Non-lytic #antibiotic #treatment in community-acquired #pneumococcal #pneumonia does not attenuate inflammation: the #PRISTINE trial (J Antimicrob Chemother., abstract)

[Source: Journal of Antimicrobial Chemotherapy, full page: (LINK). Abstract, edited.]

Non-lytic antibiotic treatment in community-acquired pneumococcal pneumonia does not attenuate inflammation: the PRISTINE trial

Geert H Groeneveld, Tanny J van der Reyden, Simone A Joosten, Hester J Bootsma, Christa M Cobbaert Jutte, J C de Vries, Ed J Kuijper, Jaap T van Dissel

Journal of Antimicrobial Chemotherapy, dkz207, https://doi.org/10.1093/jac/dkz207

Published: 18 May 2019

 

Abstract

Background

The inflammatory response in pneumococcal infection is primarily driven by immunoreactive bacterial cell wall components [lipoteichoic acid (LTA)]. An acute release of these components occurs when pneumococcal infection is treated with β-lactam antibiotics.

Objectives

We hypothesized that non-lytic rifampicin compared with lytic β-lactam antibiotic treatment would attenuate the inflammatory response in patients with pneumococcal pneumonia.

Methods

In the PRISTINE (Pneumonia treated with RIfampicin aTtenuates INflammation) trial, a randomized, therapeutic controlled, exploratory study in patients with community-acquired pneumococcal pneumonia, we looked at LTA release and inflammatory and clinical response during treatment with both rifampicin and β-lactam compared with treatment with β-lactam antibiotics only. The trial is registered in the Dutch trial registry, number NTR3751 (European Clinical Trials Database number 2012-003067-22).

Results

Forty-one patients with community-acquired pneumonia were included; 17 of them had pneumococcal pneumonia. LTA release, LTA-mediated inflammatory responses, clinical outcomes, inflammatory biomarkers and transcription profiles were not different between treatment groups.

Conclusions

The PRISTINE study demonstrated the feasibility of adding rifampicin to β-lactam antibiotics in the treatment of community-acquired pneumococcal pneumonia, but, despite solid in vitro and experimental animal research evidence, failed to demonstrate a difference in plasma LTA concentrations and subsequent inflammatory and clinical responses. Most likely, an inhibitory effect of human plasma contributes to the low immune response in these patients. In addition, LTA plasma concentration could be too low to mount a response via Toll-like receptor 2 in vitro, but may nonetheless have an effect in vivo.

Topic: antibiotics – rifampin – inflammation – immune response – community acquired  pneumonia – biological markers – cell wall – lactams – plasma – pneumococcal infections – pneumonia, pneumococcal – treatment outcome – inflammatory response – community – toll-like receptor 2 – attenuation

Issue Section: ORIGINAL RESEARCH

Keywords: Antibiotics; S. pneumoniae; Pneumonia; Beta-lactams; Rifampin.

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First successful combination of #ECMO with video-assisted thoracic surgery (#VATS) of pulmonary bullae #resection in the management of refractory #pneumothorax in a critically ill patient with #H7N9 #pneumonia and #ARDS: A case report (Medicine (Baltimore), abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Medicine (Baltimore). 2019 May;98(20):e15661. doi: 10.1097/MD.0000000000015661.

First successful combination of extracorporeal membrane oxygenation (ECMO) with video-assisted thoracic surgery (VATS) of pulmonary bullae resection in the management of refractory pneumothorax in a critically ill patient with H7N9 pneumonia and acute respiratory distress syndrome: A case report.

Huang J1, Li H1, Chen S2, Lan C3, Lin Q4, Weng H1.

Author information: 1 Department of Respiratory and Critical Care Medicine. 2 Department of Thoracic Surgery. 3 Department of Radiology. 4 Department of Pathology, Fuzhou Pulmonary Hospital of Fu Jian, Educational Hospital of Fujian Medical University, Fuzhou, China.

 

Abstract

RATIONALE:

At present, data regarding refractory pneumothorax treated with video-assisted thoracic surgery (VATS) in combination with extracorporeal membrane oxygenation (ECMO) in critically ill patients with H7N9 pneumonia have never been reported.

PATIENT CONCERNS:

A laboratory-confirmed case of human infection with avian influenza A (H7N9) virus was treated in our hospital. Acute respiratory distress syndrome (ARDS) developed and the patient was oxygenated via veno-venous ECMO due to the failure of mechanical ventilation. Unfortunately, a right refractory pneumothorax occurred. Despite treatment with pleural drainage and select bronchial occlusion, the patient still failed to improve.

DIAGNOSIS:

Fatal H7N9 pneumonia complicated with severe ARDS, pulmonary bullae, and refractory pneumothorax.

INTERVENTIONS:

Successful combination of ECMO with VATS of pulmonary bullae resection was performed and pneumothorax was cured.

OUTCOMES:

One week after the operation, ECMO was removed. However, the patient finally developed multiorgan failure (MOF) complicated by refractory hypoxemia due to progressive lung fibrosis and died 36 days after admission.

LESSONS:

Although the patient died of MOF triggered by severe lung fibrosis at last, the successful treatment of refractory pneumothorax by combination of ECMO with VATS is encouraging. Thus, when refractory pneumothorax in a patient with severe pulmonary dysfunction fails to improve through routine therapy, the treatment of pneumothorax by VATS based on ECMO support can be considered as a feasible selection.

PMID: 31096495 DOI: 10.1097/MD.0000000000015661

Keywords: Avian Influenza; H7N9; ECMO; ARDS; Pneumonia; Pneumothorax; China.

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#Outcomes of #severe #human #metapneumovirus-associated #CAP in adults (J Clin Virol., abstract)

[Source: Journal of Clinical Virology, full page: (LINK). Abstract, edited.]

Journal of Clinical Virology / Available online 15 May 2019 / In Press, Accepted Manuscript

Outcomes of severe human metapneumovirus-associated community-acquired pneumonia in adults

Sang-Ho Choi a1, Sang-Bum Hong b1, Jin Won Huh b, Jiwon Jung a, Min Jae Kim a, Yong Pil Chong a, Sung-Han Kim a, Heungsup Sung c, Hyun Jung Koo d, Kyung-Hyun Do d, Sang-Oh Lee a, Chae-Man Lim b, Yang Soo Kim a, Jun Hee Woo a, Younsuck Koh b

{a} Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; {b} Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; {c} Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea; {d} Department of Radiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea

Received 5 July 2018, Revised 2 May 2019, Accepted 13 May 2019, Available online 15 May 2019. DOI: https://doi.org/10.1016/j.jcv.2019.05.007

 

Highlights

  • We compared the outcomes of severe human metapneumovirus-associated community-acquired pneumonia (CAP) and influenza virus-associated CAP.
  • Human metapneumovirus accounted for 3.2% of severe CAP cases.
  • Influenza virus accounted for 7.0% of severe CAP cases.
  • Coinfection was more common in severe influenza virus-associated CAP patients.
  • The two groups had similar overall mortality rates.

 

Abstract

Background

The outcomes of severe human metapneumovirus (HMPV)-associated pneumonia have not been adequately evaluated.

Objectives

We aimed to investigate the incidence and outcomes of severe HMPV-associated CAP and to compare them with those of severe IFV associated CAP.

Study design

From March 2010 to August 2017, all consecutive adult patients with severe HMPV-associated CAP and severe influenza virus (IFV)-associated CAP who required intensive care unit admission were prospectively identified and followed in a 2,700-bed tertiary care hospital. The characteristics and outcomes of severe HMPV-associated CAP patients were compared with those of severe IFV-associated CAP patients.

Results

HMPV and IFV were identified in 3.2% (50) and 7.0% (109) of the 1,559 patients with severe CAP, respectively. The mortality rates were not significantly different between the HMPV and IFV groups (30-day mortality: 24.0% vs. 32.1%, p = 0.30; 60-day mortality: 32.0% vs. 38.5%, p = 0.43). Oral ribavirin therapy was not associated with improved outcome (60-day mortality: ribavirin therapy group 35.0% [7/20] vs. no ribavirin therapy group 30.0% [9/30], p = 0.71). Subgroup analyses showed no significant differences in mortality among non-immunocompromised (60-day mortality: HMPV 25.6% vs. IFV 31.1%, p = 0.55) and immunocompromised patients (60-day mortality; HMPV 54.5% vs. 54.3%, p = 0.99). The length of ICU and hospital stay did not differ between groups.

Conclusions

The incidence of HMPV infection was approximately half that of IFV infection in a cohort of patients with severe CAP. The mortality rate of severe HMPV-associated CAP was similar to that of severe IFV associated CAP.

Abbreviations: HMPV = human metapneumovirus  – CAP ) community-acquired pneumonia – ICU  = intensive care unit – IFV = influenza virus – IVIG = intravenous immunoglobulin  – APACHE = Acute Physiological and Chronic Health Evaluation –
SOFA = Sequential Organ Failure Assessment

Keywords: Pneumonia – Metapneumovirus – Influenza – Intensive care unit – Mortality

1 Both authors contributed equally to this study.

© 2019 Elsevier B.V. All rights reserved.

Keywords: Metapneumovirus; Influenza A; Pneumonia.

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#Combination #therapy targeting #platelet activation and virus #replication protects mice against lethal #influenza #pneumonia (Am J Respir Cell Mol Biol., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Am J Respir Cell Mol Biol. 2019 May 9. doi: 10.1165/rcmb.2018-0196OC. [Epub ahead of print]

Combination therapy targeting platelet activation and virus replication protects mice against lethal influenza pneumonia.

Pulavendran S1, Rudd JM2, Maram P3, Thomas PG4, Akhilesh R3, Malayer JR2, Chow VT5, Teluguakula N6.

Author information: 1 Oklahoma State University Center for Veterinary Sciences, 70729, Stillwater, Oklahoma, United States. 2 Oklahoma State University Stillwater, 7618, Physiological Sciences, Stillwater, Oklahoma, United States. 3 Oklahoma State University Stillwater, 7618, Center for Veterinary Health Sciences, Stillwater, Oklahoma, United States. 4 St. Jude Children’s Research Hospital, Immunology, Memphis, Tennessee, United States. 5 National University of Singapore, Microbiology, Singapore, Singapore, Singapore. 6 Oklahoma State University Stillwater, 7618, Physiological Sciences, Stillwater, Oklahoma, United States ; narasa@okstate.edu.

 

Abstract

Excessive neutrophils recruited during influenza pneumonia contribute to severe lung pathology through induction of neutrophil extracellular traps (NETs) and release of extracellular histones. We have recently shown that activation of platelets during influenza enhances pulmonary microvascular thrombosis leading to vascular injury and hemorrhage. Emerging evidence indicates that activated platelets also interact with neutrophils forming neutrophil-platelet aggregates (NPAs), which contribute to tissue injury. Here, we examined neutrophil-platelet interactions and evaluated formation of NPAs during influenza pneumonia. We also evaluated the efficacy of clopidogrel (CLP), an antagonist of the ADP-P2Y12 platelet receptor, alone or in combination with an antiviral agent, oseltamivir against influenza infection in mice. Our studies demonstrate increased platelet activation and induction of NPAs in influenza-infected lungs and these NPAs lead to NETs release both in in vitro and in vivo. Further, neutrophil integrin macrophage-1 antigen (Mac-1) mediated platelet binding was critical in NPAs formation and NETs release. Administration of CLP reduced platelet activation and NPA formation, but did not protect mice against lethal-influenza challenge. However, administration of CLP together with oseltamivir improved survival in mice compared to oseltamivir-alone treatment. Combination treatment reduced lung pathology, neutrophil influx, NPAs, NETs release and inflammatory cytokine release in infected-lungs. Taken together, these studies provide first report that NPAs formed during influenza contribute to acute lung injury. Targeting both platelet activation in addition to virus replication could represent an effective therapeutic option for treatment of severe influenza pneumonia.

KEYWORDS: Influenza, neutrophils, neutrophil extracellular traps, platelets, pneumonia

PMID: 31070937 DOI: 10.1165/rcmb.2018-0196OC

Keywords: Influenza A; Pneumonia; Immunopathology.

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CAL02, a novel #antitoxin liposomal agent, in severe #pneumococcal #pneumonia: a first-in-human, double-blind, placebo-controlled, randomised trial (Lancet Infect Dis., abstract)

[Source: The Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

CAL02, a novel antitoxin liposomal agent, in severe pneumococcal pneumonia: a first-in-human, double-blind, placebo-controlled, randomised trial

Prof Pierre-François Laterre, MD, Gwenhael Colin, MD, Prof Pierre-François Dequin, MD, Thierry Dugernier, MD, Thierry Boulain, MD, Samareh Azeredo da Silveira, PhD, Frédéric Lajaunias, PhD, Antonio Perez, MD, Bruno François, MD

Published: May 02, 2019 / DOI: https://doi.org/10.1016/S1473-3099(18)30805-3

 

Summary

Background

Severe community-acquired pneumonia caused by Streptococcus pneumoniae is associated with high morbidity and mortality rates. CAL02, a novel antitoxin agent with an unprecedented mode of action, consists of liposomes that capture bacterial toxins known to dysregulate inflammation, cause organ damage, and impede immune defence. We aimed to assess the safety of CAL02 as an add-on therapy to antibiotics.

Methods

This randomised, double-blind, multicentre, placebo-controlled trial was done in ten intensive care units (ICUs) in France and Belgium (but only six units enrolled patients), in patients with severe community-acquired pneumococcal pneumonia who required ICU admission and had been identified as being infected with S pneumoniae. We randomly assigned participants in two stages—the first stage randomly assigned six patients (1:1) to either low-dose CAL02 or placebo, and the second stage randomly assigned 18 patients (14:4) to either high-dose CAL02 or placebo, and stratified in four blocks (4:1, 4:1, 3:1, and 3:1), in addition to standard of care. Block randomisation was done with a computer-generated random number list. Participants, investigators, other site study personnel, the sponsor, and the sponsor’s designees involved in study management and monitoring were masked to the randomisation list and treatment assignment. Patients were treated with low-dose (4 mg/kg) or high-dose (16 mg/kg) CAL02 or placebo (saline), in addition to standard antibiotic therapy. Two intravenous doses of study treatment were infused, with a 24 h interval, at a concentration of 10 mg/mL, stepwise, over a maximum of 2 h on days 1 and 2. The primary objective of the study was to assess the safety and tolerability of low-dose and high-dose CAL02 in patients with severe community-acquired pneumonia treated with standard antibiotic therapy, and the primary analysis was done on the safety population (all patients who received at least one dose of the study treatment). Efficacy was a secondary outcome. This trial is registered with ClinicalTrials.gov, number NCT02583373.

Findings

Between March 21, 2016, and Jan 13, 2018, we screened 280 patients with community-acquired pneumonia. 19 patients were enrolled and randomly assigned, resulting in 13 patients in the CAL02 groups (three assigned to low-dose CAL02 and ten assigned to high-dose CAL02) and six in the placebo group. One patient randomly assigned to placebo was allocated to the wrong treatment group and received high-dose CAL02 instead of placebo. Thus, 14 patients received CAL02 (three received low-dose CAL02 and 11 received high-dose CAL02) and five patients received placebo, constituting the safety population. At baseline, the mean APACHE II score for the total study population was 21·5 (SD 4·9; 95% CI 19·3–23·7) and 11 (58%) of 19 patients had septic shock. Adverse events occurred in 12 (86%) of 14 patients in the CAL02 treatment groups combined and all five (100%) patients in the placebo group. Serious adverse events occurred in four (29%) of 14 patients in the CAL02 treatment groups combined and two (40%) of five patients in the placebo group. One non-serious adverse event (mild increase in triglycerides) in a patient in the high-dose CAL02 group was reported as related to study drug. However, analysis of the changes in triglyceride levels in the CAL02 groups compared with the placebo group revealed no correlation with administration of CAL02. No adverse events were linked to local tolerability events. All patients, apart from one who died in the low CAL02 group (death not related to the study drug) achieved clinical cure at the test of cure visit between days 15 and 22. The sequential organ failure assessment score decreased by mean 65·0% (95% CI 50·7–79·4) in the combined CAL02 groups compared with 29·2% (12·8–45·5) in the placebo group between baseline and day 8.

Interpretation

The nature of adverse events was consistent with the profile of the study population and CAL02 showed a promising safety profile and tolerability. However, the difference between high-dose and low-dose CAL02 could not be assessed in this study. Efficacy was in line with the expected benefits of neutralising toxins. The results of this study support further clinical development of CAL02 and provide a solid basis for a larger clinical study.

Funding

Combioxin.

Keywords: Streptococcus pneumoniae; Pneumonia; Antitoxin.

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#Purulent #bronchitis in 1917 and #pandemic #influenza in 1918 (Lancet Infect Dis., summary)

[Source: The Lancet Infectious Diseases, full page: (LINK). Summary, edited.]

Purulent bronchitis in 1917 and pandemic influenza in 1918

Jim Cox, Douglas Gill, Fiona Cox, Michael Worobey

Published: April, 2019 / DOI: https://doi.org/10.1016/S1473-3099(19)30114-8

___

A remarkable Lancet paper, which is probably the first description of the so-called 1918 Spanish influenza outbreak,1 is omitted from the journal’s Pandemic influenza: 100 years microsite. We wish to draw attention to this work, both to augment the excellent timeline of landmark events in influenza history in the microsite and to describe this early paper’s relevance to understanding the origin of the 1918 influenza pandemic.

(…)

We declare no competing interests.

Keywords: Pandemic Influenza; Spanish Flu; France; Pneumonia.

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#Pseudomonas aeruginosa stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of #lung inflammatory #injury (Thorax, abstract)

[Source: Thorax, full page: (LINK). Abstract, edited.]

Pseudomonas aeruginosa stimulates nuclear sphingosine-1-phosphate generation and epigenetic regulation of lung inflammatory injury

David L Ebenezer1, Evgeny V Berdyshev2, Irina A Bronova2, Yuru Liu3, Chinnaswamy Tiruppathi3, Yulia Komarova3, Elizaveta V Benevolenskaya1, Vidyani Suryadevara4, Alison W Ha1, Anantha Harijith5, Rubin M Tuder6, Viswanathan Natarajan3,4, Panfeng Fu3

Author affiliations: {1} Department of Biochemistry and Molecular Genetics, University of Illinois, Chicago, Illinois, USA; {2} Department of Medicine, National Jewish Health, Denver, Colorado, USA; {3} Department of Pharmacology, University of Illinois, Chicago, Illinois, USA; {4} Department of Medicine, University of Illinois, Chicago, Illinois, USA; {5} Department of Pediatrics, University of Illinois, Chicago, Illinois, USA; {6} Department of Medicine, University of Colorado, Denver, Colorado, USA

Correspondence to Dr Viswanathan Natarajan and Dr Panfeng Fu, Department of Pharmacology, University of Illinois, Chicago IL 60612, USA; visnatar@uic.edu, pfu@uic.edu

 

Abstract

Introduction 

Dysregulated sphingolipid metabolism has been implicated in the pathogenesis of various pulmonary disorders. Nuclear sphingosine-1-phosphate (S1P) has been shown to regulate histone acetylation, and therefore could mediate pro-inflammatory genes expression.

Methods 

Profile of sphingolipid species in bronchoalveolar lavage fluids and lung tissue of mice challenged with Pseudomonas aeruginosa (PA) was investigated. The role of nuclear sphingosine kinase (SPHK)2 and S1P in lung inflammatory injury by PA using genetically engineered mice was determined.

Results 

Genetic deletion of Sphk2, but not Sphk1, in mice conferred protection from PA-mediated lung inflammation. PA infection stimulated phosphorylation of SPHK2 and its localisation in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SPHK2 activity reduced PA-mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-α. The clinical significance of the findings is supported by enhanced nuclear localisation of p-SPHK2 in the epithelium of lung specimens from patients with cystic fibrosis (CF).

Conclusions 

Our studies define a critical role for nuclear SPHK2/S1P signalling in epigenetic regulation of bacterial-mediated inflammatory lung injury. Targeting SPHK2 may represent a potential strategy to reduce lung inflammatory pulmonary disorders such as pneumonia and CF.

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DOI: http://dx.doi.org/10.1136/thoraxjnl-2018-212378

 

Footnotes

VN and PF contributed equally.

Contributors 

PF, DLE, VN, CT, YK, and EVB designed the research; DLE, EVB, IAB, VS, AWH, AH, RMT and VN performed the experiments; VN, DLE and PF analyzed the data and wrote the manuscript.

Funding 

This work was partly supported by the US National Institutes of Health grant P01 Hl09850 to VN.

Competing interests 

None declared.

Ethics approval 

This study was approved by the University of Colorado Institutional Review Board.

Provenance and peer review 

Not commissioned; externally peer reviewed.

Correction notice 

This article has been corrected since it was published Online First. A correction was made to Figure 4.

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Keywords: Pseudomonas aeruginosa; Pneumonia; Acute Lung Injury.

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