Review Article Glucocorticosteroid in Treatment of Severe Pneumonia · 2019. 7. 31. · Pneumonia:...

Hindawi Publishing CorporationMediators of InflammationVolume 2013 Article ID 865635 8 pageshttpdxdoiorg1011552013865635

Review ArticleGlucocorticosteroid in Treatment of Severe Pneumonia

Felinda Ariani1 Kaixiong Liu2 Zhang Jing3 and Jieming Qu1

1 Department of Respiratory Medicine Huadong Hospital Shanghai Medical School of Fudan University 221 Yananxi RoadShanghai 200040 China

2Department of Respiratory Disease The First Affiliated Hospital Fujian Medical University 20 Chazhong RoadFuzhou 350005 China

3Department of Pulmonary Medicine Zhongshan Hospital Shanghai Medical School of Fudan University 180 Fenglin RoadShanghai 200032 China

Correspondence should be addressed to Jieming Qu jmqu0906163com

Received 9 July 2013 Accepted 2 November 2013

Academic Editor Elena Voronov

Copyright copy 2013 Felinda Ariani et al This is an open access article distributed under the Creative Commons Attribution Licensewhich permits unrestricted use distribution and reproduction in any medium provided the original work is properly cited

Airway diseases such as pneumonia constitute amajor health burden on a global scale untreated pneumoniamay develop to severepneumonia and consequently lead to to fatal episodes of mortality and morbidity The balance between inflammatory mediators iskey for the outcome of the pulmonary infection elimination of invading pathogen wasmarked by the release of cytokines and otherinflammatory mediators from alveolar macrophages and glucocorticoid steroids (GCs) acting on the inflammatory componentTreatments of severe pneumonia with GCs have been developing for years with inconclusive results In many cases GCs have beenadministered empirically without clinical evidence Recent studies assess beneficial impact on treatment of severe pneumonia bysuggesting specific dosage period of administration and tapered dosage

1 Background

Severe pneumonia patients represent a major concern forphysicians because of the high mortality and morbidity rateattributed to these episodes [1] During past decades manystrategies have been implemented with the aim of optimizingthe outcome of patients with severe lung infections State ofimmunocompromisation during severe pneumonia relatedto multiple drug-resistant infections which may contributeto severe hypoxemic respiratory failure triggering septicshock and fatal outcome associated with multiple organdysfunction syndromes Not only is colonizing of bacteriaresponsible as main coordinators but it is believed thatexcessive inflammatory cascade is also responsible in thecore of immune reaction Nowadays antimicrobial therapynot completely enough to significantly reduce mortalitynumber in severe pneumonia additional therapy such GCsmay constitute an important portion for better resolutionof pneumonia If not treated properly severe pneumoniacan eventually lead to several complications including acuterespiratory distress syndrome (ARDS) and sepsis They arecharacterized by persistent pulmonary inflammation andalveolar-capillary disruption and commonly affect critically

ill patients with an estimatedmortality rate ofmore than 50[2] We reviewed recent reports to clarify whether systemiccorticosteroids have an impact on the outcomes of patientswith severe pneumonia In addition we explored possibleexplanations for the role mechanism of corticosteroid insevere pneumonia

2 Role of Glucocorticosteroid inSepsis and ARDS

ARDS is common and frequently fatal two pathologicalfeature of lung derived from pulmonary fibrosis and sepsissecondary to pneumonia are the primary etiology of deathin patients with late ARDS (gt3 days) Cytokine levels TNFIL-6 and IL-10 were highest in CAP (82) with fatal severesepsis and lowest in CAP with no severe sepsis [3]

For many decades many studies have been observingimplication of GCs in shock or sepsis to reduce mortalitynevertheless it deals with inconclusive results At the begin-ning it was accepted to administer high-dose steroids usingeither methylprednisolone (30mgkg) or dexamethasone (3ndash6mgkg) in divided doses for 1 to 2 days to treat patients

2 Mediators of Inflammation

with severe sepsis and septic shock [4ndash6] yet later high-doseGCs showed possible harm and failed to decrease mortality[7] After all the enthusiasm to evaluate efficacy of GCs stillbecame a topic

However low doses of GCs successfully decreased mor-tality rates [8 9] Several meta-analyses confirmed the sur-vival and hemodynamic benefit concerning the use of low-dose hydrocortisone [10ndash12] Earlier clinical study of low-dose methylprednisolone (with a loading dose of 1-2mgkgfollowed by 2mgkg per day) at an early phase of postoper-ative ARDS showed suppression in fibroproliferation as anearly state response to lung injury and decreased CRP [13 14]Improved outcome such as significant reduction of cytokinein plasma and BALF improved oxygenation index decreasedlung injury score and MODS also stated benefit GCs inlate ARDS [15] In contrast high-dose steroid therapies wereassociated with increased mortality [16]

Eventually new recommendation surviving sepsis cam-paign (SSC) protocol was developed as an internationalassessment to reducemortality due to septic shock It summa-rized a few key points a stress-doseGCs therapy given only inseptic shock after blood pressure was identified to be poorlyresponsive to fluid and vasopressor therapy High doses ofGCs comparable to gt300mg hydrocortisone daily cannot beadministered in severe sepsis or septic shock It also suggestedthat GCs cannot be administered for the treatment of sepsisin the absence of shock [17]

3 Cytokine Expression in Severe Pneumonia

Cytokine plays important role in sending signals cell to cellwithin immune response The crucial role of inflammationin the lung will depend on expression complex group ofproinflammatory mediator and cytokine response Severi-ties of pneumonia are closely related to elevated uncon-trolled cytokine One cohort investigated severe sepsis asCAP followed by organ dysfunction and mortality revealedcytokine level elevation happened in 82 of all subjectswith CAP whereas cytokine concentrations were highest atonset attenuated rapidly over the first few days but remainedelevated throughout the first week Activity level of theproinflammatory IL-6 and anti-inflammatory IL-10 cytokinesignificantly upraised prior to mortality [18]

Monton et al studied demonstrated that patients whowere receiving GCs concentrations of TNF-120572 IL-1120573 IL-6 and CRP were remarkably decreased in serum and BAL(bronchoalveolar lavage) [19] Recent studies also observedthe production of IL-6 IL-17 IL-23 TNF-120572 macrophageinflammatory protein-1a monocyte chemotactic protein-1 keratinocyte-derived chemokine (KC) and interferon-glevels has superior suppression effects by the combination ofclarithromycin and dexamethasone [20]

4 Mechanism Action ofGlucocorticosteroid (GCs)

The anti-inflammatory and immuneosuppression process ofGCs defined to two mechanisms genomic mechanism and

nongenomic mechanism the prior means directly DNAbinding (transactivation) hence inactivation transcriptionfactor (transrepression) [21] First the ligand-activated GRabinds as a homodimer to Glucocorticosteroid responsiveelement (Gre) in target genes and induce transcription ofDNA code which is called transactivation Second cross-talkmechanism as a regulation of gene expression in which GC-liganded GRs upregulated or downregulate inflammatorytranscription factor proteins such as nuclear factor-120581B (NF-120581B) and activator protein-1 (AP-1) is defined as transrepres-sion [22]

Anothermechanism is GC signaling throughmembrane-associated receptors and second messengers described asnongenomic pathways This mode of action entails mech-anisms that do not directly and initially influence geneexpression and their effects are not blunted by inhibitorsof gene transcription Nongenomic mechanism involves theactivation of endothelial nitric oxide synthetase (eNOS)Binding of GCs to the GR stimulates phosphatidylinositol-31015840-kinase and Akt kinase leading to eNOS activation andnitric oxide-dependent vasorelaxation Nitric oxides partic-ipate in many of the inflammatory manifestations includingvasodilation and inflammatory cell recruitment [23 24]Dysregulation systemic inflammation stated with excessiveproduction of proinflammatory transcription factor nuclearfactor-kappaB (NF-120581B) and failing inhibitory action of anti-inflammatory transcription factor GCs receptor is central tothe pathogenesis of pulmonary and extrapulmonary organdysfunction within ARDS patients

5 Critical Illness-Related CorticosteroidInsufficiency in Severe Pneumonia (CIRCI)

Despite their excellent anti-inflammatory efficacy the useof GCs as therapeutics is often restrained due to twomajor drawbacks First long-term treatment with GCs isoften accompanied by severe side effects such as diabetesincreased risk of infection osteoporosis hypertension andso forth [25 26] Occurrence of GCs resistance also restrictsmany GC-based therapies Second reason under normalcondition hypothalamic-pituitary-adrenal (HPA) axis reg-ulates the secretion GCs suppression of HPA axis andadrenal failure may result in inadequate GCs activity to downregulate inflammatory response in severe illness patientsFew studies investigated the relationship between adrenalfunction and severity of pneumonia Increased serumcortisolconcentration was reported and shown to be linked withseverity and mortality in CAP [27 28]

Poor prognosis in ARDS patients is frequently associatedwith failure of the activated GRs to suppress the transcriptionof inflammatory cytokines at the same time peripherallygenerated TNF-120572 IL-1120573 and IL-6 that can stimulate theHPA axis levels independently or synergistically thus indi-rectly suppress the immune response [29] Alteration of GR-binding affinity also has been demonstrated in severe sepsisand septic shock [30]

As described by Annane et al patients were classified ashaving CIRCI if baseline serum cortisol level is le10 120583gdL or

Mediators of Inflammation 3

when the increase of serum cortisol after cosyntropin stimu-lation is le9 120583gdL They also suggested that the metyraponetest might be a useful tool for diagnosis of CIRCI [31]Currently the Surviving Sepsis Campaign recommends thatthe initially 200mg24 hours intravenous hydrocortisonetherapy should be considered in septic shock if patients didnot adequately respond to fluid resuscitation and vasopressoragents [17]

6 Role of Glucorticosteroid in SeverePneumonia Clinical Evidence

Severe pneumonia is one of the leading causes of IntensiveCare Unit (ICU) admission among septic patients [32] withincidence of pneumonia increasing with age septic shockinsufficient antibiotic treatment respiratory failure acutelung injury and other complex factors related to this poorprognosis The use of GCs has been debated over the past50 years Earlier in 1974 as pioneer Weitzman and Bergerreviewed the clinical trial design of studies reporting GCsuse in bacterial infections [33] At the beginning of theprevious decade high-dose GCs was generally accepted bypractitioners In 1995 meta-analyses found no benefit forhigh-dose GCs in sepsis and septic shock [34] and in thefollowing years another meta-analyses found benefit for longduration of low-dose GCs [35]

Innovative treatments of GCs in severe pneumonia haveemerged from septic shock field Initially Marik et al inves-tigated that there was no difference between placebo andlow-dose hydrocortisone (10mgkg) group [36] in contrastrole of high-dose GCs (mean plusmn SD dose of iv methylpred-nisolone 677 plusmn 508mg for 9 plusmn 7 days) assessed by Montonet al was demonstrating that GCs decreased systemic andlung inflammatory responses (IL-6 BAL neutrophilic countand CRP) in mechanically ventilated patients [37] Despiteproviding a benefit this study lacks sample size and itshould be noticed the using broad spectrum antibioticsmay attenuate inflammatory response in alveolar cells andalleviate mechanical ventilation-induced lung injury as seenin vitro of mice experiment [38]

The use of GCs has beenmore consistently debated how-ever the use of stress-dose or low-dose GCs for patients withseptic shock improve hemodynamic function and providesurvival benefit [39] Hence it become a turning point lowdoses of GCs were administered successfully in preliminarysepsis complicated with severe CAP it showed some benefitsby decreasing mortality mechanical ventilation use andlength of stay Although this study show beneficial effect ofGCs likewise previous study small number of participantmay biased efficacy of treatment [40] These investigationsrejuvenated enthusiasm to evaluate low-dose GCs treat-ment in patients with severe pneumonia The confirmatorypotential benefits including survival advantage reduced thenumber of organ system failures the length of ICU durationand mechanical ventilation [41ndash44] while others showedsome benefit two studies in end results were contradicted oreven increased in accompanying adverse effects [45]

Snijder et al in a study performed in 213CAPhospitalizedpatients showed that 40mg of prednisolone for 7 days orplacebo along with antibiotics did not show differencein clinical outcome no decline in CRP levels or fasterattenuated of fever and even lead to late failure The resultshowed a more frequent hyperglycemia (23 versus 09with 119875 = 027) as well as superinfection occurred 21versus 19 119875 = 010) and one patient in the placebogroup developed a fungal infection after he was treated withhydrocortisone The discordant results from Snijder et alregarding inclusion of patients with nonsevere pneumoniaresulted in a higher rate of adverse effects Adverse effect mayoccur due to resistance to antibiotics or GCs itself [46]

The incidence of a rebound inflammation after initialsuppression by GCs become an important issue [40 42] Inthis context GCs inhibit cytokines and other inflammatorymediators accelerated by bacterial infections that can beharmful to the host However the use of GCs also brings agreat influence in the immune function of macrophages andgranulocytes as the main cell host defenses against bacteria[47] Assumption of rebound inflammation is detected byhigher CRP in prednisolone group after 2 weeks which wasinitially declined in the first week [45] This likely indicatesthe fact that GCs do confer benefit in the earlier whetherby mechanism of cytokine suppression activation of adren-ergic or amelioration of relative adrenal insufficiency butprecaution in their use should further investigate includingsusceptibility for infection

As mentioned earlier studies published in earlier 1990swere impressed with ldquomegardquo dose GCs using either methyl-prednisolone (30mgkg) or dexamethasone (3ndash6mgkg)divided into 2 days or single bolus dose [48] Hereafter stud-ies obtained indication of harm and dramatically increasingmortality with high-dose GCs treatment for sepsis Finallylow doses of GCs lt300mgday were used successfully insepsis studies [49 50] And nowadays recommendations forthe use of GCs in septic shock for administration are of 200ndash300mgday of hydrocortisone [17]

The underlying hypotheses about successful low-doseGCs at these doses attenuated some inflammatory responses[51] Improved vasopressor responsiveness of the peripheralvessels [47] increased mean arterial pressures and systemicvascular resistance [52] boost innate immunity in patientswith septic shock [53] and coagulation disorders secondary toan infection [54] These are main reasons why low-dose GCswere recommended in two large trials Therefore physicianscan reverse shock and improve survival with GCs [55] asshown in the prospective double-blind study reported byKehet al [49] In fact this kind of strategy could also work insevere CAP however the duration of therapy is likely to be3 days to 2 weeks with a slow and progressive decreased inthe dose Study byMeijvis et al GCs were administered oncedaily for 3 days [42] in addition in study by Yildiz et al [39]GCs were administered with continuous infusion for 7 daysin addition in a study by Confalonieri et al [40] GCs wereadministered approximately for 114 days In contrast analysisresults of Salluh et al [45] with 7days continuous or orallyshowed no improvement in clinical outcomemoreover therewas also indication of rebound inflammation


7 Role of Glucorticosteroid inSpecific Condition

Progressions of disease caused by respiratory viruses areoften complicated by severe pneumonia There is strongevidence that the interactions between pandemic strain andsecondary bacterial respiratory pathogens are related to highincidence of ARDS and lung injury [56 57] Previous studiessuggested that progression of disease to respiratory failuremay be primarily mediated by host immune system despitedecreasing viral replication [58] Huge amounts of severalproinflammatory cytokines are released in lung parenchyma[59] Evidence suggested that corticosteroid use could achieveadequate control of excessive inflammation [60]

71 Influenza Most of pandemic influenza AH5N1 andpart of seasonal and pandemic H1N1 patients result indeterioration outcome they are at risk of quickly progressingto refractory hypoxemia-in need mechanical ventilationthus frequently complicated with severe pneumonia ARDSand MODS Treatment assessment of the use of GCs inhuman avian influenza is limited and lacked cases GCs havebeen used clinically in the management of H5N1 patientsassociated with ARDS in Hong Kong Vietnam Indonesiaand Thailand regarding confounding factors there was noevidence that showed a beneficial therapy of GCs in H5N1patients [56 61ndash63]

Later few animal studies have been conducted regardingGCs use in avian influenza The efficacy of dexamethasonea potent and long-lasting glucocorticoid was not responsivein inhibiting the development of acute respiratory syndromeassociated with H5N1 virus-induced ARDS in mice [64]

Carter reviewed the articles and concluded that becauseof confounding factors and the fact that no large randomizedclinical trials were conducted it was not possible to gain anyconclusions but GCs may take effect if given at a low doseand administered for a sufficient time (7ndash10 days) [60]

Since the outbreak of H1N1 a minority of patients mightlead to rapidly progressive pneumonia following acute lunginjury (ALI)mdashacute respiratory distress syndrome (ARDS)GCs have often been setting as adjuvant therapy besidesantiviral therapy and other measurements in an attempt tosuppress the damage caused by the immune response

Burn-Buisson et al found that early course of GCs(median initial dose of 270mg equivalent hydrocortisone perday for a median of 11 d) in patients with influenza AH1N1pneumonia associated with ARDS may be hazardous withhigher mortality and more likely to have superinfection [65]Beneficial effect improvement in lung injury score multipleorgan dysfunction scores and low mortality rate reportedby Quispe Laime et al prolonged low-to-moderate doseof GCs patients with severe ARDS received methylpred-nisolone (1mgkgday) and others received hydrocortisone(300mgday) for a duration of 21 plusmn 6 days [66] A betterclinical outcome also provided by Kudo et al is that GCstogether with early administration of antiviral agents topneumonia with wheezing and possibly without wheezingdue to H1N1 may prevent patientrsquos progression to severepneumonia [67]

The addition of low dose of methylprednisolone infusionat a stress dose (1mgkg24 h) as rescue therapy on 7 daysalso shows weaning from ECMO and invasive mechanicalventilation and gradually reduce CRP levels and procalci-tonin levels Others 2 studies were associated with a sig-nificance beneficial therapy in severely ill patients whichwere unresponsive to other treatments furthermore leadingto rapid improvement with resolution of the pulmonaryinfiltrates and may decreased the viral load of H1N1 [57 6869] In contrary studies by Liem et al assumed treatmentwith methylprednisolone (1ndash3mgkgday for up to 7 days)progressed to mortality (65 versus 29 119875 = 0004) [70]Other studies suggest that there was no benefit in improvingsymptoms but GCs increased in mortality rate [71ndash73]These findings were similar to those for GCs therapy in thetreatment of avian influenza [74]

GCs used in influenza patients incorporated with highermortality An important is that influenza virus is related tosevere viral pneumonia indeed diffuse alveolar damage maydevelop high viral load reflects intense cytokine reactionsand systemic inflammation It is suggested that GCsmay playa role in increased replication of the virus Certainly theeffects worsen the symptoms and disease that end up withmortality

72 SARS Since the outbreak in 2003 a respiratory diseasecaused by coronavirus or well known as SARS quickly spreadaround parts of the world many studies have demonstratedempirical GCs therapy to treat SARS At that time becausethe urgency of the international outbreak did not allow timefor efficacy studies physicians in Canada and Hong Kongtreated the earliest patients with intravenous ribavirin broad-spectrum antiviral activity and then followed by empiricalGCs therapy and other treatment [75 76]

Hien et al confirmed that early hydrocortisone admin-istration was initiated in lt7 days of illness associated withsignificantly higher subsequent plasma viral load in secondand third weeks duration of viraemia may also be prolonged[71] Ho et al recommended that initial use of pulse methyl-prednisolone (ge500mgday) has more efficacious benefitsuch as reducing ICU admission improving mechanicalventilation and mortality rate it is also equally shown to besafer compared with low dosage [77] Thus low-dosage GCsalso provided better prognosis in SARS patientrsquos symptomand improved lung function [78ndash80] In studies of SARSpatients in Guangzhou 121 of 152 critical patients (796)received GCs at a mean daily dose of 1335 plusmn 1023mg whichshowed beneficial effect of GCs on mortality and shorterhospitalization days [76]

In October 2003 WHO established an InternationalSARS Treatment Study Group in managing SARS anddemonstrated optimal treatment options to deal with SARSThis systematic review reported summary effects of ribavirinlopinavir ritonavir (LPVr) GCs type I IFN intravenousimmunoglobulin (IVIG) or convalescent plasma in relationto (1) SARS-CoV replication inhibition in vitro (2) mortalityor morbidity in SARS patients and (3) effects on ARDS inadult patients [81]


73 Pneumocystis jiroveci Pneumonia (PCP) Pneumocystisjiroveci pneumonia (PCP) remains the most common high-risk opportunistic infection in patients associated with thehuman immunodeficiency virus (HIV) PCP contributed asone of the most common deadly infectious diseases not onlyin HIV-infected patients but also in non-HIV patients withimmunosuppressed condition

The effectiveness of adjunctive GCs in reducing mor-tality and morbidity from P jirovecii pneumonia in HIVpatients has been demonstrated in a number of clinicaltrials A meta-analysis by Briel et al of six randomizedclinical trials performed in the last decade demonstratedthat adjunctive treatment with GCs was protective against Pjirovecii pneumonia The risk ratios for overall mortality foradjunctive GCs therapy were 054 (95 confidence interval038ndash079) at 1 month and 067 (049ndash093) at 3 months offollow-up It was suggested that in these patients adjuvantGCs could prevent the need for mechanical ventilation anddecrease mortality [82] The combination trimethoprim-sulfamethoxazole together with GCs as primary agent forprophylaxis therapy was responded better result in patientswith hypoxemia [83]

GCs show benefit in several HIV-related conditions andas adjunctive therapy in Pneumocystis carinii pneumoniaExisting data support the use of prednisone at 80mg perday and tapered over 3 weeks in the management of severeP jirovecii pneumonia [78] Tapering dose of GCs over 6ndash8 weeks is a reasonable option in T cell restoration It hasalso been hypothesized that GCs treatment may benefitin HIV infection by reducing autoimmune components toCD4 depletion However there were potential side effectsthat may state in immunosuppression which are relatedto higher incidence of bacterial infections herpes simplexand herpes zoster occurrence and potential development ofKaposirsquos sarcoma [84] It seems relevant whether risk factorof PJP is likely to be evolved in non-HIV settings whereimmunosuppressive agent therapy was administered GCsuse has preceded as one of the most frequent contributingagents [85ndash87]

The most frequently observed PJP underlying diseaseswere hematologic malignancies (54) solid organ trans-plantation (174) inflammatory disorders (13) and solidcancer (108) [81] Patients with brain tumor who receivedGCs are also suspected to be in risk [88 89] Lack of benefitand increased risk factor of PJP demonstrated in those highdose GCs in patients with systemic lupus erythematosuspatients [90] Besides these negative results the beneficialrole of the application in non-HIV patients assumed thatadjunctive high dose GCs (ge60mg prednisone daily equiv-alent) improved recovery in cases of severe adult non-HIVPCP [91] GCs either before together or later on with thespecific antibiotic therapy may reduce respiratory complica-tion quickly resolve architectural distortions on HRCT chestin non-HIV immunocompromised patients [92]

Until there are more lines of evidences to direct practicepractitioners should continue to evaluate and recognizepatients who are potentially to enroll treatment and prophy-laxis and consider risk and benefit of adjunctive GCs in HIVand non-HIV patients

8 Conclusion

Theevidence study about efficacy of GCs provided significantreduction in levels of markers of systemic inflammation andduration of mechanical ventilation ICU stay and decreasemortality GCs also have a wide range in diminishing therelease of cytokines such as those on plasma interleukin-6levels neutrophil counts CRP levels in serum and BAL

Even though there were not enough lines evidence sug-gesting that GCs can be considered as adjunctive treatmentdue to its harmful effect and still unknown clinical outcomewe should consider that whether the respond to GCs isineffective effective or harmful is influenced by drug dosageand duration of administration We summarized that low tomoderate dosage of GCs provides beneficial outcome Thepotential benefit effect during GCs administration may bediminished if discontinuation of treatment is not precededby slow tapering [39] and may lead to rebound inflammationnoticed by increasing CRP value [30] A better understand-ing of the interaction between systemic GCs and immuneresponse is necessary before recommending their use in thetreatment of severe pneumonia

Until the results of new studies that are already in progressare published it seems reasonable to think that some patientscould benefit from the use of GCs such as patients withsevere pneumonia of certain etiologies those with adrenalinsufficiency and those who develop septic shock with a poorresponse to the resuscitation maneuvers with liquids andperfusion of pressor amines We suggested for future studiesto pay attention to enroll a standardized treatment regimenincluding timing dosage formulation duration and lengthof tapering

Authorsrsquo Contribution

Felinda Ariani and Kaixiong Liu contributed to this paperequally

Acknowledgments

This research was sponsored by the National Basic ResearchProgram (973 Program) in China (2013 CB531402) theShanghai Subject Chief Scientist Program (07XD14012) andShanghai Leading Talent Projects (no 036 2010)

References

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[3] J A Kellum L KongM P Fink et al ldquoUnderstanding the infla-mmatory cytokine response in pneumonia and sepsis resultsof the genetic and inflammatory markers of sepsis (GenIMS)studyrdquo Archives of Internal Medicine vol 167 no 15 pp 1655ndash1663 2007

[4] R P Dellinger ldquoSteroid therapy of septic shock the decision isin the eye of the beholderrdquo Critical Care Medicine vol 36 no 6pp 1987ndash1989 2008


[5] SMcGee and J Hirschmann ldquoUse of corticosteroids in treatinginfectious diseasesrdquo Archives of Internal Medicine vol 168 no10 pp 1034ndash1046 2008

[6] W Schumer ldquoSteroids in the treatment of clinical septic shockrdquoAnnals of Surgery vol 184 no 3 pp 333ndash341 1976

[7] J Carlet ldquoFrom mega to more reasonable doses of corticos-teroids a decade to recreate hoperdquo Critical Care Medicine vol27 no 4 pp 672ndash674 1999

[8] D Annane J C Raphael P Gajdos and D Cook ldquoSteroid rep-lacement in sepsis an unexplored side of a multifaceted drugclassrdquo Critical Care Medicine vol 24 no 5 pp 899ndash900 1996

[9] J Briegel W Kellermann H Forst et al ldquoLow-dose hydrocor-tisone infusion attenuates the systemic inflammatory responsesyndromerdquo Clinical Investigator vol 72 no 10 pp 782ndash7871994

[10] J L Moran P L Graham S Rockliff and A D Bersten ldquoUp-dating the evidence for the role of corticosteroids in severesepsis and septic shock a Bayesian meta-analytic perspectiverdquoCritical Care vol 14 no 4 article R134 2010

[11] P C Minneci K J Deans S M Banks P Q Eichacker and CNatanson ldquoMeta-analysis the effect of steroids on survival andshock during sepsis depends on the doserdquo Annals of InternalMedicine vol 141 no 1 pp 47ndash56 2004

[12] D Keh and C L Sprung ldquoUse of corticosteroid therapy inpatients with sepsis and septic shock an evidence-basedreviewrdquo Critical Care Medicine vol 32 no 11 pp S527ndashS5332004

[13] H-S Lee J M Lee M S Kim H Y Kim B Hwangbo andJ I Zo ldquoLow-dose steroid therapy at an early phase of postop-erative acute respiratory distress syndromerdquo Annals of ThoracicSurgery vol 79 no 2 pp 405ndash410 2005

[14] G U Meduri E Golden A X Freire et al ldquoMethylpredniso-lone infusion in early severe ards results of a randomized con-trolled trialrdquo Chest vol 131 no 4 pp 954ndash963 2007

[15] G U Meduri A J Chinn K V Leeper et al ldquoCorticosteroidrescue treatment of progressive fibroproliferation in late ARDSpatterns of response and predictors of outcomerdquo Chest vol 105no 5 pp 1516ndash1527 1994

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[17] R PDellingerM LevyMitchellM BAndrew et al ldquoSurvivingsepsis campaign international guidelines for management ofsevere sepsis and septic shock 2012rdquoCritical CareMedicine vol41 no 2 pp 580ndash637 2013


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[23] T Rhen and J A Cidlowski ldquoAntiinflammatory action of glu-cocorticoidsmdashnew mechanisms for old drugsrdquo The New Eng-land Journal of Medicine vol 353 no 16 pp 1711ndash1723 2005

[24] A Rano A Carlos S Oriol and T Antoni ldquoAssociated inflam-matory response in pneumonia role of adjunctive therapy withglucocorticoidsrdquo Current Opinion in Infectious Diseases vol 19no 2 pp 179ndash184 2006

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[26] A K McDonough J R Curtis and K G Saag ldquoThe epidemi-ology of glucocorticoid-associated adverse eventsrdquo CurrentOpinion in Rheumatology vol 20 no 2 pp 131ndash137 2008

[27] M Kolditz M Halank B Schulte-Hubbert and G HoffkenldquoAdrenal function is related to prognosis in moderatecommunity-acquired pneumoniardquo European RespiratoryJournal vol 36 no 3 pp 615ndash621 2010

[28] S Gotoh N Nishimura O Takahashi et al ldquoAdrenal functionin patients with community-acquired pneumoniardquo EuropeanRespiratory Journal vol 31 no 6 pp 1268ndash1273 2008

[29] G U Meduri and C R Yates ldquoSystemic inflammation-associ-ated glucocorticoid resistance and outcome of ARDSrdquo Annalsof the New York Academy of Sciences vol 1024 pp 24ndash53 2004

[30] D Mesotten I Vanhorebeek and G van den Berghe ldquoThealtered adrenal axis and treatment with glucocorticoids duringcritical illnessrdquo Nature Clinical Practice Endocrinology andMetabolism vol 4 no 9 pp 496ndash505 2008

[31] D Annane E Bellissant P E Bollaert J Briegel D Keh and YKupfer ldquoCorticosteroids for severe sepsis and septic shock asystematic review and meta-analysisrdquo British Medical Journalvol 329 no 7464 pp 480ndash484 2004

[32] C Alberti C Brun-Buisson H Burchardi et al ldquoEpidemiologyof sepsis and infection in ICU patients from an internationalmulticentre cohort studyrdquo Intensive Care Medicine vol 28 no2 pp 108ndash121 2002

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[34] R Lefering and E A M Neugebauer ldquoSteroid controversy insepsis and septic shock ameta-analysisrdquoCritical CareMedicinevol 23 no 7 pp 1294ndash1303 1995


[36] P Marik P Kraus J Sribante I Havlik J Lipman and D WJohnson ldquoHydrocortisone and tumor necrosis factor in severecommunity-acquired pneumonia a randomized controlledstudyrdquo Chest vol 104 no 2 pp 389ndash392 1993

[37] C Monton S Ewig A Torres et al ldquoRole of glucocorticoids oninflammatory response in nonimmunosuppressed patientswithpneumonia a pilot studyrdquo European Respiratory Journal vol 14no 1 pp 218ndash220 1999


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[39] O Yildiz M Deganay B Aygen M Guven F Kelestimurand A Tutus ldquoPhysiological-dose steroid therapy in sepsis[ISRCTN36253388]rdquo Critical Care vol 6 no 3 pp 251ndash2582002

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[41] C Garcia-Vidal E Calbo V Pascual C Ferrer S Quintana andJ Garau ldquoEffects of systemic steroids in patients with severecommunity-acquired pneumoniardquo European Respiratory Jour-nal vol 30 no 5 pp 951ndash956 2007

[42] S C A Meijvis H Hardeman H H F Remmelts et al ldquoDex-amethasone and length of hospital stay in patients withcommunity-acquired pneumonia a randomised double-blindplacebo-controlled trialrdquo The Lancet vol 377 no 9782 pp2023ndash2030 2011

[43] K Mikami M Suzuki H Kitagawa et al ldquoEfficacy of corti-costeroids in the treatment of community-acquired pneumoniarequiring hospitalizationrdquo Lung vol 185 no 5 pp 249ndash2552007

[44] S Fernandez-Serrano J Dorca C Garcia-Vidal et al ldquoEffect ofcorticosteroids on the clinical course of community-acquiredpneumonia a randomized controlled trialrdquo Crit Care vol 15no 2 article R96 2011

[45] J I F Salluh P Povoa M Soares H C Castro-Faria-Neto F ABozza and P T Bozza ldquoThe role of corticosteroids in severecommunity-acquired pneumonia a systematic reviewrdquo CriticalCare vol 12 no 3 article R76 2008

[46] D Snijders J M A Daniels C S de Graaff T S van derWerf and W G Boersma ldquoEfficacy of corticosteroids in com-munity-acquired pneumonia a randomized double-blindedclinical trialrdquo American Journal of Respiratory and Critical CareMedicine vol 181 no 9 pp 975ndash982 2010

[47] M S Dehoux A Boutten J Ostinelli et al ldquoCompartmental-ized cytokine production within the human lung in unilateralpneumoniardquo American Journal of Respiratory and Critical CareMedicine vol 150 no 3 pp 710ndash716 1994

[48] D Annane E Bellissant P-E Bollaert et al ldquoCorticosteroids inthe treatment of severe sepsis and septic shock in adults asystematic reviewrdquo Journal of the AmericanMedical Associationvol 301 no 22 pp 2362ndash2375 2009

[49] D Keh T Boehnke S Weber-Cartens et al ldquoImmunologic andhemodynamic effects of ldquolow-doserdquo hydrocortisone in sep-tic shock a double-blind randomized placebo-controlledcrossover studyrdquo American Journal of Respiratory and CriticalCare Medicine vol 167 no 4 pp 512ndash520 2003

[50] D Annane V Sebille C Charpentier et al ldquoEffect of treatmentwith low doses of hydrocortisone and fludrocortisone on mor-tality in patients with septic shockrdquo Journal of the AmericanMedical Association vol 288 no 7 pp 862ndash871 2002

[51] M Oppert S Ralf H Claudia et al ldquoLow-dose hydrocortisoneimproves shock reversal and reduces cytokine levels in earlyhyperdynamic septic shockrdquo Critical Care Medicine vol 33 no11 pp 2457ndash2464 2005

[52] P-E Bollaert C Charpentier B Levy M Debouverie G Audi-bert and A Larcan ldquoReversal of late septic shock with supraph-ysiologic doses of hydrocortisonerdquo Critical Care Medicine vol26 no 4 pp 645ndash650 1998

[53] I Kaufmann J Briegel F Schliephake et al ldquoStress dosesof hydrocortisone in septic shock beneficial effects onopsonization-dependent neutrophil functionsrdquo Intensive CareMedicine vol 34 no 2 pp 344ndash349 2008

[54] D Annane and J-M Cavaillon ldquoCorticosteroids in sepsis frombench to bedsiderdquo Shock vol 20 no 3 pp 197ndash207 2003

[55] C L Sprung D Annane D Keh et al ldquoHydrocortisone therapyfor patients with septic shockrdquo The New England Journal ofMedicine vol 358 no 2 pp 111ndash124 2008

[56] JH Beigel J Farrar AMHan et al ldquoAvian influenzaA (H5N1)infection in humansrdquoTheNew England Journal ofMedicine vol353 no 13 pp 1374ndash1385 2005

[57] M Confalonieri R Cifaldi L Dreas M Viviani M Biolo andM Gabrielli ldquoMethylprednisolone infusion for life-threateningH1N1-virus infectionrdquo Therapeutic Advances in RespiratoryDisease vol 4 no 4 pp 233ndash237 2010

[58] J M Nicholls L L M Poon K C Lee et al ldquoLung pathologyof fatal severe acute respiratory syndromerdquoThe Lancet vol 361no 9371 pp 1773ndash1778 2003

[59] C K Wong C W K Lam A K L Wu et al ldquoPlasma inflam-matory cytokines and chemokines in severe acute respiratorysyndromerdquoClinical and Experimental Immunology vol 136 no1 pp 95ndash103 2004

[60] M J Carter ldquoA rationale for using steroids in the treatmentof severe cases of H5N1 avian influenzardquo Journal of MedicalMicrobiology vol 56 no 7 pp 875ndash883 2007

[61] I N Kandun HWibisonoM P H Endang et al ldquoThree Indo-nesian clusters of H5N1 virus infection in 2005rdquo The NewEngland Journal of Medicine vol 355 no 21 pp 2186ndash21942006

[62] K Chokephaibulkit M Uiprasertkul P Puthavathana et al ldquoAchild with avian influenza A (H5N1) infectionrdquo Pediatric Infec-tious Disease Journal vol 24 no 2 pp 162ndash166 2005

[63] T H Tran NThanh Liem NThi Dung et al ldquoAvian influenzaA (H5N1) in 10 patients in VietnamrdquoThe New England Journalof Medicine vol 350 no 12 pp 1179ndash1188 2004

[64] T Xu J Qiao L Zhao et al ldquoEffect of dexamethasone on acuterespiratory distress syndrome induced by the H5N1 virus inmicerdquo European Respiratory Journal vol 33 no 4 pp 852ndash8602009

[65] C Brun-Buisson J-C M Richard A Mercat A C MThiebaut and L Brochard ldquoEarly corticosteroids in severe infl-uenza AH1N1 pneumonia and acute respiratory distress syn-dromerdquo American Journal of Respiratory and Critical CareMedicine vol 183 no 9 pp 1200ndash1206 2011

[66] A M Quispe-Laime J D Bracco P A Barberio et al ldquoH1N1influenza A virus-associated acute lung injury response tocombination oseltamivir and prolonged corticosteroid treat-mentrdquo Intensive Care Medicine vol 36 no 1 pp 33ndash41 2010

[67] K Kudo J Takasaki T Manabe et al ldquoSystemic corticosteroidsand early administration of antiviral agents for pneumonia withacute wheezing due to influenza a(H1N1)pdm09 in Japanrdquo PLoSONE vol 7 no 2 Article ID e32280 2012

[68] C RobertsMNirmalan and SOrsquoShea ldquoSteroid-sensitive post-viral inflammatory pneumonitis (PVIP)rdquo American Journal ofRespiratory and Critical Care Medicine vol 182 no 8 pp 1089ndash1090 2010

[69] H-R Kil J-H Lee K-Y Lee J-W Rhim Y-S Youn and J-HKang ldquoEarly corticosteroid treatment for severe pneumoniacaused by 2009 H1N1 influenza virusrdquo Critical Care vol 15 no2 article 413 2011


[70] N T Liem C V Tung N D Hien et al ldquoClinical features ofhuman influenza a (H5N1) infection in Vietnam 2004ndash2006rdquoClinical Infectious Diseases vol 48 no 12 pp 1639ndash1646 2009

[71] N D Hien N H Ha N T Van et al ldquoHuman infection withhighly pathogenic avian influenza virus (H5N1) in NorthernVietnam 2004-2005rdquo Emerging Infectious Diseases vol 15 no1 pp 19ndash23 2009

[72] A Mady O S Ramadan A Yousef Y Mandourah A A Amrand M Kherallah ldquoClinical experience with severe 2009 H1N1influenza in the intensive care unit at King Saud Medical CitySaudi Arabiardquo Journal of Infection and Public Health vol 5 no1 pp 52ndash56 2012

[73] R Perez-Padilla D de la Rosa-Zamboni S Ponce de Leon et alldquoPneumonia and respiratory failure from swine-origininfluenza A (H1N1) in Mexicordquo The New England Journal ofMedicine vol 361 no 7 pp 680ndash689 2009

[74] A-N Abdel-Ghafar T Chotpitayasunondh Z Gao et alldquoUpdate on avian influenza A (H5N1) virus infection inhumansrdquoThe New England Journal of Medicine vol 358 no 3pp 220ndash273 2008

[75] N Lee D Hui A Wu et al ldquoA major outbreak of severe acuterespiratory syndrome in Hong KongrdquoTheNew England Journalof Medicine vol 348 no 20 pp 1986ndash1994 2003

[76] S M Poutanen M P H Donald B Henry et al ldquoIdentificationof severe acute respiratory syndrome in Canadardquo The NewEngland Journal of Medicine vol 348 no 20 pp 1995ndash20052003

[77] J CHoGCOoi T YMok et al ldquoHigh-dose pulse versus non-pulse corticosteroid regimens in severe acute respiratory syn-dromerdquoAmerican Journal of Respiratory andCritical CareMedi-cine vol 168 no 12 pp 1449ndash1456 2003

[78] W-D Jia X-L Deng X-P Tang et al ldquoDose of glucocorticos-teroids in the treatment of severe acute respiratory syndromerdquoNan Fang Yi Ke Da Xue Xue Bao vol 29 no 11 pp 2284ndash22872009

[79] Y-D Xu M Jiang R-C Chen and J-Q Fang ldquoEvaluation ofthe efficacy and safety of corticosteroid in the treatment of sev-ere SARS in Guangdong province with multi-factor regressionanalysisrdquo Chinese Critical Care Medicine vol 20 no 2 pp 84ndash87 2008

[80] R-C Chen X-P Tang S-Y Tan et al ldquoTreatment of severeacute respiratory syndrome with glucosteroids the Guangzhouexperiencerdquo Chest vol 129 no 6 pp 1441ndash1452 2006

[81] L J Stockman R Bellamy and P Garner ldquoSARS systematic re-view of treatment effectsrdquo PLoSMedicine vol 3 no 9 pp 1525ndash1531 2006

[82] M Briel R Boscacci H Furrer and H C Bucher ldquoAdjunctivecorticosteroids for Pneumocystis jiroveci pneumonia inpatients with HIV infection a meta-analysis of randomisedcontrolled trialsrdquo BMC Infectious Diseases vol 5 article 1012005

[83] N Patel and H Koziel ldquoPneumocystis jiroveci pneumonia inadult patients with AIDS treatment strategies and emergingchallenges to antimicrobial therapyrdquo Treatments in RespiratoryMedicine vol 3 no 6 pp 381ndash397 2004

[84] P F Volkow P Cornejo J W Zinser C E Ormsby and G Rey-es-Teran ldquoLife-threatening exacerbation of Kaposirsquos sarcomaafter prednisone treatment for immune reconstitution inflam-matory syndromerdquo AIDS vol 22 no 5 pp 663ndash665 2008

[85] F Fily S Lachkar L Thiberville L Favennec and F CaronldquoPneumocystis jirovecii colonization and infection among non

HIV-infected patientsrdquo Medecine et Maladies Infectieuses vol41 no 10 pp 526ndash531 2011

[86] F Roblot C Godet G le Moal et al ldquoAnalysis of underlyingdiseases and prognosis factors associated with Pneumocys-tis carinii pneumonia in immunocompromised HIV-negativepatientsrdquo European Journal of Clinical Microbiology and Infec-tious Diseases vol 21 no 7 pp 523ndash531 2002

[87] S H Yale and A H Limper ldquoPneumocystis carinii pneumoniain patients without acquired immunodeficiency syndrome ass-ociated illnesses and prior corticosteroid therapyrdquo Mayo ClinicProceedings vol 71 no 1 pp 5ndash13 1996

[88] KA Sepkowitz ldquoPneumocystis carinii pneumonia among pati-ents with neoplastic diseaserdquo Seminars in Respiratory Infectionsvol 7 no 2 pp 114ndash121 1992

[89] D Schiff ldquoPneumocystis pneumonia in brain tumor patientsrisk factors and clinical featuresrdquo Journal of Neuro-Oncologyvol 27 no 3 pp 235ndash240 1996

[90] B Godeau V Coutant-Perronne D L T H Du Le Thi Huonget al ldquoPneumocystis carinii pneumonia in the course of con-nective tissue disease report of 34 casesrdquo Journal of Rheumatol-ogy vol 21 no 2 pp 246ndash251 1994

[91] J G Pareja R Garland and H Koziel ldquoUse of adjunctive cor-ticosteroids in severe adult non-HIV Pneumocystis cariniipneumoniardquo Chest vol 113 no 5 pp 1215ndash1224 1998

[92] M N Vogel M Vatlach P Weissgerber et al ldquoHRCT-featuresof Pneumocystis jiroveci pneumonia and their evolutionbefore and after treatment in non-HIV immunocompromisedpatientsrdquo European Journal of Radiology vol 81 no 6 pp 1315ndash1320 2012

Submit your manuscripts athttpwwwhindawicom

Stem CellsInternational

Hindawi Publishing Corporationhttpwwwhindawicom Volume 2014


MEDIATORSINFLAMMATION

of


Behavioural Neurology

EndocrinologyInternational Journal of



Disease Markers


BioMed Research International

OncologyJournal of



Oxidative Medicine and Cellular Longevity


PPAR Research

The Scientific World JournalHindawi Publishing Corporation httpwwwhindawicom Volume 2014

Immunology ResearchHindawi Publishing Corporationhttpwwwhindawicom Volume 2014

Journal of

ObesityJournal of



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OphthalmologyJournal of


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Parkinsonrsquos Disease

Evidence-Based Complementary and Alternative Medicine

Volume 2014Hindawi Publishing Corporationhttpwwwhindawicom


with severe sepsis and septic shock [4ndash6] yet later high-doseGCs showed possible harm and failed to decrease mortality[7] After all the enthusiasm to evaluate efficacy of GCs stillbecame a topic

However low doses of GCs successfully decreased mor-tality rates [8 9] Several meta-analyses confirmed the sur-vival and hemodynamic benefit concerning the use of low-dose hydrocortisone [10ndash12] Earlier clinical study of low-dose methylprednisolone (with a loading dose of 1-2mgkgfollowed by 2mgkg per day) at an early phase of postoper-ative ARDS showed suppression in fibroproliferation as anearly state response to lung injury and decreased CRP [13 14]Improved outcome such as significant reduction of cytokinein plasma and BALF improved oxygenation index decreasedlung injury score and MODS also stated benefit GCs inlate ARDS [15] In contrast high-dose steroid therapies wereassociated with increased mortality [16]

Eventually new recommendation surviving sepsis cam-paign (SSC) protocol was developed as an internationalassessment to reducemortality due to septic shock It summa-rized a few key points a stress-doseGCs therapy given only inseptic shock after blood pressure was identified to be poorlyresponsive to fluid and vasopressor therapy High doses ofGCs comparable to gt300mg hydrocortisone daily cannot beadministered in severe sepsis or septic shock It also suggestedthat GCs cannot be administered for the treatment of sepsisin the absence of shock [17]

3 Cytokine Expression in Severe Pneumonia

Cytokine plays important role in sending signals cell to cellwithin immune response The crucial role of inflammationin the lung will depend on expression complex group ofproinflammatory mediator and cytokine response Severi-ties of pneumonia are closely related to elevated uncon-trolled cytokine One cohort investigated severe sepsis asCAP followed by organ dysfunction and mortality revealedcytokine level elevation happened in 82 of all subjectswith CAP whereas cytokine concentrations were highest atonset attenuated rapidly over the first few days but remainedelevated throughout the first week Activity level of theproinflammatory IL-6 and anti-inflammatory IL-10 cytokinesignificantly upraised prior to mortality [18]

Monton et al studied demonstrated that patients whowere receiving GCs concentrations of TNF-120572 IL-1120573 IL-6 and CRP were remarkably decreased in serum and BAL(bronchoalveolar lavage) [19] Recent studies also observedthe production of IL-6 IL-17 IL-23 TNF-120572 macrophageinflammatory protein-1a monocyte chemotactic protein-1 keratinocyte-derived chemokine (KC) and interferon-glevels has superior suppression effects by the combination ofclarithromycin and dexamethasone [20]

4 Mechanism Action ofGlucocorticosteroid (GCs)

The anti-inflammatory and immuneosuppression process ofGCs defined to two mechanisms genomic mechanism and

nongenomic mechanism the prior means directly DNAbinding (transactivation) hence inactivation transcriptionfactor (transrepression) [21] First the ligand-activated GRabinds as a homodimer to Glucocorticosteroid responsiveelement (Gre) in target genes and induce transcription ofDNA code which is called transactivation Second cross-talkmechanism as a regulation of gene expression in which GC-liganded GRs upregulated or downregulate inflammatorytranscription factor proteins such as nuclear factor-120581B (NF-120581B) and activator protein-1 (AP-1) is defined as transrepres-sion [22]

Anothermechanism is GC signaling throughmembrane-associated receptors and second messengers described asnongenomic pathways This mode of action entails mech-anisms that do not directly and initially influence geneexpression and their effects are not blunted by inhibitorsof gene transcription Nongenomic mechanism involves theactivation of endothelial nitric oxide synthetase (eNOS)Binding of GCs to the GR stimulates phosphatidylinositol-31015840-kinase and Akt kinase leading to eNOS activation andnitric oxide-dependent vasorelaxation Nitric oxides partic-ipate in many of the inflammatory manifestations includingvasodilation and inflammatory cell recruitment [23 24]Dysregulation systemic inflammation stated with excessiveproduction of proinflammatory transcription factor nuclearfactor-kappaB (NF-120581B) and failing inhibitory action of anti-inflammatory transcription factor GCs receptor is central tothe pathogenesis of pulmonary and extrapulmonary organdysfunction within ARDS patients

5 Critical Illness-Related CorticosteroidInsufficiency in Severe Pneumonia (CIRCI)

Despite their excellent anti-inflammatory efficacy the useof GCs as therapeutics is often restrained due to twomajor drawbacks First long-term treatment with GCs isoften accompanied by severe side effects such as diabetesincreased risk of infection osteoporosis hypertension andso forth [25 26] Occurrence of GCs resistance also restrictsmany GC-based therapies Second reason under normalcondition hypothalamic-pituitary-adrenal (HPA) axis reg-ulates the secretion GCs suppression of HPA axis andadrenal failure may result in inadequate GCs activity to downregulate inflammatory response in severe illness patientsFew studies investigated the relationship between adrenalfunction and severity of pneumonia Increased serumcortisolconcentration was reported and shown to be linked withseverity and mortality in CAP [27 28]

Poor prognosis in ARDS patients is frequently associatedwith failure of the activated GRs to suppress the transcriptionof inflammatory cytokines at the same time peripherallygenerated TNF-120572 IL-1120573 and IL-6 that can stimulate theHPA axis levels independently or synergistically thus indi-rectly suppress the immune response [29] Alteration of GR-binding affinity also has been demonstrated in severe sepsisand septic shock [30]

As described by Annane et al patients were classified ashaving CIRCI if baseline serum cortisol level is le10 120583gdL or






























8 Conclusion






Acknowledgments


References






































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of













































8 Conclusion






Acknowledgments


References






































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of

















































































































of






Disease Markers



OncologyJournal of





PPAR Research



Journal of

ObesityJournal of
















Review Article Glucocorticosteroid in Treatment of Severe Pneumonia · 2019. 7. 31. · Pneumonia:...

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Transcript of Review Article Glucocorticosteroid in Treatment of Severe Pneumonia · 2019. 7. 31. · Pneumonia:...