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Baz AA, Hao H, Lan S, Li Z, Liu S, Jin X, Chen S, Chu Y. Emerging insights into macrophage extracellular traps in bacterial infections. FASEB J 2024; 38:e23767. [PMID: 38924166 DOI: 10.1096/fj.202400739r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 06/28/2024]
Abstract
Macrophages possess a diverse range of well-defined capabilities and roles as phagocytes, encompassing the regulation of inflammation, facilitation of wound healing, maintenance of tissue homeostasis, and serving as a crucial element in the innate immune response against microbial pathogens. The emergence of extracellular traps is a novel strategy of defense that has been observed in several types of innate immune cells. In response to infection, macrophages are stimulated and produce macrophage extracellular traps (METs), which take the form of net-like structures, filled with strands of DNA and adorned with histones and other cellular proteins. METs not only capture and eliminate microorganisms but also play a role in the development of certain diseases such as inflammation and autoimmune disorders. The primary objective of this study is to examine the latest advancements in METs for tackling bacterial infections. We also delve into the current knowledge and tactics utilized by bacteria to elude or endure the effects of METs. Through this investigation, we hope to shed light on the intricate interactions between bacteria and the host's immune system, particularly in the context of microbicidal effector mechanisms of METs. The continued exploration of METs and their impact on host defense against various pathogens opens up new avenues for understanding and potentially manipulating the immune system's response to infections.
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Affiliation(s)
- Ahmed Adel Baz
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
- Botany and Microbiology Department, Faculty of Science, Al-Azhar University, Assiut, Egypt
| | - Huafang Hao
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Shimei Lan
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Zhangcheng Li
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Shuang Liu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Xiangrui Jin
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Shengli Chen
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
| | - Yuefeng Chu
- State Key Laboratory for Animal Disease Control and Prevention, College of Veterinary Medicine, Lanzhou University, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, China
- Gansu Province Research Center for Basic Disciplines of Pathogen Biology, Lanzhou, China
- Key Laboratory of Veterinary Etiological Biology, Key Laboratory of Ruminant Disease Prevention and Control (West), Ministry of Agricultural and Rural Affairs, Lanzhou, China
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Yu SY, Li HL, Tse YK, Li X, Ren QW, Wu MZ, Wong PF, Tse HF, Lip GYH, Yiu KH. Pre-admission and In-Hospital Statin Use is Associated With Reduced Short-Term Mortality in Infective Endocarditis. Mayo Clin Proc 2023; 98:252-265. [PMID: 36114025 DOI: 10.1016/j.mayocp.2022.06.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2021] [Revised: 04/11/2022] [Accepted: 06/02/2022] [Indexed: 02/07/2023]
Abstract
OBJECTIVE To investigate for potential protective effects of statin use among patients with infective endocarditis (IE) with consideration for underlying diseases and bacterial culture - variables which have prognostic implications and show considerable geographic variation yet are unappreciated in previous pharmacoepidemiological studies. PATIENTS AND METHODS Patients diagnosed with IE between January 1, 1996, and December 31, 2019, were identified. We estimated the effect on mortality of pre-admission statin use (≥90 cumulative days of use before index date) and in-hospital use (use beginning within 2 days of admission), compared with nonusers and discontinued users, respectively, through propensity score analytics. RESULTS Of 6700 IE patients (mean age, 58.0 years; 63.3% male [n=4251]), 776 patients had pre-admission statin use, with 626 continuing statin use following admission (in-hospital users). Pre-admission statin users had a 31% lower risk of 1-year mortality (HR, 0.69; 95% CI, 0.58 to 0.82) compared with nonusers. In-hospital users had a 48% lower risk of 1-year mortality (HR, 0.52; 95% CI, 0.34 to 0.78) compared with discontinued users. Subgroup analyses showed significant protective effects of statin use for patients with varying causative agents, underlying diseases, and with or without prosthetic valves. Results were consistent across different statins, and were dose-dependent. CONCLUSION In patients with IE, pre-admission and in-hospital use of statin, when compared with statin nonusers and discontinued users, respectively, were associated with a lower risk of 1-year mortality.
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Affiliation(s)
- Si-Yeung Yu
- Division of Cardiology, Department of Medicine, the University of Hong Kong Shenzhen Hospital, Shenzhen, China; Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Hang-Long Li
- Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Yi-Kei Tse
- Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Xue Li
- Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Qing-Wen Ren
- Division of Cardiology, Department of Medicine, the University of Hong Kong Shenzhen Hospital, Shenzhen, China; Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Mei-Zhen Wu
- Division of Cardiology, Department of Medicine, the University of Hong Kong Shenzhen Hospital, Shenzhen, China; Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Pui-Fai Wong
- Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Hung-Fat Tse
- Division of Cardiology, Department of Medicine, the University of Hong Kong Shenzhen Hospital, Shenzhen, China; Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
| | - Kai-Hang Yiu
- Division of Cardiology, Department of Medicine, the University of Hong Kong Shenzhen Hospital, Shenzhen, China; Division of Cardiology, Department of Medicine, the University of Hong Kong, Queen Mary Hospital, Hong Kong, China.
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Cima Cabal MD, Molina F, López-Sánchez JI, Pérez-Santín E, Del Mar García-Suárez M. Pneumolysin as a target for new therapies against pneumococcal infections: A systematic review. PLoS One 2023; 18:e0282970. [PMID: 36947540 PMCID: PMC10032530 DOI: 10.1371/journal.pone.0282970] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2022] [Accepted: 02/28/2023] [Indexed: 03/23/2023] Open
Abstract
BACKGROUND This systematic review evaluates pneumolysin (PLY) as a target for new treatments against pneumococcal infections. Pneumolysin is one of the main virulence factors produced by all types of pneumococci. This toxin (53 kDa) is a highly conserved protein that binds to cholesterol in eukaryotic cells, forming pores that lead to cell destruction. METHODS The databases consulted were MEDLINE, Web of Science, and Scopus. Articles were independently screened by title, abstract, and full text by two researchers, and using consensus to resolve any disagreements that occurred. Articles in other languages different from English, patents, cases report, notes, chapter books and reviews were excluded. Searches were restricted to the years 2000 to 2021. Methodological quality was evaluated using OHAT framework. RESULTS Forty-one articles describing the effects of different molecules that inhibit PLY were reviewed. Briefly, the inhibitory molecules found were classified into three main groups: those exerting a direct effect by binding and/or blocking PLY, those acting indirectly by preventing its effects on host cells, and those whose mechanisms are unknown. Although many molecules are proposed as toxin blockers, only some of them, such as antibiotics, peptides, sterols, and statins, have the probability of being implemented as clinical treatment. In contrast, for other molecules, there are limited studies that demonstrate efficacy in animal models with sufficient reliability. DISCUSSION Most of the studies reviewed has a good level of confidence. However, one of the limitations of this systematic review is the lack of homogeneity of the studies, what prevented to carry out a statistical comparison of the results or meta-analysis. CONCLUSION A panel of molecules blocking PLY activity are associated with the improvement of the inflammatory process triggered by the pneumococcal infection. Some molecules have already been used in humans for other purposes, so they could be safe for use in patients with pneumococcal infections. These patients might benefit from a second line treatment during the initial stages of the infection preventing acute respiratory distress syndrome and invasive pneumococcal diseases. Additional research using the presented set of compounds might further improve the clinical management of these patients.
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Affiliation(s)
- María Dolores Cima Cabal
- Escuela Superior de Ingeniería y Tecnología (ESIT), Universidad Internacional de La Rioja, UNIR, Logroño, La Rioja, Spain
| | - Felipe Molina
- Genética, Facultad de Ciencias, Universidad de Extremadura, Badajoz, Spain
| | - José Ignacio López-Sánchez
- Escuela Superior de Ingeniería y Tecnología (ESIT), Universidad Internacional de La Rioja, UNIR, Logroño, La Rioja, Spain
| | - Efrén Pérez-Santín
- Escuela Superior de Ingeniería y Tecnología (ESIT), Universidad Internacional de La Rioja, UNIR, Logroño, La Rioja, Spain
| | - María Del Mar García-Suárez
- Escuela Superior de Ingeniería y Tecnología (ESIT), Universidad Internacional de La Rioja, UNIR, Logroño, La Rioja, Spain
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Alves V, Araújo GR, Frases S. Off-label treatments as potential accelerators in the search for the ideal antifungal treatment of cryptococcosis. Future Microbiol 2023; 18:127-135. [PMID: 36688321 DOI: 10.2217/fmb-2022-0122] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023] Open
Abstract
Cryptococcosis is an opportunistic mycosis that mainly affects immunosuppressed patients. The treatment is a combination of three antifungal agents: amphotericin B, 5-flucytosine and fluconazole. However, these drugs have many disadvantages, such as high nephrotoxicity, marketing bans in some countries and fungal resistance. One of the solutions to find possible new drugs is pharmacological repositioning. This work presents repositioned drugs as an alternative for new antifungal therapies for cryptococcosis. All the studies here were performed in vitro or in animal models, except for sertraline, which reached phase III in humans. There is still no pharmacological repositioning approval for cryptococcosis in humans, though this review shows the potential of repurposing as a rapid approach to finding new agents to treat cryptococcosis.
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Affiliation(s)
- Vinicius Alves
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941902, Brazil
| | - Glauber Rs Araújo
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941902, Brazil
| | - Susana Frases
- Laboratório de Biofísica de Fungos, Instituto de Biofísica Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, 21941902, Brazil
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Watson K, Russell CD, Baillie JK, Dhaliwal K, Fitzgerald JR, Mitchell TJ, Simpson AJ, Renshaw SA, Dockrell DH. Developing Novel Host-Based Therapies Targeting Microbicidal Responses in Macrophages and Neutrophils to Combat Bacterial Antimicrobial Resistance. Front Immunol 2020; 11:786. [PMID: 32582139 PMCID: PMC7289984 DOI: 10.3389/fimmu.2020.00786] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2020] [Accepted: 04/07/2020] [Indexed: 12/11/2022] Open
Abstract
Antimicrobial therapy has provided the main component of chemotherapy against bacterial pathogens. The effectiveness of this strategy has, however, been increasingly challenged by the emergence of antimicrobial resistance which now threatens the sustained utility of this approach. Humans and animals are constantly exposed to bacteria and have developed effective strategies to control pathogens involving innate and adaptive immune responses. Impaired pathogen handling by the innate immune system is a key determinant of susceptibility to bacterial infection. However, the essential components of this response, specifically those which are amenable to re-calibration to improve host defense, remain elusive despite extensive research. We provide a mini-review focusing on therapeutic targeting of microbicidal responses in macrophages and neutrophils to de-stress reliance on antimicrobial therapy. We highlight pre-clinical and clinical data pointing toward potential targets and therapies. We suggest that developing focused host-directed therapeutic strategies to enhance "pauci-inflammatory" microbial killing in myeloid phagocytes that maximizes pathogen clearance while minimizing the harmful consequences of the inflammatory response merits particular attention. We also suggest the importance of One Health approaches in developing host-based approaches through model development and comparative medicine in informing our understanding of how to deliver this strategy.
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Affiliation(s)
- Katie Watson
- Department of Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom.,Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - Clark D Russell
- Department of Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom.,Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.,Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - J Kenneth Baillie
- Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Kev Dhaliwal
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
| | - J Ross Fitzgerald
- Roslin Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Timothy J Mitchell
- Institute of Microbiology and Infection, University of Birmingham, Birmingham, United Kingdom
| | - A John Simpson
- Institute of Cellular Medicine, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, United Kingdom
| | - Stephen A Renshaw
- Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield Medical School, Sheffield, United Kingdom
| | - David H Dockrell
- Department of Infection Medicine, University of Edinburgh, Edinburgh, United Kingdom.,Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom
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Association of Elevated Plasma Interleukin-18 Level With Increased Mortality in a Clinical Trial of Statin Treatment for Acute Respiratory Distress Syndrome. Crit Care Med 2020; 47:1089-1096. [PMID: 31206358 DOI: 10.1097/ccm.0000000000003816] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
OBJECTIVE A high plasma level of inflammasome mediator interleukin-18 was associated with mortality in observational acute respiratory distress syndrome cohorts. Statin exposure increases both inflammasome activation and lung injury in mouse models. We tested whether randomization to statin therapy correlated with increased interleukin-18 in the ARDS Network Statins for Acutely Injured Lungs from Sepsis trial. DESIGN Retrospective analysis of randomized controlled clinical trial. SETTING Multicenter North American clinical trial, the ARDS Network Statins for Acutely Injured Lungs from Sepsis. PATIENTS Six hundred eighty-three subjects with infection-related acute respiratory distress syndrome, representing 92% of the original trial population. INTERVENTIONS Random assignment of rosuvastatin or placebo for up to 28 days or 3 days after ICU discharge. MEASUREMENTS AND MAIN RESULTS We measured plasma interleukin-18 levels in all Statins for Acutely Injured Lungs from Sepsis patients with sample available at day 0 (baseline, n = 683) and day 3 (after randomization, n = 588). We tested the association among interleukin-18 level at baseline, rising interleukin-18, and the impact of statin therapy on 60-day mortality, adjusting for severity of illness. Baseline plasma interleukin-18 level greater than or equal to 800 pg/mL was highly associated with 60-day mortality, with a hazard of death of 2.3 (95% CI, 1.7-3.1). Rising plasma interleukin-18 was also associated with increased mortality. For each unit increase in log2 (interleukin-18) at day 3 compared with baseline, the hazard of death increased by 2.3 (95% CI, 1.5-3.5). Subjects randomized to statin were significantly more likely to experience a rise in plasma interleukin-18 levels. Subjects with acute kidney injury, shock, low baseline interleukin-18, and those not receiving systemic corticosteroids were more likely to experience rising interleukin-18. Randomization to statin therapy was associated with rising in interleukin-18 in all of those subsets, however. CONCLUSIONS Elevated baseline plasma interleukin-18 was associated with higher mortality in sepsis-induced acute respiratory distress syndrome. A rise in plasma interleukin-18 was also associated with increased mortality and was more common in subjects randomized to statin therapy in this clinical trial.
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7
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Kim MC, Yun SC, Lee SO, Choi SH, Kim YS, Woo JH, Kim SH. Association between Tuberculosis, Statin Use, and Diabetes: A Propensity Score-Matched Analysis. Am J Trop Med Hyg 2020; 101:350-356. [PMID: 31264561 DOI: 10.4269/ajtmh.18-0983] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Statins have anti-inflammatory and immunomodulatory properties that may affect the development of tuberculosis (TB). We assessed the association between use of statins and the risk of active TB by propensity score matching. Furthermore, we analyzed the impact of statins on TB in patients according to the presence or absence of diabetes. The study was based on the National Health Insurance database and its subset database of the "medical checkup" population of South Korea. We identified 123,468 statin users and 439,546 non-statin users. After propensity score matching, 28,018 statin users and the same number of non-statin users were finally analyzed. The development of active TB was monitored in these matched pairs over 11 years. In the propensity score-matching analysis, the number of active TB cases was 30 in 30,303 person-years (0.99 per 1,000 person-years; 95% CI, 0.64-1.35) in the statin users and 235 in 167,857 person-years (1.40 per 1,000 person-years; 95% CI, 1.22-1.58) in the non-statin users. Statin users had a significantly lower risk of TB than non-statin users: hazard ratio (HR) 0.67 (95% CI, 0.46-0.98) (P = 0.04). A subgroup analysis showed that statin use reduced the risk of TB in subjects without diabetes, but not in patients with diabetes: HRs were, respectively, 0.28 (95% CI, 0.13-0.60) (P = 0.001) and 1.05 (95% CI, 0.66-1.67) (P = 0.84). There is epidemiologic evidence that statin decreases the risk of active TB. However, the protective effect of statins against TB is attenuated by diabetes.
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Affiliation(s)
- Min-Chul Kim
- Division of Infectious Diseases, Department of Internal Medicine, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Sung-Cheol Yun
- Department of Clinical Epidemiology and Biostatistics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang-Oh Lee
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sang-Ho Choi
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Yang Soo Kim
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Jun Hee Woo
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Sung-Han Kim
- Department of Infectious Diseases, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
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Parihar SP, Guler R, Brombacher F. Statins: a viable candidate for host-directed therapy against infectious diseases. Nat Rev Immunol 2019; 19:104-117. [PMID: 30487528 DOI: 10.1038/s41577-018-0094-3] [Citation(s) in RCA: 106] [Impact Index Per Article: 17.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Statins were first identified over 40 years ago as lipid-lowering drugs and have been remarkably effective in treating cardiovascular diseases. As research advanced, the protective effects of statins were additionally attributed to their anti-inflammatory, antioxidative, anti-thrombotic and immunomodulatory functions rather than lipid-lowering abilities alone. By promoting host defence mechanisms and inhibiting pathological inflammation, statins increase survival in human infectious diseases. At the cellular level, statins inhibit the intermediates of the host mevalonate pathway, thus compromising the immune evasion strategies of pathogens and their survival. Here, we discuss the potential use of statins as an inexpensive and practical alternative or adjunctive host-directed therapy for infectious diseases caused by intracellular pathogens, such as viruses, protozoa, fungi and bacteria.
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Affiliation(s)
- Suraj P Parihar
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town-Component, Cape Town, South Africa. .,Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC), Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. .,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. .,Division of Medical Microbiology, Department of Pathology, University of Cape Town, Cape Town, South Africa.
| | - Reto Guler
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town-Component, Cape Town, South Africa.,Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC), Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Frank Brombacher
- International Centre for Genetic Engineering and Biotechnology (ICGEB), Cape Town-Component, Cape Town, South Africa. .,Institute of Infectious Diseases and Molecular Medicine (IDM), Department of Pathology, Division of Immunology and South African Medical Research Council (SAMRC), Immunology of Infectious Diseases, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa. .,Wellcome Centre for Infectious Diseases Research in Africa (CIDRI-Africa) and Institute of Infectious Disease and Molecular Medicine (IDM), Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa.
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Geneviève LD, Martani A, Mallet MC, Wangmo T, Elger BS. Factors influencing harmonized health data collection, sharing and linkage in Denmark and Switzerland: A systematic review. PLoS One 2019; 14:e0226015. [PMID: 31830124 PMCID: PMC6907832 DOI: 10.1371/journal.pone.0226015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2019] [Accepted: 11/18/2019] [Indexed: 02/06/2023] Open
Abstract
INTRODUCTION The digitalization of medicine has led to a considerable growth of heterogeneous health datasets, which could improve healthcare research if integrated into the clinical life cycle. This process requires, amongst other things, the harmonization of these datasets, which is a prerequisite to improve their quality, re-usability and interoperability. However, there is a wide range of factors that either hinder or favor the harmonized collection, sharing and linkage of health data. OBJECTIVE This systematic review aims to identify barriers and facilitators to health data harmonization-including data sharing and linkage-by a comparative analysis of studies from Denmark and Switzerland. METHODS Publications from PubMed, Web of Science, EMBASE and CINAHL involving cross-institutional or cross-border collection, sharing or linkage of health data from Denmark or Switzerland were searched to identify the reported barriers and facilitators to data harmonization. RESULTS Of the 345 projects included, 240 were single-country and 105 were multinational studies. Regarding national projects, a Swiss study reported on average more barriers and facilitators than a Danish study. Barriers and facilitators of a technical nature were most frequently reported. CONCLUSION This systematic review gathered evidence from Denmark and Switzerland on barriers and facilitators concerning data harmonization, sharing and linkage. Barriers and facilitators were strictly interrelated with the national context where projects were carried out. Structural changes, such as legislation implemented at the national level, were mirrored in the projects. This underlines the impact of national strategies in the field of health data. Our findings also suggest that more openness and clarity in the reporting of both barriers and facilitators to data harmonization constitute a key element to promote the successful management of new projects using health data and the implementation of proper policies in this field. Our study findings are thus meaningful beyond these two countries.
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Affiliation(s)
| | - Andrea Martani
- Institute for Biomedical Ethics, University of Basel, Basel, Switzerland
| | | | - Tenzin Wangmo
- Institute for Biomedical Ethics, University of Basel, Basel, Switzerland
| | - Bernice Simone Elger
- Institute for Biomedical Ethics, University of Basel, Basel, Switzerland
- University Center of Legal Medicine, University of Geneva, Geneva, Switzerland
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Wildes TJ, Grippin A, Fasanya H, Dyson KA, Brantly M. Effect of atorvastatin on humoral immune response to 23-valent pneumococcal polysaccharide vaccination in healthy volunteers: The StatVax randomized clinical trial. Vaccine 2019; 37:1313-1324. [PMID: 30686636 DOI: 10.1016/j.vaccine.2019.01.023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 01/04/2019] [Accepted: 01/14/2019] [Indexed: 12/15/2022]
Abstract
BACKGROUND The immunomodulatory effects of statins on vaccine response remain uncertain. Therefore, the objective of this study was to determine if atorvastatin enhances pneumococcal-specific antibody titer following 23-valent pneumococcal polysaccharide vaccination. METHODS Double-blind, placebo-controlled, single-center randomized clinical trial entitled StatVax. Subjects were enrolled between June and July 2014 and followed up through September 2014. 33 healthy volunteers signed informed consent after volunteer sampling. 11 participants were excluded; 22 healthy volunteers without prior pneumococcal vaccination were enrolled and completed the study. Participants were randomized to receive a 28-day course of 40 mg atorvastatin (n = 12) or matching lactose placebo (n = 10). On day 7 of treatment, Pneumovax 23 was administered intramuscularly. The primary outcome was fold change in total pneumococcal-specific antibody titer determined by a ratio of post-vaccination titer over baseline titer. Secondary outcomes included serotype-specific pneumococcal antibody titer, seroconversion, complete blood counts (CBC), erythrocyte sedimentation rate (ESR), and serum cytokine analysis. RESULTS Of the 22 randomized patients (mean age, 23.86; SD, 4.121; 11 women [50%]), 22 completed the trial. Total anti-pneumococcal antibody titer in the atorvastatin group went from a baseline mean of 32.58 (SD, 15.96) to 147.7 (SD, 71.52) μg/mL at 21 days post-vaccination while titer in the placebo group went from a mean of 30.81 (SD, 13.04) to 104.4 (SD, 45) μg/mL. When comparing fold change between treatment groups, there was a significant increase in fold change of total anti-pneumococcal antibody titer in the atorvastatin group compared to the placebo group (2-way ANOVA, p = .0177). CONCLUSIONS Atorvastatin enhances antigen-specific primary humoral immune response to a T cell-independent pneumonia vaccination. Pending confirmation by larger cohort studies of target populations, peri-vaccination conventional doses of statins can become a novel adjuvant for poorly-immunogenic polysaccharide-based vaccines. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT02097589.
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Affiliation(s)
- Tyler J Wildes
- University of Florida MD-PhD Program, College of Medicine, Gainesville, FL, USA; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, FL, USA.
| | - Adam Grippin
- University of Florida MD-PhD Program, College of Medicine, Gainesville, FL, USA; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Henrietta Fasanya
- University of Florida MD-PhD Program, College of Medicine, Gainesville, FL, USA; University of Florida Health Cancer Center, Department of Radiation Oncology, Gainesville, FL, USA
| | - Kyle A Dyson
- University of Florida MD-PhD Program, College of Medicine, Gainesville, FL, USA; University of Florida Brain Tumor Immunotherapy Program, Preston A. Wells, Jr. Center for Brain Tumor Therapy, Lillian S. Wells Department of Neurosurgery, McKnight Brain Institute, University of Florida, Gainesville, FL, USA
| | - Mark Brantly
- University of Florida MD-PhD Program, College of Medicine, Gainesville, FL, USA; University of Florida Division of Pulmonary and Critical Care Medicine, Gainesville, FL, USA
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11
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Oh TK, Song IA, Cho YJ, Lim C, Jeon YT, Bae HJ, Jo YH. Preadmission Statin Therapy Is Associated with a Lower Incidence of Acute Kidney Injury in Critically Ill Patients: A Retrospective Observational Study. J Clin Med 2018; 8:jcm8010025. [PMID: 30585236 PMCID: PMC6351906 DOI: 10.3390/jcm8010025] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 12/17/2018] [Accepted: 12/20/2018] [Indexed: 12/24/2022] Open
Abstract
This study aimed to investigate the association between preadmission statin use and acute kidney injury (AKI) incidence among critically ill patients who needed admission to the intensive care unit (ICU) for medical care. Medical records of patients admitted to the ICU were reviewed. Patients who continuously took statin for >1 month prior to ICU admission were defined as statin users. We investigated whether preadmission statin use was associated with AKI incidence within 72 h after ICU admission and whether the association differs according to preadmission estimated glomerular filtration rate (eGFR; in mL min−1 1.73 m−2). Among 21,236 patients examined, 5756 (27.1%) were preadmission statin users and 15,480 (72.9%) were non-statin users. Total AKI incidence within 72 h after ICU admission was 31% lower in preadmission statin users than in non-statin users [odds ratio (OR), 0.69; 95% confidence interval (CI), 0.61–0.79; p < 0.001]. This association was insignificant among individuals with eGFR <30 mL min−1 1.73 m−2 (p > 0.05). Our results suggested that preadmission statin therapy is associated with a lower incidence of AKI among critically ill patients; however, this effect might not be applicable for patients with eGFR <30 mL min−1 1.73 m−2.
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Affiliation(s)
- Tak Kyu Oh
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea.
| | - In-Ae Song
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea.
| | - Young-Jae Cho
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University Bundang Hospital, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea.
| | - Cheong Lim
- Department of Thoracic and Cardiovascular Surgery, Seoul National University Bundang Hospital, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea.
| | - Young-Tae Jeon
- Department of Anesthesiology and Pain Medicine, Seoul National University Bundang Hospital, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea.
| | - Hee-Joon Bae
- Department of Neurology, Stroke Center, Seoul National University Bundang Hospital, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea.
| | - You Hwan Jo
- Department of Emergency Medicine, Seoul National University Bundang Hospital, Gumi-ro 173 Beon-gil, Bundang-gu, Seongnam 13620, Korea.
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12
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Lüthje P, Walker S, Kamolvit W, Mohanty S, Pütsep K, Brauner A. Statins influence epithelial expression of the anti-microbial peptide LL-37/hCAP-18 independently of the mevalonate pathway. Clin Exp Immunol 2018; 195:265-276. [PMID: 30216432 DOI: 10.1111/cei.13217] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/03/2018] [Indexed: 12/14/2022] Open
Abstract
Anti-microbial resistance increases among bacterial pathogens and new therapeutic avenues needs to be explored. Boosting innate immune mechanisms could be one attractive alternative in the defence against infectious diseases. The cholesterol-lowering drugs, statins, have been demonstrated to also affect the immune system. Here we investigate the effect of statins on the expression of the human cathelicidin anti-microbial peptide (CAMP) LL-37/hCAP-18 [encoded by the CAMP gene] and explore the underlying mechanisms in four epithelial cell lines of different origin. Simvastatin induced CAMP expression in bladder epithelial cells telomerase-immortalized uroepithelial cells (TERT-NHUCs), intestinal cells HT-29 and keratinocytes HEKa, but not in airway epithelial cells A549. Gene induction in HEKa cells was reversible by mevalonate, while this effect was independent of the cholesterol biosynthesis pathway in TERT-NHUCs. Instead, inhibition of histone deacetylases by simvastatin seems to be involved. For HT-29 cells, both mechanisms may contribute. In addition, simvastatin increased transcription of the vitamin D-activating enzyme CYP27B1 which, in turn, may activate LL-37/hCAP-18 production. Taken together, simvastatin is able to promote the expression of LL-37/hCAP-18, but cell line-specific differences in efficacy and the involved signalling pathways exist.
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Affiliation(s)
- P Lüthje
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.,Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | - S Walker
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | - W Kamolvit
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | - S Mohanty
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
| | - K Pütsep
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
| | - A Brauner
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.,Division of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden
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13
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Lorente L. New prognostic biomarkers of mortality in patients undergoing liver transplantation for hepatocellular carcinoma. World J Gastroenterol 2018; 24:4230-4242. [PMID: 30310256 PMCID: PMC6175764 DOI: 10.3748/wjg.v24.i37.4230] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2018] [Revised: 08/18/2018] [Accepted: 08/24/2018] [Indexed: 02/06/2023] Open
Abstract
The outcome prediction of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT) was classically established using various macromorphological factors and serum alpha-fetoprotein levels prior to LT. However, other biomarkers have recently been reported to be associated with the prognosis of HCC patients undergoing to LT. This review summarizes clinical data on these new biomarkers. High blood levels of malondialdehyde, total antioxidant capacity, caspase-cleaved cytokeratin-18, soluble CD40 ligand, substance P, C-reactive protein, and vascular endothelial growth factor, increased neutrophil to lymphocyte ratio and platelet to lymphocyte ratio in blood, high peripheral blood expression of human telomerase reverse transcriptase messenger ribonucleic acid, and high HCC expression of dickkopf-1 have recently been associated with decreased survival rates. In addition, high blood levels of des-gamma-carboxy prothrombin, and high HCC expression of glypican-3, E-cadherin and beta-catenin have been associated with increased HCC recurrence. Additional research is necessary to establish the prognostic role of these biomarkers in HCC prior to LT. Furthermore, some of these biomarkers are also interesting because their potential modulation could help to create new research lines for improving the outcomes of those patients.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Santa Cruz de Tenerife 38320, Spain
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14
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Oda M, Kurosawa M, Yamamoto H, Domon H, Kimura T, Isono T, Maekawa T, Hayashi N, Yamada N, Furue Y, Kai D, Terao Y. Sulfated vizantin induces formation of macrophage extracellular traps. Microbiol Immunol 2018; 62:310-316. [PMID: 29577412 DOI: 10.1111/1348-0421.12589] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2018] [Revised: 03/15/2018] [Accepted: 03/20/2018] [Indexed: 01/19/2023]
Abstract
Vizantin is an insoluble adjuvant that activates macrophages and lymphocytes. Recently, 2,2',3,3',4,4'-hexasulfated-vizantin (sulfated vizantin), which enables solubilization of vizantin, was developed by the present team. Sulfated vizantin was found to enhance bactericidal activity against multi-drug resistant Pseudomonas aeruginosa in RAW264.7 cells. In addition, spread of P. aeruginosa was inhibited in RAW264.7 cells treated with sulfated vizantin. When only sulfated vizantin and P. aeruginosa were incubated, sulfated vizantin did not affect growth of P. aeruginosa. Formation of DNA-based extracellular traps (ETs), a novel defense mechanism in several types of innate immune cells, helps to eliminate pathogens. In the present study, ET-forming macrophages constituted the majority of immune cells. Sulfated vizantin induced ET formation in RAW264.7 cells, whereas a Ca-chelating reagent, EDTA, and T-type calcium channel blocker, tetrandrine, inhibited ET formation and attenuated inhibition of spread of P. aeruginosa in sulfated vizantin-treated cells. Thus, sulfated vizantin induces ET formation in phagocytic cells in a Ca-dependent manner, thus preventing spread of P. aeruginosa. Hence, sulfated vizantin may be useful in the management of infectious diseases.
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Affiliation(s)
- Masataka Oda
- Division of Microbiology and Infectious Diseases, Graduate School ot Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigara, 95 l-8514, Japan.,Department of Microbiology and Infection Control Science, Kyoto Pharmaceutical University, 5 Misasagi, Yamashina, Kyoto, 607-8414, Japan
| | - Mie Kurosawa
- Division of Microbiology and Infectious Diseases, Graduate School ot Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigara, 95 l-8514, Japan
| | - Hirofumi Yamamoto
- Department of Chemistry and Functional Molecule, Faculty of Pharmaceutical Sciences, Tokushima Bunri University, 180 Yamashiro-cho, Tokushima, 770-8514, Japan
| | - Hisanori Domon
- Division of Microbiology and Infectious Diseases, Graduate School ot Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigara, 95 l-8514, Japan
| | - Tatsuya Kimura
- Division of Microbiology and Infectious Diseases, Graduate School ot Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigara, 95 l-8514, Japan
| | - Toshihito Isono
- Division of Microbiology and Infectious Diseases, Graduate School ot Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigara, 95 l-8514, Japan
| | - Tomoki Maekawa
- Research Center for Advanced Oral Science, Graduate School of Medical and Dental Sciences, Niigata University, 2-5274 Gakkocho-dori, Chuo-ku, Niigata, 951-8514, Japan
| | - Naoki Hayashi
- Department of Microbiology and Infection Control Science, Kyoto Pharmaceutical University, 5 Misasagi, Yamashina, Kyoto, 607-8414, Japan
| | - Noriteru Yamada
- Department of Microbiology and Infection Control Science, Kyoto Pharmaceutical University, 5 Misasagi, Yamashina, Kyoto, 607-8414, Japan
| | - Yui Furue
- Department of Microbiology and Infection Control Science, Kyoto Pharmaceutical University, 5 Misasagi, Yamashina, Kyoto, 607-8414, Japan
| | - Daichi Kai
- Department of Microbiology and Infection Control Science, Kyoto Pharmaceutical University, 5 Misasagi, Yamashina, Kyoto, 607-8414, Japan
| | - Yutaka Terao
- Division of Microbiology and Infectious Diseases, Graduate School ot Medical and Dental Sciences, Niigata University, 2-5274, Gakkocho-dori, Chuo-ku, Niigara, 95 l-8514, Japan
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15
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Statins increase the risk of herpes zoster: A propensity score-matched analysis. PLoS One 2018; 13:e0198263. [PMID: 29902266 PMCID: PMC6001979 DOI: 10.1371/journal.pone.0198263] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 05/16/2018] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVES Statins, which are lipid-lowering agents, have anti-inflammatory and immunomodulatory properties that may affect the occurrence of various infectious diseases. We assessed whether statins increase the risk of herpes zoster (HZ) with propensity score-matching. METHODS The study was based on the National Health Insurance database and its subset database of the "medical check-up" population of South Korea. These cohorts consist of about one million and 570,000 people, respectively, representative of the entire population of South Korea. We identified 103,930 statin users and 430,685 non-statin users. After propensity score-matching, 25,726 statin users and the same number of non-statin users were finally analyzed. The development of HZ was monitored in these matched pairs over the 11 years from 2003 to 2013. RESULTS Statin users had a significantly higher risk of HZ than non-statin users: hazard ratio (HR) 1.25 (95% CI, 1.15 to 1.37) (p < .0001). The risk of HZ associated with statins was especially high in the elderly: HR 1.39 (95% CI, 1.12 to 1.73) in the over 70-year-olds (p = 0.003) and HR 1.18 (95% CI, 1.00 to 1.39) in the 60-to-69-year-olds (p = 0.056). Furthermore, there was a significant p for trend in terms of cumulative dose effect between the risk of HZ and the duration of statin use (p < .0001). CONCLUSIONS These epidemiologic findings provide strong evidence for an association between HZ and statin use, and suggest that unnecessary statins should be avoided.
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16
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Huang FC, Huang SC. Differential Effects of Statins on Inflammatory Interleukin-8 and Antimicrobial Peptide Human Β-Defensin 2 Responses in Salmonella-Infected Intestinal Epithelial Cells. Int J Mol Sci 2018; 19:1650. [PMID: 29865262 PMCID: PMC6032317 DOI: 10.3390/ijms19061650] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2018] [Revised: 05/26/2018] [Accepted: 05/30/2018] [Indexed: 12/16/2022] Open
Abstract
Alternative therapies are needed to reduce the use of antibiotics and incidence of drug-resistant Salmonellosis. Previous studies have revealed important roles of statins in regulating innate immunity. Therefore, we investigated the effects of statins on innate immunity in Salmonella-infected intestinal epithelial cells (IECs), which are involved in mucosal innate immunity. SW480 cells and Akt siRNA- or vitamin D receptor (VDR) siRNA-transfected SW480 cells were infected by wild-type S. Typhimurium strain SL1344 in the presence or absence of statins. The mRNA or protein expression was analyzed by real-time quantitative PCR or western blot analysis, respectively. Simvastatin or fluvastatin caused IL-8 (interleukin-8) suppression, but increased hBD-2 mRNA expression in Salmonella-infected SW480 cells. Both statins enhanced phosphorylated Akt and VDR expressions. Akt or VDR knockdown by siRNA counteracted the suppressive effect of simvastatin on IL-8 expression, whereas VDR knockdown diminished the enhanced hBD-2 expression in Salmonella-infected SW480 cells. Therefore, we observed differential regulation of statins on inflammatory IL-8 and anti-microbial hBD-2 expressions in Salmonella-infected IECs via PI3K/Akt signaling and VDR protein expression, respectively. The enhanced activity of antimicrobial peptides by statins in Salmonella-infected IECs could protect the host against infection, and modulation of pro-inflammatory responses could prevent the detrimental effects of overwhelming inflammation in the host.
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Affiliation(s)
- Fu-Chen Huang
- Department of Pediatrics, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung 833, Taiwan.
| | - Shun-Chen Huang
- Department of Pathology, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung 833, Taiwan.
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17
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Treatment with Atorvastatin Provides Additional Benefits to Imipenem in a Model of Gram-Negative Pneumonia Induced by Klebsiella pneumoniae in Mice. Antimicrob Agents Chemother 2018; 62:AAC.00764-17. [PMID: 29463546 DOI: 10.1128/aac.00764-17] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2017] [Accepted: 02/03/2018] [Indexed: 12/14/2022] Open
Abstract
The clinical pathogen Klebsiella pneumoniae is a relevant cause of nosocomial infections, and resistance to current treatment with carbapenem antibiotics is becoming a significant problem. Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) used for controlling plasma cholesterol levels. There is clinical evidence showing other effects of statins, including decrease of lung inflammation. In the current study, we show that pretreatment with atorvastatin markedly attenuated lung injury, which was correlated with a reduction in the cellular influx into the alveolar space and lungs and downmodulation of the production of proinflammatory mediators in the initial phase of infection in C57BL/6 mice with K. pneumoniae However, atorvastatin did not alter the number of bacteria in the lungs and blood of infected mice, despite decreasing local inflammatory response. Interestingly, mice that received combined treatment with atorvastatin and imipenem displayed better survival than mice treated with vehicle, atorvastatin, or imipenem alone. These findings suggest that atorvastatin could be an adjuvant in host-directed therapies for multidrug-resistant K. pneumoniae, based on its powerful pleiotropic immunomodulatory effects. Together with antimicrobial approaches, combination therapy with anti-inflammatory compounds could improve the efficiency of therapy during acute lung infections.
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18
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Karlsson EA, Schultz-Cherry S, Rosch JW. Protective Capacity of Statins during Pneumonia Is Dependent on Etiological Agent and Obesity. Front Cell Infect Microbiol 2018; 8:41. [PMID: 29497602 PMCID: PMC5819214 DOI: 10.3389/fcimb.2018.00041] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 01/31/2018] [Indexed: 01/14/2023] Open
Abstract
Acute respiratory infections are a leading cause of death worldwide. Clinical data is conflicted regarding whether statins improve outcomes for pneumonia. Potential confounding factors including specific etiology of pneumonia as well as obesity could potentially mask protective benefit. Obesity is a risk factor for high cholesterol, the main target for statin therapy. We demonstrate that statin intervention conferred no protective benefit in the context of wild-type mice regardless of infectious agent. Statin intervention conferred either a protective benefit, during influenza infection, or detrimental effect, in the case of pneumococcal infection, in obese animals. These data suggest etiology of pneumonia in the context of obesity could be dramatically altered by the protective effects of statin therapy during bacterial and viral pneumonia.
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Affiliation(s)
- Erik A Karlsson
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Stacey Schultz-Cherry
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, United States
| | - Jason W Rosch
- Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, TN, United States
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19
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Lee M, Lee CC, Lai CC, Hsu TC, Porta L, Lee M, Chang SS, Chien KL, Chen YM. Preadmission statin use improves the outcome of less severe sepsis patients - a population-based propensity score matched cohort study. Br J Anaesth 2017; 119:645-654. [DOI: 10.1093/bja/aex294] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023] Open
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20
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High serum soluble CD40L levels previously to liver transplantation in patients with hepatocellular carcinoma are associated with mortality at one year. J Crit Care 2017; 43:316-320. [PMID: 29020665 DOI: 10.1016/j.jcrc.2017.09.032] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2017] [Revised: 08/29/2017] [Accepted: 09/15/2017] [Indexed: 12/17/2022]
Abstract
PURPOSE CD40L and its soluble form (sCD40L) are proteins of the tumor necrosis factor superfamily (TNFSF) that exhibit prothrombotic and proinflammatory properties when binding to CD40, which is a cell surface receptor of the tumor necrosis factor receptor superfamily (TNFRSF). High circulating levels of sCD40L have been associated with poor prognosis in patients with hepatocellular carcinoma (HCC). However, it is unknown whether there is an association between circulating sCD40L levels and survival in patients with HCC underwent to liver transplantation (LT), and this was the objective of that study. METHODS Serum sCD40L levels were measured in a total of 139 patients before LT (124 survivors at 1year of LT and 15 non-survivors). The end-point study was 1year survival after liver LT. RESULTS We found that 1-year non-surviving patients showed higher serum sCD40L levels than survivor patients (p=0.02). We found in logistic regression analysis that serum sCD40L levels higher than 321pg/mL (Odds Ratio=6.86; 95% confidence interval=2.06-22.76; p=0.002) and age of LT deceased donor were associated with death at 1year. CONCLUSIONS The new finding of our study was that high serum sCD40L levels previously to LT in patients with HCC are associated with higher mortality at one year.
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21
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Kosjerina Z, Vukoja M, Vuckovic D, Kosjerina Ostric V, Jevtic M. Pneumonia: Features registered in autopsy material. Acta Clin Belg 2017; 72:232-237. [PMID: 27654403 DOI: 10.1080/17843286.2016.1232774] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
BACKGROUND Despite improvements in clinical practice, pneumonia remains one of the leading causes of death worldwide. Pathologic findings from autopsy reports could provide more precise and valid data on characteristics of pneumonia patients. METHODS We retrospectively reviewed autopsy reports of deceased patients admitted to the Institute for Pulmonary Diseases of Vojvodina in Sremska Kamenica, Serbia, between 1994 and 2003. The patients were classified into two groups: group 1 (n = 161) comprised patients in whom pneumonia was the main cause of death, while group 2 (n = 165) consisted of patients in whom pneumonia was confirmed at autopsy but had various different causes of death. RESULTS From 1776 patients who underwent autopsy 326 (18.3%) were diagnosed with pneumonia. The most common underlying diseases were atherosclerosis (29.4%), chronic obstructive pulmonary disease (COPD) (26.7%), and malignancies (20.2%). Pneumonia was the main cause of death in 161 cases (group 1) while in group 2 major causes of death were heart failure (HF) (26.7%), acute myocardial infarction (AMI) (16.4%), and pulmonary embolism (PE) (10.9%). Multilobar involvement (91% vs.27%), pulmonary effusion (29% vs.14%), and lung abscess (23.6% vs.8.5%) were more frequently found in group 1, compared to group 2. CONCLUSION In patients with pneumonia who underwent autopsy most common underlying diseases were atherosclerosis, COPD, and malignancies, while major causes of death were: progression of pneumonia, HF, AMI, and PE.
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Affiliation(s)
- Zdravko Kosjerina
- Pathology Department, Institute for Pulmonary Diseases of Vojvodina, University of Novi Sad, Sremska Kamenica, Serbia
| | - Marija Vukoja
- Pathophysiology Department, Institute for Pulmonary Diseases of Vojvodina, University of Novi Sad, Sremska Kamenica, Serbia
| | - Dejan Vuckovic
- Pathology Department, Institute for Pulmonary Diseases of Vojvodina, University of Novi Sad, Sremska Kamenica, Serbia
| | - Vesna Kosjerina Ostric
- Pulmology Department, Institute for Pulmonary Diseases of Vojvodina, University of Novi Sad, Sremska Kamenica, Serbia
| | - Marija Jevtic
- Center for Hygiene and Human Ecology, Institute for Public Health of Vojvodina, University of Novi Sad, Novi Sad, Serbia
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22
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Lorente L, Martín MM, Pérez-Cejas A, Ferreres J, Solé-Violán J, Labarta L, Díaz C, Jiménez A. Non-survivor septic patients have persistently higher serum sCD40L levels than survivors. J Crit Care 2017; 41:177-182. [PMID: 28570959 DOI: 10.1016/j.jcrc.2017.05.021] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2017] [Revised: 04/17/2017] [Accepted: 05/20/2017] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Soluble CD40 ligand (sCD40L) is a protein with proinflammatory and prothrombotic effects. Previously we found higher circulating sCD40L levels in non-survivor than in survivor patients at sepsis diagnosis. Now some questions arise such as how are serum sCD40L levels during the first week of severe sepsis?, is there an association between serum sCD40L levels during the first week and mortality?, and serum sCD40L levels during the first week could be used as sepsis mortality biomarker?. This study was developed to answer these asks. METHODS Study from 6 Spanish Intensive Care Units with 291 severe septic patients. There were determined serum levels of sCD40L and tumor necrosis factor (TNF)-alpha during the first week. The end-point study was 30-day mortality. RESULTS We found that serum sCD40L at days 1, 4, and 8 could predict mortality at 30days, and are associated with mortality. CONCLUSIONS The novel findings of our study were that there were higher serum sCD40L levels persistently during the first week in non-survivor than in survivor patients, that there is an association between serum sCD40L levels during the first week and sepsis mortality, and that serum sCD40L levels during the first week could be used as sepsis mortality biomarker.
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Affiliation(s)
- Leonardo Lorente
- Intensive Care Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain.
| | - María M Martín
- Intensive Care Unit, Hospital Universitario Nuestra Señora Candelaria, Crta Rosario s/n, Santa Cruz Tenerife 38010, Spain.
| | - Antonia Pérez-Cejas
- Laboratory Deparment, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain.
| | - José Ferreres
- Intensive Care Unit, Hospital Clínico Universitario de Valencia, Avda. Blasco Ibáñez no17-19, Valencia 46004, Spain.
| | - Jordi Solé-Violán
- Intensive Care Unit. Hospital Universitario Dr. Negrín, Barranco de la Ballena s/n, Las Palmas de Gran Canaria 35010, Spain.
| | - Lorenzo Labarta
- Intensive Care Unit, Hospital San Jorge de Huesca, Avenida Martínez de Velasco no36, Huesca 22004, Spain.
| | - César Díaz
- Intensive Care Unit, Hospital Insular, Plaza Dr. Pasteur s/n, Las Palmas de Gran Canaria 35016, Spain.
| | - Alejandro Jiménez
- Research Unit, Hospital Universitario de Canarias, Ofra, s/n, La Laguna 38320, Tenerife, Spain.
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Statin Use Is Associated With a Lower Risk of TB. Chest 2017; 152:598-606. [PMID: 28479115 DOI: 10.1016/j.chest.2017.04.170] [Citation(s) in RCA: 66] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2017] [Revised: 03/31/2017] [Accepted: 04/25/2017] [Indexed: 01/17/2023] Open
Abstract
BACKGROUND Statins are widely used to lower cholesterol levels and cardiovascular risk. Further, studies have shown that statins may decrease the risks of infectious diseases and infection-related mortality; however, the association between statin use and active TB disease remains unclear. METHODS Using the Taiwan National Health Insurance Research Database, we conducted a nationwide population-based study. Patients taking statins between 2000 and 2013, without antecedent TB disease, were included. Data from 102,424 statin users and 202,718 age-, sex-, and enrollment date-matched subjects were analyzed. The two cohorts were monitored until December 31, 2013, for incident TB disease. The definition of TB disease was validated using the claims database of Taipei Veterans General Hospital. RESULTS The statin and matched cohorts were observed for 571,568 and 1,027,385 person-years, respectively. Of the total 305,142 subjects, 1,264 (0.41%) developed subsequent TB disease. Validation study confirmed the accuracy of the definition of TB disease (sensitivity, 96.3%), with excellent interobserver agreement (κ = 1.00). Multivariate analysis revealed a reduced risk of TB disease among the statin cohort (hazard ratio [HR], 0.53; 95% CI, 0.47-0.61; P < .001). Compared with the matched group, statin use showed a dose-response relationship with the incident TB disease risk (<180 cumulative defined daily doses [cDDDs]: HR, 1.06; 95% CI, 0.91-1.24; P = .477; 180 to 365 cDDDs: HR, 0.57; 95% CI, 0.45-0.72; P < .001; >365 cDDDs: HR, 0.27; 95% CI, 0.22-0.33; P < .001). CONCLUSIONS Statin use associates with a lower risk of incident TB disease.
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Ribeiro NDQ, Costa MC, Magalhães TFF, Carneiro HCS, Oliveira LV, Fontes ACL, Santos JRA, Ferreira GF, Araujo GRDS, Alves V, Frases S, Paixão TA, de Resende Stoianoff MA, Santos DA. Atorvastatin as a promising anticryptococcal agent. Int J Antimicrob Agents 2017; 49:695-702. [PMID: 28450174 DOI: 10.1016/j.ijantimicag.2017.04.005] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2016] [Revised: 01/16/2017] [Accepted: 01/22/2017] [Indexed: 11/25/2022]
Abstract
Cryptococcosis caused by Cryptococcus gattii leads to pneumonia and meningoencephalitis, and has a high mortality rate worldwide due to the inadequacy of available therapy and increasing drug resistance. There is a need to develop effective treatments, and drug repositioning is an interesting alternative to achieve new strategies to treat cryptococcosis. Atorvastatin (ATO), a statin currently used to treat hypercholesterolaemia, was tested in this study as an adjuvant to control infections caused by C. gattii. Several aspects of the effect of ATO on the host and the yeast were evaluated, with particular focus on the association of ATO with fluconazole (FLC), which (i) reduced ergosterol content in the cell membrane and altered properties of the polysaccharide capsule of C. gattii; (ii) increased the production of reactive oxygen species by macrophages; and (iii) reduced yeast phagocytosis and the intracellular proliferation rate. In an animal model, infected mice treated with ATO + FLC showed increased survival, improved clinical condition, and reduced fungal burden in the lungs and brain. This study is the first to perform in vivo tests with ATO + FLC for the treatment of cryptococcosis. The results suggest that ATO may be an important adjuvant for the treatment of cryptococcosis.
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Affiliation(s)
- Noelly de Queiroz Ribeiro
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | - Marliete Carvalho Costa
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | | | - Hellem Cristina Silva Carneiro
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | - Lorena Vívien Oliveira
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | - Alide Caroline Lima Fontes
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | - Julliana Ribeiro Alves Santos
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil; Laboratório de Micologia, Universidade Ceuma, São Luís, Maranhão, Brazil
| | - Gabriela Freitas Ferreira
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil; Departamento de Farmácia, Universidade Federal de Juiz de Fora-Campus Governador Valadares, Governador Valadares, Brazil
| | - Glauber Ribeiro de Sousa Araujo
- Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Vinícius Alves
- Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Susana Frases
- Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Tatiane Alves Paixão
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil
| | | | - Daniel Assis Santos
- Departamento de Microbiologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Minas Gerais, Brazil.
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Wiemken TL, Kelley RR, Fernandez-Botran R, Mattingly WA, Arnold FW, Furmanek SP, Restrepo MI, Chalmers JD, Peyrani P, Cavallazzi R, Bordon J, Aliberti S, Ramirez JA. Using cluster analysis of cytokines to identify patterns of inflammation in hospitalized patients with community-acquired pneumonia: a pilot study. THE UNIVERSITY OF LOUISVILLE JOURNAL OF RESPIRATORY INFECTIONS 2017; 1:3-11. [PMID: 28393141 DOI: 10.18297/jri/vol1/iss1/1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
INTRODUCTION Patients with severe community-acquired pneumonia (CAP) are believed to have an exaggerated inflammatory response to bacterial infection. Therapies aiming to modulate the inflammatory response have been largely unsuccessful, perhaps reflecting that CAP is a heterogeneous disorder that cannot be modulated by a single anti-inflammatory approach. We hypothesize that the host inflammatory response to pneumonia may be characterized by distinct cytokine patterns, which can be harnessed for personalized therapies. METHODS Here, we use hierarchical cluster analysis of cytokines to examine if patterns of inflammatory response in 13 hospitalized patients with CAP can be defined. This was a secondary data analysis of the Community-Acquired Pneumonia Inflammatory Study Group (CAPISG) database. The following cytokines were measured in plasma and sputum on the day of admission: interleukin (IL)-1β, IL-1 receptor antagonist (IL-1ra), IL-6, CXCL8 (IL-8), IL-10, IL-12p40, IL-17, interferon (IFN)γ, tumor necrosis factor (TNF)α, and CXCL10 (IP-10). Hierarchical agglomerative clustering algorithms were used to evaluate clusters of patients within plasma and sputum cytokine determinations. RESULTS A total of thirteen patients were included in this pilot study. Cluster analysis identified distinct inflammatory response patterns of cytokines in the plasma, sputum, and the ratio of plasma to sputum. CONCLUSIONS Inflammatory response patterns in plasma and sputum can be identified in hospitalized patients with CAP. Characterization of the local and systemic inflammatory response may help to better discriminate patients for enrollment into clinical trials of immunomodulatory therapies.
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Affiliation(s)
- Timothy L Wiemken
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Robert R Kelley
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Rafael Fernandez-Botran
- University of Louisville Department of Pathology and Laboratory Medicine, Louisville, Kentucky, USA
| | - William A Mattingly
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Forest W Arnold
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Stephen P Furmanek
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Marcos I Restrepo
- Department of Pulmonary Diseases, South Texas Veterans Health Care System and University of Texas at San Antonio, San Antonio, Texas, USA
| | - James D Chalmers
- Department of Respiratory Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom
| | - Paula Peyrani
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Rodrigo Cavallazzi
- University of Louisville Division of Pulmonary, Critical Care, and Sleep Disorders Medicine, Louisville, Kentucky USA
| | - Jose Bordon
- Providence Hospital Section of Infectious Diseases, Washington DC, USA
| | - Stefano Aliberti
- Department of Health Sciences, University of Milano - Bicocca, Respiratory Unit, AO San Gerardo, Monza, Italy
| | - Julio A Ramirez
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
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Preadmission Use of Calcium Channel Blockers and Outcomes After Hospitalization With Pneumonia: A Retrospective Propensity-Matched Cohort Study. Am J Ther 2017; 24:e30-e38. [PMID: 26280292 DOI: 10.1097/mjt.0000000000000312] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
In sepsis, an overwhelming immune response, as mediated by the release of various inflammatory mediators, can lead to shock, multiple organ damage, and even death. Pneumonia is the leading cause of sepsis. In animal septic models, sepsis could induce uncontrolled calcium (Ca) leaking, raising cytosolic Ca to a toxic level, causing irreversible cellular injuries and organ failure. All types of calcium channel blockers (CCBs), by inhibiting Ca influx, have been shown to decrease overall mortality in various septic animal models. However, to our best knowledge, no clinical study had been conducted to investigate the beneficial effect(s) of CCBs in sepsis. We conducted a retrospective propensity-matched cohort study after screening 2214 patients hospitalized for pneumonia from year 2012 to 2014 at our institution. We identified 387 preadmission CCB users and 387 nonusers by propensity score matching. Logistic regression analysis was then used to determine the association between preadmission CCB use and outcomes in pneumonia. Our study showed that the odds for development of severe sepsis was significantly lower in the CCB user group [odds ratio (OR), 0.466; 95% confidence interval (CI), 0.311-0.697; P = 0.002]. Preadmission CCB use was associated with a lower risk of contracting bacteremia (OR, 0.498; 95% CI, 0.262-0.99; P = 0.0327), lower risk of acute respiratory insufficiency (OR, 0.573; 95% CI, 0.412-0.798; P = 0.001), lower risk of intensive care unit admission (OR, 0.602; 95% CI, 0.432-0.840; P = 0.0028). In conclusion, our study suggested preadmission CCB use was associated with a reduction in the risks of development of respiratory insufficiency, bacteremia, and severe sepsis in patients admitted to the hospital with pneumonia.
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Wiemken TL, Kelley RR, Fernandez-Botran R, Mattingly WA, Arnold FW, Furmanek SP, Restrepo MI, Chalmers JD, Peyrani P, Cavallazzi R, Bordon J, Aliberti S, Ramirez JA. Using cluster analysis of cytokines to identify patterns of inflammation in hospitalized patients with community-acquired pneumonia: a pilot study. THE UNIVERSITY OF LOUISVILLE JOURNAL OF RESPIRATORY INFECTIONS 2017. [PMID: 28393141 DOI: 10.18297/jri/vol1/iss1/1/] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
INTRODUCTION Patients with severe community-acquired pneumonia (CAP) are believed to have an exaggerated inflammatory response to bacterial infection. Therapies aiming to modulate the inflammatory response have been largely unsuccessful, perhaps reflecting that CAP is a heterogeneous disorder that cannot be modulated by a single anti-inflammatory approach. We hypothesize that the host inflammatory response to pneumonia may be characterized by distinct cytokine patterns, which can be harnessed for personalized therapies. METHODS Here, we use hierarchical cluster analysis of cytokines to examine if patterns of inflammatory response in 13 hospitalized patients with CAP can be defined. This was a secondary data analysis of the Community-Acquired Pneumonia Inflammatory Study Group (CAPISG) database. The following cytokines were measured in plasma and sputum on the day of admission: interleukin (IL)-1β, IL-1 receptor antagonist (IL-1ra), IL-6, CXCL8 (IL-8), IL-10, IL-12p40, IL-17, interferon (IFN)γ, tumor necrosis factor (TNF)α, and CXCL10 (IP-10). Hierarchical agglomerative clustering algorithms were used to evaluate clusters of patients within plasma and sputum cytokine determinations. RESULTS A total of thirteen patients were included in this pilot study. Cluster analysis identified distinct inflammatory response patterns of cytokines in the plasma, sputum, and the ratio of plasma to sputum. CONCLUSIONS Inflammatory response patterns in plasma and sputum can be identified in hospitalized patients with CAP. Characterization of the local and systemic inflammatory response may help to better discriminate patients for enrollment into clinical trials of immunomodulatory therapies.
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Affiliation(s)
- Timothy L Wiemken
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Robert R Kelley
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Rafael Fernandez-Botran
- University of Louisville Department of Pathology and Laboratory Medicine, Louisville, Kentucky, USA
| | - William A Mattingly
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Forest W Arnold
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Stephen P Furmanek
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Marcos I Restrepo
- Department of Pulmonary Diseases, South Texas Veterans Health Care System and University of Texas at San Antonio, San Antonio, Texas, USA
| | - James D Chalmers
- Department of Respiratory Medicine, Ninewells Hospital and Medical School, Dundee, United Kingdom
| | - Paula Peyrani
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
| | - Rodrigo Cavallazzi
- University of Louisville Division of Pulmonary, Critical Care, and Sleep Disorders Medicine, Louisville, Kentucky USA
| | - Jose Bordon
- Providence Hospital Section of Infectious Diseases, Washington DC, USA
| | - Stefano Aliberti
- Department of Health Sciences, University of Milano - Bicocca, Respiratory Unit, AO San Gerardo, Monza, Italy
| | - Julio A Ramirez
- University of Louisville Division of Infectious Diseases, Louisville, Kentucky, USA
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Shin JY, Eberg M, Ernst P, Filion KB. Statin potency and the risk of hospitalization for community-acquired pneumonia. Br J Clin Pharmacol 2017; 83:1319-1327. [PMID: 27943383 DOI: 10.1111/bcp.13208] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2016] [Revised: 10/28/2016] [Accepted: 11/23/2016] [Indexed: 12/27/2022] Open
Abstract
AIM Previous studies suggest that statins may have beneficial respiratory effects. However, it is unclear if these purported benefits vary with statin potency. Our objective was to determine if higher potency statins, compared with lower potency statins, were associated with a reduced risk of hospitalization for community-acquired pneumonia (HCAP). METHODS We conducted a nested case-control analysis of a retrospective, population-based cohort of new users of statins using data extracted from the UK's Clinical Practice Research Datalink and Hospital Episode Statistics. For each HCAP case, we used risk set sampling to randomly select up to 10 controls, matched on sex, age, cohort entry date and follow-up duration. We used conditional logistic regression with high-dimensional propensity scores to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for HCAP with current use of higher potency statin vs. lower potency statins. RESULTS A total of 217 721 patients entered the cohort on a lower potency statin and 130 707 entered on a higher potency statin; these patients resulted in 2251 cases of HCAP during 561 886 person-years of observation (rate: 4.0 HCAP per 1000 persons per year, 95% CI: 3.8-4.2). The analysis included 22 178 matched controls. Compared with lower potency statins, higher potency statins were associated with an increased rate of HCAP (HR: 1.14, 95% CI: 1.03-1.27). Higher potency statins were also associated with an increased rate of fatal HCAP (HR: 1.29, 95% CI: 1.04-1.59). CONCLUSIONS Higher potency statins were not associated with a decreased risk of HCAP compared with lower potency statins.
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Affiliation(s)
- Ju-Young Shin
- Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.,Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Maria Eberg
- Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada
| | - Pierre Ernst
- Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Kristian B Filion
- Center for Clinical Epidemiology, Lady Davis Institute, Jewish General Hospital, Montreal, Quebec, Canada.,Department of Epidemiology, Biostatistics, and Occupational Health, McGill University, Montreal, Quebec, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada
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Wagner J, Abdel-Rahman SM. Pediatric Statin Administration: Navigating a Frontier with Limited Data. J Pediatr Pharmacol Ther 2016; 21:380-403. [PMID: 27877092 DOI: 10.5863/1551-6776-21.5.380] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Increasingly, children and adolescents with dyslipidemia qualify for pharmacologic intervention. As they are for adults, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors (statins) are the mainstay of pediatric dyslipidemia treatment when lifestyle modifications have failed. Despite the overall success of these drugs, the magnitude of variability in dose-exposure-response profiles contributes to adverse events and treatment failure. In children, the cause of treatment failures remains unclear. This review describes the updated guidelines for screening and management of pediatric dyslipidemia and statin disposition pathway to assist the provider in recognizing scenarios where alterations in dosage may be warranted to meet patients' specific needs.
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Affiliation(s)
- Jonathan Wagner
- Ward Family Heart Center, Children's Mercy Hospital, Kansas City, Missouri ; Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri ; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
| | - Susan M Abdel-Rahman
- Division of Clinical Pharmacology, Toxicology and Therapeutic Innovation, Children's Mercy Hospital, Kansas City, Missouri ; Department of Pediatrics, University of Missouri-Kansas City School of Medicine, Kansas City, Missouri
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Zumla A, Rao M, Wallis RS, Kaufmann SHE, Rustomjee R, Mwaba P, Vilaplana C, Yeboah-Manu D, Chakaya J, Ippolito G, Azhar E, Hoelscher M, Maeurer M. Host-directed therapies for infectious diseases: current status, recent progress, and future prospects. THE LANCET. INFECTIOUS DISEASES 2016; 16:e47-63. [PMID: 27036359 PMCID: PMC7164794 DOI: 10.1016/s1473-3099(16)00078-5] [Citation(s) in RCA: 250] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/17/2015] [Revised: 01/16/2016] [Accepted: 02/02/2016] [Indexed: 12/13/2022]
Abstract
Despite extensive global efforts in the fight against killer infectious diseases, they still cause one in four deaths worldwide and are important causes of long-term functional disability arising from tissue damage. The continuing epidemics of tuberculosis, HIV, malaria, and influenza, and the emergence of novel zoonotic pathogens represent major clinical management challenges worldwide. Newer approaches to improving treatment outcomes are needed to reduce the high morbidity and mortality caused by infectious diseases. Recent insights into pathogen–host interactions, pathogenesis, inflammatory pathways, and the host's innate and acquired immune responses are leading to identification and development of a wide range of host-directed therapies with different mechanisms of action. Host-directed therapeutic strategies are now becoming viable adjuncts to standard antimicrobial treatment. Host-directed therapies include commonly used drugs for non-communicable diseases with good safety profiles, immunomodulatory agents, biologics (eg monoclonal antibodies), nutritional products, and cellular therapy using the patient's own immune or bone marrow mesenchymal stromal cells. We discuss clinically relevant examples of progress in identifying host-directed therapies as adjunct treatment options for bacterial, viral, and parasitic infectious diseases.
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Affiliation(s)
- Alimuddin Zumla
- Centre for Clinical Microbiology, Division of Infection and Immunity, University College London (UCL), London, UK; National Institute for Health Research Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK
| | - Martin Rao
- Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden
| | | | | | | | - Peter Mwaba
- University of Zambia-UCL Medical School (UNZA-UCLMS) Research and Training Project, University Teaching Hospital, Lusaka, Zambia; Ministry of Health, Lusaka, Zambia
| | - Cris Vilaplana
- Unitat de Tuberculosi Experimental Fundació Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol CIBER Enfermedades Respiratorias, Can Ruti Campus, Edifici Laboratoris de Recerca, Barcelona, Spain
| | - Dorothy Yeboah-Manu
- Bacteriology Department, Noguchi Memorial Institute for Medical Research, University of Ghana, Legon, Ghana
| | | | - Giuseppe Ippolito
- National Institute for Infectious Diseases, Lazzaro Spallanzani, Rome, Italy
| | - Esam Azhar
- Special Infectious Agents Unit, King Fahd Medical Research Centre, and Medical Laboratory Technology Department, Faculty of Applied Medical Sciences, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Michael Hoelscher
- Division of Infectious Diseases and Tropical Medicine, Medical Centre of the University of Munich, Munich, Germany; DZIF German Centre for Infection Research, Munich, Germany
| | - Markus Maeurer
- Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden; Centre for Allogeneic Stem Cell Transplantation, Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Polverino E, Bothamley GH, Goletti D, Heyckendorf J, Sotgiu G, Aliberti S. The best of respiratory infections from the 2015 European Respiratory Society International Congress. ERJ Open Res 2016; 2:00049-2016. [PMID: 27730203 PMCID: PMC5034596 DOI: 10.1183/23120541.00049-2016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 05/27/2016] [Indexed: 12/01/2022] Open
Abstract
The breadth and quality of scientific presentations on clinical and translational research into respiratory infections at the 2015 European Respiratory Society (ERS) International Congress in Amsterdam, the Netherlands, establishes this area as one of the leadings fields in pulmonology. The host-pathogen relationship in chronic obstructive pulmonary disease, and the impact of comorbidities and chronic treatment on clinical outcomes in patients with pneumonia were studied. Various communications were dedicated to bronchiectasis and, in particular, to different prognostic and clinical aspects of this disease, including chronic infection with Pseudomonas and inhaled antibiotic therapy. Recent data from the World Health Organization showed that Europe has the highest number of multidrug-resistant tuberculosis cases and the poorest countries have the least access to suitable treatments. Latent tuberculosis and different screening programmes were also discussed with particular attention to risk factors such as HIV infection and diabetes. Several biomarkers were proposed to distinguish between active tuberculosis and latent infection. Major treatment trials were discussed (REMOX, RIFQUIN and STREAM). The possibility of once-weekly treatment in the continuation phase (RIAQUIN) was especially exciting. The continuing rise of Mycobacterium abscessus as a significant pathogen was noted. This article reviews some of the best contributions from the Respiratory Infections Assembly to the 2015 ERS International Congress.
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Affiliation(s)
- Eva Polverino
- Fundació Clinic, Hospital Clinic of Barcelona – Institut d'Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Ciber de Enfermedades Respiratorias, Barcelona, Spain
- These authors contributed equally
| | - Graham H. Bothamley
- Dept of Respiratory Medicine, Homerton University Hospital, London, UK
- These authors contributed equally
| | - Delia Goletti
- Translational Research Unit, Dept of Epidemiology and Preclinical Research, National Institute for Infectious Diseases, Rome, Italy
| | - Jan Heyckendorf
- Division of Clinical Infectious Diseases, German Center for Infection Research, Research Center, Borstel, Germany
| | - Giovanni Sotgiu
- Clinical Epidemiology and Medical Statistics Unit, Dept of Biomedical Sciences, University of Sassari, Medical Education and Professional Development Unit, Sassari, Italy
| | - Stefano Aliberti
- Dept of Pathophysiology and Transplantation, University of Milan, Cardio-Thoracic Unit and Cystic Fibrosis Adult Center, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
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Zumla A, Rao M, Dodoo E, Maeurer M. Potential of immunomodulatory agents as adjunct host-directed therapies for multidrug-resistant tuberculosis. BMC Med 2016; 14:89. [PMID: 27301245 PMCID: PMC4908783 DOI: 10.1186/s12916-016-0635-1] [Citation(s) in RCA: 48] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2016] [Accepted: 06/02/2016] [Indexed: 01/15/2023] Open
Abstract
Treatment of multidrug-resistant tuberculosis (MDR-TB) is extremely challenging due to the virulence of the etiologic strains of Mycobacterium tuberculosis (M. tb), the aberrant host immune responses and the diminishing treatment options with TB drugs. New treatment regimens incorporating therapeutics targeting both M. tb and host factors are urgently needed to improve the clinical management outcomes of MDR-TB. Host-directed therapies (HDT) could avert destructive tuberculous lung pathology, facilitate eradication of M. tb, improve survival and prevent long-term functional disability. In this review we (1) discuss the use of HDT for cancer and other infections, drawing parallels and the precedent they set for MDR-TB treatment, (2) highlight preclinical studies of pharmacological agents commonly used in clinical practice which have HDT potential, and (3) outline developments in cellular therapy to promote clinically beneficial immunomodulation to improve treatment outcomes in patients with pulmonary MDR-TB. The use of HDTs as adjuncts to MDR-TB therapy requires urgent evaluation.
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Affiliation(s)
- Alimuddin Zumla
- Division of Infection and Immunity, University College London, and NIHR Biomedical Research Centre, UCL Hospitals NHS Foundation Trust, London, UK
| | - Martin Rao
- F79, Therapeutic Immunology (TIM) division, Department of Laboratory Medicine (LABMED), Karolinska University Hospital Huddinge, 14186, Stockholm, Sweden
| | - Ernest Dodoo
- F79, Therapeutic Immunology (TIM) division, Department of Laboratory Medicine (LABMED), Karolinska University Hospital Huddinge, 14186, Stockholm, Sweden
| | - Markus Maeurer
- F79, Therapeutic Immunology (TIM) division, Department of Laboratory Medicine (LABMED), Karolinska University Hospital Huddinge, 14186, Stockholm, Sweden. .,Centre for Allogeneic Stem Cell Transplantation (CAST), Karolinska University Hospital Huddinge, Stockholm, Sweden.
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Pleiotropic effects of statins on acute kidney injury: involvement of Krüppel-like factor 4. Clin Exp Nephrol 2016; 21:175-181. [PMID: 27294581 DOI: 10.1007/s10157-016-1286-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 05/26/2016] [Indexed: 01/19/2023]
Abstract
Statins, the inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, are potent cholesterol-lowering drugs used for primary and secondary prevention of coronary artery disease. They also possess multiple beneficial effects independent of their cholesterol-lowering properties, which are called as their "pleiotropic" effects. The results of recent studies have revealed that statins exert their pleiotropic effects in the kidneys, in that they are protective against acute kidney injury (AKI). Moreover, Krüppel-like factor 4, a zinc-finger transcription factor, in endothelial cells has been identified as a novel mediator of statins. This article summarizes the pleiotropic effects of statins on AKI, and reviews the recent progress in our understanding of the regulatory mechanisms involved in statin-mediated protection against AKI.
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Abstract
HIV-infected individuals are at an increased risk of cardiovascular disease (CVD) and other HIV-related co-morbidities. This is due in part to dyslipidemia associated with antiretroviral therapy and increased inflammation and immune activation from chronic HIV infection. Statins not only have potent lipid-lowering properties but are also anti-inflammatory and immunomodulators. Studies suggest that statin therapy in the HIV-infected population may decrease the risk of CVD and other non-AIDS-defining co-morbidities. This review summarizes the recent literature on statin use in the HIV setting.
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Affiliation(s)
- Allison Ross Eckard
- Departments of Pediatrics and Medicine, Divisions of Infectious Diseases, Medical University of South Carolina, 135 Rutledge Ave, MSC 752, Charleston, SC, 29425, USA,
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Sørensen OE, Borregaard N. Neutrophil extracellular traps - the dark side of neutrophils. J Clin Invest 2016; 126:1612-20. [PMID: 27135878 DOI: 10.1172/jci84538] [Citation(s) in RCA: 371] [Impact Index Per Article: 41.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Neutrophil extracellular traps (NETs) were discovered as extracellular strands of decondensed DNA in complex with histones and granule proteins, which were expelled from dying neutrophils to ensnare and kill microbes. NETs are formed during infection in vivo by mechanisms different from those originally described in vitro. Citrullination of histones by peptidyl arginine deiminase 4 (PAD4) is central for NET formation in vivo. NETs may spur formation of autoantibodies and may also serve as scaffolds for thrombosis, thereby providing a link among infection, autoimmunity, and thrombosis. In this review, we present the mechanisms by which NETs are formed and discuss the physiological and pathophysiological consequences of NET formation. We conclude that NETs may be of more importance in autoimmunity and thrombosis than in innate immune defense.
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Host-directed therapies for antimicrobial resistant respiratory tract infections. Curr Opin Pulm Med 2016; 22:203-11. [DOI: 10.1097/mcp.0000000000000271] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Dang TT, Majumdar SR, Marrie TJ, Eurich DT. Recurrent pneumonia: a review with focus on clinical epidemiology and modifiable risk factors in elderly patients. Drugs Aging 2016; 32:13-9. [PMID: 25491559 DOI: 10.1007/s40266-014-0229-6] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Community-acquired pneumonia (CAP) is one of the most common reasons for physician visits and hospitalizations in North America. Rates of CAP increase with age and CAP is associated with significant morbidity and mortality, especially in the elderly. Though there is much written about the epidemiology and risk factors of incident (first episode) pneumonia, much less is known about recurrent pneumonia. Rates of recurrent pneumonia within 3-5-years of an episode of CAP are 9-12% with a median time to recurrence of 123-317 days and mortality ranging from 4 to 10%. Age ≥65-years-old and impaired functional status are the only patient characteristics that are independently associated with increased risk of recurrence. In terms of modifiable risk factors, only the use of proton-pump inhibitors and systemic and inhaled corticosteroids have consistently been associated with increased risk of recurrent pneumonia, while angiotensin-converting enzyme (ACE) inhibitors may exert a protective effect. Many chronic medical conditions typically associated with increased incident pneumonia-such as chronic obstructive pulmonary disease (COPD), neurological disease (resulting in dysphagia or silent aspiration), and heart failure-were not associated with increased risk of recurrent pneumonia. However, those who are immune-suppressed (e.g., immunoglobulin deficiencies) may be at increased risk of recurrent pneumonia. In summary, among those who survive an episode of pneumonia, recurrence is not uncommon, particularly in the elderly. Following recovery from an episode of pneumonia, patients should be evaluated for risk factors that would predispose to a second episode including seeking evidence of immunosuppression in younger patients and medication optimization, particularly in the elderly.
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Affiliation(s)
- T T Dang
- Department of Medicine, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada
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Polgreen LA, Cook EA, Brooks JM, Tang Y, Polgreen PM. Increased statin prescribing does not lower pneumonia risk. Clin Infect Dis 2015; 60:1760-6. [PMID: 25759433 DOI: 10.1093/cid/civ190] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2014] [Accepted: 03/03/2015] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Investigators have attributed protective effects of statins against pneumonia and other infections. However, these reports are based on observational data where treatments are not assigned randomly. We aimed to determine if the protective effects of statins against pneumonia are due to nonrandom treatment assignment. METHODS We built a cohort consisting of 124 695 Medicare beneficiaries diagnosed with an acute myocardial infarction (AMI) for which we had complete claims data. We considered patients who survived at least 30 days post-AMI (full sample), or who survived for 1 year post-AMI (survivors). First, we used ordinary least squares (OLS) and logit models to determine if receiving a statin was protective against pneumonia. Second, to control for nonrandom treatment assignment, we performed an instrumental variables analysis using geographic treatment rates as an instrument. All models included patient demographics, medications, diagnoses, length of hospital stay, and out-of-pocket drug costs as covariates. Our outcome measure was a pneumonia diagnosis during the 1 year following AMI. RESULTS A total of 76 994 patients (61.9%) filled a statin prescription, and 19 078 (15.3%) were diagnosed with pneumonia. Using OLS, the statin coefficient was -0.016 (P < .001), indicating that statins are associated with a reduction in pneumonia. Using instrumental variables, we find that statin prescriptions are not associated with a reduction in pneumonia. For the full sample, statin coefficients ranged from -0.001 to -0.01 (P > .6). CONCLUSIONS For patients with AMI, the protective effect of statins against pneumonia is most likely the result of nonrandom treatment assignment (ie, a healthy-user bias).
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Affiliation(s)
| | - Elizabeth A Cook
- Clinical Trials Data Management Center, University of Iowa, Iowa City
| | - John M Brooks
- Health Services Policy and Management, University of South Carolina, Columbia
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Viasus D, Garcia-Vidal C, Simonetti AF, Dorca J, Llopis F, Mestre M, Morandeira-Rego F, Carratalà J. The effect of simvastatin on inflammatory cytokines in community-acquired pneumonia: a randomised, double-blind, placebo-controlled trial. BMJ Open 2015; 5:e006251. [PMID: 25564143 PMCID: PMC4289727 DOI: 10.1136/bmjopen-2014-006251] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
OBJECTIVES It has been suggested that statins have an effect on the modulation of the cytokine cascade and on the outcome of patients with community-acquired pneumonia (CAP). The aim of this prospective, randomised, double-blind, placebo-controlled trial was to determine whether statin therapy given to hospitalised patients with CAP improves clinical outcomes and reduces the concentration of inflammatory cytokines. SETTING A tertiary teaching hospital in Barcelona, Spain. PARTICIPANTS Thirty-four patients were randomly assigned and included in an intention-to-treat analysis (19 to the simvastatin group and 15 to the placebo group). INTERVENTION Patients were randomly assigned to receive 20 mg of simvastatin or placebo administered in the first 24 h of hospital admission and once daily thereafter for 4 days. OUTCOME Primary end point was the time from hospital admission to clinical stability. The secondary end points were serum concentrations of inflammatory cytokines and partial pressure of arterial oxygen/fractional inspired oxygen (PaO2/FiO2) at 48 h after treatment administration. RESULTS The trial was stopped because enrolment was much slower than originally anticipated. The baseline characteristics of the patients and cytokine concentrations at the time of enrolment were similar in the two groups. No significant differences in the time from hospital admission to clinical stability were found between study groups (median 3 days, IQR 2-5 vs 3 days, IQR 2-5; p=0.47). No significant differences in PaO2/FiO2 (p=0.37), C reactive protein (p=0.23), tumour necrosis factor-α (p=0.58), interleukin 6 (IL-6; p=0.64), and IL-10 (p=0.61) levels at 48 h of hospitalisation were found between simvastatin and placebo groups. Similarly, transaminase and total creatine kinase levels were similar between study groups at 48 h of hospitalisation (p=0.19, 0.08 and 0.53, respectively). CONCLUSIONS Our results suggest that the use of simvastatin, 20 mg once daily for 4 days, since hospital admission did not reduce the time to clinical stability and the levels of inflammatory cytokines in hospitalised patients with CAP. TRIAL REGISTRATION NUMBER ISRCTN91327214.
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Affiliation(s)
- Diego Viasus
- Biotechnology and Clinical Research Groups, Department of Internal Medicine, Faculty of Medicine, Universidad del Norte, Barranquilla, Colombia
- Department of Infectious Diseases, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Carolina Garcia-Vidal
- Department of Infectious Diseases, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Antonella F Simonetti
- Department of Infectious Diseases, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Dorca
- Department of Respiratory Medicine, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
| | - Ferran Llopis
- Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain
- Department of Emergency Medicine, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Mariona Mestre
- Department of Immunology, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Francisco Morandeira-Rego
- Department of Immunology, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Jordi Carratalà
- Department of Infectious Diseases, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
- Department of Emergency Medicine, Hospital Universitari de Bellvitge—IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
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Beneficial effects of perioperative statins for major pulmonary resection. J Thorac Cardiovasc Surg 2014; 149:1532-8. [PMID: 25623903 DOI: 10.1016/j.jtcvs.2014.12.016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2014] [Revised: 12/05/2014] [Accepted: 12/07/2014] [Indexed: 01/09/2023]
Abstract
OBJECTIVES Statins improve overall outcomes after noncardiac surgery. The primary aim of the study was to determine whether use of perioperative atorvastatin reduced the rate of postoperative complications in patients undergoing pulmonary resection. METHODS This was a prospective, randomized, placebo-controlled, double-blind trial of patients undergoing elective pulmonary resection who received atorvastatin (40 mg daily) or placebo beginning 1 week before surgery and continued for 1 week postoperatively. Patient characteristics and postoperative complications were recorded. Plasma inflammatory markers were sampled at baseline, in the post-anesthesia care unit, and on postoperative day 3. Because of difficulty enrolling statin-naive patients, the study was stopped at the interim analysis. RESULTS Postoperative complications occurred in 16 of 72 patients (22%) receiving placebo and in 8 of 65 patients (12%) receiving atorvastatin (P = .13). For patients undergoing major anatomic resection, there were 24 complications in 15 of 45 placebo-treated patients and 8 complications in 7 of 43 atorvastatin-treated patients (P = .04). Plasma levels of C-reactive protein, tumor necrosis factor-α, and myeloperoxidase did not differ between the 2 treatment arms during the study. CONCLUSIONS After a 2-week perioperative course of atorvastatin (40 mg) in statin-naïve patients undergoing major pulmonary resection, we found evidence of a reduction in the number of clinically important cardiovascular and pulmonary complications compared with placebo. These promising results merit evaluation in a larger, perhaps multicenter study.
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Gamst J, Christiansen CF, Rasmussen BS, Rasmussen LH, Thomsen RW. Pre-existing atrial fibrillation and risk of arterial thromboembolism and death following pneumonia: a population-based cohort study. BMJ Open 2014; 4:e006486. [PMID: 25398678 PMCID: PMC4244399 DOI: 10.1136/bmjopen-2014-006486] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
OBJECTIVES To examine the effect of pre-existing atrial fibrillation (AF) and associated therapy on the risk of arterial thromboembolism (ATE) and death following pneumonia. DESIGN, SETTING AND PARTICIPANTS Population-based cohort study (1997-2012) of 88,315 patients with first-time hospitalisation with pneumonia in Northern Denmark. RESULTS Of the included patients (median age 73.4 years), 8880 (10.1%) had pre-existing AF. The risk of ATE within 30 days of admission was 5.2% in patients with AF and 3.6% in patients without AF. After adjustment for higher age and comorbidity, the adjusted HR (aHR) with AF was 1.06 (95% CI 0.96 to 1.18). Among patients with AF, reduced risk of ATE was observed in vitamin-K antagonist users compared with non-users (aHR 0.74 (95% CI 0.61 to 0.91)). Thirty-day mortality was 20.1% in patients with AF and 13.9% in patients without AF. Corresponding 1-year mortalities were 43.7% and 30.3%. The aHRs for 30-day and 1-year mortality with AF were 1.00 (95% CI 0.94 to 1.05) and 1.01 (95% CI 0.98 to 1.05). In patients with AF, reduced mortality risk was observed in users of vitamin-K antagonists (aHR 0.70 (95% CI 0.63 to 0.77)) and β-blockers (aHR 0.77 (95% CI 0.70 to 0.85). Increased mortality was found in digoxin users (aHR 1.16 (95% CI 1.06 to 1.28)). CONCLUSIONS Pre-existing AF is frequent in patients hospitalised with pneumonia and a marker of increased risk of ATE and death, explained by higher patient age and comorbidity. Prognosis is closely related to preadmission medical treatment for AF.
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Affiliation(s)
- Jacob Gamst
- Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aalborg, Denmark
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
- Department of Anaesthesia and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark
- Aalborg Atrial Fibrillation Study Group, Aalborg, Denmark
| | - Christian Fynbo Christiansen
- Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aalborg, Denmark
| | - Bodil Steen Rasmussen
- Department of Anaesthesia and Intensive Care Medicine, Aalborg University Hospital, Aalborg, Denmark
| | - Lars Hvilsted Rasmussen
- Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
- Aalborg Atrial Fibrillation Study Group, Aalborg, Denmark
| | - Reimar Wernich Thomsen
- Department of Clinical Epidemiology, Institute of Clinical Medicine, Aarhus University Hospital, Aalborg, Denmark
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Mehl A, Harthug S, Lydersen S, Paulsen J, Åsvold BO, Solligård E, Damås JK, Edna TH. Prior statin use and 90-day mortality in Gram-negative and Gram-positive bloodstream infection: a prospective observational study. Eur J Clin Microbiol Infect Dis 2014; 34:609-17. [PMID: 25373530 PMCID: PMC4356896 DOI: 10.1007/s10096-014-2269-6] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2014] [Accepted: 10/20/2014] [Indexed: 01/31/2023]
Abstract
In several studies on patients with bloodstream infection (BSI), prior use of statins has been associated with improved survival. Gram-positive and Gram-negative bacteria alert the innate immune system in different ways. We, therefore, studied whether the relation between prior statin use and 90-day total mortality differed between Gram-positive and Gram-negative BSI. We conducted a prospective observational cohort study of 1,408 adults with BSI admitted to Levanger Hospital between January 1, 2002, and December 31, 2011. Data on the use of statins and other medications at admission, comorbidities, functional status, treatment, and outcome were obtained from the patients’ hospital records. The relation of statin use with 90-day mortality differed between Gram-negative and Gram-positive BSI (p-value for interaction 0.01). Among patients with Gram-negative BSI, statin users had significantly lower 90-day total mortality [odds ratio (OR) 0.42, 95 % confidence interval (CI) 0.23–0.75, p = 0.003]. The association remained essentially unchanged after adjusting for the effect of sex, age, functional status before the infection, and underlying diseases that were considered confounders (adjusted OR 0.38, 95 % CI 0.20–0.72, p = 0.003). A similar analysis of patients with Gram-positive BSI showed no association of statin use with mortality (adjusted OR 1.22, 95 % CI 0.69–2.17, p = 0.49). The present study suggests that prior statin use is associated with a lower 90-day total mortality in Gram-negative BSI, but not in Gram-positive BSI.
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Affiliation(s)
- A Mehl
- Department of Medicine, Levanger Hospital, Nord-Trøndelag Hospital Trust, Post Box 333, 7601, Levanger, Norway,
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Yang Z, Huang YCT, Koziel H, de Crom R, Ruetten H, Wohlfart P, Thomsen RW, Kahlert JA, Sørensen HT, Jozefowski S, Colby A, Kobzik L. Female resistance to pneumonia identifies lung macrophage nitric oxide synthase-3 as a therapeutic target. eLife 2014; 3. [PMID: 25317947 PMCID: PMC4215537 DOI: 10.7554/elife.03711] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2014] [Accepted: 10/12/2014] [Indexed: 12/21/2022] Open
Abstract
To identify new approaches to enhance innate immunity to bacterial pneumonia, we investigated the natural experiment of gender differences in resistance to infections. Female and estrogen-treated male mice show greater resistance to pneumococcal pneumonia, seen as greater bacterial clearance, diminished lung inflammation, and better survival. In vitro, lung macrophages from female mice and humans show better killing of ingested bacteria. Inhibitors and genetically altered mice identify a critical role for estrogen-mediated activation of lung macrophage nitric oxide synthase-3 (NOS3). Epidemiologic data show decreased hospitalization for pneumonia in women receiving estrogen or statins (known to activate NOS3). Pharmacologic targeting of NOS3 with statins or another small-molecule compound (AVE3085) enhanced macrophage bacterial killing, improved bacterial clearance, and increased host survival in both primary and secondary (post-influenza) pneumonia. The data identify a novel mechanism for host defense via NOS3 and suggest a potential therapeutic strategy to reduce secondary bacterial pneumonia after influenza.
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Affiliation(s)
- Zhiping Yang
- Department of Environmental Health, Harvard School of Public Health, Boston, United States
| | - Yuh-Chin T Huang
- Human Studies Division, National Health and Environmental Effects Research Laboratory, US Environmental Protection Agency, Chapel Hill, United States
| | - Henry Koziel
- Division of Pulmonary, Critical Care and Sleep Medicine, Beth Israel Deaconness Medical Center, Boston, United States
| | - Rini de Crom
- Department of Cell Biology and Genetics, Erasmus University Medical Center, Rotterdam, Netherlands
| | - Hartmut Ruetten
- Diabetes Division, Sanofi Research and Development, Frankfurt, Germany
| | - Paulus Wohlfart
- Diabetes Division, Sanofi Research and Development, Frankfurt, Germany
| | - Reimar W Thomsen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Johnny A Kahlert
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Henrik Toft Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Szczepan Jozefowski
- Department of Immunology, Jagiellonian University Medical College, Kraków, Poland
| | - Amy Colby
- Department of Environmental Health, Harvard School of Public Health, Boston, United States
| | - Lester Kobzik
- Department of Environmental Health, Harvard School of Public Health, Boston, United States
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Malekinejad H, Khoramjouy M, Hobbenaghi R, Amniattalab A. Atorvastatin attenuates the paraquat-induced pulmonary inflammation via PPARγ receptors: a new indication for atorvastatin. PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY 2014; 114:79-89. [PMID: 25175654 DOI: 10.1016/j.pestbp.2014.06.011] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/19/2014] [Revised: 06/24/2014] [Accepted: 06/26/2014] [Indexed: 02/08/2023]
Abstract
This study was carried out to highlight the role of PPARγ receptors and atorvastatin's protective effect on paraquat (PQ)-induced inflammation in the lungs. Forty-two male Wistar rats were exposed either against saline as control or PQ (3.5 mg/kg, IP) as test groups for 14 days. The test groups were nominated as: PQ, pioglitazone (PGT, 10 mg/kg, orally), atorvastatin (STN, 10 mg/kg, orally), PGT+STN, PGT+GW9662 (1 mg/kg) and STN+GW9662 (1 mg/kg). PGT and STN significantly (P<0.05) reduced the PQ-elevated myeloperoxidase activity, nitric oxide and malondialdehyde contents of the lungs and IL-6 and TNF-α concentrations in serum. Histopathological studies revealed alveolar edema and hemorrhages along with hyaline exudates in alveoli confirming that PGT and STN reduced the damages. Immunohistochemistry studies showed that the PQ-induced inflammation resulted in a severe recruitment of CD68(+) macrophages, which PGT and STN remarkably diminished them. STN regulated the PQ-up-regulated COX-2 expression. The antagonistic effect of GW9662 as an absolute antagonist of PPARγ receptors on anti-inflammatory effect of STN in the regulation of COX-2 expression was observed. These data provide a molecular proof(s) of the STN-produced protective effects on the PQ-induced pulmonary inflammation, which is antagonized by PPARγ antagonist indicating its anti-inflammatory effects via PPARγ receptors. Moreover, a new indication for atorvastatin is suggested.
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Affiliation(s)
- Hassan Malekinejad
- Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran.
| | - Mona Khoramjouy
- Department of Pharmacology & Toxicology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Rahim Hobbenaghi
- Department of Pathology, Faculty of Veterinary Medicine, Urmia University, Urmia, Iran
| | - Amir Amniattalab
- Department of Pathology, Islamic Azad University, Urmia Branch, Urmia, Iran
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Yang TF, Chu H, Ou SM, Li SY, Chen YT, Shih CJ, Tsai LW. Effect of statin therapy on mortality in patients with infective endocarditis. Am J Cardiol 2014; 114:94-9. [PMID: 24819895 DOI: 10.1016/j.amjcard.2014.03.064] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2014] [Revised: 03/28/2014] [Accepted: 03/28/2014] [Indexed: 11/29/2022]
Abstract
The aim of our study was to determine whether pre-emptive statin therapy was associated with improved outcome of infective endocarditis (IE). We conducted a nationwide, population-based, propensity score-matched cohort study with the Taiwan's National Health Insurance Research Database. All patients with IE between January 2000 and December 2010 were enrolled. The primary outcome was in-hospital mortality. The secondary outcome included all-cause mortality within the first 3 months, 6 months, and one year after the diagnosis of IE. Among 13,584 patients with IE, we applied propensity score-matching on a 1:4 ratio, in which 370 statin users were matched to 1,480 statin non-users. Compared with statin non-users, statin users had a significantly lower risk of in-hospital mortality (adjusted hazard ratio [aHR] 0.65, 95% confidence interval [CI], 0.49-0.86). The reduction in mortality from IE remained significant for follow-up 3 months (aHR 0.68, 95% CI, 0.53-0.88), 6 months (aHR 0.73, 95% CI, 0.58-0.91), and 12 months (aHR 0.68, 95% CI, 0.55-0.84). Statin therapy was associated with a reduced risk of ICU admission rates, shock events, the need for mechanical ventilation, but not significantly with the need for heart valvular replacement surgery. In conclusion, our study found that statin therapy is associated with a reduced risk of in-hospital and subsequent mortality of IE.
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Affiliation(s)
- Ten-Fang Yang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan; Graduate Institute of Biomedical Informatics, Taipei Medical University and Evidence Based Medicine Center, Taipei Medical University Hospital, Taipei, Taiwan
| | - Hsi Chu
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Chest, Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan
| | - Shuo-Ming Ou
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Szu-Yuan Li
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Division of Nephrology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yung-Tai Chen
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medicine, Taipei City Hospital, Heping Fuyou Branch, Taipei, Taiwan
| | - Chia-Jen Shih
- School of Medicine, National Yang-Ming University, Taipei, Taiwan; Department of Medicine, Taipei Veterans General Hospital, Yuanshan Branch, Yilan, Taiwan
| | - Lung-Wen Tsai
- Graduate Institute of Biomedical Informatics, Taipei Medical University and Evidence Based Medicine Center, Taipei Medical University Hospital, Taipei, Taiwan.
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Morel J, Singer M. Statins, fibrates, thiazolidinediones and resveratrol as adjunctive therapies in sepsis: could mitochondria be a common target? Intensive Care Med Exp 2014; 2:9. [PMID: 26266909 PMCID: PMC4512973 DOI: 10.1186/2197-425x-2-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2013] [Accepted: 01/30/2014] [Indexed: 02/07/2023] Open
Abstract
Through their pleiotropic actions, statins, fibrates, thiazolidinediones and resveratrol can target multiple mechanisms involved in sepsis. Their actions on mitochondrial function are of interest in a pathological state where bioenergetic failure may play a key role in the development of organ dysfunction. We review these four drug groups as potential adjunctive therapies in sepsis with a particular focus upon mitochondria. Systematic review of clinical and experimental trials was done with a literature search using the PubMed database. Search terms included statins, fibrates, thiazolidinediones, resveratrol, mitochondria, sepsis, peroxisome proliferator-activated receptors, inflammation, oxidative stress and organ dysfunction. With the exception of statins, most of the compelling evidence for the use of these agents in sepsis comes from the experimental literature. The agents all exert anti-inflammatory and anti-oxidant properties, plus protective effects against mitochondrial dysfunction and stimulation of mitochondrial biogenesis. Improved outcomes (organ dysfunction, survival) have been reported in a variety of sepsis models. Notably, positive outcome effects were more commonly seen when the agents were given as pre- rather than post-treatment of sepsis. Statins, fibrates, thiazolidinediones and resveratrol prevent sepsis-induced injury to organs and organelles with outcome improvements. Their effects on mitochondrial function may be integral in offering this protection. Definitive clinical trials are needed to evaluate their utility in septic patients or those at high risk of developing sepsis.
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Affiliation(s)
- Jerome Morel
- Département d'anesthésie réanimation, Centre Hospitalier Universitaire de Saint Etienne, 42055, Saint Etienne, France,
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Wan YD, Sun TW, Kan QC, Guan FX, Zhang SG. Effect of statin therapy on mortality from infection and sepsis: a meta-analysis of randomized and observational studies. Crit Care 2014; 18:R71. [PMID: 24725598 PMCID: PMC4056771 DOI: 10.1186/cc13828] [Citation(s) in RCA: 68] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2013] [Accepted: 03/25/2014] [Indexed: 02/01/2023] Open
Abstract
INTRODUCTION Observational data have suggested that statin therapy may reduce mortality in patients with infection and sepsis; however, results from randomized studies are contradictory and do not support the use of statins in this context. Here, we performed a meta-analysis to investigate the effects of statin therapy on mortality from infection and sepsis. METHODS We searched electronic databases (PubMed and Embase) for articles published before November 2013. Randomized or observational studies reporting the effects of statin therapy on mortality in patients with infection or sepsis were eligible. Randomized and observational studies were separately pooled with relative risks (RRs) and random-effects models. RESULTS We examined 5 randomized controlled trials with 867 patients and 27 observational studies with 337,648 patients. Among the randomized controlled trials, statins did not significantly decrease in-hospital mortality (RR, 0.98; 95% confidence interval (CI), 0.73 to 1.33) or 28-day mortality (RR, 0.93; 95% CI, 0.46 to 1.89). However, observational studies indicated that statins were associated with a significant decrease in mortality with adjusted data (RR, 0.65; 95% CI, 0.57 to 0.75) or unadjusted data (RR, 0.74; 95% CI, 0.59 to 0.94). CONCLUSIONS Limited evidence suggests that statins may not be associated with a significant reduction in mortality from infection and sepsis. Although meta-analysis from observational studies showed that the use of statins was associated with a survival advantage, these outcomes were limited by high heterogeneity and possible bias in the data. Therefore, we should be cautious about the use of statins in infection and sepsis.
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Affiliation(s)
- You-Dong Wan
- Department of Integrated ICU, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
| | - Tong-Wen Sun
- Department of Integrated ICU, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
| | - Quan-Cheng Kan
- Pharmaceutical Department, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, PR China
| | - Fang-Xia Guan
- Academy of Medical Science, Henan Province, Zhengzhou, PR China
| | - Shu-Guang Zhang
- Department of Integrated ICU, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Zhengzhou 450052, China
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Postma MJ, Milne G, S Nelson EA, Pyenson B, Basili M, Coker R, Oxford J, Garrison LP. Pharmaceutical interventions for mitigating an influenza pandemic: modeling the risks and health-economic impacts. Expert Rev Anti Infect Ther 2014; 8:1431-9. [DOI: 10.1586/eri.10.136] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
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Saha L. Role of statin on mortality outcome in pneumonia patients: A meta-analysis. World J Meta-Anal 2014; 2:91. [DOI: 10.13105/wjma.v2.i3.91] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2014] [Revised: 05/23/2014] [Accepted: 06/18/2014] [Indexed: 02/05/2023] Open
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Torres A, Peetermans WE, Viegi G, Blasi F. Risk factors for community-acquired pneumonia in adults in Europe: a literature review. Thorax 2013; 68:1057-65. [PMID: 24130229 PMCID: PMC3812874 DOI: 10.1136/thoraxjnl-2013-204282] [Citation(s) in RCA: 425] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Background Community-acquired pneumonia (CAP) causes considerable morbidity and mortality in adults, particularly in the elderly. Methods Structured searches of PubMed were conducted to identify up-to-date information on the incidence of CAP in adults in Europe, as well as data on lifestyle and medical risk factors for CAP. Results The overall annual incidence of CAP in adults ranged between 1.07 to 1.2 per 1000 person-years and 1.54 to 1.7 per 1000 population and increased with age (14 per 1000 person-years in adults aged ≥65 years). Incidence was also higher in men than in women and in patients with chronic respiratory disease or HIV infection. Lifestyle factors associated with an increased risk of CAP included smoking, alcohol abuse, being underweight, having regular contact with children and poor dental hygiene. The presence of comorbid conditions, including chronic respiratory and cardiovascular diseases, cerebrovascular disease, Parkinson's disease, epilepsy, dementia, dysphagia, HIV or chronic renal or liver disease all increased the risk of CAP by twofold to fourfold. Conclusion A range of lifestyle factors and underlying medical conditions are associated with an increased risk of CAP in European adults. Understanding of the types of individual at greatest risk of CAP can help to ensure that interventions to reduce the risk of infection and burden of disease are targeted appropriately.
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Affiliation(s)
- Antoni Torres
- Servei de Pneumologia, Hospital Clínic de Barcelona, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), CIBER de Enfermedades Respiratorias (CIBERes), University of Barcelona, Barcelona, Spain
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