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Importance There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF). Objective To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF. Design, Setting, and Participants The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2. Interventions Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks. Main Outcomes and Measures The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George’s Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life). Results At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was –124.6 mL (95% CI, −178.0 to −71.2 mL) with 600 mg of ziritaxestat vs –147.3 mL (95% CI, −199.8 to −94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, −52.3 to 97.6 mL]), and –173.9 mL (95% CI, −225.7 to −122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, −26.7 mL [95% CI, −100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was –173.8 mL (95% CI, −209.2 to −138.4 mL) with 600 mg of ziritaxestat vs –176.6 mL (95% CI, −211.4 to −141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, −46.9 to 52.4 mL]) and –174.9 mL (95% CI, −209.5 to −140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, −47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo. Conclusions and Relevance Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment. Trial Registration ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444

Against the background of the pandemic caused by infection with the SARS-CoV-2, the German Society for Pneumology and Respiratory Medicine (DGP e.V.), in cooperation with other associations, has designated a team of experts in order to answer the currently pressing questions about therapy strategies in dealing with COVID-19 patients suffering from acute respiratory insufficiency (ARI).The position paper is based on the current knowledge that is evolving daily. Many of the published and cited studies require further review, also because many of them did not undergo standard review processes.Therefore, this position paper is also subject to a continuous review process and will be further developed in cooperation with the other professional societies.This position paper is structured into the following five topics:1. Pathophysiology of acute respiratory insufficiency in patients without immunity infected with SARS-CoV-22. Temporal course and prognosis of acute respiratory insufficiency during the course of the disease3. Oxygen insufflation, high-flow oxygen, non-invasive ventilation and invasive ventilation with special consideration of infectious aerosol formation4. Non-invasive ventilation in ARI5. Supply continuum for the treatment of ARIKey points have been highlighted as core statements and significant observations. Regarding the pathophysiological aspects of acute respiratory insufficiency (ARI), the pulmonary infection with SARS-CoV-2 COVID-19 runs through three phases: early infection, pulmonary manifestation and severe hyperinflammatory phase.There are differences between advanced COVID-19-induced lung damage and those changes seen in Acute Respiratory Distress Syndromes (ARDS) as defined by the Berlin criteria. In a pathophysiologically plausible - but currently not yet histopathologically substantiated - model, two types (L-type and H-type) are distinguished, which correspond to an early and late phase. This distinction can be taken into consideration in the differential instrumentation in the therapy of ARI.The assessment of the extent of ARI should be carried out by an arterial or capillary blood gas analysis under room air conditions and must include the calculation of the oxygen supply (measured from the variables of oxygen saturation, the Hb value, the corrected values of the Hüfner number and the cardiac output). In principle, aerosols can cause transmission of infectious viral particles. Open systems or leakage systems (so-called vented masks) can prevent the release of respirable particles. Procedures in which the invasive ventilation system must be opened, and endotracheal intubation must be carried out are associated with an increased risk of infection.The protection of personnel with personal protective equipment should have very high priority because fear of contagion must not be a primary reason for intubation. If the specifications for protective equipment (eye protection, FFP2 or FFP-3 mask, gown) are adhered to, inhalation therapy, nasal high-flow (NHF) therapy, CPAP therapy or NIV can be carried out according to the current state of knowledge without increased risk of infection to the staff. A significant proportion of patients with respiratory failure presents with relevant hypoxemia, often also caused by a high inspiratory oxygen fraction (FiO2) including NHF, and this hypoxemia cannot be not completely corrected. In this situation, CPAP/NIV therapy can be administered under use of a mouth and nose mask or a respiratory helmet as therapy escalation, as long as the criteria for endotracheal intubation are not fulfilled.In acute hypoxemic respiratory insufficiency, NIV should be performed in an intensive care unit or in a comparable unit by personnel with appropriate expertise. Under CPAP/NIV, a patient can deteriorate rapidly. For this reason, continuous monitoring with readiness to carry out intubation must be ensured at all times. If CPAP/NIV leads to further progression of ARI, intubation and subsequent invasive ventilation should be carried out without delay if no DNI order is in place.In the case of patients in whom invasive ventilation, after exhausting all guideline-based measures, is not sufficient, extracorporeal membrane oxygenation procedure (ECMO) should be considered to ensure sufficient oxygen supply and to remove COVor dem Hintergrund der Pandemie durch Infektionen mit dem SARS-CoV-2 hat die Deutsche Gesellschaft für Pneumologie und Beatmungsmedizin (DGP e.V.) federführend in Kooperation mit weiteren Verbänden ein Expertenteam benannt, um die zur Zeit drängenden Fragen zu Therapiestrategien im Umgang mit COVID-19-Patienten, die an akut respiratorischer Insuffizienz (ARI) leiden, zu beantworten. Das Positionspapier basiert auf dem momentanen aktuellen Wissen, das sich täglich weiterentwickelt. Viele der publizierten und zitierten Studien bedürfen weiterer Überprüfungen, auch weil viele kein übliches Review-Verfahren durchlaufen haben Daher unterliegt auch dieses Positionspapier einer ständigen Überprüfung und wird in Zusammenarbeit in der Zusammenarbeit mit den anderen Fachgesellschaften weiterentwickelt.Dieses Positionspapier wurde in die folgenden fünf Themenfelder gegliedert:1. Pathophysiologie der akuten respiratorischen Insuffizienz bei Infektionen mit SARS-CoV-2 bei Patienten ohne Immunität2. Zeitlicher Verlauf und Prognose der akuten respiratorischen Insuffizienz im Laufe der Erkrankung3. Sauerstoff-Insufflation, High-Flow Sauerstoff, nicht-invasive Beatmung und invasive Beatmung unter besonderer Berücksichtigung der infektiösen Aerosolbildung4. Nicht-Invasive Beatmung bei der ARI5. Versorgungskontinuum zur Behandlung der ARIZentrale Punkte wurden hierbei als Kernaussagen und Feststellungen herausgehoben. Bezüglich pathophysiologischer Aspekte der akuten respiratorischen Insuffizienz (ARI) verläuft die pulmonale Infektion mit SARS-CoV-2 COVID-19 in drei Phasen: Frühe Infektion, pulmonale Manifestation und schwere hyperinflammatorische Phase.Der fortgeschrittene COVID-19-induzierte Lungenschaden weist häufig Unterschiede zu den bekannten Veränderungen entsprechend der Definition des Acute Respiratory Distress Syndrome (ARDS) nach den Berlin-Kriterien auf.In einem pathophysiologisch plausiblen – zur Zeit aber noch nicht histopathologisch untermauerten – Modell wird in zwei Typen (L-Typ und H-Typ) unterschieden, die einer frühen und späten Phase entsprechen. Diese Unterscheidung kann für die apparative Differenzialtherapie der ARI erwogen werden.Die Einschätzung des Ausmaßes der ARI soll durch eine arterielle oder kapilläre Blutgasanalyse bei Raumluft erfolgen und die Errechnung des Sauerstoffangebotes (bemisst sich aus den Variablen der Sauerstoffsättigung, des Hb-Wertes, der Hüfnerʼschen Korrekturzahl sowie des Herzminutenvolumens) beinhalten.Durch Aerosole ist eine Übertragung von infektiösen, Viren-haltigen Partikeln prinzipiell möglich. Offene Systeme bzw. Leckage-Systeme (sog. vented Masken) können die Abgabe von respirablen Partikeln erhöhen. Prozeduren, bei denen das invasive Beatmungssystem geöffnet werden muss, sowie die endotracheale Intubation sind mit einem erhöhten Infektionsrisiko verbunden.Der Schutz des Personals durch persönliche Schutzausrüstung soll sehr hohe Priorität haben, weil die Angst vor Ansteckung kein primärer Intubationsgrund sein darf. Bei Einhaltung der Vorgaben zu Schutzausrüstung (Augenschutz, FFP2- bzw. FFP-3 Maske, Kittel) kann eine Inhalationstherapie, nasale High Flow (NHF) -Therapie, eine CPAP-Therapie oder eine NIV nach jetzigem Kenntnisstand vom Personal ohne erhöhtes Infektionsrisiko durchgeführt werden.Ein signifikanter Anteil der respiratorisch insuffizienten Patienten präsentiert sich mit einer relevanten Hypoxämie, die häufig auch durch eine hohe inspiratorische Sauerstofffraktion (FiO2) inklusive NHF nicht vollständig korrigiert werden kann.In dieser Situation können die CPAP/NIV-Therapie unter Verwendung einer Mund-Nasen-Maske oder eines Beatmungshelms als Therapieeskalation durchgeführt werden, solange die Kriterien für eine endotracheale Intubation nicht erfüllt sind.Die NIV bei akuter hypoxämischer Insuffizienz sollte auf der Intensivstation oder in einer vergleichbaren Struktur mit entsprechender personeller Expertise erfolgen. Unter CPAP/NIV kann es zu einer raschen Verschlechterung kommen. Aus diesem Grund soll ein ständiges Monitoring unter ständiger Intubationsbereitschaft gewährleistet sein. Kommt es unter CPAP/NIV zur weiteren Progression des ARI, sollte ohne zeitliche Verzögerung die Intubation und nachfolgende invasive Beatmung erfolgen, wenn keine DNI-Order vorliegt.Bei Patienten, bei denen eine invasive Beatmung unter Ausschöpfung aller leitliniengerechter Maßnahmen nicht ausreicht, um eine ausreichende Sauerstoffaufnahme und CO

Sleep disordered breathing (SDB) is highly prevalent with a male to female predominance of two to one, and is more common in middle-aged and elderly subjects [1]. Affected patients often present with comorbidities such as obesity, cardiovascular disease (systemic hypertension, heart failure, atrial fibrillation), and diabetes mellitus Type II [2]. The strong overlap between the profile for SDB patients and the identified risk factors for adverse outcomes of COVID-19 infection that include age, male gender, and cardio-metabolic comorbidity [3] suggest that SDB patients may benefit from effective therapy if confronted with COVID-19 infection [4].