction in hypercapnia when adjusting ventilator settings. This study investigated the effect of long-term NPPV, targeted to markedly reduce hypercapnia, on survival in patients with advanced, stable hypercapnic COPD. METHODS This investigator-initiated, prospective, multicentre, randomised, controlled clinical trial enrolled patients with stable GOLD stage IV COPD and a partial carbon dioxide pressure (PaCO2) of 7 kPa (51.9 mm Hg) or higher and pH higher than 7.35. NPPV was targeted to reduce baseline PaCO2 by at least 20% or to achieve PaCO2 values lower than 6.5 kPa (48.1 mm Hg). Patients were randomly assigned (in a 1:1 ratio) via a computer-generated randomisation sequence with a block size of four, to continue optimised standard treatment (control group) or to receive additional NPPV for at least 12 months (intervention group). The primary outcome was 1-year all-cause mortality. Analysis was by intention to treat. The intervention was unblinded, but outcome assessment was blinded to treatment assignment. This study is registered with ClinicalTrials.gov, number NCT00710541. FINDINGS Patients were recruited from 36 respiratory units in Germany and Austria, starting on Oct 29, 2004, and terminated with a record of the vital status on July 31, 2011. 195 patients were randomly assigned to the NPPV group (n=102) or to the control group (n=93). All patients from the control group and the NPPV group were included in the primary analysis. 1-year mortality was 12% (12 of 102 patients) in the intervention group and 33% (31 of 93 patients) in the control group; hazard ratio 0.24 (95% CI 0.11-0.49; p=0.0004). 14 (14%) patients reported facial skin rash, which could be managed by changing the type of the mask. No other intervention-related adverse events were reported. INTERPRETATION The addition of long-term NPPV to standard treatment improves survival of patients with hypercapnic, stable COPD when NPPV is targeted to greatly reduce hypercapnia. FUNDING German Lung Foundation; ResMed, Germany; Tyco Healthcare, Germany; and Weinmann, Germany.

The discovery of α1-antitrypsin and its role in health and disease

α1-Antitrypsin (AAT) is the archetype member of the serine protease inhibitor (SERPIN) supergene family. The AAT deficiency is most often associated with the Z mutation, which results in abnormal Z AAT folding in the endoplasmic reticulum of hepatocytes during biogenesis. This causes intra-cellular retention of the AAT protein rather than efficient secretion with consequent deficiency of circulating AAT. The reduced serum levels of AAT contribute to the development of chronic obstructive pulmonary disease (COPD) and the accumulation of abnormally folded AAT protein increases risk for liver diseases. In this review we show that with the discovery of AAT deficiency in the early 60s as a genetically determined predisposition to the development of early-onset emphysema, intensive investigations of enzymatic mechanisms that produce lung destruction in COPD were pursued. To date, the role of AAT in other than lung and liver diseases has not been extensively examined. Current findings provide new evidence that, in addition to protease inhibition, AAT expresses anti-inflammatory, immunomodulatory and antimicrobial properties, and highlight the importance of this protein in health and diseases. In this review co-occurrence of several diseases with AAT deficiency is discussed.

Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment.

Alpha-1 antitrypsin deficiency is an inherited disease affecting the lung and liver. The typical pulmonary manifestation is chronic obstructive pulmonary disease and emphysema. Severe chronic obstructive pulmonary disease may occur in young adulthood, and terminal respiratory insufficiency causes premature death in many patients. In the liver, alpha-1 antitrypsin deficiency may manifest as benign neonatal hepatitis syndrome; a small percentage of adults develop liver fibrosis, with progression to cirrhosis and hepatocellular carcinoma. The alpha-1 antitrypsin molecule is a serine protease inhibitor that is predominantly produced in the liver. Its most important physiologic functions are the protection of pulmonary tissue from aggressive proteolytic enzymes and regulation of pulmonary immune processes. Diagnosis of alpha-1 antitrypsin deficiency can be established by measurement of the serum alpha-1 antitrypsin concentration or by genetic analysis. Treatment is similar to the usual treatment for patients with chronic obstructive pulmonary disease. A further option is substitution therapy with human alpha-1 antitrypsin. The targets of treatment are the prevention of the accelerated decline of pulmonary function, reduction of lung infections, and improvements in exercise capacity.

Global and local epidemiology of community-acquired pneumonia: the experience of the CAPNETZ Network.

Community-acquired pneumonia (CAP) is a major cause of morbidity and mortality worldwide. Young children and the elderly are disproportionately affected by CAP. Lower respiratory tract infections (LRTIs), including CAP, were ranked third in a list of the 30 leading causes of death worldwide in 1990. Mortality rates are low (< 2%) in CAP patients treated as outpatients, but are higher (5 to 20%) among patients hospitalized for CAP, and are highest (up to 50%) in patients admitted to the intensive care unit. Several risk factors are known to be associated with increases in mortality, the most important of which are age > 65 years, male gender, and comorbidities such as chronic heart failure, advanced chronic obstructive pulmonary disease, neurological diseases, and liver cirrhosis. Patients living in nursing homes may have a special risk for multiresistant bacterial infection. The incidence of CAP varies worldwide by country, age, and gender. Further, data about epidemiology, etiology, morbidity, mortality, and economical burden of diseases differ between countries. In this review, we present recent data regarding the incidence, etiology, and rate of antibiotic resistance among CAP patients from the German Network for Community Acquired Pneumonia (CAPNETZ) registry and review data from several European countries.

Noninvasive ventilation in pulmonary rehabilitation of COPD patients

Noninvasive positive pressure ventilation (NIPPV) has been shown to improve exercise tolerance and health-related quality of life in patients with advanced COPD. This study tested the feasibility of nocturnal NIPPV as an additional tool in a hospital-based pulmonary rehabilitation program. This prospective observational trial included forty COPD patients in GOLD stage IV. NIPPV was successfully introduced and accepted during sleep by all patients. All patients received pressure support ventilation for 7.9+/-0.5h per day with an inspiratory support of 17.5+/-4.4 cmH(2)O, and an expiratory pressure of 4.5+/-0.9 cmH(2)O. The outcome of pulmonary rehabilitation in patients receiving nocturnal NIPPV was compared with the results of forty matched control patients who underwent the same program. Rehabilitation with nocturnal NIPPV resulted in the 6-minute walk test and in the longest non-stop walk distance in improvements of 82 and 89 m, respectively, while patients without nocturnal ventilatory support improved by 50 and 51 m (p<0.04 and p<0.03 between groups, respectively). Further significant improvements were found for FEV(1), lung hyperinflation, and blood gases in the NIPPV treated, but not in the control subjects. Health-related quality of life, assessed by the SF-36 questionnaire, improved moderately or largely in patients receiving NIPPV in the categories role-physical, vitality, social function, and mental health. Control subjects improved moderately in vitality only. In conclusion, nocturnal NIPPV is feasible and enhances the effects of pulmonary rehabilitation in advanced stage COPD.

Recurrent tendinitis after treatment with two different fluoroquinolones

Tendinopathies with and without tendon rupture are rare adverse events, occurring mainly following older fluoroquinolones, but recently also to an increasing extent following levofloxacin. We report the first case of tendinitis after treatment with moxifloxacin, and of recurrent tendinitis after treatment with 2 different fluoroquinolones. From these findings we conclude hitherto unexplained class effect of fluoroquinolones in respect of the development of tendinitis.

Diagnostic delay and clinical modifiers in alpha-1 antitrypsin deficiency

Background: Alpha-1 antitrypsin deficiency (AATD) is one of the most prevalent inherited diseases in Whites, but identification of affected patients and establishment of the diagnosis is still unsatisfactory. This study assessed the latencies and numbers of physicians involved in identifying AATD patients, and the importance of smoking, vaccination status, and specific augmentation therapy on the course of the disease. Method: Patients from Germany and Austria underwent a single written interview with 28 items. Five hundred and ninety-six patients were addressed and 44.9% replied. Results: The age at symptom onset was 39.1±10.1 years, and the diagnosis was established at the age of 45.1±10.9 years. From the 6-year delay in establishing the diagnosis, 1.4±1.7 (range 0.5—10.5) years were due to patients’ reluctance to seek medical attention. There were 3.2±2.4 (range 1—13) physicians involved in establishing the diagnosis. Smoking was associated with an earlier onset of respiratory symptoms and lower exercise capacity. Vaccination against pneumococci and/or influenza, and augmentation therapy resulted in significantly fewer exacerbations and fewer emergency room visits. Airway infections and passive smoking during childhood were not found to influence the onset of respiratory symptoms. Conclusions: In conclusion, there is still a large delay between symptom onset and AATD diagnosis. Smoking history, vaccination status, and augmentation therapy have an important impact on the course of the disease.

Saccharomyces boulardii induced sepsis: successful therapy with voriconazole after treatment failure with fluconazole.

Saccharomyces boulardii is frequently used for prevention and treatment of all forms of diarrhoea. We report the case of a 19-y-old white male with an underlying severe neurological disease, who developed a fungal sepsis after prophylactic application of a drug containing S. boulardii. Initial treatment with fluconazole was not successful. After the application of voriconazole, the sepsis resolved completely. This is the first clinical report of a successful treatment of Saccharomyces sepsis with voriconazole.

Performance of enhanced liver fibrosis plasma markers in asymptomatic individuals with ZZ α1-antitrypsin deficiency.

Objectives Alpha1-antitrypsin deficiency (AATD) is a common genetic cause of chronic liver disease. According to retrospective studies, up to 25% of those with homozygous ZZ (Glu 342 to Lys) AATD suffer from liver cirrhosis and/or liver cancer in late adulthood. We hypothesized that the plasma markers for liver fibrosis, necrosis, and apoptosis may identify AATD individuals at higher risk for liver diseases. Methods The study cohort included 52 clinically healthy ZZ AATD individuals of 34 years of age, identified in the Swedish neonatal screening of 1972–1974, and 81 age-matched controls with normal MM AAT variant. We analyzed plasma levels of the enhanced liver fibrosis (ELF) panel, including plasma tissue inhibitor of metalloprotease-1, amino-terminal propeptide of type III collagen and hyaluronic acid (HA), and the M30 and M65 antigens, markers for apoptosis/necrosis. Results Higher levels of tissue inhibitor of metalloprotease-1 (52%, P<0.001), amino-terminal propeptide of type III collagen (12%, P<0.05), HA (17% not significant), and M65 (13.4%, P=0.043) were found in ZZ than in MM patients. In the ZZ group, plasma levels of AAT correlated with M65 (P<0.01) and with HA (P<0.05). On the basis of the ELF panel, M30 and M65, a logistic regression model enabled us to correctly classify 81.2% of the originally grouped ZZ and MM cases with a sensitivity of 73.1% and a specificity of 86.4%. Conclusion The ELF markers are associated with ZZ AATD at early adulthood, and can be considered as a useful tool to identify ZZ cases at an increased risk of developing liver diseases later in life.

Does augmentation with alpha1-antitrypsin affect neutrophil extracellular traps formation?

Alpha1-Antitrypsin (AAT) is a major circulating inhibitor of neutrophil proteases, specifically elastase that has broad substrate specificity and can degrade many connective tissue matrix constituents. Severe inherited Z (Glu342Lys) deficiency of AAT (AATD) is characterized by a low serum AAT level (less than 20% of normal which is 11μM/L), the protease/antiprotease balance shift in favor of the elastase and an increased risk of early onset pulmonary emphysema. This lends support to the protease-antiprotease imbalance theory of the pathogenesis of emphysema and to AAT augmentation therapy.