PurposeThe CIGMA study investigated a novel human polyclonal antibody preparation (trimodulin) containing ~ 23% immunoglobulin (Ig) M, ~ 21% IgA, and ~ 56% IgG as add-on therapy for patients with severe community-acquired pneumonia (sCAP).MethodsIn this double-blind, phase II study (NCT01420744), 160 patients with sCAP requiring invasive mechanical ventilation were randomized (1:1) to trimodulin (42 mg IgM/kg/day) or placebo for five consecutive days. Primary endpoint was ventilator-free days (VFDs). Secondary endpoints included 28-day all-cause and pneumonia-related mortality. Safety and tolerability were monitored. Exploratory post hoc analyses were performed in subsets stratified by baseline C-reactive protein (CRP; ≥ 70 mg/L) and/or IgM (≤ 0.8 g/L).ResultsOverall, there was no statistically significant difference in VFDs between trimodulin (mean 11.0, median 11 [n = 81]) and placebo (mean 9.6; median 8 [n = 79]; p = 0.173). Twenty-eight-day all-cause mortality was 22.2% vs. 27.8%, respectively (p = 0.465). Time to discharge from intensive care unit and mean duration of hospitalization were comparable between groups. Adverse-event incidences were comparable. Post hoc subset analyses, which included the majority of patients (58–78%), showed significant reductions in all-cause mortality (trimodulin vs. placebo) in patients with high CRP, low IgM, and high CRP/low IgM at baseline.ConclusionsNo significant differences were found in VFDs and mortality between trimodulin and placebo groups. Post hoc analyses supported improved outcome regarding mortality with trimodulin in subsets of patients with elevated CRP, reduced IgM, or both. These findings warrant further investigation.Trial registration: NCT01420744.Electronic supplementary materialThe online version of this article (10.1007/s00134-018-5143-7) contains supplementary material, which is available to authorized users.

ZusammenfassungCOVID-19, ausgelöst durch Coronavirus SARS-CoV-2, ist eine neue, sich pandemisch ausbreitenden Infektionserkrankung, welche aktuell weltweit zu einer erheblichen Belastung der Gesundheitssysteme geführt hat. Krankenhausmitarbeiter stellen in Ländern mit hoher Krankheitsaktivität, wie China oder Italien, einen signifikanten Anteil der an COVID-19 Erkrankten und Verstorbenen dar. Bronchoskopische Untersuchungen führen beim untersuchten Patienten zu Hustenreiz und Aerosolbildung und beinhalten daher ein erhöhtes Infektionsrisiko für das Untersuchungsteam und für andere Patienten. In der aktuellen Pandemie sind daher besondere Maßnahmen bei der Durchführung bronchoskopischer Untersuchungen zu beachten, um das Infektionsrisiko zu senken.

Background: Triple combinations of cystic fibrosis (CF) transmembrane conductance regulator (CFTR) modulators demonstrate enhanced clinical efficacy in CF patients with F508del mutation, compared with modest effects of dual combinations. GLPG2737 was developed as a novel corrector for triple combination therapy. Methods: This multicenter, randomized, double-blind, placebo-controlled, phase 2a study evaluated GLPG2737 in F508del homozygous subjects who had been receiving lumacaftor 400 mg/ivacaftor 250 mg for ≥12 weeks. The primary outcome was change from baseline in sweat chloride concentration. Other outcomes included assessment of pulmonary function, respiratory symptoms, safety, tolerability, and pharmacokinetics. Results: Between November 2017 and April 2018, 22 subjects were enrolled and randomized to oral GLPG2737 (75 mg; n = 14) or placebo (n = 8) capsules twice daily for 28 days. A significant decrease from baseline in mean sweat chloride concentration occurred at day 28 for GLPG2737 versus placebo (least-squares-mean difference − 19.6 mmol/L [95% confidence interval (CI)-36.0, −3.2], p = .0210). The absolute improvement, as assessed by least-squares-mean difference in change from baseline, in forced expiratory volume in 1 s (percent predicted) at day 28 for GLPG2737 versus placebo was 3.4% (95% CI-0.5, 7.3). Respiratory symptoms in both groups remained stable. Mild/moderate adverse events occurred in 10 (71.4%) and 8 (100%) subjects receiving GLPG2737 and placebo, respectively. Lower exposures of GLPG2737 (and active metabolite M4) were observed than would be expected if administered alone (as lumacaftor induces CYP3A4). Lumacaftor and ivacaftor exposures were as expected.

Rationale: In clinical trials, homogeneous emphysema patients have responded well to upper lobe volume reduction but not lower lobe volume reduction. Materials/Methods: To understand the physiological basis for this observation, a computer model was developed to simulate the effects of upper and lower lobe lung volume reduction on RV/TLC and lung recoil in homogeneous emphysema. Results: Patients with homogeneous emphysema received either upper or lower lobe volume reduction therapy based on findings of radionucleotide scintigraphy scanning. CT analysis of lobar volumes showed that patients undergoing upper (n = 18; −265 mL/site) and lower lobe treatment (LLT; n = 11; −217 mL/site) experienced similar reductions in lung volume. However, only upper lobe treatment (ULT) improved FEV1 (+11.1 ± 14.7 versus −4.4 ± 15.8%) and RV/TLC (−5.4 ± 8.1 versus −2.4 ± 8.6%). Model simulations provided an unexpected explanation for this response. Increases in transpulmonary pressure subsequent to volume reduction increased RV/TLC in upper lobe alveoli, while caudal shifts in airway closure decreased RV/TLC in lower lobe alveoli. ULT, which eliminates apical alveoli with high RV/TLC values, lowers the average RV/TLC of the lung. Conversely, LLT, which eliminates caudal alveoli with low RV/TLC values, has less effect. Conclusion: LLT in homogeneous emphysema is uniformly less effective than ULT.

ZusammenfassungDie Pandemie ausgelöst durch SARS-CoV-19 geht weltweit unverändert mit einer bedeutsamen Morbidität und Mortalität einher, sodass Schutzmaßnahmen zur Verhinderung der Transmission des Virus weiterhin notwendig sind. Mitarbeiter im Gesundheitswesen sind einem höheren Risiko ausgesetzt, und dies gilt insbesondere im Rahmen sog. Aerosol-generierender Verfahren wie der Bronchoskopie. Seit der Veröffentlichung konsentierter Empfehlungen zur Durchführung einer Bronchoskopie unter diesen Bedingungen vor mehr als einem halben Jahr hat sich die Gefahrenlage nicht wesentlich verändert, aber aufgrund des erheblichen Erkenntnisgewinns in der Zwischenzeit war ein Update der Empfehlungen notwendig. Die erneuerten Empfehlungen umfassen u. a. die Verminderung der Aerosolentstehung, den persönlichen Schutz der beteiligten Personen sowie Maßnahmen zur besseren Organisation der Abläufe in der Endoskopie, um eine sichere Durchführung auch in Zeiten von COVID-19 zu gewährleisten.