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Corticosteroids in Severe Pneumonia

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Corticosteroids in Severe Pneumonia Eur Respir J 2008; 32: 259–264 DOI: 10.1183/09031936.00154107 CopyrightßERS Journals Ltd 2008 PERSPECTIVE Corticosteroids in severe pneumonia O. Sibila*,#,+, C. Agustı´",+ and A. Torres",+ ABSTRACT: The mortality rate in severe community- or hospital-acquired pneumonia is very high, AFFILIATIONS ranging 20–50%. Despite advances in antimicrobial therapy and supportive measures, this rate *Respiratory Dept, Son Dureta University Hospital, Palma de has not changed in recent years, suggesting that other factors are also responsible for the poor Mallorca, and outcome. An abnormal increase in the local and systemic inflammatory response is associated #Caubet-Cimera Foundation, with poor outcome, and this occurs despite adequate antibiotic therapy. Bunyola, and " There is evidence that acute administration of corticosteroids decreases the inflammatory Respiratory Dept, Institut Clı´nic del To`rax, Hospital Clı´nic, Institut response and might decrease mortality in severe pneumonia. This has been shown in one small d’Investigacions Biome`diques August randomised controlled study, terminated prematurely due to 0% mortality in the intervention arm. In Pi i Sunyer, Barcelona, and addition, an experimental study showed that glucocorticosteroids decrease lung inflammatory +Ciber Enfermedades Respiratorias, response and lung bacterial burden, confirming the results obtained through in vitro investigations. Spain. Although these results are promising and suggest a novel role of glucocorticosteroids in CORRESPONDENCE pneumonia, the inherent risks and potential side-effects of these drugs require further controlled A. Torres clinical trials in order to better define the target population before their general use in clinical Servei de Pneumologia practice. Specifically, dosage, period of administration, titration, tapering and side-effects are Institut Clinic del To´rax Hospital Clinic some of the key questions that need to be investigated. Villarroel 170 08036 KEYWORDS: Community-acquired pneumonia, corticosteroids, inflammatory response, nosoco- Barcelona mial pneumonia, severe pneumonia Spain Fax: 34 932275549 E-mail: [email protected] neumonia is the most prevalent infectious response, with the interaction of several defence respiratory disease. It entails high mor- mechanisms and the production of a number of Received: P bidity and mortality and large healthcare inflammatory mediators and acute phase proteins. November 16 2007 system expenses. Community-acquired pneumo- The aim of this inflammatory response is to Accepted after revision: February 18 2008 nia (CAP) is one of the 10 leading causes of death control the progression of the infection and to worldwide. Approximately 20% of CAP patients destroy microorganisms, and consists of several STATEMENT OF INTEREST require hospitalisation, 25% of whom are pro-inflammatory (tumour necrosis factor (TNF)-a None declared. admitted to an intensive care unit (ICU) and and interleukin (IL)-1b, -6 and -8) and anti- have a mortality rate of 30–50% [1]. inflammatory cytokines (IL-10, IL-1 receptor antagonist and the soluble 55-kDa and 75-kDa Despite progress in life-support measures and anti- TNF receptors). Cytokines promote the migration microbial therapy, the mortality of severe pneumo- of defence cells, such as neutrophils, lymphocytes nia has not varied since the mid-1990s [2, 3], and platelets, through the circulatory system to suggesting that other factors are of crucial impor- inflammatory sites [6]. tance in the evolution of this respiratory infection. One of the key factors determining the progres- All of this process is beneficial as long as it is sion of pneumonia is the host inflammatory limited to the control of local infection. If this response, which seems to be increased exces- reaction is overproportioned, several systemic sively in nonresponding severe pneumonia [4, 5]. consequences negatively influence the clinical The purpose of the present article is to review the progression of the infection [7]. evidence in the literature supporting a beneficial This excessive inflammatory response is asso- role of glucocorticosteroids (GCs) as an adjuvant ciated with the release of inflammatory mediators treatment in severe pneumonia. that can be detected in serum or bronchoalveolar lavage fluid (BALF) and have been shown to be INFLAMMATORY RESPONSE ASSOCIATED of diagnostic and prognostic value. WITH PNEUMONIA European Respiratory Journal It is well known that the arrival of pathogens in the The association between the overproduction of Print ISSN 0903-1936 c alveolar space creates a complex inflammatory pro-inflammatory cytokines, such as TNF-a or Online ISSN 1399-3003 EUROPEAN RESPIRATORY JOURNAL VOLUME 32 NUMBER 2 259 CORTICOSTEROIDS IN SEVERE PNEUMONIA O. SIBILA ET AL. IL-6, in serum and fatality in septic shock patients has TABLE 1 Effect of glucocorticosteroids on gene confirmed that cytokines are markers of severity and probably transcription major mediators involved in the pathogenesis of septic shock [8]. Studies concerning severe pneumonia have shown that, Increased gene transcription (transactivation) despite the inflammatory response initially being compart- Lipocortin 1 mentalised [9], an increase in inflammatory cytokine levels in b2-receptors serum is also detected and related to poor prognosis [10–13]. Secretory leukoprotease inhibitor Clara cell proteins (CC10 and phospholipase A2 inhibitor) In addition, a recent study by YENDE et al. [14] has demon- IL-1 receptor antagonist strated that patients with high levels of circulating inflamma- Inhibitor of nuclear factor-kB tory cytokines in clinical stability (prior to infection) have a IL-10 higher risk of suffering from CAP, suggesting a crucial role of Decreased gene transcription (transrepression) the inflammatory response in all aspects of the pathogenicity of Cytokines (IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-8, IL-11, IL-13, this infection. TNF-a, and G-CSF and GM-CSF) Chemokines (RANTES, eotoxin, MIP-1a, and monocyte GLUCOCORTICOSTEROIDS AND THE INFLAMMATORY chemotactic protein-1 and -3) RESPONSE: MOLECULAR MECHANISMS Enzymes (inducible nitric oxide synthetase, cyclooxygenase 2, GCs inhibit the expression and action of many cytokines cytoplasmic phospholipase A2) involved in the inflammatory response associated with Adhesion molecules (intercellular adhesion molecule-1 and pneumonia. GCs are mainly transported in the blood com- vascular cell adhesion molecule-1) plexed to transcortin (or corticosteroid-binding globulin) and Receptors (IL-2 receptor and tachykinin 1 (neurokinin-1)) albumin, although a small proportion is in a free metabolically activate state. The free GC molecules readily cross the plasma CC10: Clara cell 10-kDa protein; IL: interleukin; TNF-a: tumour necrosis membrane into the cytoplasm. Once in the cytoplasm, GCs factor-a; G-CSF: granulocyte colony-stimulating factor; GM-CSF: granulocyte- bind to their specific receptor, the GC receptor (GR)a.GRa macrophage colony-stimulating factor; RANTES: regulated on activation, exists as a heterocomplex located in the cytoplasm of nearly all normal T-cell expressed and secreted; MIP: macrophage inflammatory protein. human cells [15]. The anti-inflammatory and immunosuppres- sive effects of GCs are due to three molecular mechanisms [15, 16]. First, the ligand-activated GRa binds as a homodimer to specific DNA sequences, so-called GR-responsive elements, role of the associated inflammatory response to infection has usually located in the promoter regions of target genes, in been well demonstrated. In this critical infection, current order to induce transcription, a phenomenon called transacti- recommendations support the use of hydrocortisone at a ? -1 vation. Secondly, indirect negative regulation of gene expres- physiological dose (i.e. 200–300 mg hydrocortisone day ). sion (transrepression) is achieved by GR–protein interaction. These recommendations were based on the encouraging The ligand-activated receptor binds as a monomer to key pro- results of four small trials and subsequently one larger trial inflammatory transcription factors, such as activator protein-1 [19–23]. All five trials reported fewer deaths in patients who and nuclear factor-kB. The resulting complex inhibits the received GCs. A meta-analysis of these trials suggested that the initiation of transcription of relevant genes. This mechanism use of corticosteroids reduced mortality [24]. As the balance of has been shown to be involved in the inhibition of different gene evidence regarding GC treatment for septic shock shifted products that play a central role in inflammation (table 1). The towards the positive, a very important investigation, published third mechanism is GC signalling through membrane-associated in 2008, brought more shadows than light. This study receptors and second messengers (so-called nongenomic path- represents the largest multicentric randomised placebo- ways). The best-described nongenomic mechanism involves the controlled trial conducted on this topic to date, involving 499 activation of endothelial nitric oxide synthetase (eNOS). patients with septic shock. The main result of this study was Nontranscriptional activation of eNOS by GR represents a that hydrocortisone at a physiological dose does not decrease physiologically important signalling pathway by which GCs mortality in a general population of patients with septic shock, exert their rapid anti-inflammatory effects. Binding of GCs to the even though the drug hastens reversal of shock [25]. All in all, GR stimulates
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