Pneumonia 2009 Antoni Torres 1 and Jordi Rello 2 1 Servicio de Neumolog a, Instituto Cl nico del Torax, Hospital Cl nic i Provincial de Barcelona-Institut dInvestigacions Biome`diques August Pi i Sunyer, Universidad de Barcelona-Centro de Investigacion Biomedica en Red (CIBER) de Enfermedades Respiratorias, Barcelona; and 2 Servei de Cures Intensives, Hospital Universitari Joan XXIII, Universitat Rovira i Virgili-CIBER de Enfermedades Respiratorias, Tarragona, Spain Community-acquired and nosocomial pneumonia are frequent infectious problems that face clinicians in daily practice. Dif- ferentiation between community-acquired pneumonia and nos- ocomial pneumonia is based on different etiopathogenesis, microbiology, diagnosis, treatment, and outcome. These are strong reasons for presenting the new 2009 information sepa- rately. Community-acquired pneumonia (CAP) has an incidence ranging between 3 and 40 per 1,000 inhabitants per year (in- creasing with age), with rates of hospitalization between 40 and 60%. The rate at which patients with CAP are admitted to the intensive care unit (ICU) is approximately 10%. The overall mortality rate of hospitalized patients is 10%. In the eld of CAPresearch, 2009 brought newinformation on newguidelines, prognostic scales for hospital and ICUadmission, the utility of biomarkers for tailoring antibiotics and outcome prediction, new microbiological causes of CAP including H1N1 virus, advances toward better antibiotic treatment, and important clinical evidence regarding risk and prognosis factors. Nosocomial pneumonia (NP) is frequent in intensive care units, especially inpatients intubatedfor more than48 hours, with an approximate incidence of 20% and of 10 to 15 per 1,000 days of mechanical ventilation. Whennosocomial pneumonia presents in mechanically ventilated patients it is known as ventilator- associated pneumonia (VAP). The attributable mortality is ap- proximately 30%, although this gure is not universally accepted. Preventing NPand VAPis the most cost-effective measure in this type of infection, and we have focused our 2009 review of NP and VAP on this topic. A rich body of new information regarding prevention was gathered in 2009; this information includes new guidelines, andinsights onposition, oral care, endotracheal tubes, noninvasive mechanical ventilation, and most especially, bundles for implementation. COMMUNITY-ACQUIRED PNEUMONIA Guidelines At the end of 2009 the British Thoracic Society guidelines for the management of CAP in adults (1) were published. These excel- lent recommendations are based on a straightforward search of the literature and a sound system of evidence of grading. However, they did not include information published during 2009. They differ from the last Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines (2) in the following main aspects: (1) preference for the CRB-65 (instead of the Pneumonia Severity Index [PSI]) prognostic scale to assess severity, (2) inclusion of C-reactive protein for non- response assessment, (3) noncoverage of atypical microorgan- isms in patients with low-severity CAP, (4) reservation of quinolones as an alternative antibiotic treatment, and (5) recom- mendation of a combination of a broad-spectrum b-lactamase withclarithromycin for severe CAP. Our mainconcernwiththese recommendations is the lack of coverage of atypical microorgan- isms, because they are frequent in patients with low-severity disease. In addition, Legionella pneumophila may cause pneu- monia in all class severities. The American Academy of Emergency Medicine has pub- lished a white paper (3) and position statement on the measure- ment of time to rst antibiotic for pneumonia in emergency departments. The main conclusion of this position paper is that the measurement of time to rst antibiotic dose, because of the inconsistent results (class Cindication) andoveruse of antibiotics, must be discontinued. In our opinion this statement is too drastic and disregards all the consistent information about patients with CAP and sepsis (see below). This subset of patients with CAP, probably the target population for this measure, may represent more than 30% of patients arriving with CAP at emergency departments (4). Prediction of Mortality/Criteria for Hospital and ICU Admission Criteria for hospital or ICUadmission determine one of the most important decisions in the management of CAP. The PSI and CURB-65 prognostic scales have been extensively validated and show similar results for the prediction of 30-day mortality. Capelastegui and colleagues (5) validated a newprognostic index for 90-day mortality (published in Thorax). This score allows clinicians to stratify patients into three categories of 90-day mortality: low risk (3.5%), intermediate risk (17.2%), and high risk (43.5%). The 2007 IDSA/ATS guidelines (2) issued major and minor criteria for patients with CAP admitted to the ICU; these criteria were validated in 2009 (6). One of the pending questions concerns the early detection of patients with severe CAP who do not present major evidence (need for mechanical ventilation or septic shock) for ICU admission. In this regard, Renaud and colleagues (7) developed an international prediction rule including 11 variables with different assigned scores. The area under the curve was 0.81 for the overall population. In- terestingly, one observational study conrms the independent (Received in original form January 8, 2010; accepted in nal form February 8, 2010) Supported by 2009 SGR 911, CIBER de Enfermedades Respiratorias (CIBERES CB06/06/0028); CIBERES is an initiative of ISCIII. Correspondence and requests for reprints should be addressed to Antoni Torres, M.D., Ph.D., Servei de Pneumologia, Villarroel 170, 08036 Barcelona, Spain. E- mail: atorres@ub.edu; and Jordi Rello, M.D., Ph.D., Servei de Pneumologia, Mallafre Guasch, 4, 43007 Tarragona, Spain. E-mail: jrello.hj23.ics@gencat.cat This article has an online supplement, which is accessible from this issues table of contents at www.atsjournals.org Am J Respir Crit Care Med Vol 181. pp 782787, 2010 DOI: 10.1164/rccm.201001-0030UP Internet address: www.atsjournals.org value of thrombocytopenia (already known) and thrombocytosis in predicting 30-day mortality (8). Hypoglycemia at admission was also an independent factor associated with increased 30-day mortality (odds ratio [OR], 2.25), along with need for mechanical ventilation (OR, 3.8) and need for inotropic support (OR, 2.9), in a prospective observational study (9). Finally, Rello and colleagues (10) developed a severity- assessment score based on the PIRO concept. The PIRO (predisposition, insult, response, organ dysfunction) score per- formed better than the APACHE (Acute Physiology And Chronic Health Evaluation) II score and ATS/IDSA criteria at predicting 28-day mortality. However, immunosuppression was included as one of the predisposing factors and, in fact, all previous information refers to nonimmunosuppressed patients. Given all this available information, our recommendation is to use the simple modied ATS criteria to decide on ICU admission (7), as they performed as well as the new IDSA/ATS criteria (2). Biomarkers The use of biomarkers in the management of CAP has gained popularity. The most widely used biomarker is procalcitonin, a hormokine released in serum in the presence of bacterial infections. Schuetz and colleagues (11) reported in JAMAa non- inferiority randomized trial for the utility of antibiotics in lower respiratory tract infection, using a guidance protocol based on several thresholds of procalcitonin compared with standard management guidelines. The population included almost 70% of patients withCAP. This strategy provided similar outcomes for both arms of the study, but antibiotic exposure and antibiotic- associated adverse effects were lower in the procalcitonin-guided arm. Procalcitonin is also useful for predicting 30-day mortality when associated with prognostic scales (12) and for predicting clinical stability (13). In these latter two studies C-reactive protein performed as well as procalcitonin. Other biomarkers such as proadrenomedullin and copeptin are promising. Our opinion is that the measurement of biomarkers should be in- corporated into current guidelines for a better prediction of mortality. The use of biomarkers to guide antibiotic treatment in CAP needs to be conrmed by more investigators, in addition to those of the Swiss group. Diagnosis and Etiology A controversial issue is the potential utility of blood cultures in all hospitalized patients with CAP. Falguera and colleagues (14) developed a simple clinical score to predict bacteremia, using referrals and internal validation cohorts. The use of this score may reduce the burden on the microbiology laboratory. Pneu- mococcal pneumonia is the most frequent cause of CAP. A higher genomic bacterial load of Streptococcus pneumoniae in blood is associated with higher risk of septic shock and death in that population. Several studies published in 2009 provide important insights regarding the microbial etiology of CAP: Mycoplasma pneumo- niae is a frequent cause of CAPpresenting as low-severity disease (15); community-acquired necrotizing pneumonia caused by methicillin-resistant Staphylococcus aureus carrying the gene for Panton-Valentine leukocidin is an emerging infection with an incidence of 0.51 to 0.64 cases per 100,000 inhabitants (16); nally, the incidence of Enterobacteriaceae (1.3%) and Pseudo- monas aeruginosa (0.4%) is lowinhospitalizedpatients withCAP when the health careassociated pneumonia population is ex- cluded (17). Health careassociated pneumonia should be considered a distinct subset of pneumonia, associated with more severe disease, longer hospital stay, and higher mortality rates (18), as shown by Venditti and colleagues in the Annals of Internal Medicine. Microbial etiology in the United States includes a high percentage of methicillin-resistant S. aureus and P. aeruginosa; these ndings do not agree with European data. As recommen- ded by Brito and Niederman (19), we need a better stratication of risk factors to cover multidrug resistance in health care associated pneumonia. Our recommendation is that risk strati- cation to cover multiresistant organisms in both CAP and health careassociated pneumonia should be reviewed and updated. Viruses that cause community-acquired pneumonia are often overwhelmed by clinicians and are a frequent cause of mixed CAP (associated with S. pneumoniae and H. inuenzae). These mixed cases are more severe than cases due to monomicrobial etiology. Understanding viralbacterial interactions is an im- portant goal of basic animal and viral research to better prevent CAP in the future (20, 21). The H1N1 pandemic has given us the opportunity to observe and treat severe pneumonia cases caused by this virus. Obser- vational studies from Mexico (22), Australia and New Zealand (23, 25), Canada (24), China (25), and Spain (26) have characterized these cases: median age of 3035 years, morbid obesity as a main risk factor, frequent need for mechanical ventilation (70%), and development of adult respiratory distress syndrome and overall mortality at 90 days of 18%. Reports from the southern hemisphere have been extremely useful for management of these patients in the northern hemisphere, providing an example of how clinical science, when rapidly reported, plays a key role in saving lives in this type of disease. Treatment Antimicrobial treatment includes several aspects, such as early administration of the appropriate antibiotics, type and duration of antibiotics, and, in the most severe cases, coadjuvant therapy. Some insights into these issues were provided in 2009. For example, in a prospective multicenter, observational study, Ferrer and colleagues (27) showed that early administration of antibiotics is the most benecial approach in terms of survival of patients with severe sepsis (30% of patients with pneumonia). Analyses from Community-acquired Pneumonia Organization data in elderly patients with CAP (28) also conrmed the benecial effects on outcome (between 17 and 8% mortality) when physicians adhered to empirical antibiotic treatment rec- ommended by the IDSA/ATS guidelines. In terms of the type of antibiotic treatment, two prospective studies suggest that adding macrolides to b-lactams results in better mortality when com- pared with b-lactam single-drug therapy in hospitalized patients with CAP (29) or when compared with the combination of b-lactam plus quinolone in patients with CAP admitted to the ICU (30). Targeted treatment is always recommended in CAP. However, in a prospective randomized study, Falguera and colleagues (14) found a lower percentage of relapses in patients treated empirically compared with 25 patients in whom targeted treatment was based on urinary antigen results (S. pneumoniae and L. pneumophila). The explanation for these striking ndings is that the overall accuracy of urinary antigens does not exceed 70%. Coadjuvant therapies aimed at modulating increased inam- matory or hypercoagulability states are potential coadjuvant treatments for severe CAP. In 2009, Laterre and colleagues (31) reported negative results of a post-hoc analysis of patients with severe CAP from a phase III study of severe sepsis comparing tifacogin (human tissue factor pathway inhibitor) with placebo. In a small randomized trial of severe sepsis (39 patients, with 50% of the patients having pneumonia), administration of Pulmonary and Critical Care Updates 783 granulocyte-macrophage colony-stimulating factor (which re- verses monocyte deactivation) resulted in improved outcomes (but not mortality) compared with a placebo (32). This strategy was aimed at reverting sepsis-associated immunosuppression. Investigators have explored coadjuvant therapies against S. pneumoniae infection in animal models. Administration of pro- tein synthesis inhibitors leads to less inammation and increased survival in a mouse model of inuenzavirus superinfected with S. pneumoniae (a frequent clinical situation) (33). Another positive approach explored by Witzenrath and colleagues (34) was the administration of puried bacteriophage endolysin in a mouse model of severe pneumococcal CAP. The administra- tion of corticosteroids in CAP is a controversial issue. Snijders and colleagues (35) performed a randomized double blinded clinical trial comparing the administration of corticosteroids plus antibiotics with antibiotics alone. There were not differences in outcome. However, the inclusion of patients with very severe CAP (which should be the target population) was low. Conse- quently, the results of this study do not solve the controversy of administrating corticosteroids in severe CAP. Risk, Prognosis, and Prevention Among the risk factors for acquiring community-acquired pneu- monia, previous treatment with inhaled steroids has been a mat- ter of debate, particularly in patients with chronic obstructive pulmonary disease. In 2009, Sin and colleagues (36) published a meta-analysis of individual data on 7,042 patients (3,801 re- ceived inhaled budesonide and 3,241 control treatment). The results of the study showed that treating patients with chronic obstructive pulmonary disease for 12 months withbudesonide did not increase the risk of acquiring CAP in these patients. In terms of prognosis, a large study from Germany (37) provides reliable data on the mortality of hospitalized patients with CAP. Overall mortality was 14% but decreased to 8% (a more realistic gure) when nursing home and chronically bedridden patients were excluded. This study, again, suggests that patients with health careassociated pneumonia are a different population, at least in terms of mortality. Two studies from the same group (Clinical Research, Investigation, and Systems Modeling of Acute Illness [CRISMA]) found more intimate and individual mechanisms to explain worse outcomes in CAP. In one of these studies (38), the lower 30-day, 90-day, and 1-year survival in CAP was associated with increased systemic inammation and brinolysis and de- creased antithrombin III and factor IX. In the other study (39), high expression of the C-macrophage migration inhibitory factor allele was associated with lower 90-day mortality. Prevention of pneumococcal pneumonia was comprehen- sively reviewed by Van der Poll and Opal in the Lancet (40). Both inuenza and S. pneumoniae vaccination were shown to be useful for this purpose. The covalently linked polysaccharide S. pneumoniae vaccine has been in use for almost 10 years and has been successful. The seven-valent conjugate vaccine has reduced the incidence of invasive disease in children. Despite the effec- tiveness of the conjugated vaccines, disturbing patterns in the epidemiology of the disease are nowobserved, with an increase in invasive disease attributable to nonvaccine serotypes. Serotype 19A is the most important concern. An expanded conjugated vaccine including serotypes not covered in the present vaccines might be useful. Nosocomial Pneumonia There is a striking paradox in the literature supporting high- prole measures to reduce ventilator-associated pneumonia (VAP): many studies show reductions in VAP rates but almost none show any impact on the length of time patients spend on mechanical ventilation, length of stay in the intensive care unit or hospital, or mortality. VAP prevention measures that work by reducing bacterial colonization preferentially lower the frequency of these mislabeled, more benign events. The para- dox makes changes in VAP rates alone an unreliable measure of whether VAP prevention measures are truly benecial to patients (41). Mosier and Pham (42) reported an evidence-based recom- mendation for the prevention, diagnosis, and treatment of VAP in adult burn patients. Many controversies still remain in the management of hospital-acquired pneumonia and VAP (43). Three European societiesthe European Respiratory Society, the European Society of Intensive Care Medicine, and the European Society of Clinical Microbiology and Infectious Diseaseswere inter- ested in producing a document on hospital-acquired pneumonia and VAP with a European perspective (44). They chose controversial topics in the eld and others that were not covered by the latest IDSA/ATS guidelines. The panel dened 20 consensual points that were circulated several times among the members of the panel until total agreement was reached. A combination of evidence and clinical-based medicine was used to reach this consensus. Ventilator-associated pneumonia has been poorly studied in Africa, but is likely to be a signicant problem, with resulting increased morbidity and mortality in the pediatric intensive care unit population. This guideline (45) aims to review the evidence and recommendations for prevention and management of VAP in children and to provide, where possible, clear advice to aid the care of these children, and to limit costly and unnecessary therapies. Evidence-based practical clinical guidelines are pro- vided for South Africa. Risk factors for VAP are multiple and susceptible to in- tervention. A multidisciplinary team of authors (46) reviewed these factors and identied those most susceptible to interven- tion by nonpharmacological measures. They emphasized the importance of oral and airway care and the critical role of respiratory therapists and nurses. In addition, hand hygiene in health care workers and regular oral care with chlorhexidine are viewed as important measures for VAP prevention, as pre- sented in this well-conducted review (46). A visionary article by Craven (47) provides highlights from guidelines and publications discussing VAP prevention strate- gies and examining barriers to their implementation. Prevention and implementation of cost-effective strategies to reduce risk and improve patient outcomes should be prioritized. Clearly, prevention programs should be specic and may vary among hospitals, but a multidisciplinary prevention team with a leader should be set up to establish priorities, and benchmarking goals, to analyze data, and to sow the seeds of change for risk reduction. A randomized clinical trial with blinded outcome assessment was conducted in 262 consecutive patients in a medicalsurgical intensive care unit of a cancer hospital in Brazil (48). Closed tracheal suction systems with heat and moisture exchangers were used with both groups and were changed regularly. All patients were nursed with backrest elevation to 45 degrees. Medical or surgical personnel, who were blinded to group allocations, requested suctioning when any of the following occurred: visible or audible secretions, ventilatorpatient asyn- chrony, or increased peak inspiratory pressures or decreased tidal volumes attributed to secretions. Respiratory therapists performed the suctioning according to a standardized procedure that included preoxygenation. The therapist instilled 8 ml of normal saline before suctioning in the intervention group only. 784 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 181 2010 Signicantly fewer patients in the saline group (14 of 130) developed VAP than in the control group (31 of 132): relative risk reduction, 0.54 (95% condence interval [CI], 0.180.74). This indicates that one patient will avoid developing VAP for every eight patients in whom saline instillation is used. Signif- icant benets of saline infusion were also seen in the incidence of microbiologically proven VAP (9 vs. 21 per 1,000 days of mechanical ventilation; P 5 0.01) and in the time to rst VAP (P 5 0.02). The groups did not differ signicantly in terms of secondary outcomes. Shorr and colleagues (49) conducted a cost-effectiveness analysis of the economic outcomes of VAP prevention associ- ated with silver-coated endotracheal tubes. Authors used a sim- ple decision model based on a hypothetical 1,000-patient cohort intubated with silver-coated or uncoated tubes. After multiple analyses, the authors concluded that the silver-coated endotra- cheal tubes represented a strategy for preventing VAP that may yield hospital savings. Two studies investigated the impact of patient position on the incidence of VAP. Alexiou and colleagues (50) performed a systematic search for randomized control trials and analyzed data extracted from three randomized control trials studying the semirecumbent 45 degree position and four randomized control trials studying the prone position with a total of 337 and 1,018 patients, respectively. The odds of developing VAP were signicantly lower among patients in the semirecumbent, 45 degree position compared with the supine position (OR, 0.46; 95% CI, 0.270.82). The comparison between prone and supine positions showed a moderate trend toward better outcomes regarding the incidence of clinically diagnosed VAP among patients in the prone position (OR, 0.80; 95% CI, 0.601.08). An additional study (51) indicated that the prone position did not protect against the risk of VAP. Several studies evaluated the effect of various hygiene techniques for VAP prevention. Popovich and colleagues (52) examined the effectiveness of patient cleansing with chlorhex- idine (CHX) on rates of nosocomial infection. Bathing with CHX was associated with a signicant decrease in the rate of central venous catheterassociated bloodstream infections and in the rate of blood culture contamination, but rates of VAP did not change signicantly. Hutchins and colleagues (53) reported a quality improve- ment project, based on a combined technique of oral care with a suction toothbrush, and cleansing of the oral cavity with suction swabs treated with hydrogen peroxide. After the instate- ment of the quality-improvement project, VAP rates decreased from 12.6 cases per 1,000 ventilator days to 4.12. Koeman and colleagues (54) enrolled patients requiring mechanical ventilation for 48 hours or more in a randomized, double-blind, placebo-controlled trial with three arms: chlo- rhexidine (CHX 2%), chlorhexidinecolistin (CHX/COL), and placebo (PLAC). The daily risk of VAP was reduced in both interventional arms when compared with the placebo group. Unfortunately, no differences in duration of mechanical venti- lation, intensive care unit stay, or intensive care unit survival could be demonstrated. Pobo and colleagues (55) reported a simple, blind prospective randomized trial of adult patients intubated for more than 48 hours. Patients were randomized to oral care every 8 hours with 0.12% CHX digluconate (standard group) or standard oral care plus electric tooth brushing. After an interim analysis, the toothbrush group and standard group had comparable rates of VAP: The groups did not differ in mortality, antibiotic-free days, duration of mechanical ventilation, and ICU length of stay. Authors concludedthat toothbrushing didnot improve a strategy of standard oral care with CHX. Another negative study (56) conrmed that 7-day ventilator circuit change did not contribute to increased rates of VAP in a pediatric ICU, thereby conrming that it may be used to save on workload and supply costs. A prospective, randomized study (57) randomized patients to receive enteral feeding. One group received nasoduodenal (ND) feeding and the other group received nasogastric (NG) feeding. Results showed that the ND group had higher average daily calorie and protein intake compared with the NG group and achieved nutritional goals earlier. The ND feeding group also had a lower rate of vomiting and VAP in the medical ICU setting. An important controversy is whether early versus late tracheostomy is of benet in developing VAP. This study (58) included 158 ICU patients more than 65 years of age who underwent tracheotomy. The early tracheotomy group included 43 patients and 115 patients were included in the late group. A statistically signif- icant difference in the rate of VAP was observed in the early tracheotomy group (20.29% VAP; 95% CI, 20.46 to 20.12), suggesting that early tracheostomy in elderly patients is associ- ated with less VAP. A promising group of studies reviewed the value of care bundles to prevent VAP (59, 60). The Institute of Healthcare Improvement (Cambridge, MA) has led the change with its ventilator bundle aimed at VAP prevention. In a systematic literature review (59), four studies met the inclusion criteria. The review revealed major methodological aws in design, reporting, and results of the studies, including bias, confounding, and lack of generalizability. These authors concluded that the ventilatory bundle is not a viable quality measure in the intensive care unit at this time. The standard ventilatory bundle was modied (60) to include a group of respiratory therapistdriven protocols, and postim- plementation observed a signicant reduction in VAP from a median of 14.1 cases per 1,000 ventilator days. Another study (61) assessed whether the implementation of an electronic dashboard would improve compliance with the bundle parame- ters and reduce rates of VAP in a surgical ICU. Average compliance with the ventilator bundles improved from 39% in August 2007 to 89% in July 2008 (P , 0.01). Rates of VAP decreased from a mean of 15.2 to 9.3 events per 1,000 ventilator days after introduction of the dashboard (P , 0.01). This study suggests that implementation of an electronic dashboard im- proves compliance with a ventilatory bundle and may reduce rates of VAP. A modied ventilatory bundle, including oral care and subglottic secretion drainage, was implemented in a Brazilian hospital (62). Their ndings suggest that reducing VAP to zero is not feasible and reduction involves multiple performance measures and interventions. An excellent review assessed the value of care bundles (63) in preventing VAP. The authors concluded that the ventilator bundle was an effective method for reducing VAP rates in ICUs. However, they suggested that the ventilator bundle should be modied and expanded to include specic processes of care that have been denitively shown to be effective in VAP reduction or a specic VAP bundle created to focus on VAP prevention. Interestingly, a European panel of experts developed a prevention bundle based on evidence from Euro- pean guidelines (64). The original contribution is that authors scored potential variables, using multi-criteria decision analysis. Five variables, including oral care and sedation control, were recommended. Further studies have to validate the European care bundle in a clinical setting. Avoiding intubation or reintubation and shortening the period of mechanical ventilation are measures included in bundles for VAP prevention. Noninvasive mechanical venti- Pulmonary and Critical Care Updates 785 lation may avoid intubation or reintubation with the conse- quent shortening the period of mechanical ventilation. In a randomized trial published in the Lancet (65), Ferrer and colleagues demonstrated that noninvasive mechanical ventila- tion applied in extubated patients with chronic respiratory disorders who developed hypercapnia during the T-piece trial decreases the rate of reintubation, VAP, and mortality at 90 days. Conict of Interest Statement: A.T. has received consultancy fees from Astellas, Bayer, and Covidien (all for $1,001$5,000); he has received advisory board fees from Astellas ($1,001$5,000); he has received industry-sponsored grants from Pzer ($10,001$50,000). 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