Novel translational approaches to the search for precision therapies for acute respiratory distress syndrome.

In the 50 years since acute respiratory distress syndrome (ARDS) was first described, substantial progress has been made in identifying the risk factors for and the pathogenic contributors to the syndrome and in characterising the protein expression patterns in plasma and bronchoalveolar lavage fluid from patients with ARDS. Despite this effort, however, pharmacological options for ARDS remain scarce. Frequently cited reasons for this absence of specific drug therapies include the heterogeneity of patients with ARDS, the potential for a differential response to drugs, and the possibility that the wrong targets have been studied. Advances in applied biomolecular technology and bioinformatics have enabled breakthroughs for other complex traits, such as cardiovascular disease or asthma, particularly when a precision medicine paradigm, wherein a biomarker or gene expression pattern indicates a patient's likelihood of responding to a treatment, has been pursued. In this Review, we consider the biological and analytical techniques that could facilitate a precision medicine approach for ARDS

Oxygenation inhibits the physiological tissue-protecting mechanism and thereby exacerbates acute inflammatory lung injury

Acute respiratory distress syndrome (ARDS) usually requires symptomatic supportive therapy by intubation and mechanical ventilation with the supplemental use of high oxygen concentrations. Although oxygen therapy represents a life-saving measure, the recent discovery of a critical tissue-protecting mechanism predicts that administration of oxygen to ARDS patients with uncontrolled pulmonary inflammation also may have dangerous side effects. Oxygenation may weaken the local tissue hypoxia-driven and adenosine A2A receptor (A2AR)-mediated anti-inflammatory mechanism and thereby further exacerbate lung injury. Here we report experiments with wild-type and adenosine A2AR-deficient mice that confirm the predicted effects of oxygen. These results also suggest the possibility of iatrogenic exacerbation of acute lung injury upon oxygen administration due to the oxygenation-associated elimination of A2AR-mediated lung tissue-protecting pathway. We show that this potential complication of clinically widely used oxygenation procedures could be completely prevented by intratracheal injection of a selective A2AR agonist to compensate for the oxygenation-related loss of the lung tissue-protecting endogenous adenosine. The identification of a major iatrogenic complication of oxygen therapy in conditions of acute lung inflammation attracts attention to the need for clinical and epidemiological studies of ARDS patients who require oxygen therapy. It is proposed that oxygen therapy in patients with ARDS and other causes of lung inflammation should be combined with anti-inflammatory measures, e.g., with inhalative application of A2AR agonists. The reported observations may also answer the long-standing question as to why the lungs are the most susceptible to inflammatory injury and why lung failure usually precedes multiple organ failure

Regulation of vascular endothelial growth factor bioactivity in patients with acute lung injury

Background: Reduced bioactive vascular endothelial growth factor (VEGF) has been demonstrated in several inflammatory lung conditions including the acute respiratory distress syndrome (ARDS). sVEGFR-1, a soluble form of VEGF-1 receptor, is a potent natural inhibitor of VEGF. We hypothesised that sVEGFR-1 plays an important role in the regulation of the bioactivity of VEGF within the lung in patients with ARDS. Methods: Forty one patients with ARDS, 12 at risk of developing ARDS, and 16 normal controls were studied. Bioactive VEGF, total VEGF, and sVEGFR-1 were measured by ELISA in plasma and bronchoalveolar lavage (BAL) fluid. Reverse transcriptase polymerase chain reaction for sVEGFR-1 was performed on BAL cells. Results: sVEGFR-1 was detectable in the BAL fluid of 48% (20/41) of patients with early ARDS (1.4– 54.8 ng/ml epithelial lining fluid (ELF)) compared with 8% (1/12) at risk patients (p = 0.017) and none of the normal controls (p = 0.002). By day 4 sVEGFR-1 was detectable in only 2/18 ARDS patients (p = 0.008). Patients with detectable sVEGFR-1 had lower ELF median (IQR) levels of bioactive VEGF than those without detectable sVEGFR-1 (1415.2 (474.9–3192) pg/ml v 4761 (1349–7596.6) pg/ml, median difference 3346 pg/ml (95% CI 305.1 to 14711.9), p = 0.016), but there was no difference in total VEGF levels. BAL cells expressed mRNA for sVEGFR-1 and produced sVEGFR-1 protein which increased following incubation with tumour necrosis factor a. Conclusion: This study shows for the first time the presence of sVEGFR-1 in the BAL fluid of patients with ARDS. This may explain the presence of reduced bioactive VEGF in patients early in the course of ARDS

Rationale for Prolonged Glucocorticoid Use in Pediatric ARDS: What the Adults Can Teach Us.

Based on molecular mechanisms and physiologic data, a strong association has been established between dysregulated systemic inflammation and progression of acute respiratory distress syndrome (ARDS). In ARDS patients, glucocorticoid receptor-mediated downregulation of systemic inflammation is essential to restore homeostasis, decrease morbidity and improve survival and can be significantly enhanced with prolonged low-to-moderate dose glucocorticoid treatment. A large body of evidence supports a strong association between prolonged glucocorticoid treatment-induced downregulation of the inflammatory response and improvement in pulmonary and extrapulmonary physiology. The balance of the available data from eight controlled trials (n = 622) provides consistent strong level of evidence for improving patient-centered outcomes and hospital survival. The sizable increase in mechanical ventilation-free days (weighted mean difference, 6.48 days; CI 95% 2.57-10.38, p < 0.0001) and intensive care unit-free days (weighted mean difference, 7.7 days; 95% CI, 3.13-12.20, p < 0.0001) by day 28 is superior to any investigated intervention in ARDS. For treatment initiated before day 14 of ARDS, the increased in hospital survival (70 vs. 52%, OR 2.41, CI 95% 1.50-3.87, p = 0.0003) translates into a number needed to treat to save one life of 5.5. Importantly, prolonged glucocorticoid treatment is not associated with increased risk for nosocomial infections (22 vs. 27%, OR 0.61, CI 95% 0.35-1.04, p = 0.07). Treatment decisions involve a tradeoff between benefits and risks, as well as costs. This low-cost, highly effective therapy is familiar to every physician and has a low risk profile when secondary prevention measures are implemented

Inhaled Interleukin-10 before and after induction of experimental endotoxemia in the rat : effects on the inflammatory response

To determine the effects of inhaled IL-10 at different doses and different time points on the pulmonary and systemic inflammatory response during endotoxemia, 48 ventilated, anaesthetized rats (mean body weight ± standard deviation, 500 ± 33g) were randomly assigned to six groups (n = 8, each). Interleukin-10 was nebulised either prior to or following the intravenous injection of LPS (5mg/kg) at two doses (5.0 mycro-g or 0.5 mycro-g) in our groups. Eight rats received the same insult with no further treatment (LPS-only group). Another eight rats served as controls without endotoxemia but with aerosolized phosphate-buffered saline, the solvent of IL-10 (Sham group). Concentrations of TNF-alpha, IL-1beta, IL-6, and IFN-gamma were analyzed in plasma and bronchoalveolar lavage fluid (BALF). In addition, the nitrite release from ex-vivo cultured alveolar macrophages was determined. As compared to the LPS-only group, the concentrations of the proinflammatory cytokines TNF-alpha, IL-1beta, IL-6, and IFN-gamma in plasma were significantly reduced in the group, which inhaled 5 mycro-g IL-10 before LPS injection (p< 0.0125). Spontaneous nitrite release from exvivo cultured alveolar macrophages was suppressed in this group (p< 0.0125). Inhalation of 0.5 mycro-g IL-10 before LPS injection and both dosages of IL-10 inhalation (5 mycro-g or 0.5 mycro-g) after LPS injection did not significantly influence either inflammatory cytokine concentrations in BALF, in plasma or the nitrite release from ex-vivo cultured alveolar macrophages. In this study, inhaled IL-10 only demonstrated anti-inflammatory effects when it was administered at 5 mycro-g prior to the induction of experimental endotoxemia. Interleukin-10 aerosol had no effect when it was given either following induction of endotoxemia or given at a lower dosage (which here was 0.5 mycro-g) either before or following injection of lipopolysaccharide.Das "Acute Respiratory Distress Syndrome" (ARDS) ist eine akut auftretende, überwiegend Sepsis-induzierte, inflammatorische Erkrankung der Lunge mit hoher Letalität. Ein komplexes Netzwerk aus Zytokinen und anderen proinflammatorischen Mediatoren unterhält die pulmonale Entzündungreaktion. Dem Zytokin Interleukin-10 (IL-10) könnte in diesem Zusammenhang aufgrund seines spezifisch antiinflammatorischen und immunmodulierenden Wirkspektrums eine therapeutische Bedeutung zukommen. In tierexperimentellen Untersuchungen konnten die protektiven Wirkungen von systemisch appliziertem Interleukin-10 bezüglich verringerter Wirkspiegel proinflammatorischer Mediatoren sowie des Überlebens der Versuchstiere bei Sepsis belegt werden. In einer Untersuchung an ARDS-Erkrankten wiesen Patienten, deren bronchoalveoläre Lavage (BAL) hohe Konzentrationen an Interleukin-10 enthielt, eine signifikant niedrigere Letalität auf als Patienten mit niedriger IL-10-Konzentration. Die Inhalation von IL-10 über den Luftweg könnte lokal in der Lunge die Freisetzung von Entzündungsmediatoren verringern und so den Verlauf eines ARDS positiv beeinflussen. Im Rahmen einer bereits durchgeführten Studie der eigenen Arbeitsgruppe konnte gezeigt werden, dass die Inhalation von IL-10 (0.19 mycro-g/Tier) vor Induktion einer experimentellen Endotoxinämie (Beobachtungszeitraum 6h) zur signifikanten Reduktion proinflammatorischer Zytokine im Plasma sowie der BAL führte. Daneben bewirkte IL-10 Aerosol eine signifikante Verringerung der Nitritproduktion aus ex vivo kultivierten Alveolarmakrophagen (AM). Mit der vorliegenden Studie sollte untersucht werden, ob vernebeltes IL-10 auch in einer geringeren Dosierung als in der ersten Studie angewandt antiinflammatorisch wirksam ist. Daneben sollte geklärt werden, ob der Zeitpunkt der Applikation des IL-10 Aerosol relevant ist. Konkret sollte untersucht werden, ob die Inhalation von IL-10 erst nach Induktion der experimentellen Endotoxinämie ebenfalls antinflammatorisches Potential besitzt. Die Generierung und Verneblung des IL-10 Aerosols erfolgte in der vorliegenden Untersuchung mittels eines speziell für diesen Einsatz von der eigenen Arbeitsgruppe entwickelten und charakterisierten Verneblersystems. Der Vernebler produziert stabil Aerosopartikel, deren Größenverteilung (rund 2 mycro-m) mit hoher Wahrscheinlichkeit in alvelären Bereichen deponiert. Die alveoläre Depositionsfraktion des Verneblers beträgt rund 4% und liegt damit in einem Bereich, der aus der Humanmedizin für die Verneblung bei intubierten Patienten bekannt ist. An 48 narkotisierten, kontrolliert beatmeten Ratten wurde die antiinflammatorische Wirkung eines IL-10-Aerosols untersucht. Die Induktion des experimentellen Lungenschadens erfolgte durch intravenöse Injektion von Endotoxin (Lipopolysaccharid; LPS, in einer Dosierung von 5mg/kg). Als löslicher Bestandteil der Membran gram-negativer Bakterien führt LPS über die Freisetzung proinflammatorischer Substanzen zu entzündlichen Reaktionen, die lokal beschränkt oder auch systemisch auftreten können. Bei Versuchstieren unterschiedlicher Spezies bewirkt die systemische Applikation von LPS pulmonale Veränderungen, die denen des septisch bedingten ARDS des Menschen qualitativ entsprechen. Die Tiere wurden zufällig in eine der sechs Versuchsgruppen eingeteilt (je n=8): Die LPS-Gruppe erhielt eine LPS-Injektion (5 mg/kg/KG) ohne anschließende therapeutische Intervention. Die mit IL-10 behandelten Tiere erhielten das IL-10-Aerosol entweder vor oder nach Induktion der experimentellen Endotoxinämie nach unten genanntem Protokoll. In einer Kontroll (Sham)-Gruppe wurde die Auswirkung von Narkose, chirurgischer Präparation, Beatmung und Aerosolapplikation (IL-10-Trägerlösung; phosphatgepufferte Kochsalzlösung) evaluiert. Neben der in vivo Beobachtung von Hämodynamik (Herzfrequenz, mittlerer arterieller Blutdruck), Lungenmechanik, arteriellen Blutgasen und Blutbild, untersuchten wir anhand von Blutproben und einer Bronchoalveolären Lavage (BAL) die systemische und pulmonale Inflammation (inflammatorische Zytokine TNFalpha, IL-1beta, IL-6 und IFNgamma in Plasma und BAL). Die Verneblung von IL-10 erfolgte in zwei Dosierungen und zu zwei Zeitpunkten: in einer Gruppe wurde IL-10 in einer Dosierung von 5.0 mycro-g (0.19 mycro-g/Tier) vor, und in einer weiteren Gruppe nach Induktion der experimentellen Endotoxinämie vernebelt. In zwei weiteren Versuchgruppen wurde IL-10 in einer Dosierung von 0.5 mycro-g (0.019 mycro-g/Tier) ebenfalls vor sowie nach Injektion von LPS vernebelt. Die Endotoxinämie führte nur zu geringen Verschlechterungen der klinischen Parameter, aber sowohl pulmonal (BAL) als auch systemisch (Plasma) zeigte sich ein Anstieg proinflammatorischer Mediatoren. Gegenüber den Tieren, deren Endotoxinämie unbehandelt blieb, bewirkte nur die Inhalation von IL-10 in der höheren Dosierung (5 mycro-g) das signifikante Abfallen der proinflammatorischen Zytokine TNFalpha, IL-1beta, IL-6 und IFNgamma im Plasma sowie der Freisetzung von Nitrit aus kultivierten AM. IL-10 Aerosol hatte in keiner Dosierung respektive zu keinem Applikationszeitpunkt antiinflammatorische Effekte auf die Zytokinkonzentrationen in der BAL. Die präemptive Vernebelung von IL-10 in einer Dosierung von 5 mycro-g (0.19 mycro-g/Tier) vor Induktion einer experimentellen Endotoxinämie zeigte sowohl auf die AM Kultur als auch systemisch (Plasma) antinflammatorisches Wirkprofil. Demgegenüber zeigte IL-10 keine antinflammatorische Effekte, wenn es erst nach Injektion von LPS oder aber in geringerer Dosierung vernebelt wurde. Zur antiinflammatorischen Therapie der experimentellen Endotoxinämie durch LPS Injektion in der Spezies Ratte erscheint IL-10 Aerosol nur wirksam, wenn es in ausreichender Dosierung (5 mycro-g) sowie vor Injektion von LPS appliziert wird

The acute respiratory distress syndrome in 2013.

Acute lung injury and the acute respiratory distress syndrome are major causes of morbidity and mortality in critically ill patients. This review focuses on new developments in definitions, epidemiology, clinical and basic research, and promising new directions in treatment. There is new information about the potential contribution of environmental factors, especially exposure to cigarette smoke. Pathologic findings in ARDS have been limited to case reports of open lung biopsies and post-mortem studies but there is some new information from a recent pathology study relative to the frequency of diffuse alveolar damage and the severity of arterial hypoxemia. Further, therapy with lung-protective ventilation and fluid conservative protocol has improved outcomes, but several new trials are in progress to test several promising strategies

An unusual presentation of a case of human psittacosis

Background: Chlamydia psittaci is a gram-negative, obligate intracellular organism. Birds are the main reservoir, but also non-avian domestic animals and humans can be infected. In humans it mostly causes respiratory infections due to occupational exposure with varying severity. Sensitive and specific diagnostic tests are needed to define psittacosis in humans as these tests also allow rapid tracing of the animal source. However, diagnosis in humans is often based on time-consuming culture techniques and antibody detection assays as in many countries, the existing molecular diagnostic tests for psittacosis are not reimbursed by the public health insurance. Case presentation: An 82-year old female was referred to the hospital with a non-productive cough since four weeks and since one week fever up to 39 degrees C, myalgia, generalized skin rash, acral edema and generalized weakness under treatment with moxifloxacin. Blood analysis showed signs of inflammation with mild eosinophilia. Chest CT showed multiple peripheral ground glass opacities with consolidation in both lungs. Pulmonary function testing only showed a mild decrease in diffusion capacity. Viral and bacterial serology were negative. As the patient kept a pet parakeet for over ten years, a nested PCR for C. psittaci was performed on a nasopharyngeal swab of the patient and on feces of the parakeet. Both returned positive for the same genotype. Genotyping was performed by a genotype-specific real-time PCR. The patient fully recovered after a ten-day course of azithromycin. Conclusion: Due to non-specific signs during psittacosis, early detection of the infection and differentiation from hypersensitivity pneumonitis can be challenging. Culture and antibody titers for C. psittaci have a lower sensitivity than PCR-testing due to several factors. We present a case of human psittacosis (presenting as pneumonia) with diagnosis based on clinical findings confirmed by means of nested PCR. This case suggests the added value of PCR in suspect cases despite negative serology. Our current paper underlines the need for a broader implementation of PCR for early diagnosis of human psittacosis and thus early initiation of correct antibiotic treatment with reduction of morbidity and mortality