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Major advances in managing community-acquired pneumonia Waseem Asrar Khan and Mark Woodhead* Address: Department of Respiratory Medicine, Manchester Royal Infirmary, Manchester * Corresponding author: Mark Woodhead (mark.woodhead@cmft.nhs.uk) F1000Prime Reports 2013, 5:43 (doi:10.12703/P5-43) This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License (http://creativecommons.org/licenses/by-nc/3.0/legalcode), which permits unrestricted u
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  Major advances in managing community-acquired pneumonia   Waseem Asrar Khan and Mark Woodhead*  Address: Department of Respiratory Medicine, Manchester Royal Infirmary, Manchester *Corresponding author: Mark Woodhead (mark.woodhead@cmft.nhs.uk ) F1000Prime Reports  2013,  5 :43 (doi:10.12703/P5-43)This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial License(http://creativecommons.org/licenses/by-nc/3.0/legalcode), which permits unrestricted use, distribution, and reproduction in any medium,provided the srcinal work is properly cited. You may not use this work for commercial purposes.The electronic version of this article is the complete one and can be found at: http://f1000.com/prime/reports/m/5/43 Abstract This article is a non-systematic review of selected recent publications in community-acquiredpneumonia, including a comparison of various guidelines. Risk stratification of patients has recentlybeen advanced by the addition of several useful biomarkers. The issue of single versus dual antibiotictreatment remains controversial and awaits a conclusive randomized controlled trial. However, in themeantime, there is a working consensus that more severe patients should receive dual therapy. Epidemiology / risk factors  A knowledge of the risk factors for community-acquiredpneumonia and those at risk of worse outcomes isimportant in management of the disease. Mental illnessand use of benzodiazepines and angiotensin converting enzyme inhibitors have recently been highlighted aspossibly having a causal link with pneumonia [1-3]. Aetiology   Aetiology worldwide Periodic studies of community-acquired pneumoniamicrobial aetiology are vital to confirm whether causalpathogen frequencies have, or have not, changed to guideempirical antibiotic therapy strategies. A prospectivepopulation-based study in Spain of both inpatients andoutpatients found that   Streptococcus pneumoniae  (55.7%) was the most common agent, followed by   Coxiella burnetii (18.5%),  Mycoplasma pneumoniae  (15.9%), respiratory  viruses(14.4%),Chlamydiaspecies(10.6%)and Legionellapneumophila  (4.4%) [4]. The microbiology of community-acquired pneumonia appears to be unchanged from that found in earlier studies. The high prevalence of C.  burnetii has been reported in previous studies from Spain. Patientsinfected with conventional bacteria such as  S. pneumoniae had a higher hospitalization rate, higher CURB65 (diseaseseverity) scores at admission and more adverse clinicaloutcomes, such as severe sepsis, septic shock, ICUadmission and longer length of stay compared to those withatypicalandviralcausesofpneumonia.Limitationsinthe study included an absence of sputum cultures andpossible population bias. Outpatient community-acquired pneumonia  A total of 568 outpatient community-acquired pneumo-nia episodes in Barcelona were recently studied [5]. Aetiology was established in a third of these cases andS.  pneumoniae  was again the most common proven path-ogen,followedbymycoplasmaandthenlegionella. Viral causes In another study, the data for 198 patients were analysedfrom a prospective cohort of community-acquired pneu-monia or healthcare-associated pneumonia in a 28-bedmedical intensive care unit (ICU) [6]. These were patientsthat were severe enough to be admitted to the intensivecare unit. The breakdown was that 35% of patients had abacterial infection and 36% had a viral infection. Of thelatter, the following viruses were identified  –  rhino virus(23.6%), para influenza virus (20.8%), human metap-neumovirus (18.1%), influenza virus (16.7%), andrespiratory syncytial virus (13.9%). Mortalities of patients with bacterial, viral, and bacterial-viral co-infections weresimilar. Limitations of the study included a reliance onupper respiratory specimens. Lack of pharmacologicaltherapies for most viral causes limits the value of thisinformation at the current time. Page 1 of 7 (page number not for citation purposes) Published: 01 October 2013© 2013 Faculty of 1000 Ltd  Novel coronavirus  A recent case report in Saudi Arabia has led to thediscovery of a sixth new coronavirus. The patient hadpneumonia and acute respiratory distress syndrome withmulti-organ dysfunction syndrome and died 11 daysafter admission [7]. This has also been recently referred to asthe Middle East respiratory syndrome coronavirus.Human Coronavirus-Erasmus Medical Center (HCoV-EMC) is the first human corona virus in lineage C of thebetacoronavirus genus. Its closest relatives are corona- viruses HKU4 and HKU5 found in bats. Additional casesin the Middle East have raised concerns over the potentialfor more widespread dissemination. Influenza viruses Bacterial co-infection was present in 33% of 128 con-secutive adult patients hospitalized with a diagnosis of influenza A (H1N1) and community-acquired pneumo-nia. Predictors of bacterial co-infection included under-lyingchronicobstructivepulmonarydisease(COPD)andahigher platelet count at admission. Bacterial co-infection was not related to increased mortality [8].H5N1 continues to cause sporadic human infections inEgyptandSouthEastAsia,butmorealarmingistherecent emergenceofH7N9asa causeofhumanillness[9].Casesreported so far suggest a link with birds as the source withlittle or no human-to-human spread. Severe multi-organfailure with mortality of about one third is reported [10]. Severity scores  All guidelines recommend severity scoring tools inconjunction with clinical assessment in adult community-acquired pneumonia management, although controversy remains about which scoring system to use and whento use it. PSI score Recentsystematicreviewsshowedthatallofthestandardscoring methods of the pneumonia severity index (PSI),CURB65,andCRB65showedmoderatetogoodaccuracy in predicting 30-day mortality in these patients and risk of death [11] (see Tables 1 and 2 for more details). PSI appeared to have a significant advantage in terms of itsnegativelikelihoodratio,thereforeindicatingitssuperior ability at identifying low risk patients. CURB65  A higher positive predictive value than the PSI systemsuggests that CURB65/CRB65 may be superior for identifying high-risk patients in terms of mortality anddecisions with regards to admission of high-risk patients(see Table 3 for more details). Table 1. PSI scoringCriteria Points Add/subtractpointsGeneral a) Age in years 1 point per year Addb) Gender 10 points forwomenSubtract c) Nursing home resident 10 points Add Past medical history  a) Cancer 30 points Addb) Liver disease 20 points Addc) CHF 10 points Addd) CVA 10 points Adde) CKD 10 points Add Examination findings a) Altered consciousness 20 points Addb) Breathing rate >30 rpm 20 points Addc) Systolic BP <90 mmHg 20 points Addd) Temperature not 95-104 F(35-40 C) 15 points Adde) Heart rate > 125 bpm 10 points Add Labs: arterial blood gas (ABG) a) Arterial pH <7.35 30 points Addb) PaO2 <60 mmHg (<90% O2 SATS) 10 points Add Labs: Serum Chemistry  a) Serum sodium <130 mEq/L 20 points Addb) Blood urea nitrogen (BUN)>64 mg/dl20 points Addc) Serum glucose >250 mg/dl 10 points Add Labs: blood count a) Haematocrit <30% 10 points Add Other  a) Chest Xray- pleural effusion 10 points AddAbbreviations:CHF,congestiveheartfailure;CVA,cerebrovascularaccident;CKD, chronic kidney disease Table 2. Scoring and interpretation of PSI scoringScoring Interpretation Class 1: Points 0: Mortality 0.1%(low risk)Outpatient management Class 2: Points <70: Mortality 0.6%(low risk)Outpatient management Class 3: Points 71-90: Mortality 2.8%(low risk)Consider short observationhospital stayClass 4: Points 91-130: Mortality 8.2%(moderate risk)Inpatient management Class 5: Points >130: Mortality 29.2%(high risk)Inpatient management  Table 3. Explanation of CURB scoringCURB scoring Points addedC onfusion of new onset (defined as an abbreviatedmental test score of 8 or less)1 point  U rea greater than 7 mmol/l 1 point  R  espiratory rate of 30 breaths per minute or greater 1 point  B lood pressure less than 90 mmHg systolic or diastolicblood pressure 60 mmHg or less1 point Age  65  or older 1 point The risk of death at 30 days increases as the score increases: 0 points  —  0.7%, 1 point   —  3.2%, 2 points  —  13.0%, 3 points  —  17.0%, 4 points  —  41.5%,5 points  —  57.0% Page 2 of 7 (page number not for citation purposes) F1000Prime Reports  2013,  5 :43 http://f1000.com/prime/reports/m/5/43  CURB65-guided antibiotic therapy was associated witha significant decrease in broad-spectrum antibiotic use. The intervention was safe with no impact on mortality,treatment failure or clinical response [12]. CRB-65  A recent study of the CRB65 score investigated whether it  wasusefulinpatientswithlowerrespiratorytractinfectionin a primary care setting but showed that it had littlecorrelation with severe symptom duration or hospitalisa-tion [13]. In this study, however, respiratory rate andblood pressure were infrequently measured (22.7% and31.9% respectively), suggesting that clinical practice would have to change if this score were to be usedroutinely. Another study of CRB65 score investigated whether thecut off age of 65 had any impact in terms of severity of patients presenting with pneumonia [14]. This study includednearly700,000patientshospitalisedinGermany between 2008 and 2010. The age of 65 (resulting inCRB ≥ 65)wasareasonablethresholdfortheassessmentof theriskofdeathfromcommunity-acquiredpneumoniainthe total population, although age group 80 (CRB ≥ 80)had the highest risk of death [14]. In patients aged lessthan 65 years, death prediction was best below age of 50, with excellent prediction of low-risk patients. In patientsaged 65 or over with nursing home-acquired pneumonia,the optimal age group for death prediction continued tobe 80 (CRB ≥ 80).  ATS / IDSA severity criteria  The American Thoracic Society-Infectious DiseasesSociety of America (ATS-IDSA) rule consists of two major (mechanicalventilationorshock)andnineminorcriteria. The rule is considered positive in the presence of onemajor or three minor criteria. A meta-analysis found the ATS minor criteria, S-community-acquired pneumoniascore, and SMART-COP to have good predictive charac-teristics for ICU admission [15]. Biomarkers Serum glucose  A recent predictive cohort study [16] found that anincreased serum glucose level at admission to hospitaland no pre-existing diabetes was a predictor of deathat 28 and 90 days in 6891 patients with community-acquired pneumonia. Whether this adds to the use of ascoring system and whether blood glucose management alters the outcome in community-acquired pneumonia isnot known. Although the PSI scoring system includesserumglucose,thispaperinvestigatedserumglucoseasanindependent risk factor in predicting death in patients with community-acquired pneumonia. Procalcitonin  A systematic review of procalcitonin as a prognostic marker in community-acquired pneumonia found that complications during admission, severity of disease anddeath within a month correlated with high levels of procalcitonin but no definite cut off level was found.Procalcitonin with a cut-off point of 0.15 ng/ml was thebest predictor for bacterial aetiology and to select patientseligible for outpatient care in another study [17]. They suggested that levels of procalcitonin and C reactiveprotein positively correlate with increasing severity of community-acquired pneumonia and may have a role indisease prediction, perhaps in patients with low CURB65scores [18]. Limitations of the study included study heterogeneity and risk of publication bias. Using aprocalcitonin algorithm on antibiotic guidance reducedantibiotic use without increased complications. Goodcompliancewiththeprocalcitoninalgorithmwaspossiblein real-life conditions but had to be reinforced by other measures to achieve an optimal benefit [19]. Limitationshereincludedobservationaldesignanduncleardiagnostic criteria. Pro-adrenomedullin  Another recent study showed that increased pro-adrenomedullin (proADM) levels closely correlated withincreasedseverityscoresandshowedapredictivepowerinboth long and short term complications in patients withcommunity-acquired pneumonia, especially when usedin conjunction with PSI and CURB65. An admissionproADM level of 0.646 nmol correlated in such a fashionthat 92% of the 139 patients in PSI classes 4 and 5 wouldhave been correctly classified [20]. This was a singlehospital study and serial biomarkers were not usedthroughout the study. Another study also reflected that proADMmaybehelpfulinindividualriskstratificationof community-acquiredpneumoniapatientswithahighPSIscore in the Emergency Department, allowing better identification of patients at risk of death [21]. IL-6, IL-10 and lipopolysaccharide-binding protein  The highest levels of IL-6, IL-10 and lipopolysaccharide-binding protein (LBP) correlated best with a CURB65score of 3 and 4 and the accuracy of CURB65 was greatly enhancedbytheuseofIL-6levels[22].Thesearebestusedas a predictor of severity of community-acquired pneu-monia rather than prognosis. Serum cortisol  Serum cortisol level predicts mortality and critical diseaseindependently of clinical scores and inflammatory bio-markers. A recent study showed that increased serumcortisol level was associated with the development of critical disease and increased 30-day-mortality in Page 3 of 7 (page number not for citation purposes) F1000Prime Reports  2013,  5 :43 http://f1000.com/prime/reports/m/5/43  hospitalised community-acquired pneumonia-patients.Serum cortisol level improved the predictive power of the CRB65 score and showed independent prognostic significance [23]. The main limitation of the study wasthat controlling for the time point of blood sampling could not be done, so diurnal concentration changes may have influenced the results. Management Guidelines See Table 4 for a comparison of selected features inNational and International community-acquired pneu-monia Guidelines, drawn from [24-26]. Risk stratification and admission to ICU  ATS/IDSA  These guidelines make it quite clear that severity illnessscoressuchasCURB65andPSIshouldbeusedtoidentify patients for outpatient management. Physicians areadvised to take into account factors such as availability ofoutpatientsupportresources.CURB65scores ≥ 2suggest hospital admission. Direct admission to ICU shouldbe made upon factors such as septic shock requiring  vasopressor support and /or respiratory failure requiring intubation and ventilation. British thoracic society   The British Thoracic Society (BTS) guidelines are quiteclear that the scoring system of CURB65 in conjunction with clinical assessment is the main requirement indeciding point of care admission of community-acquiredpneumonia patients. Those with a score of CURB65 0 or 1canbemanagedquitesafelyasoutpatients.PatientswithCURB65 score of 2 should be considered for hospitaladmission, as there is a significant increase in mortality  withthisgroup.ThosewithCURB65scoresof3andaboveshould be reviewed by senior clinicians, and patients with CURB65 scores of 4 and above should be seriously considered for ICU admission. Persistent hypoxia, pro-gressive hypercapnoea, shock or reduced consciousnessare indications for transfer to critical care. European respiratory society / european society of clinical microbiology and infectious diseases  These guidelines make it very clear that the decision tohospitalise community-acquired pneumonia patients isa clinical decision. A CRB score of 1 or more (except if age  ≥ 65 is the only criterion met) suggests that hospita-lisation should be considered. Factors such as acuterespiratory failure, septic shock and decompensatedcomorbidities should be considered for early referral tointensive care.  Antibiotics  –   dual vs single  There has always been a debate with regards to the valueof single (B-lactam or macrolide) versus dual (B-lactamplus macrolide) antibiotic therapy   –  a question that has never been addressed by a good-quality randomisedcontrolled trial. Although there are some differences in the antibioticsrecommended for first-line treatment in the Guidelines( Table 4) there is consensus that patients with moresevere community-acquired pneumonia should be givendual therapy. A total of 23 studies with approximately 137,000 patients were included in a recent meta-analysisofthe efficacy ofmacrolides inpatients hospitalised withcommunity-acquired pneumonia [27]. Macrolide-basedregimens were associated with a significant 22% reduc-tion in mortality compared to non-macrolides. Table 4. Recommended community-acquired pneumonia therapy and management from published international guidelinesBTS guidelines [24] ATS/IDSA guidelines [25] ERS/ESCMID guidelines [26] Low severity patients* Use CURB65 score with clinical judgement Treat with oral amoxicillin or(doxycycline or clarithromycinif hypersensitive).Use CURB65 or PSI score to guideOutpatient treatment Stratify by risk for drug resistant  S. pneumoniae Low risk: Treat with macrolide or doxycyclineHigh risk: Treat with respiratory fluoroquinoloneor b-lactam+macrolideUse CRB65 to guideOutpatient treatment Treat with one of: aminopenicillin ± macrolideAminopenicillin/b-lactamase inhibitor ± macrolideNon-antipseudomonal cephalosporinCefotaxime or ceftriaxone ± macrolideLevofloxacinMoxifloxacinPenicillin g ± macrolide Moderate/highseverity patients* CURB65 score 3 or moreconsider ICUTreat with  b -lactam plusmacrolide ivConsider ICU for sepsis or >2 minor severitycriteriaIncreasedComorbidities or prior antimicrobials (within3 months) treat with respiratory fluoroquinoloneor beta lactam plus macrolide ivConsider ICU for respiratory failure or sepsis or>2 minor severity criteriaStratify by risk for  Pseudomonas aeruginosa Non-antipseudomonal treat with cephalosporin III +macrolideOrMoxifloxacinorlevofloxacin±non-antipseudomonalcephalosporin III*These are not necessarily the terms used in the guidelines but give a broad translation of what the guidelines state. Page 4 of 7 (page number not for citation purposes) F1000Prime Reports  2013,  5 :43 http://f1000.com/prime/reports/m/5/43

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